# Patent

## Title
Heterobicyclic metalloprotease inhibitors

## Abstract

The present invention relates generally to amide containing heterobicyclic compounds having the following formulas:




wherein R1, R2, D, and Q are as defined in the specification. More particularly, the present invention provides a new class of amide containing heterobicyclic compounds, that exhibit an increased potency in relation to currently known MMP-13 and MMP-3 inhibitors.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. application Ser. No. 12/370,418, filed Feb. 12, 2009, now abandoned which is a continuation of U.S. application Ser. No. 11/602,140, filed Nov. 20, 2006, abandoned, which is a continuation in part of U.S. application Ser. No. 11/440,087, filed May 22, 2006, abandoned, which claims the benefit of U.S. Provisional Application No. 60/734,991, filed Nov. 9, 2005, U.S. Provisional Application No. 60/706,465, filed Aug. 8, 2005, and U.S. Provisional Application No. 60/683,470, filed May 20, 2005, the contents of each of which are hereby incorporated by reference.


FIELD OF THE INVENTION
The present invention relates generally to amide containing heterobicyclic metalloprotease inhibiting compounds, and more particularly to heterobicyclic MMP-13 inhibiting compounds.
BACKGROUND OF THE INVENTION
Matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS=a disintegrin and metalloproteinase with thrombospondin motif) are a family of structurally related zinc-containing enzymes that have been reported to mediate the breakdown of connective tissue in normal physiological processes such as embryonic development, reproduction, and tissue remodelling. Over-expression of MMPs and aggrecanases or an imbalance between extracellular matrix synthesis and degradation has been suggested as factors in inflammatory, malignant and degenerative disease processes. MMPs and aggrecanases are, therefore, targets for therapeutic inhibitors in several inflammatory, malignant and degenerative diseases such as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation (which leads to restenosis and ischemic heart failure) and tumor metastasis.
The ADAMTSs are a group of proteases that are encoded in 19 ADAMTS genes in humans. The ADAMTSs are extracellular, multidomain enzymes whose functions include collagen processing, cleavage of the matrix proteoglycans, inhibition of angiogenesis and blood coagulation homoeostasis (Biochem. J. 2005, 386, 15-27; Arthritis Res. Ther. 2005, 7, 160-169; Curr. Med. Chem. Anti-Inflammatory Anti-Allergy Agents 2005, 4, 251-264).
The mammalian MMP family has been reported to include at least 20 enzymes, (Chem. Rev. 1999, 99, 2735-2776). Collagenase-3 (MMP-13) is among three collagenases that have been identified. Based on identification of domain structures for individual members of the MMP family, it has been determined that the catalytic domain of the MMPs contains two zinc atoms; one of these zinc atoms performs a catalytic function and is coordinated with three histidines contained within the conserved amino acid sequence of the catalytic domain. MMP-13 is over-expressed in rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, breast carcinoma, squamous cell carcinomas of the head and neck, and vulvar squamous cell carcinoma. The principal substrates of MMP-13 are fibrillar collagens (types I, II, III) and gelatins, proteoglycans, cytokines and other components of ECM (extracellular matrix).
The activation of the MMPs involves the removal of a propeptide, which features an unpaired cysteine residue complexes the catalytic zinc (II) ion. X-ray crystal structures of the complex between MMP-3 catalytic domain and TIMP-1 and MMP-14 catalytic domain and TIMP-2 also reveal ligation of the catalytic zinc (II) ion by the thiol of a cysteine residue. The difficulty in developing effective MMP inhibiting compounds comprises several factors, including choice of selective versus broad-spectrum MMP inhibitors and rendering such compounds bioavailable via an oral route of administration.
MMP-3 (stromelysin-1; transin-1) is another member of the MMP family (Woesner; FASEB J. 1991; 5:2145-2154). Human MMP-3 was initially isolated from cultured human synoviocytes. It is also expressed by chondrocytes and has been localized in OA cartilage and synovial tissues (Case; Am. J. Pathol. 1989 December; 135(6):1055-64).
MMP-3 is produced by basal keratinocytes in a variety of chronic ulcers. MMP-3 mRNA and Protein were detected in basal keratinocytes adjacent to but distal from the wound edge in what probably represents the sites of proliferating epidermis. MMP-3 may this prevent the epidermis from healing (Saarialho-Kere, J. Clin. Invest. 1994 July; 94(1):79-88)).
MMP-3 serum protein levels are significantly elevated in patients with early and long-term rheumatoid arthritis (Yamanaka; Arthritis Rheum. 2000 April; 43(4):852-8) and in osteoarthritis patients (Bramono; Clin Orthop Relat Res. 2004 November; (428):272-85) as well as in other inflammatory diseases like systemic lupus erythematosis and ankylosing spondylitis (Chen, Rheumatology 2006 April; 45(4):414-20.).
MMP-3 acts on components of the ECM as aggrecan, fibronectin, gelatine, laminin, elastin, fibrillin and others and on collagens of type III, IV, V, VII, KX, X (Bramono; Clin Orthop Relat Res. 2004 November; (428):272-85). On collagens of type II and IX, MMP-3 exhibits telopeptidase activity (Sandell, Arthritis Res. 2001; 3(2):107-13; Eyre, Clin Orthop Relat Res. 2004 October; (427 Suppl):S118-22.). MMP-3 can activate other MMP family members as MMP-1; MMP-7; MMP-8; MMP-9 and MMP-13 (Close, Ann Rheum Dis 2001 November; 60 Suppl 3:iii62-7).
MMP-3 is involved in the regulation of cytokines and chemokines by releasing TGFβ1 from the ECM, activating TNFα, inactivation of IL-1β and release of IGF (Parks, Nat Rev Immunol. 2004 August; 4(8):617-29). A potential role for MMP-3 in the regulation of macrophate infiltration is based on the ability of the enzyme to converse active MCP species into antagonistic peptides (McQuibban, Blood. 2002 Aug. 15; 100(4):1160-7.).
SUMMARY OF THE INVENTION
The present invention relates to a new class of heterobicyclic amide containing pharmaceutical agents which inhibits metalloproteases. In particular, the present invention provides a new class of metalloprotease inhibiting compounds that exhibit potent MMP-13 inhibiting activity and/or activity towards MMP-3, MMP-8, MMP-12, ADAMTS-4, and ADAMTS-5.
The present invention provides several new classes of amide containing heterobicyclic metalloprotease compounds, of which some are represented by the following general formulas:




wherein all variables in the preceding Formulas (I) to (VI) are as defined hereinbelow.

The heterobicyclic metalloprotease inhibiting compounds of the present invention may be used in the treatment of metalloprotease mediated diseases, such as rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer (e.g. but not limited to melanoma, gastric carcinoma or non-small cell lung carcinoma), inflammation, atherosclerosis, multiple sclerosis, chronic obstructive pulmonary disease, ocular diseases (e.g. but not limited to ocular inflammation, retinopathy of prematurity, macular degeneration with the wet type preferred and corneal neovascularization), neurologic diseases, psychiatric diseases, thrombosis, bacterial infection, Parkinson's disease, fatigue, tremor, diabetic retinopathy, vascular diseases of the retina, aging, dementia, cardiomyopathy, renal tubular impairment, diabetes, psychosis, dyskinesia, pigmentary abnormalities, deafness, inflammatory and fibrotic syndromes, intestinal bowel syndrome, allergies, Alzheimers disease, arterial plaque formation, oncology, periodontal, viral infection, stroke, atherosclerosis, cardiovascular disease, reperfusion injury, trauma, chemical exposure or oxidative damage to tissues, chronic wound healing, wound healing, hemorroid, skin beautifying, pain, inflammatory pain, bone pain and joint pain, acne, acute alcoholic hepatitis, acute inflammation, acute pancreatitis, acute respiratory distress syndrome, adult respiratory disease, airflow obstruction, airway hyperresponsiveness, alcoholic liver disease, allograft rejections, angiogenesis, angiogenic ocular disease, arthritis, asthma, atopic dermatitis, bronchiectasis, bronchiolitis, bronchiolitis obliterans, burn therapy, cardiac and renal reperfusion injury, celiac disease, cerebral and cardiac ischemia, CNS tumors, CNS vasculitis, colds, contusions, cor pulmonae, cough, Crohn's disease, chronic bronchitis, chronic inflammation, chronic pancreatitis, chronic sinusitis, crystal induced arthritis, cystic fibrosis, delayted type hypersensitivity reaction, duodenal ulcers, dyspnea, early transplantation rejection, emphysema, encephalitis, endotoxic shock, esophagitis, gastric ulcers, gingivitis, glomerulonephritis, glossitis, gout, graft vs. host reaction, gram negative sepsis, granulocytic ehrlichiosis, hepatitis viruses, herpes, herpes viruses, HIV, hypercapnea, hyperinflation, hyperoxia-induced inflammation, hypoxia, hypersensitivity, hypoxemia, inflammatory bowel disease, interstitial pneumonitis, ischemia reperfusion injury, kaposi's sarcoma associated virus, liver fibrosis, lupus, malaria, meningitis, multi-organ dysfunction, necrotizing enterocolitis, osteoporosis, periodontitis, chronic periodontitis, peritonitis associated with continous ambulatory peritoneal dialysis (CAPD), pre-term labor, polymyositis, post surgical trauma, pruritis, psoriasis, psoriatic arthritis, pulmatory fibrosis, pulmatory hypertension, renal reperfusion injury, respiratory viruses, restinosis, right ventricular hypertrophy, sarcoidosis, septic shock, small airway disease, sprains, strains, subarachnoid hemorrhage, surgical lung volume reduction, thrombosis, toxic shock syndrome, transplant reperfusion injury, traumatic brain injury, ulcerative colitis, vasculitis, ventilation-perfusion mismatching, and wheeze.
In particular, the heterobicyclic metalloprotease inhibiting compounds of the present invention may be used in the treatment of MMP-13 mediated osteoarthritis and may be used for other MMP-13 mediated symptoms, inflammatory, malignant and degenerative diseases characterized by excessive extracellular matrix degradation and/or remodelling, such as cancer, and chronic inflammatory diseases such as arthritis, rheumatoid arthritis, osteoarthritis atherosclerosis, abdominal aortic aneurysm, inflammation, multiple sclerosis, and chronic obstructive pulmonary disease, and pain, such as inflammatory pain, bone pain and joint pain.
The present invention also provides heterobicyclic metalloprotease inhibiting compounds that are useful as active ingredients in pharmaceutical compositions for treatment or prevention of metalloprotease—especially MMP-13—mediated diseases. The present invention also contemplates use of such compounds in pharmaceutical compositions for oral or parenteral administration, comprising one or more of the heterobicyclic metalloprotease inhibiting compounds disclosed herein.
The present invention further provides methods of inhibiting metalloproteases, by administering formulations, including, but not limited to, oral, rectal, topical, intravenous, parenteral (including, but not limited to, intramuscular, intravenous), ocular (ophthalmic), transdermal, inhalative (including, but not limited to, pulmonary, aerosol inhalation), nasal, sublingual, subcutaneous or intraarticular formulations, comprising the heterobicyclic metalloprotease inhibiting compounds by standard methods known in medical practice, for the treatment of diseases or symptoms arising from or associated with metalloprotease, especially MMP-13, including prophylactic and therapeutic treatment. Although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. The compounds from this invention are conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
The heterobicyclic metalloprotease inhibiting compounds of the present invention may be used in combination with a disease modifying antirheumatic drug, a nonsteroidal anti-inflammatory drug, a COX-2 selective inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, a biological response modifier or other anti-inflammatory agents or therapeutics useful for the treatment of chemokines mediated diseases.


DETAILED DESCRIPTION OF THE INVENTION
The terms “alkyl” or “alk”, as used herein alone or as part of another group, denote optionally substituted, straight and branched chain saturated hydrocarbon groups, preferably having 1 to 10 carbons in the normal chain, most preferably lower alkyl groups. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g., to form a benzyl group), cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH2—CO—), substituted carbamoyl ((e)(R11)N—CO— wherein R10 or R11 are as defined below, except that at least one of R10 or R11 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH).
The terms “lower alk” or “lower alkyl” as used herein, denote such optionally substituted groups as described above for alkyl having 1 to 4 carbon atoms in the normal chain.
The term “alkoxy” denotes an alkyl group as described above bonded through an oxygen linkage (—O—).
The term “alkenyl”, as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon double bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include ethenyl, propenyl, isobutenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH2—CO—), substituted carbamoyl ((R10)(R11)N—CO— wherein R10 or R11 are as defined below, except that at least one of R10 or R11 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH).
The term “alkynyl”, as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon triple bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH2—CO—), substituted carbamoyl ((R10)(R11)N—CO— wherein R10 or R11 are as defined below, except that at least one of R10 or R11 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH).
The term “cycloalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated cyclic hydrocarbon ring systems, containing one ring with 3 to 9 carbons. Exemplary unsubstituted such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, and cyclododecyl. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The term “bicycloalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated cyclic bridged hydrocarbon ring systems, desirably containing 2 or 3 rings and 3 to 9 carbons per ring. Exemplary unsubstituted such groups include, but are not limited to, adamantyl, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane and cubane. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The term “spiroalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated hydrocarbon ring systems, wherein two rings of 3 to 9 carbons per ring are bridged via one carbon atom. Exemplary unsubstituted such groups include, but are not limited to, spiro[3.5]nonane, spiro[4.5]decane or spiro[2.5]octane. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The term “spiroheteroalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated hydrocarbon ring systems, wherein two rings of 3 to 9 carbons per ring are bridged via one carbon atom and at least one carbon atom is replaced by a heteroatom independently selected from N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized. Exemplary unsubstituted such groups include, but are not limited to, 1,3-diaza-spiro[4.5]decane-2,4-dione. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The terms “ar” or “aryl”, as used herein alone or as part of another group, denote optionally substituted, homocyclic aromatic groups, preferably containing 1 or 2 rings and 6 to 12 ring carbons. Exemplary unsubstituted such groups include, but are not limited to, phenyl, biphenyl, and naphthyl. Exemplary substituents include, but are not limited to, one or more nitro groups, alkyl groups as described above or groups described above as alkyl substituents.
The term “heterocycle” or “heterocyclic system” denotes a heterocyclyl, heterocyclenyl, or heteroaryl group as described herein, which contains carbon atoms and from 1 to 4 heteroatoms independently selected from N, O and S and including any bicyclic or tricyclic group in which any of the above-defined heterocyclic rings is fused to one or more heterocycle, aryl or cycloalkyl groups. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolinyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, oxindolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl.
Further examples of heterocycles include, but not are not limited to, “heterobicycloalkyl” groups such as 7-oxa-bicyclo[2.2.1]heptane, 7-aza-bicyclo[2.2.1]heptane, and 1-aza-bicyclo[2.2.2]octane.
“Heterocyclenyl” denotes a non-aromatic monocyclic or multicyclic hydrocarbon ring system of about 3 to about 10 atoms, desirably about 4 to about 8 atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur atoms, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. Ring sizes of rings of the ring system may include 5 to 6 ring atoms. The designation of the aza, oxa or thia as a prefix before heterocyclenyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The heterocyclenyl may be optionally substituted by one or more substituents as defined herein. The nitrogen or sulphur atom of the heterocyclenyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. “Heterocyclenyl” as used herein includes by way of example and not limitation those described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960), the contents all of which are incorporated by reference herein. Exemplary monocyclic azaheterocyclenyl groups include, but are not limited to, 1,2,3,4-tetrahydrohydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Exemplary oxaheterocyclenyl groups include, but are not limited to, 3,4-dihydro-2H-pyran, dihydrofuranyl, and fluorodihydrofuranyl. An exemplary multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl.
“Heterocyclyl,” or “heterocycloalkyl,” denotes a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms, desirably 4 to 8 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Ring sizes of rings of the ring system may include 5 to 6 ring atoms. The designation of the aza, oxa or thia as a prefix before heterocyclyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The heterocyclyl may be optionally substituted by one or more substituents which may be the same or different, and are as defined herein. The nitrogen or sulphur atom of the heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
“Heterocyclyl” as used herein includes by way of example and not limitation those described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960). Exemplary monocyclic heterocyclyl rings include, but are not limited to, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
“Heteroaryl” denotes an aromatic monocyclic or multicyclic ring system of about 5 to about 10 atoms, in which one or more of the atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Ring sizes of rings of the ring system include 5 to 6 ring atoms. The “heteroaryl” may also be substituted by one or more substituents which may be the same or different, and are as defined herein. The designation of the aza, oxa or thia as a prefix before heteroaryl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. A nitrogen atom of a heteroaryl may be optionally oxidized to the corresponding N-oxide. Heteroaryl as used herein includes by way of example and not limitation those described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960). Exemplary heteroaryl and substituted heteroaryl groups include, but are not limited to, pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, benzoazaindole, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzthiazolyl, dioxolyl, furanyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, oxazinyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinazolinyl, quinolinyl, tetrazinyl, tetrazolyl, 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, thiatriazolyl, thiazinyl, thiazolyl, thienyl, 5-thioxo-1,2,4-diazolyl, thiomorpholino, thiophenyl, thiopyranyl, triazolyl and triazolonyl.
The phrase “fused” means, that the group, mentioned before “fused” is connected via two adjacent atoms to the ring system mentioned after “fused” to form a bicyclic system. For example, “heterocycloalkyl fused aryl” includes, but is not limited to, 2,3-dihydro-benzo[1,4]dioxine, 4H-benzo[1,4]oxazin-3-one, 3H-Benzooxazol-2-one and 3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one.
The term “amino” denotes the radical —NH2 wherein one or both of the hydrogen atoms may be replaced by an optionally substituted hydrocarbon group. Exemplary amino groups include, but are not limited to, n-butylamino, tert-butylamino, methylpropylamino and ethyldimethylamino.
The term “cycloalkylalkyl” denotes a cycloalkyl-alkyl group wherein a cycloalkyl as described above is bonded through an alkyl, as defined above. Cycloalkylalkyl groups may contain a lower alkyl moiety. Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopentylethyl, cyclohexylpropyl, cyclopropylpropyl, cyclopentylpropyl, and cyclohexylpropyl.
The term “arylalkyl” denotes an aryl group as described above bonded through an alkyl, as defined above.
The term “heteroarylalkyl” denotes a heteroaryl group as described above bonded through an alkyl, as defined above.
The term “heterocyclylalkyl,” or “heterocycloalkylalkyl,” denotes a heterocyclyl group as described above bonded through an alkyl, as defined above.
The terms “halogen”, “halo”, or “hal”, as used herein alone or as part of another group, denote chlorine, bromine, fluorine, and iodine.
The term “haloalkyl” denotes a halo group as described above bonded though an alkyl, as defined above. Fluoroalkyl is an exemplary group.
The term “aminoalkyl” denotes an amino group as defined above bonded through an alkyl, as defined above.
The phrase “bicyclic fused ring system wherein at least one ring is partially saturated” denotes an 8- to 13-membered fused bicyclic ring group in which at least one of the rings is non-aromatic. The ring group has carbon atoms and optionally 1-4 heteroatoms independently selected from N, O and S. Illustrative examples include, but are not limited to, indanyl, tetrahydronaphthyl, tetrahydroquinolyl and benzocycloheptyl.
The phrase “tricyclic fused ring system wherein at least one ring is partially saturated” denotes a 9- to 18-membered fused tricyclic ring group in which at least one of the rings is non-aromatic. The ring group has carbon atoms and optionally 1-7 heteroatoms independently selected from N, O and S. Illustrative examples include, but are not limited to, fluorene, 10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 2,2a,7,7a-tetrahydro-1H-cyclobuta[a]indene.
The term “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Examples therefore may be, but are not limited to, sodium, potassium, choline, lysine, arginine or N-methyl-glucamine salts, and the like.
The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, p. 1445, the disclosure of which is hereby incorporated by reference.
The phrase “pharmaceutically acceptable” denotes those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
The phrase “pharmaceutically acceptable carrier” denotes media generally accepted in the art for the delivery of biologically active agents to mammals, e.g., humans. Such carriers are generally formulated according to a number of factors well within the purview of those of ordinary skill in the art to determine and account for. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, well known to those of ordinary skill in the art. Non-limiting examples of a pharmaceutically acceptable carrier are hyaluronic acid and salts thereof, and microspheres (including, but not limited to poly(D,L)-lactide-co-glycolic acid copolymer (PLGA), poly(L-lactic acid) (PLA), poly(caprolactone (PCL) and bovine serum albumin (BSA)). Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources, e.g., Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the contents of which are incorporated herein by reference.
Pharmaceutically acceptable carriers particularly suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscarmellose sodium, cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
The compositions of the invention may also be formulated as suspensions including a compound of the present invention in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension. In yet another embodiment, pharmaceutical compositions of the invention may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of suitable excipients.
Carriers suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin or cetyl alcohol. The suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
Cyclodextrins may be added as aqueous solubility enhancers. Preferred cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of α-, β-, and γ-cyclodextrin. The amount of solubility enhancer employed will depend on the amount of the compound of the present invention in the composition.
The term “formulation” denotes a product comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical formulations of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutical carrier.
The term “N-oxide” denotes compounds that can be obtained in a known manner by reacting a compound of the present invention including a nitrogen atom (such as in a pyridyl group) with hydrogen peroxide or a peracid, such as 3-chloroperoxy-benzoic acid, in an inert solvent, such as dichloromethane, at a temperature between about −10-80° C., desirably about 0° C.
The term “polymorph” denotes a form of a chemical compound in a particular crystalline arrangement. Certain polymorphs may exhibit enhanced thermodynamic stability and may be more suitable than other polymorphic forms for inclusion in pharmaceutical formulations.
The compounds of the invention can contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. According to the invention, the chemical structures depicted herein, and therefore the compounds of the invention, encompass all of the corresponding enantiomers and stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
The term “racemic mixture” denotes a mixture that is about 50% of one enantiomer and about 50% of the corresponding enantiomer relative to all chiral centers in the molecule. Thus, the invention encompasses all enantiomerically-pure, enantiomerically-enriched, and racemic mixtures of compounds of Formulas (I) through (VI).
Enantiomeric and stereoisomeric mixtures of compounds of the invention can be resolved into their component enantiomers or stereoisomers by well-known methods. Examples include, but are not limited to, the formation of chiral salts and the use of chiral or high performance liquid chromatography “HPLC” and the formation and crystallization of chiral salts. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972); Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N. Manda (1994 John Wiley & Sons, Inc.), and Stereoselective Synthesis A Practical Approach, Mihaly Nogradi (1995 VCH Publishers, Inc., NY, N.Y.). Enantiomers and stereoisomers can also be obtained from stereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
“Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced.
Unless moieties of a compound of the present invention are defined as being unsubstituted, the moieties of the compound may be substituted. In addition to any substituents provided above, the moieties of the compounds of the present invention may be optionally substituted with one or more groups independently selected from:
C1-C4 alkyl;
C2-C4 alkenyl;
C2-C4 alkynyl;
CF3;
halo;
OH;
O—(C1-C4 alkyl);
OCH2F;
OCHF2;
OCF3;
ONO2;
OC(O)—(C1-C4 alkyl);
OC(O)—(C1-C4 alkyl);
OC(O)NH—(C1-C4 alkyl);
OC(O)N(C1-C4 alkyl)2;
OC(S)NH—(C1-C4 alkyl);
OC(S)N(C1-C4 alkyl)2;
SH;
S—(C1-C4 alkyl);
S(O)—(C1-C4 alkyl);
S(O)2—(C1-C4 alkyl);
SC(O)—(C1-C4 alkyl);
SC(O)O—(C1-C4 alkyl);
NH2;
N(H)—(C1-C4 alkyl);
N(C1-C4 alkyl)2;
N(H)C(O)—(C1-C4 alkyl);
N(CH3)C(O)—(C1-C4 alkyl);
N(H)C(O)—CF3;
N(CH3)C(O)—CF3;
N(H)C(S)—(C1-C4 alkyl);
N(CH3)C(S)—(C1-C4 alkyl);
N(H)S(O)2—(C1-C4 alkyl);
N(H)C(O)NH2;
N(H)C(O)NH—(C1-C4 alkyl);
N(CH3)C(O)NH—(C1-C4 alkyl);
N(H)C(O)N(C1-C4 alkyl)2;
N(CH3)C(O)N(C1-C4 alkyl)2;
N(H)S(O)2NH2);
N(H)S(O)2NH—(C1-C4 alkyl);
N(CH3)S(O)2NH—(C1-C4 alkyl);
N(H)S(O)2N(C1-C4 alkyl)2;
N(CH3)S(O)2N(C1-C4 alkyl)2;
N(H)C(O)O—(C1-C4 alkyl);
N(CH3)C(O)O—(C1-C4 alkyl);
N(H)S(O)2O—(C1-C4 alkyl);
N(CH3)S(O)2O—(C1-C4 alkyl);
N(CH3)C(S)NH—(C1-C4 alkyl);
N(CH3)C(S)N(C1-C4 alkyl)2;
N(CH3)C(S)O—(C1-C4 alkyl);
N(H)C(S)NH2;
NO2;
CO2H;
CO2—(C1-C4 alkyl);
C(O)N(H)OH;
C(O)N(CH3)OH:
C(O)N(CH3)OH;
C(O)N(CH3)O—(C1-C4 alkyl);
C(O)N(H)—(C1-C4 alkyl);
C(O)N(C1-C4 alkyl)2;
C(S)N(H)—(C1-C4 alkyl);
C(S)N(C1-C4 alkyl)2;
C(NH)N(H)—(C1-C4 alkyl);
C(NH)N(C1-C4 alkyl)2;
C(NCH3)N(H)—(C1-C4 alkyl);
C(NCH3)N(C1-C4 alkyl)2;
C(O)—(C1-C4 alkyl);
C(NH)—(C1-C4 alkyl);
C(NCH3)—(C1-C4 alkyl);
C(NOH)—(C1-C4 alkyl);
C(NOCH3)—(C1-C4 alkyl);
CN;
CHO;
CH2OH;
CH2O—(C1-C4 alkyl);
CH2NH2;
CH2N(H)—(C1-C4 alkyl);
CH2N(C1-C4 alkyl)2;
aryl;
heteroaryl;
cycloalkyl; and
heterocyclyl.
In some cases, a ring substituent may be shown as being connected to the ring by a bond extending from the center of the ring. The number of such substituents present on a ring is indicated in subscript by a number. Moreover, the substituent may be present on any available ring atom, the available ring atom being any ring atom which bears a hydrogen which the ring substituent may replace. For illustrative purposes, if variable Rx were defined as being:




this would indicate a cyclohexyl ring bearing five Rx substituents. The Rx substituents may be bonded to any available ring atom. For example, among the configurations encompassed by this are configurations such as:





These configurations are illustrative and are not meant to limit the scope of the invention in any way.
In one embodiment of the present invention, the amide containing heterobicyclic metalloprotease compounds may be represented by the general Formula (I):




wherein:

R1 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl,
wherein R1 is optionally substituted one or more times, or
wherein R1 is optionally substituted by one R16 group and optionally substituted by one or more R9 groups;
R2 is selected from the group consisting of hydrogen and alkyl, wherein alkyl is optionally substituted one or more times or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O)x, or NR50 and which is optionally substituted one or more times;
R3 is NR20R21;
R4 in each occurrence is independently selected from the group consisting of R10, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, haloalkyl, CF3, (C0-C6)-alkyl-COR10, (C0-C6)-alkyl-OR10, (C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NO2, (C0-C6)-alkyl-CN, (C0-C6)-alkyl-S(O)yOR10, (C0-C6)-alkyl-S(O)yNR10R11, (C0-C6)-alkyl-NR10CONR11SO2R30, (C0-C6)-alkyl-S(O)xR10, (C0-C6)-alkyl-OC(O)R10, (C0-C6)-alkyl-OC(O)NR10R11, (C0-C6)-alkyl-C(═NR10)NR10R11, (C0-C6)-alkyl-NR10C(═NR11)NR10R11, (C0-C6)-alkyl-C(O)OR10, (C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10SO2R11, (C0-C6)-alkyl-C(O)—NR11—CN, O—(C0-C6)-alkyl-C(O)NR10R11, S(O)x—(C0-C6)-alkyl-C(O)OR10, S(O)x—(C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10—(C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NR10—C(O)R10, (C0-C6)-alkyl-NR10—C(O)OR10, (C0-C6)-alkyl-NR10—C(O)—NR10R11, (C0-C6)-alkyl-NR10—S(O)yNR10R11, (C0-C6)-alkyl-NR10—S(O)yR10, O—(C0-C6)-alkyl-aryl and O—(C0-C6)-alkyl-heteroaryl,
wherein each R4 group is optionally substituted one or more times, or
wherein each R4 group is optionally substituted by one or more R14 groups;
R5 in each occurrence is independently selected from the group consisting of hydrogen, alkyl, C(O)NR10R11, aryl, arylalkyl, SO2NR10R11 and C(O)OR10, wherein alkyl, aryl and arylalkyl are optionally substituted one or more times;
R9 in each occurrence is independently selected from the group consisting of R10, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, CHF2, CF3, OR10, SR10, COOR10, CH(CH3)CO2H, (C0-C6)-alkyl-COR10, (C0-C6)-alkyl-OR10, (C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NO2, (C0-C6)-alkyl-CN, (C0-C6)-alkyl-S(O)yOR10, (C0-C6)-alkyl-P(O)2OH, (C0-C6)-alkyl-S(O)yNR10R11, (C0-C6)-alkyl-NR10CONR11SO2R30, (C0-C6)-alkyl-S(O)xR10, (C0-C6)-alkyl-OC(O)R10, (C0-C6)-alkyl-OC(O)NR10R11, (C0-C6)-alkyl-C(═NR10)NR10R11, (C0-C6)-alkyl-NR10C(═NR11)NR10R11, (C0-C6)-alkyl-NR10C(═N—CN)NR10R11, (C0-C6)-alkyl-C(═N—CN)NR10R11, (C0-C6)-alkyl-NR10C(═N—NO2)NR10R11, (C0-C6)-alkyl-C(═N—NO2)NR10R11, (C0-C6)-alkyl-C(O)OR10, (C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10SO2R11, C(O)NR10—(C0-C6)-alkyl-heteroaryl, C(O)NR10—(C0-C6)-alkyl-aryl, S(O)2NR10—(C0-C6)-alkyl-aryl, S(O)2NR10—(C0-C6)-alkyl-heteroaryl, S(O)2NR10-alkyl, S(O)2—(C0-C6)-alkyl-aryl, S(O)2—(C0-C6)-alkyl-heteroaryl, (C0-C6)-alkyl-C(O)—NR11—CN, O—(C0-C6)-alkyl-C(O)NR10R11, S(O)x—(C0-C6)-alkyl-C(O)OR10, S(O)x—(C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10—(C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NR10—C(O)R10, (C0-C6)-alkyl-NR10—C(O)OR10, (C0-C6)-alkyl-NR10—C(O)—NR10R11, (C0-C6)-alkyl-NR10—S(O)yNR10R11, (C0-C6)-alkyl-NR10—S(O)yR11, O—(C0-C6)-alkyl-aryl and O—(C0-C6)-alkyl-heteroaryl,
wherein each R9 group is optionally substituted, or
wherein each R9 group is optionally substituted by one or more R14 groups;
R10 and R11 in each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted one or more times, or R10 and R11 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O)x, or NR50 and which is optionally substituted one or more times;
R14 is independently selected from the group consisting of hydrogen, alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclylalkyl and halo, wherein alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times;
R16 is selected from the group consisting of cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl fused heteroarylalkyl, (i) and (ii):




wherein cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl are optionally substituted one or more times;

R20 is selected from the group consisting of hydrogen and alkyl, wherein alkyl is optionally substituted one or more times;
R21 is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, and
wherein R21 is optionally substituted one or more times, or
wherein R21 is optionally substituted by one or more R9 groups;
R22 is selected from the group consisting of hydrogen, hydroxy, halo, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, NO2, NR10R11, CN, SR10, SSR10, PO3R10, NR10NR10R11, NR10N═CR10R11, NR10SO2R11, C(O)OR10, C(O)NR10R11, SO2R10, SO2NR10R11 and fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times;
R30 is selected from the group consisting of alkyl and (C0-C6)-alkyl-aryl, wherein alkyl and aryl are optionally substituted;
R50 in each occurrence is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, C(O)R80, C(O)NR80R81, SO2R80 and SO2NR80R81, wherein alkyl, aryl, and heteroaryl are optionally substituted one or more times;
R80 and R81 in each occurrence are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted, or R80 and R81 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally a heteroatom selected from O, S(O)x, —NH, and —N(alkyl) and which is optionally substituted one or more times;
E is selected from the group consisting of a bond, CR10R11, O, NR5, S, S═O, S(═O)2, C(═O), N(R10)(C═O), (C═O)N(R10), N(R10)S(═O)2, S(═O)2N(R10), C═N—OR11, —C(R10R11)C(R10R11)—, —CH2—W1— and




Q is a 5- or 6-membered ring selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted one or more times with R4;
D is a member selected from the group consisting of CR22 and N;
U is selected from the group consisting of C(R5R10), NR5, O, S, S═O and S(═O)2;
W1 is selected from the group consisting of O, NR5, S, S═O, S(═O)2, N(R10)(C═O), N(R10)S(═O)2 and)S(═O)2N(R10);
X is selected from the group consisting of a bond and (CR10R11)wE(CR10R11)w;
g and h are independently selected from 0-2;
w is independently selected from 0-4;
x is selected from 0 to 2;
y is selected from 1 and 2; and
N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.
In another embodiment, compounds of Formula (I) may be selected from Group I(a):







wherein:

R51 is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and haloalkyl, wherein alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and haloalkyl are optionally substituted one or more times.
In still another embodiment, compounds of Formula (I) may be selected from:




In yet another embodiment, compounds of Formula (I) may be selected from:




In some embodiments, R3 of the compounds of Formula (I) may be selected from Substituent Group 1:




wherein:
R7 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, halo, R4 and NR10R11, wherein alkyl and cycloalkyl are optionally substituted one or more times, or optionally two R7 groups together at the same carbon atom form ═O, ═S or ═NR10;
A and B are independently selected from the group consisting of CR9, CR9R10, NR10, N, O and S(O)x;
G, L, M and T are independently selected from the group consisting of CR9 and N;
m and n are independently selected from 0-3, provided that:

    
    
        (1) when E is present, m and n are not both 3;
        (2) when E is —CH2—W1—, m and n are not 3; and
        (3) when E is a bond, m and n are not 0; and
    
    


p is selected from 0-6;
wherein the dotted line represents a double bond between one of: carbon “a” and A, or carbon “a” and B.
For example, in some embodiments, R3 of the compounds of Group 1(a) may be selected from Substituent Group 1 as defined hereinabove.
In some embodiments, R3 of Formula (I) may be selected from Substituent Group I(2):







wherein:
R is selected from the group consisting of C(O)NR10R11, COR10, SO2NR10R11, SO2R10, CONHCH3 and CON(CH3)2, wherein C(O)NR10R11,COR10, SO2NR10R11, SO2R10, CONHCH3 and CON(CH3)2 are optionally substituted one or more times; and
r is selected from 1-4.
For example, in some embodiments, R3 of the compounds of Group I(a) may be selected from Substituent Group 2, as defined hereinabove.
In yet a further embodiment, R3 of Formula (I) may be selected from Substituent Group 3:







For example, in some embodiments, R3 of the structures of Group I(a) may be selected from Substituent Group 3 as defined hereinabove.
In another embodiment, R9 may be selected from Substituent Group 4:










wherein:
R52 is selected from the group consisting of hydrogen, halo, CN, hydroxy, alkoxy, fluoroalkoxy, alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, haloalkyl, C(O)NR10R11 and SO2NR10R11, wherein alkoxy, fluoroalkoxy, alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, and haloalkyl are optionally substituted one or more times.
For example, in some embodiments, R9 of Substituent Group 3 may be selected from Substituent Group 4 as defined hereinabove.
In yet a further embodiment, R3 of the structures of Formula (I) may be Substituent Group 16:




For example, in some embodiments, R3 of the structures of Group I(a) may be selected from Substituent Group 16 as defined hereinabove.
In still a further embodiment, R3 of Formula (I) may be selected from Substituent Group 5:




wherein:

R9 is selected from the group consisting of hydrogen, fluoro, halo, CN, alkyl, CO2H,




For example, in some embodiments, R3 of the structures of Group I(a) may be selected from Substituent Group 5 as defined hereinabove.
In another embodiment, RI of Formula (I) may be selected from Substituent Group 6:




wherein:
R18 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR10R11, CO2R10, OR10, OCF3, OCHF2, NR19CONR10R11, NR10COR11, NR10SO2R11, NR10SO2NR10R11, SO2NR10R11 and NR10R11, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl are optionally substituted one or more times;
R25 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, CO2R10, C(O)NR10R11 and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally substituted one or more times;
B1 is selected from the group consisting of NR10, O and S(O)x;
D2, G2, L2, M2 and T2 are independently selected from the group consisting of CR18 and N; and
Z is a 5- to 8-membered ring selected from the group consisting of cycloalkyl, heterocycloalkyl, or a 5- to 6-membered ring selected from the group consisting of aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted one or more times.
For example, in another embodiment, R1 of the structures of Group I(a) may be selected from Substituent Group 6 as defined hereinabove.
In yet another embodiment, R1 of the structures of Group I(a) may be selected from Substituent Group 7:






















For example, in some embodiments, R1 of the structures of Group I(a) may be selected from Substituent Group 7 as defined hereinabove.
In still another embodiment, R1 of Formula (I) may be selected from Substituent Group 8:







wherein:
R12 and R13 are independently selected from the group consisting of hydrogen, alkyl and halo, wherein alkyl is optionally substituted one or more times, or optionally R12 and R13 together form ═O, ═S or ═NR10;
R18 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR10R11, CO2R10, OR10, OCF3, OCHF2, NR10CONR10R11, NR10SO2NR10R11, SO2NR10R11 and NR10R11, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times;
R19 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR10R11, CO2R10, OR10, OCF3, OCHF2, NR10CONR10R11, NR10COR11, NR10SO2R11, NR10SO2NR10R11, SO2NR10R11 and NR10R11, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times, or optionally two R19 groups together at one carbon atom form ═O, ═S or ═NR10;
R25 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, CO2R10, C(O)NR10R11 and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally substituted one or more times;
J and K are independently selected from the group consisting of CR10R18, NR10, O and S(O)x;
A1 is selected from the group consisting of NR10, O and S(O)x; and
D2, G2, J2, L2, M2 and T2 are independently selected from the group consisting of CR18 and N.
For example, some embodiments, R1 of the structures of Group I(a) may be selected from Substituent Group 8 as defined hereinabove.
In a further embodiment, R1 of Formula (I) may be selected from Substituent Group 9:













For example, in some embodiments, R1 of the structures of Group I(a) may be selected from Substituent Group 9 as defined hereinabove.
In yet a further embodiment, R1 of Formula (I) may be selected from Substituent Group 10:







wherein:
R18 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR10R11, CO2R10, OR10, OCF3, OCHF2, NR10CONR10R11, NR10COR11, NR10SO2R11, NR10SO2NR10R11, SO2NR10R11 and NR10R11, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times;
R19 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR10R11, CO2R10, OR10, OCF3, OCHF2, NR10CONR10R11, NR10COR11, NR10SO2R11, NR10SO2NR10R11, SO2NR10R11 and NR10R11, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times, or optionally two R10 groups together at one carbon atom form ═O, ═S or ═NR10;
R25 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, CONR10R11 and haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times;
L2, M2, and T2 are independently selected from the group consisting of CR18 and N;
D3, G3, L3, M3, and T3 are independently selected from N, CR18, (i), or (ii),




with the proviso that one of L3, M3, T3, D3, and G3 is (i) or (ii)
B1 is selected from the group consisting of NR10, O and S(O)x; and
Q2 is a 5- to 8-membered ring selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, which is optionally substituted one or more times with R19.
For example, in some embodiments, R1 of the structures of Group I(a) may be selected from Substituent Group 10 as defined herinabove.
In still a further embodiment, R1 of Formula (I) may be selected from Substituent Group 11:










For example, in some embodiments, R1 of the structures of Group I(a) may be selected from Substituent Group 11 as defined hereinabove.
In another embodiment, R1 of Formula (I) may be selected from Substituent Group 12:










For example, in some embodiments, R1 of the structures of Group I(a) may be selected from Substituent Group 12 as defined hereinabove.
In yet another embodiment, the amide containing heterobicyclic metalloprotease compounds may be represented by the general Formula (II):




and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof,
wherein:
R1 in each occurrence may be the same or different and is as defined hereinabove;
R2 in each occurrence may be the same or different and is as defined hereinabove; and
all remaining variables are as defined hereinabove.
In still another embodiment, the compound of Formula (II) may be selected from Group II(a):







wherein all variables are as defined hereinabove.
In a further embodiment, the compound of Formula (II) may be selected from:




In yet a further embodiment, the compound of Formula (II) may be selected from:




In still a further embodiment, at least one R1 of Formula (II) may be selected from Substituent Group 13:







wherein:

R6 is independently selected from the group consisting of R9, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, C(O)OR10, CH(CH3)CO2H, (C0-C6)-alkyl-COR10, (C0-C6)-alkyl-OR10, (C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NO2, (C0-C6)-alkyl-CN, (C0-C6)-alkyl-S(O)yOR10, (C0-C6)-alkyl-P(O)2OH, (C0-C6)-alkyl-S(O)yNR10R11, (C0-C6)-alkyl-NR10CONR11SO2R30, (C0-C6)-alkyl-S(O)xR10, (C0-C6)-alkyl-OC(O)R10, (C0-C6)-alkyl-OC(O)NR10R11, (C0-C6)-alkyl-C(═NR10)NR10R11, (C0-C6)-alkyl-NR10C(═NR11)NR10R11, (C0-C6)-alkyl-NR10C(═N—CN)NR10R11, (C0-C6)-alkyl-C(═N—CN)NR10R11, (C0-C6)-alkyl-NR10C(═N—NO2)NR10R11, (C0-C6)-alkyl-C(═N—NO2)NR10R11, (C0-C6)-alkyl-C(O)OR10, (C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10SO2R11, C(O)NR10—(C0-C6)-alkyl-heteroaryl, C(O)NR10—(C0-C6)-alkyl-aryl, S(O)2NR10—(C0-C6)-alkyl-aryl, S(O)2NR10—(C0-C6)-alkyl-heteroaryl, S(O)2NR10-alkyl, S(O)2—(C0-C6)-alkyl-aryl, S(O)2—(C0-C6)-alkyl-heteroaryl, (C0-C6)-alkyl-C(O)—NR11—CN, O—(C0-C6)-alkyl-C(O)NR10R11, S(O)x—(C0-C6)-alkyl-C(O)OR10, S(O)x—(C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10—(C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NR10—C(O)OR10, (C0-C6)-alkyl-NR10—C(O)—NR10R11, (C0-C6)-alkyl-NR10—S(O)yNR10R11, (C0-C6)-alkyl-NR10—S(O)yR11, O—(C0-C6)-alkyl-aryl and O—(C0-C6)-alkyl-heteroaryl, wherein each R6 group is optionally substituted by one or more R14 groups;
R9 is independently selected from the group consisting of hydrogen, alkyl, halo, CHF2, CF3, OR10, NR10R11, NO2, and CN, wherein alkyl is optionally substituted one or more times;
D4, G4, L4, M4, and T4 are independently selected from CR6 and N; and
all remaining variables are as defined hereinabove.
For example, in some embodiments, at least one R1 of the structures of Group II(a) may independently be selected from Substituent Group 13 as defined hereinabove.
In another embodiment, at least one R1 of Formula (II) may be selected from Substituent Group 14:




For example, in some embodiments, at least one R1 of Group II(a) may independently be selected from Substituent Group 14 as defined hereinabove.
In yet another embodiment, R6 of Substituent Group 14 may be selected from hydrogen, halo, CN, OH, CH2OH, CF3, CHF2, OCF3, OCHF2, COCH3, SO2CH3, SO2CF3, SO2NH2, SO2NHCH3, SO2N(CH3)2, NH2, NHCOCH3, N(COCH3)2, NHCONH2, NHSO2CH3, alkoxy, alkyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, CO2H,




R9 is independently selected from the group consisting of hydrogen, fluoro, chloro, CH3, CF3, CHF2, OCF3, and OCHF2;
R25 is selected from the group consisting of hydrogen, CH3, COOCH3, COOH, and CONH2.
In yet another embodiment, at least one R1 of Formula (II) may be selected from Substituent Group 15:











































For example, in some embodiments, at least one R1 of Group II(a) may be selected from Substituent Group 15 as defined hereinabove.
In still another embodiment, at least one R1 of Formula (II) may be selected from Substituent Group 8:







wherein all variables are as defined hereinabove.
For example, in some embodiments, at least one R1 of Group II(a) may be selected from Substituent Group 8 as defined hereinabove.
In a further embodiment, at least one R1 of Formula (II) may be selected from Substituent Group 9:
















For example, in some embodiments, at least one R1 of Group II(a) may be selected from Substituent Group 9 as defined hereinabove.
In yet a further embodiment, one R1 of Formula (II) may be selected from Substituent Group 10:







wherein all variables are as defined hereinabove.
For example, in some embodiments, one R1 of Group II(a) may be selected from Substituent Group 10 as defined hereinabove.
In still a further embodiment, one R1 of Formula (II) may independently be selected from Substituent Group 11:










For example, in some embodiments, one R1 of Group II(a) may be selected from Substituent Group 11 as defined hereinabove.
In one embodiment, one R1 of Formula (II) may be selected from Substituent Group 12:










For example, in some embodiments, one R1 of Group II(a) may be selected from Substituent Group 12 as defined hereinabove.
In some embodiments:
A) the first occurrence of R1 of Formula (II) is selected from Substituent Group 13:







B) the second occurrence R1 of Formula (II) is selected from Substituent Group 8 and Substituent Group 10:











wherein all variables are as defined hereinabove.
For example in some embodiments, the first occurrence of R1 of the structures of Group II(a) may be selected from Substituent Group 13 as defined hereinabove, and the second occurrence of R1 may be selected from Substituent Group 10 as defined hereinabove.
In another embodiment of the present invention, the amide containing heterobicyclic metalloprotease compounds may be represented by the general Formula (III):




and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof,
wherein all variables are as defined hereinabove.
In yet another embodiment, the compounds of Formula (III) may be selected from Group III(a):







wherein all variables are as defined hereinabove.

In still another embodiment, the compounds of Formula (III) may be selected from:




In a further embodiment, the compounds of Formula (III) may be selected from:




In yet a further embodiment, R3 of Formula (III) may be selected from Substituent Group 1:




wherein all variables are as defined hereinabove.
For example, in some embodiments, R3 of the structures of Group III(a) may be selected from Substituent Group 1 as defined hereinabove.
In still a further embodiment, R3 of Formula (III) may be selected from Substituent Group 2:







wherein all variables are as defined hereinabove.
In still a further embodiment, R3 of the structures of Group III(a) may be selected from Substituent Group 2 as defined hereinabove.
In one embodiment, R3 of Formula (III) may be selected from Substituent Group 3:







For example, in some embodiments, R3 of the structures of Group III(a) may be selected from Substituent Group 3 as defined hereinabove.
In one embodiment, R9 of the structures of Substituent Group 3 may be selected from:







wherein all variables are as defined hereinabove.
In another embodiment, R3 of Formula (III) may be Substituent Group 16:




For example, in some embodiments, R3 of the structures of Group III(a) may be Substituent Group 16 as defined hereinabove.
In yet another embodiment, R3 of Formula (III) may be selected from Substituent Group 5:




wherein:

R9 is selected from hydrogen, fluoro, halo, CN, alkyl, CO2H,




For example, in some embodiments, R3 of the structures of Group III(a) may be selected from Substituent Group 5 as defined hereinabove.
In still another embodiment, R1 of the structures of Formula (III) may be selected from Substituent Group 6:




wherein all variables are as defined hereinabove.
For example, in some embodiments, R1 of the structures of Group III(a) may be selected from Substituent Group 6 as defined hereinabove.
In a further embodiment, R1 of Formula (III) may be selected from Substituent Group 7:



















For example, in some embodiments, R1 of the structures of Group III(a) may be selected from Substituent Group 7 as defined hereinabove.
In yet a further embodiment, R1 of Formula (III) may be selected from Substituent Group 8:







wherein all variables are as defined hereinabove.
For example, in some embodiments, R1 of the structures of Group III(a) may be selected from Substituent Group 8 as defined hereinabove.
In still a further embodiment, R1 of Formula (III) may be selected from Substituent Group 9:













For example, in some embodiments, R1 of the structures of Group III(a) may be selected from Substituent Group 9 as defined hereinabove.
In one embodiment, R1 of Group III(a) may be selected from Substituent Group 10.







wherein all variables are as defined hereinabove.
For example, in some embodiments, R1 of the structures of Group III(a) may be selected from Substituent Group 10 as defined hereinabove.
In another embodiment, R1 of Formula (III) may be selected from Substituent Group 11:










wherein all variables are as defined hereinabove.
For example, in some embodiments, R1 of the structures of Group III(a) may be selected from Substituent Group 11 as defined hereinabove.
In yet another embodiment, R1 of Formula (III) may be selected from Substituent Group 12:










For example, in some embodiments, R1 of the structures of Group III(a) may be selected from Substituent Group 12 as defined hereinabove.
In one embodiment of the present invention, the amide containing heterobicyclic metalloprotease compounds may be represented by the general Formula (IV):




and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof,
wherein:
R23 is selected from the group consisting of hydrogen, hydroxy, halo, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, NO2, NR10R11, CN, SR10, SSR10, PO3R10, NR10NR10R11, NR10N═CR10R11, NR10SO2R11, C(O)OR10, and fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times;
W is a 5- or 6-membered ring selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted one or more times with R4; and
all remaining variables are as defined herein above.
In another embodiment, the compounds of Formula (IV) may be selected from Group IV(a):




wherein:

R51 is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and haloalkyl, wherein alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and haloalkyl are optionally substituted one or more times;
K1 is O, S(O)x, or NR51; and
all remaining variables are as defined hereinabove.
In yet another embodiment, the compounds of Formula (IV) may be selected from Group IV(b):







In still another embodiment, R3 of Formula (IV) may be selected from Substituent Group 1:




wherein all variables are as defined hereinabove.
For example, in some embodiments, R3 of the structures of Groups IV(a) and (b) may be selected from Substituent Group 1 as defined hereinabove.
In a further embodiment, R3 of Formula (IV) may be selected from Substituent Group 2:







wherein all variables are as defined hereinabove.
For example, in some embodiments, R3 of the structures of Groups IV(a) and (b) may be selected from Substituent Group 2 as defined hereinabove.
In yet a further embodiment, R3 of Formula (IV) may be selected from Substituent Group 3







For example, in some embodiments, R3 of the structures of Groups IV(a) and (b) may be selected from Substituent Group 3 as defined hereinabove.
In still a further embodiment, R9 of Substituent Group 3 may be selected from:







wherein all variables are as defined hereinabove.
In one embodiment, R3 of Formula (IV) may be Substituent Group 16:




For example, in some embodiments, R3 of the structures of Groups IV(a) and (b) may be Substituent Group 16 as defined hereinabove.
In another embodiment, R3 of Formula (IV) may be selected from Substituent Group 5:




wherein R9 is selected from hydrogen, fluoro, halo, CN, alkyl, CO2H,




For example, in some embodiments, R3 of the structures of Groups IV(a) and (b) may be selected from Substituent Group 5 as defined hereinabove.
In yet another embodiment, RI of Formula (IV) may be selected from Substituent Group 6:




wherein all variables are as defined hereinabove.
For example, in some embodiments, R1 of the structures of Groups IV(a) and (b) may be selected from Substituent Group 6 as defined hereinabove.
In still another embodiment, R1 of Formula (IV) may be selected from Substituent Group 7:



















For example, in some embodiments, R1 of the structures of Groups IV(a) and (b) may be selected from Substituent Group 7 as defined hereinabove.
In a further embodiment, R1 of Formula (IV) may be selected from Substituent Group 8:







wherein all variables are as defined hereinabove.
For example, in some embodiments, R1 of the structures of Groups IV(a) and (b) may be selected from Substituent Group 8 as defined hereinabove.
In yet a further embodiment, R1 of Formula (IV) may be selected from Substituent Group 9:













For example, in some embodiments, R1 of the structures of Groups IV(a) and (b) may be selected from Substituent Group 9 as defined hereinabove.
In still a further embodiment, R1 of Formula (IV) may be selected from Substituent Group 10:







wherein all variables are as defined hereinabove.
For example, in some embodiments, R1 of the structures of Groups IV(a) and (b) may be selected from Substituent Group 10 as defined hereinabove.
In one embodiment, R1 of Formula (IV) may be selected from Substituent Group 11:










For example, in some embodiments, R1 of the structures of Groups IV(a) and (b) may be selected from Substituent Group 11 as defined hereinabove.
In another embodiment, R1 of Formula (IV) may be selected from Substituent Group 12:










For example, in some embodiments, R1 of the structures of Groups IV(a) and (b) may be selected from Substituent Group 12 as defined hereinabove.
In still another embodiment of the present invention, the amide containing heterobicyclic metalloprotease compounds may be represented by the general Formula (V):




and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof,
wherein:
R1 in each occurrence may be the same or different and is as defined hereinabove;
R2 in each occurrence may be the same or different and is as defined hereinabove; and
all remaining variables are as defined hereinabove.
In a further embodiment, compounds of Formula (V) may be selected from Group V(a):




wherein all variables are as defined hereinabove.

In yet a further embodiment, the compounds of Formula (V) may be selected from Group V(b):







In still a further embodiment, at least one R1 of Formula (V) may be selected from Substituent Group 13:










wherein all variables are as defined hereinabove.

For example, in some embodiments, at least one R1 of the structures of Groups V(a) and (b) may be selected from Substituent Group 13 as defined hereinabove.
In one embodiment, at least one R1 of the compounds of Formula (V) may be selected from Substituent Group 14:










For example, in some embodiments, at least one R1 of the structures of Groups V(a) and (b) may be selected from Substituent Group 14 as defined hereinabove.
In another embodiment, R6 of Substituent Group 14 may be selected from hydrogen, halo, CN, OH, CH2OH, CF3, CHF2, OCF3, OCHF2, COCH3, SO2CH3, SO2CF3, SO2NH2, SO2NHCH3, SO2N(CH3)2, NH2, NHCOCH3, N(COCH3)2, NHCONH2, NHSO2CH3, alkoxy, alkyl, CO2H,




wherein
R9 is independently selected from the group consisting of hydrogen, fluoro, chloro, CH3, CF3, CHF2, OCF3, and OCHF2;
R25 is selected from the group consisting of hydrogen, CH3, COOCH3, COOH, and CONH2.
In yet another embodiment, at least one R1 of Formula (V) may be selected from Substituent Group 15:














































For example, in some embodiments, at least one R1 of the structures of Groups V(a) and (b) may be selected from Substituent Group 15 as defined hereinabove.
In still another embodiment, at least one R1 of Formula (V) may be selected from Substituent Group 8:







wherein all variables are as defined hereinabove.
For example, in some embodiments, at least one R1 of the structures of Groups V(a) and (b) may be selected from Substituent Group 8 as defined hereinabove.
In a further embodiment, at least one R1 of Formula (V) may be selected from Substituent Group 9:
















For example, in some embodiments, at least one R1 of the structures of Groups V(a) and (b) may be selected from Substituent Group 9 as defined hereinabove.
In yet a further embodiment, one R1 of Formula (V) may be selected from Substituent Group 10:







wherein all variables are as defined hereinabove.
For example, in some embodiments, one R1 of the structures of Groups V(a) and (b) may be selected from Substituent Group 10 as defined hereinabove.
In still a further embodiment, each R1 of Formula (V) may be independently selected from Substituent Group 11:










For example, in some embodiments, one R1 of the structures of Groups V(a) and (b) may be selected from Substituent Group 11 as defined hereinabove.
In one embodiment, one R1 of Formula (V) may be selected from Substituent Group 12:










For example, in some embodiments, one R1 of the structures of Groups V(a) and (b) may be selected from Substituent Group 12 as defined hereinabove.
In some embodiments:
A) the first occurrence of R1 of Formula (V) is selected from Substituent Group 13:










and

B) the second occurrence of R1 of Formula (V) is selected from Substituent Group 10:











wherein all variables are as defined hereinabove.
For example in some embodiments, the first occurrence of R1 of the structures of Groups V(a) and (b) may be selected from Substituent Group 13 as defined hereinabove, and the second occurrence of R1 of the structures of Groups V(a) and (b) may be selected from Substituent Group 10 as defined hereinabove.
In another embodiment of the present invention, the amide containing heterobicyclic metalloprotease compounds may be represented by the general Formula (VI):




and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof,
wherein all variables are as defined hereinabove.
In yet another embodiment, the compounds of Formula (VI) may be selected from Group VI(a):




wherein all variables are as defined hereinabove.

In still another embodiment, the compounds of Formula (VI) may be selected from Group VI(b):







In a further embodiment, R3 of Formula (VI) may be selected from Substituent Group 1:




wherein all variables are as defined hereinabove.
For example, in some embodiments, R3 of the structures of Groups VI(a) and (b) may be selected from Substituent Group 1 as defined hereinabove.
In yet a further embodiment, R3 of Formula (VI) may be selected from Substituent Group 2:







wherein all variables are as defined hereinabove.
For example, in some embodiments, in some embodiments, R3 of the structures of Groups VI(a) and (b) may be selected from Substituent Group 2 as defined hereinabove.
In still a further embodiment, R3 of Formula (VI) may be selected from Substituent Group 3:




For example, in some embodiments, R3 of the structures of Groups VI(a) and (b) may be selected from Substituent Group 3 as defined hereinabove.
In one embodiment, each R9 of Substituent Group 3 may independently be selected from:







wherein all variables are as defined hereinabove.
In another embodiment, R3 of Formula (VI) may be Substituent Group 16:




For example, in some embodiments, R3 of the structures of Groups VI(a) and (b) may be selected from Substituent Group 16 as defined hereinabove.
In yet another embodiment, R3 of Formula (VI) may be selected from Substituent Group 5:




wherein:

R9 is selected from the group consisting of hydrogen, fluoro, halo, CN, alkyl, CO2H,




For example, in some embodiments, R3 of the structures of Groups VI(a) and (b) may be selected from Substituent Group 5 as defined hereinabove.
In still another embodiment, R1 of the compounds of Formula (VI) may be selected from Substituent Group 6:




wherein all variables are as defined hereinabove.
For example, in some embodiments, R1 of the structures of Groups VI(a) and (b) may be selected from Substituent Group 6 as defined hereinabove.
In a further embodiment, R1 of Formula (VI) may be selected from Susbstituent Group 7:






















For example, in some embodiments, R1 of the structures of Groups VI(a) and (b) may be selected from Substituent Group 7 as defined hereinabove.
In yet a further embodiment, R1 of Formula (VI) may be selected from Substituent Group 8:







wherein all variables are as defined hereinabove.
For example, For example, in some embodiments, R1 of the structures of Groups VI(a) and (b) may be selected from Substituent Group 8 as defined hereinabove.
In still a further embodiment, R1 of Formula (VI) may be selected from Substituent Group 9:
















For example, in some embodiments, R1 of the structures of Groups VI(a) and (b) may be selected from Substituent Group 9 as defined hereinabove.
In one embodiment, R1 of Formula (VI) may be selected from Substituent Group 10:







wherein all variables are as defined hereinabove.
For example, in some embodiments, R1 of the structures of Groups VI(a) and (b) may be selected from Substituent Group 10 as defined hereinabove.
In another embodiment, R1 of Formula (VI) may be selected from Substituent Group 11:










For example, in some embodiments, R1 of the structures of Groups VI(a) and (b) may be selected from Substituent Group 11 as defined hereinabove.
In yet another embodiment, R1 of Formula (VI) may be selected from Substituent Group 12:













For example, in some embodiments, R1 of the structures of Groups VI(a) and (b) may be selected from Substituent Group 12 as defined hereinabove.
In another embodiment, the present invention provides a compound selected from:







wherein all variables are as defined hereinabove.
In still another embodiment, the present invention provides a compound selected from:










wherein all variables are as defined hereinabove.
In still another embodiment, the present invention provides a compound selected from:



















































































































or a pharmaceutically acceptable salt thereof.
In a further embodiment, the present invention provides a compound selected from:































or a pharmaceutically acceptable salt thereof.

In yet a further embodiment, the present invention provides a compound selected from:
























































or a pharmaceutically acceptable salt thereof.

In still a further embodiment, the present invention provides a compound selected from:











































or a pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention provides a compound selected from:



























































































































































































































































or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

In still another embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

In yet a further embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

In still a further embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.
In yet another embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

In still another embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

In still another embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

In yet a further embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

In still a further embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

In still another embodiment, the present invention provides a compound having the structure:




or a pharmaceutically acceptable salt thereof.

The present invention is also directed to pharmaceutical compositions which include any of the amide containing heterobicyclic metalloproteases of the invention described hereinabove. In accordance therewith, some embodiments of the present invention provide a pharmaceutical composition which may include an effective amount of an amide containing heterobicyclic metalloprotease compound of the present invention and a pharmaceutically acceptable carrier.
In one embodiment, the present invention provides a pharmaceutical composition including an effective amount of the compound of Formula (I) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof, and a pharmaceutically acceptable carrier.
In yet another embodiment, the present invention provides a pharmaceutical composition including an effective amount of the compound of Formula (II) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof, and a pharmaceutically acceptable carrier.
In another embodiment, the present invention provides a pharmaceutical composition including an effective amount of the compound of Formula (III) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof, and a pharmaceutically acceptable carrier.
In still another embodiment, the present invention provides a pharmaceutical composition including an effective amount of the compound of Formula (IV) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof, and a pharmaceutically acceptable carrier.
In a further embodiment, the present invention provides a pharmaceutical composition including an effective amount of the compound of Formula (V) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof, and a pharmaceutically acceptable carrier.
In yet a further embodiment, the present invention provides a pharmaceutical composition including an effective amount of the compound of Formula (VI) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof, and a pharmaceutically acceptable carrier.
The present invention is also directed to methods of inhibiting metalloproteases and methods of treating diseases or symptoms mediated by an metalloprotease enzyme, particularly an MMP-13, MMP-8, MMP-3, MMP-12 and/or an ADAMTS-4 enzyme, and more particulary an MMP-13 enzyme and/or an MMP-3 enzyme. Such methods include administering a bicyclic metalloprotease inhibiting compound of the present invention, or a pharmaceutically acceptable salt thereof. Examples of diseases or symptoms mediated by an metalloprotease mediated enzyme include, but are not limited to, rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer (e.g. but not limited to melanoma, gastric carcinoma or non-small cell lung carcinoma), inflammation, atherosclerosis, multiple sclerosis, chronic obstructive pulmonary disease, ocular diseases (e.g. but not limited to ocular inflammation, retinopathy of prematurity, macular degeneration with the wet type preferred and corneal neovascularization), neurologic diseases, psychiatric diseases, thrombosis, bacterial infection, Parkinson's disease, fatigue, tremor, diabetic retinopathy, vascular diseases of the retina, aging, dementia, cardiomyopathy, renal tubular impairment, diabetes, psychosis, dyskinesia, pigmentary abnormalities, deafness, inflammatory and fibrotic syndromes, intestinal bowel syndrome, allergies, Alzheimers disease, arterial plaque formation, oncology, periodontal, viral infection, stroke, atherosclerosis, cardiovascular disease, reperfusion injury, trauma, chemical exposure or oxidative damage to tissues, wound healing, hemorroid, skin beautifying, pain, inflammatory pain, bone pain and joint pain, acne, acute alcoholic hepatitis, acute inflammation, acute pancreatitis, acute respiratory distress syndrome, adult respiratory disease, airflow obstruction, airway hyperresponsiveness, alcoholic liver disease, allograft rejections, angiogenesis, angiogenic ocular disease, arthritis, asthma, atopic dermatitis, bronchiectasis, bronchiolitis, bronchiolitis obliterans, burn therapy, cardiac and renal reperfusion injury, celiac disease, cerebral and cardiac ischemia, CNS tumors, CNS vasculitis, colds, contusions, cor pulmonae, cough, Crohn's disease, chronic bronchitis, chronic inflammation, chronic pancreatitis, chronic sinusitis, crystal induced arthritis, cystic fibrosis, delayted type hypersensitivity reaction, duodenal ulcers, dyspnea, early transplantation rejection, emphysema, encephalitis, endotoxic shock, esophagitis, gastric ulcers, gingivitis, glomerulonephritis, glossitis, gout, graft vs. host reaction, gram negative sepsis, granulocytic ehrlichiosis, hepatitis viruses, herpes, herpes viruses, HIV, hypercapnea, hyperinflation, hyperoxia-induced inflammation, hypoxia, hypersensitivity, hypoxemia, inflammatory bowel disease, interstitial pneumonitis, ischemia reperfusion injury, kaposi's sarcoma associated virus, lupus, malaria, meningitis, multi-organ dysfunction, necrotizing enterocolitis, osteoporosis, periodontitis, peritonitis associated with continous ambulatory peritoneal dialysis (CAPD), pre-term labor, polymyositis, post surgical trauma, pruritis, psoriasis, psoriatic arthritis, pulmatory fibrosis, pulmatory hypertension, renal reperfusion injury, respiratory viruses, restinosis, right ventricular hypertrophy, sarcoidosis, septic shock, small airway disease, sprains, strains, subarachnoid hemorrhage, surgical lung volume reduction, thrombosis, toxic shock syndrome, transplant reperfusion injury, traumatic brain injury, ulcerative colitis, vasculitis, ventilation-perfusion mismatching, wheeze
In one embodiment, the present invention provides a method of inhibiting a metalloprotease, particularly MMP-13, MMP-8, MMP-3, MMP-12 and/or ADAMTS-4, and more particulary MMP-13, which includes administering to a subject in need of such treatment a compound of Formula (I) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.
In one embodiment, the present invention provides a method of inhibiting a metalloprotease, particularly MMP-13, MMP-8, MMP-3, MMP-12 and/or ADAMTS-4, and more particulary MMP-13, which includes administering to a subject in need of such treatment a compound of Formula (II) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.
In yet another embodiment, the present invention provides a method of inhibiting a metalloprotease, particularly MMP-13, MMP-8, MMP-3, MMP-12 and/or ADAMTS-4, and more particulary MMP-13, which includes administering to a subject in need of such treatment a compound of Formula (III) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.
In still another embodiment, the present invention provides a method of inhibiting a metalloprotease, particularly MMP-13, MMP-8, MMP-3, MMP-12 and/or ADAMTS-4, and more particulary MMP-13 and/or MMP-3, which includes administering to a subject in need of such treatment a compound of Formula (IV) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.
In a further embodiment, the present invention provides a method of inhibiting a metalloprotease, particularly MMP-13, MMP-8, MMP-3, MMP-12 and/or ADAMTS-4, and more particulary MMP-13 and/or MMP-3, which includes administering to a subject in need of such treatment a compound of Formula (V) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.
In yet a further embodiment, the present invention provides a method of inhibiting a metalloprotease, particularly MMP-13, MMP-8, MMP-3, MMP-12 and/or ADAMTS-4, and more particularly MMP-13 and/or MMP-3, which includes administering to a subject in need of such treatment a compound of Formula (VI) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.
In still a further embodiment, the present invention provides a method of treating an metalloprotease mediated disease, particulary a MMP-13 mediated disease, a MMP-8 mediated disease, a MMP-3 mediated disease, a MMP-12 mediated disease and/or an ADAMTS-4 mediated disease and more particulary a MMP-13 mediated disease, which includes administering to a subject in need of such treatment an effective amount of a compound of Formula (I) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.
In one embodiment, the present invention provides a method of treating an metalloprotease mediated disease, particulary a MMP-13 mediated disease, a MMP-8 mediated disease, a MMP-3 mediated disease, a MMP-12 mediated disease and/or an ADAMTS-4 mediated disease and more particulary a MMP-13 mediated disease, which includes administering to a subject in need of such treatment an effective amount of a compound of Formula (II) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.
In another embodiment, the present invention provides a method of treating an metalloprotease mediated disease, particulary a MMP-13 mediated disease, a MMP-8 mediated disease, a MMP-3 mediated disease, a MMP-12 mediated disease and/or an ADAMTS-4 mediated disease and more particulary a MMP-13 mediated disease, which includes administering to a subject in need of such treatment an effective amount of a compound of Formula (III) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.
In another embodiment, the present invention provides a method of treating an metalloprotease mediated disease, particulary a MMP-13 mediated disease, a MMP-8 mediated disease, a MMP-3 mediated disease, a MMP-12 mediated disease and/or an ADAMTS-4 mediated disease and more particulary MMP-13 mediated disease and/or MMP-3 mediated disease, which includes administering to a subject in need of such treatment an effective amount of a compound of Formula (IV) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.
In another embodiment, the present invention provides a method of treating an metalloprotease mediated disease, particulary a MMP-13 mediated disease, a MMP-8 mediated disease, a MMP-3 mediated disease, a MMP-12 mediated disease and/or an ADAMTS-4 mediated disease and more particulary a MMP-13 mediated disease and/or MMP-3 mediated disease, which includes administering to a subject in need of such treatment an effective amount of a compound of Formula (V) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.
In another embodiment, the present invention provides a method of treating an metalloprotease mediated disease, particulary a MMP-13 mediated disease, a MMP-8 mediated disease, a MMP-3 mediated disease, a MMP-12 mediated disease and/or an ADAMTS-4 mediated disease and more particulary a MMP-13 mediated disease and/or MMP-3 mediated disease, which includes administering to a subject in need of such treatment an effective amount of a compound of Formula (VI) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.
Illustrative of the diseases which may be treated with such methods are: rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer, inflammation, atherosclerosis, multiple sclerosis, chronic obstructive pulmonary disease, ocular diseases, neurological diseases, psychiatric diseases, thrombosis, bacterial infection, Parkinson's disease, fatigue, tremor, diabetic retinopathy, vascular diseases of the retina, aging, dementia, cardiomyopathy, renal tubular impairment, diabetes, psychosis, dyskinesia, pigmentary abnormalities, deafness, inflammatory and fibrotic syndromes, intestinal bowel syndrome, allergies, Alzheimer's disease, arterial plaque formation, oncology, periodontal, viral infection, stroke, atherosclerosis, cardiovascular disease, reperfusion injury, trauma, chemical exposure or oxidative damage to tissues, wound healing, hemorroids, skin beautifying, pain, inflammatory pain, bone pain and joint pain.
In some embodiments, of the present invention, the amide containing heterobicyclic metalloprotease compounds defined above are used in the manufacture of a medicament for the treatment of a disease or symptom mediated by an MMP enzyme, particularly an MMP-13, MMP-8, MMP-3, MMP-12 and/or an ADAMTS-4 enzyme, and more particulary an MMP-13 enzyme and/or an MMP-3 enzyme.
In some embodiments, the amide containing heterobicyclic metalloprotease compounds defined above may be used in combination with a drug, active, or therapeutic agent such as, but not limited to: (a) a disease modifying antirheumatic drug, such as, but not limited to, methotrexate, azathioptrineluflunomide, penicillamine, gold salts, mycophenolate, mofetil, and cyclophosphamide; (b) a nonsteroidal anti-inflammatory drug, such as, but not limited to, piroxicam, ketoprofen, naproxen, indomethacin, and ibuprofen; (c) a COX-2 selective inhibitor, such as, but not limited to, rofecoxib, celecoxib, and valdecoxib; (d) a COX-1 inhibitor, such as, but not limited to, piroxicam; (e) an immunosuppressive, such as, but not limited to, methotrexate, cyclosporin, leflunimide, tacrolimus, rapamycin, and sulfasalazine; (f) a steroid, such as, but not limited to, p-methasone, prednisone, cortisone, prednisolone, and dexamethasone; (g) a biological response modifier, such as, but not limited to, anti-TNF antibodies, TNF-α antagonists, IL-1 antagonists, anti-CD40, anti-CD28, IL-10, and anti-adhesion molecules; and (h) other anti-inflammatory agents or therapeutics useful for the treatment of chemokine mediated diseases, such as, but not limited to, p38 kinase inhibitors, PDE4 inhibitors, TACE inhibitors, chemokine receptor antagonists, thalidomide, leukotriene inhibitors, and other small molecule inhibitors of pro-inflammatory cytokine production.
In one embodiment, the present invention provides a pharmaceutical composition which includes:

    
    
        A) an effective amount of a compound of Formula (I) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof;
        B) a pharmaceutically acceptable carrier; and
        C) a member selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; and (h) a small molecule inhibitor of pro-inflammatory cytokine production.
    
    


In another embodiment, the present invention provides a pharmaceutical composition which includes:

    
    
        A) an effective amount of a compound of Formula (II) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof;
        B) a pharmaceutically acceptable carrier; and
        C) a member selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; and (h) a small molecule inhibitor of pro-inflammatory cytokine production.
    
    


In still another embodiment, the present invention provides a pharmaceutical composition which includes:

    
    
        A) an effective amount of a compound of Formula (III) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof;
        B) a pharmaceutically acceptable carrier; and
        C) a member selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; and (h) a small molecule inhibitor of pro-inflammatory cytokine production.
    
    


In a further embodiment, the present invention provides a pharmaceutical composition which includes:

    
    
        A) an effective amount of a compound of Formula (IV) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof;
        B) a pharmaceutically acceptable carrier; and
        C) a member selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; and (h) a small molecule inhibitor of pro-inflammatory cytokine production.
    
    


In yet a further embodiment, the present invention provides a pharmaceutical composition which includes:

    
    
        A) an effective amount of a compound of Formula (V) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof;
        B) a pharmaceutically acceptable carrier; and
        C) a member selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; and (h) a small molecule inhibitor of pro-inflammatory cytokine production.
    
    


In yet a further embodiment, the present invention provides a pharmaceutical composition which includes:

    
    
        A) an effective amount of a compound of Formula (VI) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof;
        B) a pharmaceutically acceptable carrier; and
        C) a member selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; and (h) a small molecule inhibitor of pro-inflammatory cytokine production.

Biological Activity

    
    


The inhibiting activity towards different metalloproteases of the heterobicyclic metalloprotease inhibiting compounds of the present invention may be measured using any suitable assay known in the art. A standard in vitro assay for measuring the metalloprotease inhibiting activity is described in Examples 1700 to 1704. The heterobicyclic metalloprotease inhibiting compounds show activity towards MMP-3, MMP-8, MMP-12, MMP-13, ADAMTS-4 and/or ADAMTS-5.
The heterobicyclic metalloprotease inhibiting compounds of the invention have an MMP-13 inhibition activity (IC50 MMP-13) ranging from below 0.1 nM to about 20 μM, and typically, from about 0.2 nM to about 2 μM. Heterobicyclic metalloprotease inhibiting compounds of the invention desirably have an MMP inhibition activity ranging from about 0.2 nM to about 20 nM. Table 1 lists typical examples of heterobicyclic metalloprotease inhibiting compounds of the invention that have an MMP-13 activity lower than 5 nM (Group A) and from 5 nM to 20 μM (Group B).







TABLE 1







Summary of MMP-13 Activity for Compounds








Group
Ex. #





A
32, 37, 49, 63, 66, 73, 115, 159, 235, 317, 318, 319, 322, 328,



332, 337, 339, 340, 341, 343, 346, 348, 349, 351, 358, 359, 365,



379, 395, 397, 398, 399, 402, 403, 418, 419, 423, 425, 428, 430,



440, 442, 443, 449, 453, 459, 469, 476, 480, 1748, 1749, 1751,



1758, 1759, 1768, 1778, 1782, 1820, 1861, 1864, 1865, 1875,



1876, 1878, 1880, 1887, 1890, 1894, 1912, 1920, 1922, 1948,



1949, 2065, 2081, 2093, 2095, 2100, 2182, 2188, 2206, 2207,



2212, 2221, 2244, 2328, 2341.


B
3, 4, 36, 71, 86, 93, 113, 126, 156, 158, 161, 231, 244, 246, 280,



308, 323, 347, 355, 363, 367, 400, 411, 420, 432, 461, 464, 466,



467, 479, 483, 1767, 1779, 1780, 1787, 1805, 1821, 1829, 1872,



1884, 1881, 1891, 1893, 1895, 1911, 1913, 1917, 1921, 1923,



1943, 1951, 1952, 2146, 2163, 2165, 2183, 2222, 2225, 2227,



2253, 2256, 2258, 2261, 2263, 2267, 2268, 2269, 2283, 2284,



2285, 2288, 2291, 2294, 2295, 2297, 2299, 2321, 2324, 2332,



2333, 2336, 2338, 2339, 2343, 2346, 2389, 2390, 2392.









Heterobicyclic metalloprotease inhibiting compounds, in particular compounds of Formula (V) of the invention have an MMP-3 inhibition activity (IC50 MMP-3) ranging from below 5 nM to about 20 μM, and typically, from about 3 nM to about 2 μM. Heterobicyclic metalloprotease inhibiting compounds of the invention desirably have an MMP inhibition activity ranging from about 0.2 nM to about 20 nM. Table 2 lists typical examples of heterobicyclic metalloprotease inhibiting compounds of the invention that have an MMP-3 activity lower than 100 nM (Group A) and from 100 nM to 20 μM (Group B).







TABLE 2







Summary of MMP-3 Activity for Compounds








Group
Ex. #





A
2300, 2301, 2304, 2309, 2314, 2315, 2319, 2320, 2321,



2323, 2330, 2331, 2332, 2333, 2342, 2346.


B
159, 318, 328, 346, 348, 349, 395, 397, 419, 459,



484, 2346, 2303, 2305, 2310, 2316.









Some heterobicyclic metalloprotease inhibiting compounds of the invention have an MMP-8 inhibition activity (IC50 MMP-8) ranging from about 2 μM to about 20 W. Examples of heterobicyclic metalloprotease inhibiting compounds of the invention that have an MMP-8 activity below 20 μM are Ex. #31, 318, 346, 395 and 397.
Some heterobicyclic metalloprotease inhibiting compounds of the invention have an MMP-12 inhibition activity (IC50 MMP-12) ranging from below 1 μM to about 20 μM. Examples of heterobicyclic metalloprotease inhibiting compounds of the invention that have an MMP-12 activity below 20 μM are Ex. #318, 322, 346, 395, 397, 418, 430, 440 and 459.
Heterobicyclic metalloprotease inhibiting compounds, in particular compounds of Formula (V) of the invention, show an MMP-3 mediated proteoglycan degradation ranging from below 50 nM to about 20 μM. Typical examples of heterobicyclic metalloprotease inhibiting compounds of the invention that have an IC50-range of 20 to 40 nM in the MMP-3 Mediated Proteoglycan Degradation Assay (Ex. #1705) are Ex. #483 and 2343.
Heterobicyclic metalloprotease inhibiting compounds, in particular compounds of Formula (V) of the invention, of the invention show an inhibition of MMP-3 mediated pro-collagenase 3 activation ranging from below 50 nM to about 20 μM. Typical examples of heterobicyclic metalloprotease inhibiting compounds of the invention that have an IC50-range of 10 to 30 nM in the Assay for Determining Inhibition of MMP-3 mediated Pro-Collagenase 3 Activation (Ex. #1706) are Ex. #483 and 2343.
The synthesis of metalloprotease inhibiting compounds of the invention and their biological activity assay are described in the following examples which are not intended to be limiting in any way.
Schemes
Provided below are schemes according to which compounds of the present invention may be prepared. In schemes described herein, each of RARB and RCRD may be the same or different, and each may independently be selected from R1R2 and R20R21 as defined hereinabove. Each of Xa, Ya, and Za shown in the schemes below may be the same or different, and each may independently be selected from N and CR4. Xb shown in the schemes below in each occurrence may be the same or different and is independently selected from O, S, and NR51. Yb shown in the schemes below in each occurrence may be the same and is independently selected from CR4 and N.
In some embodiments the compounds of Formula (I)-(III) are synthesized by the general methods shown in Scheme 1 to Scheme 3.




Methyl acetopyruvate is condensed (e.g. MeOH/reflux, aqueous HCl/100° C. or glacial AcOH/95° C.) with an amino substituted 5-membered heterocycle (e.g. 1H-pyrazol-5-amine) to afford a bicyclic ring system as a separable mixture of regioisomer A and regioisomer B (Scheme 1).




The regioisomer A of the bicyclic ring system from Scheme 1 (e.g. 7-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acid methyl ester) is oxidized (e.g. selenium dioxide/120-130° C. and then Oxone®/room temperature) to afford the corresponding carboxylic acid (Scheme 2). Activated acid coupling (e.g. oxalyl chloride, PyBOP, PyBrOP, EDCI/HOAt or HATU/HOAt) with RARBNH (e.g. 4-fluoro-3-methyl-benzylamine) in a suitable solvent gives the desired amide after purification. Saponification (e.g. aqueous LiOH/dioxane, NaOH/MeOH or TMSnOH/80° C.) and further activated acid coupling (e.g. oxalyl chloride, PyBOP, PyBrOP, EDCI/HOAt, HATU/HOAt, N-cyclohexyl-carbodiimide-N′-methyl-polystyrene or polystyrene-IIDQ) with RCRDNH gives the desired bicyclic bisamide inhibitor after purification. If necessary, the R group can be further manipulated (e.g. saponification of a COOMe group in R).




The regioisomer B of the bicyclic ring system from Scheme 1 (e.g. 5-methyl-pyrazolo[1,5-a]pyrimidine-7-carboxylic acid methyl ester) is treated similarly as shown in Scheme 2 to give the desired bicyclic bisamide inhibitor after purification (Scheme 3). If necessary, the R group can be further manipulated (e.g. saponification of a COOMe group in R).
In some embodiments the compounds of Formula (I)-(III) are synthesized by the general methods shown in Scheme 4 to Scheme 8.




2-Chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester is reduced (e.g. NaBH4/MeOH) to the corresponding alcohol and protected with a suitable protecting group [PG, e.g. (2-methoxyethoxy)methyl] (Scheme 4). The obtained intermediate is stirred with hydrazine hydrate at 70° C. to afford the corresponding hydrazino pyrimidine after concentration. Cyclization with a suitable reagent (e.g. triethylortho formate) gives the protected hydroxymethyl substituted bicyclic ring system as a separable mixture of regioisomer A and regioisomer B.




The regioisomer A of the protected hydroxymethyl substituted bicyclic ring system from Scheme 4 (e.g. 7-(2-methoxy-ethoxymethoxymethyl)-5-methyl-[1,2,4]triazolo[4,3-a]pyrimidine) is deprotected (e.g. HCl/THF) and then oxidized (e.g. KMnO4 in aqueous Na2CO3/50° C.) to afford the corresponding carboxy substituted bicyclic ring system (Scheme 5). Esterification (e.g. thionyl chloride/MeOH) and oxidation (e.g. selenium dioxide/70° C.) of this intermediate gives the corresponding carboxylic acid. Activated acid coupling (e.g. oxalyl chloride, PyBOP, PyBrOP, EDCI/HOAt or HATU/HOAt) with RARBNH (e.g. 4-fluoro-3-methyl-benzylamine) in a suitable solvent gives the desired amide after purification. Saponification (e.g. aqueous LiOH/dioxane, NaOH/MeOH or TMSnOH/80° C.) and further activated acid coupling (e.g. oxalyl chloride, PyBOP, PyBrOP, EDCI/HOAt, HATU/HOAt) with RCRDNH gives the desired bicyclic bisamide inhibitor after purification. If necessary, the R group can be further manipulated (e.g. saponification of a COOMe group in R).




The regioisomer B of the protected hydroxymethyl substituted bicyclic ring system from Scheme 4 (e.g. 5-(2-methoxy-ethoxymethoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-a]pyrimidine) is treated similarly as shown in Scheme 5 to give the desired bicyclic bisamide inhibitor after purification (Scheme 6). If necessary, the R group can be further manipulated (e.g. saponification of a COOMe group in R).




2-Chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester is oxidized (e.g. selenium dioxide/105° C.) to the corresponding carboxylic acid (Scheme 7). Activated acid coupling (e.g. oxalyl chloride) with RARBNH (e.g. 4-fluoro-3-methyl-benzylamine) in a suitable solvent gives the desired amide after purification. Saponification (e.g. aqueous LiOH/THF) and further activated acid coupling (e.g. PyBOP) with RCRDNH (e.g. 4-aminomethyl-benzoic acid methyl ester) gives the corresponding benzotriazol-1-yloxy substituted pyrimidine bisamide.




A benzotriazol-1-yloxy substituted pyrimidine bisamide from Scheme 7 (e.g. 4-({[2-(benzotriazol-1-yloxy)-6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoic acid methyl ester) is stirred with hydrazine hydrate at room temperature to afford the corresponding hydrazino pyrimidine bisamide after concentration (Scheme 8). Cyclization with a suitable reagent (e.g. phosgene) gives the corresponding bicyclic bisamide inhibitor as a mixture of regioisomer A and regioisomer B. If necessary, the R group can be further manipulated (e.g. saponification of a COOMe group in R).
In some embodiments the compounds of Formula (IV)-(VI) are synthesized by the general methods shown in Scheme 9 to Scheme 12.




An ester and amino substituted heterocycle (e.g. 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester) is condensed (e.g. EtOH/reflux) with formamidine to give a hydroxy substituted bicyclic ring system (Scheme 9). This intermediate is then converted into the corresponding bromo derivative using a suitable reagent (e.g. POBr3/80° C.). The resulting bromide is heated to (e.g. 80° C.) with a suitable catalyst (e.g. Pd(OAc)2, dppf) and base (e.g. Et3N) under a carbon monoxide atmosphere in a suitable solvent (e.g. MeOH) to give the corresponding bicyclic methylester after purification. Nitration (e.g. concentrated HNO3/0° C. to room temperature) and saponification (e.g. aqueous LiOH) gives the corresponding nitro substituted bicyclic carboxylic acid. Activated acid coupling (e.g. EDCI/HOAt) with RARBNH (e.g. 6-aminomethyl-4H-benzo[1,4]oxazin-3-one) in a suitable solvent gives the desired amide. This intermediate is stirred with a suitable catalyst (e.g. Pd/C) and acid (e.g. AcOH) under a hydrogen atmosphere to afford corresponding amino substituted bicyclic amide after purification.




Commercially available 2-fluoro-3-oxo-butyric acid ethyl ester is condensed (e.g. MeOH/reflux) with thiourea to give thecorresponding fluoro pyrimidinone derivative (Scheme 10). Removal of the sulphur with a catalyst (e.g. Raney-nickel) at elevated temperature (e.g. 100° C.) in a suitable solvent (e.g. H2O) gives the corresponding fluoro pyrimidine derivative. This intermediate is converted into the corresponding bromo derivative by heating with base (e.g. K2CO3) and a suitable reagent (e.g. POBr3) in a suitable solvent (e.g. CH3CN). The resulting bromide is heated to (e.g. 80° C.) with a suitable catalyst (e.g. Pd(OAc)2, dppf) and base (e.g. Et3N) under a carbon monoxide atmosphere in a suitable solvent (e.g. MeOH) to give the corresponding fluoro pyrimidine carboxylic acid methyl ester after purification. Oxidation of the methyl group with a suitable reagent (e.g. selenium dioxide) in a suitable solvent (e.g. 1,4-dioxane) at elevated temperature (e.g. 120° C.) in a sealed vessel affords the corresponding fluoro pyrimidine monoacid monoester. Coupling of the acid derivative using an activated acid method (e.g. EDCI, HOAt, DMF, base) with RARBNH (e.g. 3-chloro-4-fluoro benzylamine) affords the desired products after purification. Saponification of the remaining ester moiety with base (e.g. aqueous KOH) affords the corresponding free acid derivatives. This derivatives are converted to the corresponding amides via the formation of their acid chlorides using suitable conditions (e.g. oxalyl chloride, DMF, 0-5° C.), followed by treatment with anhydrous NH3 (e.g. 0.5M in 1,4-dioxane) and subsequent purification. Dehydration under suitable conditions (e.g. oxalyl chloride, DMF, pyridine, 0-5° C.) affords the corresponding nitriles after workup. Cyclization of these derivatives with a suitable reagent (e.g. hydrazine) in a suitable solvent (e.g. 1,4-dioxane) affords the corresponding 3-hydroxy-1H-pyrazolo[4,3-d]pyrimidin derivatives. (Scheme 10).




The amino substituted bicyclic amide from scheme 9 (e.g. 3-amino-1H-pyrazolo[4,3-d]pyrimidine-7-carboxylic acid 3-chloro-4-fluoro-benzylamide) and the carbonyl compound (CO)RCRD (e.g. 4-fluorobenzaldehyde) is stirred with a suitable reducing agent (e.g. NaCNBH3) and a small amount of acid (e.g. AcOH) in a suitable solvent (e.g. MeOH) to give the corresponding bicyclic inhibitor after purification (Scheme 11). If necessary, the R group can be further manipulated (e.g. saponification of a COOMe group in R).




The amino substituted bicyclic amide from scheme 9 (e.g. 7-amino-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amide is stirred with the acid chloride RCCOCl or with the acid anhydride (RCCO)2O (e.g. acetic anhydride) in a suitable solvent (e.g. pyridine) to give the corresponding bicyclic inhibitor after purification (Scheme 12). If necessary, the R group can be further manipulated (e.g. saponification of a COOMe group in R).
EXAMPLES AND METHODS
All reagents and solvents were obtained from commercial sources and used without further purification. Proton spectra (1H-NMR) were recorded on a 400 MHz and a 250 MHz NMR spectrometer in deuterated solvents. Purification by column chromatography was performed using silica gel, grade 60, 0.06-0.2 mm (chromatography) or silica gel, grade 60, 0.04-0.063 mm (flash chromatography) and suitable organic solvents as indicated in specific examples. Preparative thin layer chromatography was carried out on silica gel plates with UV detection.
Preparative Examples 1-395, 805 and 836-1051 are directed to intermediate compounds useful in preparing the compounds of the present invention.
Preparative Example 1




Step A

Under a nitrogen atmosphere a 1M solution of BH3.THF complex in THF (140 mL) was added dropwise over a 3 h period to an ice cooled solution of commercially available 3-bromo-2-methyl-benzoic acid (20.0 g) in anhydrous THF (200 mL). Once gas evolution had subsided, the cooling bath was removed and mixture stirred at room temperature for 12 h. The mixture was then poured into a mixture of 1N aqueous HCl (500 mL) and ice and then extracted with Et2O (3×150 mL). The combined organic phases were dried (MgSO4), filtered and concentrated to afford the title compound as a colorless solid (18.1 g, 97%). 1H-NMR (CDCl3) δ=7.50 (d, 1H), 7.30 (d, 1H), 7.10 (t, 1H), 4.70 (s, 2H), 2.40 (s, 3H).
Step B
Under a nitrogen atmosphere PBr3 (5.52 mL) was added over a 10 min period to an ice cooled solution of the title compound from Step A above (18.1 g) in anhydrous CH2Cl2 (150 mL). The cooling bath was removed and mixture stirred at room temperature for 12 h. The mixture was cooled (0-5° C.), quenched by dropwise addition of MeOH (20 mL), washed with saturated aqueous NaHCO3 (2×150 mL), dried (MgSO4), filtered and concentrated to afford the title compound as a viscous oil (23.8 g, 97%). 1H-NMR (CDCl3) δ=7.50 (d, 1H), 7.25 (d, 1H), 7.00 (t, 1H), 4.50 (s, 2H), 2.50 (s, 3H).
Step C
Under a nitrogen atmosphere a 1.5M solution of lithium diispropylamide in cyclohexane (63 mL) was added dropwise to a cooled (−78° C., acetone/dry ice) solution of 1BuOAc in anhydrous THF (200 mL). The mixture was stirred at −78° C. for 1 h, then a solution of the title compound from Step B above (23.8 g) in THF (30 mL) was added and the mixture was stirred for 12 h while warming to room temperature. The mixture was concentrated, diluted with Et2O (300 mL), washed with 0.5N aqueous HCl (2×100 mL), dried (MgSO4), filtered and concentrated to afford the title compound as a pale-yellow viscous oil (21.5 g, 80%). 1H-NMR (CDCl3) δ=7.50 (d, 1H), 7.25 (d, 1H), 7.00 (t, 1H), 3.00 (t, 2H), 2.50 (t, 2H), 2.40 (s, 3H), 1.50 (s, 9H).
Step D
A mixture of the title compound from Step C above (21.5 g) and polyphosphoric acid (250 g) was placed in a preheated oil bath (140° C.) for 10 min while mixing the thick slurry occasionally with a spatula. The oil bath was removed, ice and H2O (1 L) was added and the mixture was stirred for 2 h. The precipitate was isolated by filtration, washed with H2O (2×100 mL) and dried to afford the title compound (16.7 g, 96%). 1H-NMR (CDCl3) δ=7.50 (d, 1H), 7.20 (d, 1H), 7.00 (t, 1H), 3.00 (t, 2H), 2.65 (t, 2H), 2.40 (s, 3H).
Step E
Under a nitrogen atmosphere oxalyl chloride (12.0 mL) was added dropwise to an ice cooled solution of the title compound from Step D above (11.6 g) in anhydrous CH2Cl2 (100 mL). The resulting mixture was stirred for 3 h and then concentrated. The remaining dark residue was dissolved in anhydrous CH2Cl2 (300 mL) and AlCl3 (6.40 g) was added. The mixture was heated to reflux for 4 h, cooled and poured into ice water (500 mL). The aqueous phase was separated and extracted with CH2Cl2 (2×100 mL). The combined organic phases were dried (MgSO4), filtered and concentrated to afford the title compound as a light brown solid (10.6 g, 98%). 1H-NMR (CDCl3) δ=7.65 (d, 1H), 7.50 (d, 1H), 3.05 (t, 2H), 2.70 (t, 2H), 2.40 (s, 3H).
Step F
Using a syringe pump, a solution of the title compound from Step E above (9.66 g) in anhydrous CH2Cl2 (70 mL) was added over a 10 h period to a cooled (−20° C., internal temperature) mixture of a 1M solution of (S)-(−)-2-methyl-CBS-oxazaborolidine in toluene (8.6 mL) and a 1M solution of BH3.Me2S complex in CH2Cl2 (43.0 mL) in CH2Cl2 (200 mL). The mixture was then quenched at −20° C. by addition of MeOH (100 mL), warmed to room temperature, concentrated and purified by flash chromatography (silica, Et2O/CH2Cl2) to afford the title compound as a colorless solid (8.7 g, 90%). (CDCl3) δ=7.50 (d, 1H), 7.20 (d, 1H), 5.25 (m, 1H), 3.10 (m, 1H), 2.90 (m, 1H), 2.50 (m, 1H), 2.35 (s, 3H), 2.00 (m, 1H).
Step G
Under a nitrogen atmosphere NEt3 (15.9 mL) and methanesulfonyl chloride (4.5 mL) were added subsequently to a cooled (−78° C., acetone/dry ice) solution of the title compound from Step F above (8.7 g) in anhydrous CH2Cl2 (200 mL). The mixture was stirred at −78° C. for 90 min, then NH3 (−150 mL) was condensed into the mixture using a dry ice condenser at a rate of  ̃3 mL/min and stirring at −78° C. was continued for 2 h. Then the mixture was gradually warmed to room temperature allowing the NH3 to evaporate. 1N aqueous NaOH (200 mL) was added, the organic phase was separated and the aqueous phase was extracted with CH2Cl2 (2×100 mL). The combined organic phases were dried (MgSO4), filtered and concentrated. The remaining light brown oil was dissolved in Et2O (200 mL) and a 4M solution of HCl in 1,4-dioxane (10 mL) was added. The formed precipitate was collected and dried to give the title compound (9.0 g, 90%). [M-NH3Cl]+=209/211.
Step H
To an ice cooled solution of the title compound from Step G above (5.2 g) in anhydrous CH2Cl2 (50 mL) were subsequently added di-tert-butyl dicarbonate (5.0 g) and NEt3 (9.67 mL). The resulting mixture was stirred for 3 h, concentrated, diluted with Et2O (250 mL), washed with saturated aqueous NaHCO3 (100 mL) and saturated aqueous NaCl (100 mL), dried (MgSO4), filtered and concentrated to afford the title compound as a colorless solid (7.28 g, 97%). 1H-NMR (CDCl3, free base) δ=7.40 (m, H), 7.00 (d, 1H), 4.30 (t, 1H) 2.90 (m, 1H), 2.80 (m, 1H), 2.60 (m, 1H), 2.30 (s, 3H), 1.80 (m, 1H).
Step I
Under a nitrogen atmosphere a mixture of the title compound from Step H above (7.2 g), Zn(CN)2 (5.2 g) and Pd(PPh3)4 (2.6 g) in anhydrous DMF (80 mL) was heated to 100° C. for 18 h, concentrated and purified by flash chromatography (silica, CH2Cl2/EtOAc) to afford the title compound as an off-white solid (4.5 g, 75%). 1H-NMR (CDCl3) δ=7.50 (d, 1H), 7.20 (d, 1H), 5.15 (m, 1H), 4.75 (m, 1H), 2.95 (m, 1H), 2.80 (m, 1H), 2.70 (m, 1H), 2.40 (s, 3H), 1.90 (m, 1H), 1.50 (s, 9H).
Preparative Example 2




Step A

The title compound from the Preparative Example 1, Step I (1.0 g) was suspended in 6N aqueous HCl (20 mL), heated to 100° C. for 12 h and concentrated to give the title compound as a colorless solid. (834 mg, >99%). [M-NH3C1]+=175.
Step B
Anhydrous HCl gas was bubbled through an ice cooled solution of the title compound from Step A above (1.0 g) in anhydrous MeOH (20 mL) for 2-3 min. The cooling bath was removed, the mixture was heated to reflux for 12 h, cooled to room temperature and concentrated to give the title compound as a colorless solid (880 mg, 83%). [M-NH3Cl]+=189.
Preparative Example 3




Step A

A mixture of commercially available 5-bromo-indan-1-one (1.76 g), hydroxylamine hydrochloride (636 mg) and NaOAc (751 mg) in MeOH (40 mL) was stirred at room temperature for 16 h and then diluted with H2O (100 mL). The formed precipitate was collected by filtration, washed with H2O (3×20 mL) and dried to afford the title compound as a colorless solid (1.88 g, >99%). [MH]+=226/228.
Step B
Under an argon atmosphere a 1M solution of LiAlH4 in Et2O (42.4 mL) was slowly added to a cooled (−78° C., acetone/dry ice) solution of the title compound from Step A above (1.88 g) in Et2O (20 mL). Then the cooling bath was removed and the mixture was heated to reflux for 5 h. The mixture was cooled (0-5° C.) and H2O (1.6 mL), 15% aqueous NaOH (1.6 mL) and H2O (4.8 mL) were carefully and sequentially added. The resulting mixture was filtered through a plug of Celite® and concentrated to give the title compound as a clear oil (1.65 g, 94%). [MH]+=212/214.
Step C
To a boiling solution of the title compound from Step B above (1.13 g) in MeOH (2.3 mL) was added a hot solution of commercially available N-acetyl-L-leucine (924 mg) in MeOH (3 mL). The solution was allowed to cool to room temperature, which afforded a white precipitate. The precipitate was collected by filtration, washed with MeOH (2 mL) and recrystallized from MeOH (2×). The obtained solid was dissolved in a mixture of 10% aqueous NaOH (20 mL) and Et2O (20 mL), the organic phase was separated and the aqueous phase was extracted with Et2O. The combined organic phases were dried (MgSO4), filtered and concentrated to give the title compound as a clear oil (99 mg, 18%). [MH]+=212/214.
Step D
To a solution of the title compound from Step C above (300 mg) in THF (10 mL) were subsequently added di-tert-butyl dicarbonate (370 mg) and NEt3 (237 μL). The resulting mixture was stirred at room temperature for 16 h, concentrated and purified by chromatography (silica, hexanes/EtOAc) to afford the title compound as a clear oil (460 mg, >99%). [MNa]+=334/336.
Step E
Under an argon atmosphere a mixture of the title compound from Step D above (460 mg), Zn(CN)2 (200 mg) and Pd(PPh3)4 (89 mg) in anhydrous DMF (5 mL) was heated in a sealed vial to 110° C. for 18 h. The mixture was cooled to room temperature and diluted with Et2O (20 mL) and H2O (20 mL). The organic phase was separated and the aqueous phase was extracted with Et2O (4×10 mL). The combined organic phases were washed with H2O (3×10 mL) and saturated aqueous NaCl (10 mL), dried (MgSO4), filtered, concentrated and purified by chromatography (silica, hexanes/EtOAc) to afford the title compound as a clear oil (170 mg, 47%). [MH]+=259.
Preparative Example 4




Step A

The title compound from the Preparative Example 3, Step E (1.0 g) was suspended in 6N aqueous HCl (50 mL), heated under closed atmosphere to 110-112° C. for 20 h and concentrated to give the title compound (827 mg, >99%). [M-Cl]+=178.
Step B
The title compound from Step A above (827 mg) was dissolved in anhydrous MeOH (150 mL) and saturated with anhydrous HCl gas. The resulting mixture was heated to reflux for 20 h, cooled to room temperature and concentrated. The remaining oil was taken up in CH2Cl2 and washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and concentrated to give the title compound as an oil which slowly crystallized into a light brown solid (660 mg, 89%). [MH]+=192.
Preparative Example 5




Step A

To a solution of hydroxylamine hydrochloride (2.78 g) in dry MeOH (100 mL) was added a 30 wt % solution of NaOMe in MeOH (7.27 mL). The resulting white suspension was stirred at room temperature for 15 min and a solution of the title compound from the Preparative Example 3, Step E (5.17 g) in dry MeOH (100 mL) was added. The mixture was heated to reflux for 20 h (complete conversion checked by HPLC/MS, [MH]+=292) and then cooled to room temperature. Diethyl carbonate (48.2 g) and a 30 wt % solution of NaOMe in MeOH (7.27 mL) were added successively and the resulting mixture was heated to reflux for 24 h. The mixture was concentrated, diluted with 1M aqueous NH4Cl (200 mL) and extracted with CH2Cl2/MeOH (60:40, 500 mL) and CH2Cl2 (3×200 mL). The combined organic layers were dried (MgSO4), filtered, concentrated and purified by flash chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a white solid (3.89 g, 61%) [MNa]+=340.
Preparative Example 6




Step A

The title compound from the Preparative Example 1, Step I (1.37 mg) was treated similarly as described in the Preparative Example 5, Step A to afford the title compound as a white solid (845 mg, 51%). [MNa]+=354.
Preparative Example 7




Step A

To an ice cooled solution of the title compound from the Preparative Example 2, Step B (5.94 g) in dry CH2Cl2 (50 mL) were subsequently added di-tert-butyl dicarbonate (1.6 g) and NEt3 (1 mL). The mixture was stirred for 3 h, concentrated, diluted with Et2O (250 mL), washed with saturated aqueous NaHCO3 (100 mL) and saturated aqueous NaCl (100 mL), dried (MgSO4), filtered and concentrated to afford the title compound as a colorless solid (7.28 g, 97%). [MNa]+=328.
Step B
To a mixture of the title compound from Step A above (7.28 g) in THF (60 mL) was added 1M aqueous LiOH (60 mL). The mixture was stirred at 50° C. for 2 h, concentrated, diluted with H2O, adjusted to pH 5 with HCl and extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated to afford the title compound as colorless solid (1.87 g, 27%). [MNa]+=314.
Step C
At 80° C. N,N-dimethylformamide di-tert-butyl acetal (6.2 mL) was added to a solution of the title compound from Step B above (1.87 g) in dry toluene (15 mL). The mixture was stirred at 80° C. for 3 h, cooled to room temperature, concentrated and purified by chromatography (silica, CH2Cl2) to afford the title compound as a colorless solid (820 mg, 38%). [MNa]+=370.
Step D
To a solution of the title compound from Step C above (820 mg) in tBuOAc (40 mL) was added concentrated H2SO4 (0.65 mL). The resulting mixture was stirred at room temperature for 5 h, concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to afford the title compound as a colorless solid (640 mg, 99%). [M-NH2]+=231.
Preparative Example 8




Step A

To a solution of the title compound from the Preparative Example 3, Step E (153 mg) in EtOH (10 mL) were added NEt3 (0.16 mL) and hydroxylamine hydrochloride (81 mg). The mixture was heated to reflux for 4 h, then concentrated, dissolved in THF (5 mL) and pyridine (0.19 mL) and cooled to 0° C. Trifluoroacetic anhydride (0.25 mL) was added and the mixture was stirred for 16 h. Concentration and purification by chromatography (silica, hexanes/EtOAc) afforded the title compound as a white solid (217 mg, >99%). [MNa]+=392.
Preparative Example 9




Step A

To a solution of the title compound from the Preparative Example 4, Step A (33.7 mg) in 1,4-dioxane/H2O (1:1, 2 mL) were added NaOH (97.4 mg) and di-tert-butyl dicarbonate (68.7 mg). The resulting mixture was stirred at room temperature overnight, diluted with EtOAc, washed with 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO4), and concentrated to give a white solid (34.6 mg, 71%). [MNa]+=300.
Step B
To a solution of the title compound from Step A above (34.6 mg) in CH2Cl2 (1 mL) were added oxalyl chloride (33 μL) and DMF (2 mL). The mixture was stirred at room temperature for 2 h and concentrated. The remaining residue was dissolved in CH2Cl2 (1 mL) and added to a cold (−78° C.) saturated solution of NH3 in CH2Cl2 (1 mL). The mixture was stirred at −78° C. for 1 h, warmed to room temperature, concentrated, redissolved in CH2Cl2 (5 mL), filtered, and concentrated to give a white solid (25.9 mg, 75%). [MNa]+=299.
Preparative Example 10




Step A

To mixture of the title compound from the Preparative Example 7, Step B (536 mg) and allyl bromide (1.6 mL) in CHCl3/THF (1:1, 20 mL) were added Bu4NHSO4 (70 mg) and a 1M solution of LiOH in H2O (10 mL) and the resulting biphasic mixture was stirred at 40° C. overnight. The organic phase was separated, concentrated, diluted with CHCl3, washed with H2O, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (610 mg, >99%). [MNa]+=354.
Preparative Example 11




Step A

To a solution of the title compound from the Preparative Example 9, Step A (97 mg) in dry DMF (5 mL) were added K2CO3 (97 mg) and allyl bromide (22 μL). The mixture was stirred overnight, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (81 mg, 68%). [MNa]+=340.
Preparative Example 12




Step A

To a solution of commercially available 2-amino-4-chloro-phenol (5.0 g) and NaHCO3 (7.7 g) in acetone/H2O was slowly added 2-bromopropionyl bromide (4 mL) at room temperature, before the mixture was heated to reflux for 3 h. The acetone was evaporated and the formed precipitate was isolated by filtration, washed with H2O and dried to afford the title compound as brown crystals (6.38 g, 93%). [MH]+=198.
Preparative Example 13




Step A

To a solution of commercially available 2-amino-4-chloro-phenol (5.0 g) and NaHCO3 (7.7 g) in acetone/H2O (4:1, 200 mL) was slowly added 2-bromo-2-methylpropionyl bromide (8.3 mL) at room temperature, before the mixture was heated at  ̃90° C. overnight. The acetone was evaporated and the formed precipitate was filtered off, washed with H2O (100 mL) and recrystallized from acetone/H2O (1:1) to afford the title compound as a pale brown solid (4.8 g, 33%). [MH]+=212.
Preparative Example 14




Step A

To a solution of commercially available 7-hydroxy-3,4-dihydro-1H-quinolin-2-one (1.63 g) in THF (20 mL) was added NaH (95%, 0.28 g). The mixture was stirred at room temperature for 5 min, N-phenyl-bis(trifluoromethanesulfonimide) (4.0 g) was added and stirring at room temperature was continued for 2 h. The mixture was cooled to 0° C., diluted with H2O (40 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound (2.29 g, 78%). [MH]+=296.
Preparative Example 15




Step A

Commercially available 5-chloro-2-methylbenzoxazole (1.5 g), KCN (612 mg), dipiperidinomethane (720 μL), Pd(OAc)2 (80 mg) and 1,5-bis-(diphenylphosphino)pentane (315 mg) were dissolved in dry toluene (20 mL), degassed and heated at 160° C. in a sealed pressure tube under an argon atmosphere for 24 h. The mixture was diluted with EtOAc, washed subsequently with saturated aqueous NH4Cl and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a colorless solid (372 mg, 26%). 1H-NMR (CDCl3) δ=7.90 (s, 1H), 7.48-7.58 (s, 2H), 2.63 (s, 3H).
Preparative Example 16




Step A

A solution of 5-bromo-2-fluorobenzylamine hydrochloride (5.39 g), K2CO3 (7.74 g) and benzyl chloroformate (3.8 mL) in THF/H2O was stirred at room temperature for 90 min. The resulting mixture was concentrated, diluted with EtOAc, washed with 10% aqueous citric acid, saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and slurried in pentane. The formed precipitate was collected by filtration to give the title compound as colorless needles (7.74 g, >99%). [MH]+=338/340.
Preparative Example 17




Step A

To a suspension of commercially available 5-bromo-2-fluoro-benzoic acid (4.52 g) in dry toluene (200 mL) were added NEt3 (3.37 mL) and diphenylphosphoryl azide (5.28 mL). The resulting clear solution was heated to reflux for 161/2 h, then benzyl alcohol (2.51 mL) was added and heating to reflux was continued for 3 h. The mixture was concentrated and purified by flash chromatography (silica, cyclohexane/EtOAc) to afford the title compound (2.96 g, 46%). [MH]+=324/326.
Preparative Example 18




Step A

A solution of commercially available 4-bromophenol (3.36 g), 3-chloro-butan-2-one (2.2 mL) and K2CO3 (4 g) in acetone (40 mL) was heated to reflux for 3 h. Then an additional amount of 3-chloro-butan-2-one and K2CO3 was added and heating to reflux was continued overnight. The mixture was concentrated, dissolved in EtOAc, washed with H2O, 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated. The obtained colorless oil was added dropwise at 100° C. to phosphorous oxychloride (4.7 mL). The resulting mixture was stirred at 100° C. for 1 h, cooled to room temperature and ice, followed by EtOAc was added. The organic layer was separated, washed subsequently with saturated aqueous NaCl and saturated aqueous NaHCO3, concentrated and purified by chromatography (silica, cyclohexane) to afford the title compound as a bright yellow solid (2.55 g, 58%). 1H-NMR (CDCl3) δ=7.50 (s, 1H), 7.20-7.30 (m, 2H), 2.33 (s, 3H), 2.10 (s, 3H).
Preparative Example 19




Step A

A 2.5M solution of BuLi in hexane (13.6 mL) was diluted in THF (50 mL) and cooled to −78° C. (dry ice/acetone). To this solution were subsequently added 2,2,6,6-tetramethylpiperidine (4.8 g) and commercially available 2-(trifluoromethyl)pyridine (5 g). The mixture was stirred at −78° C. for 2 h and then a solution of iodine (17.3 g) in THF (50 mL) was added. The cooling bath was removed and the mixture was stirred at room temperature overnight. Then the mixture was quenched with 1M aqueous Na2S2O3 (50 mL), the organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2) to afford the title compound as a pale yellow solid (6.3 g, 68%). 1H-NMR (CDCl3) δ=8.63 (dd, 1H), 8.36 (d, 1H), 7.20 (dd, 1H).
Step B
A 2.5M solution of BuLi in hexane (7.2 mL) was diluted in THF (30 mL) and cooled to −78° C. (dry ice/acetone). To this solution were subsequently and dropwise added iPr2NH (2.5 mL) and the title compound from Step A above (4.9 g). The mixture was stirred at −78° C. for 2 h, quenched at −78° C. with MeOH (2 mL), concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as yellow needles (1.6 g, 32%). 1H-NMR (CDCl3) δ=8.40 (d, 1H), 8.06 (s, 1H), 7.90 (d, 1H).
Preparative Example 20




Step A

A suspension of commercially available 6-chloro-4H-benzo[1,4]oxazin-3-one (3.2 g) and CuCN (2.9 g) in dry N-methyl-pyrrolidin-2-one (15 mL) was placed in a preheated oil bath ( ̃250° C.). After stirring at this temperature overnight, the mixture was concentrated, diluted with H2O (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with H2O (2×200 mL) and saturated aqueous NaCl (200 mL), dried (MgSO4), filtered and concentrated. The remaining residue crystallized from EtOAc/toluene to afford the title compound as a tan solid (720 mg, 24%). [MH]+=175.
Preparative Examples 21-24
Following a similar procedure as described in the Preparative Example 20, except using the intermediates indicated in Table I-1 below, the following compounds were prepared.










TABLE I-1





Prep. Ex. #
intermediate
product
yield







21








39% [MH]+ = 189


 


22








45% [MH]+ = 203


 


23








74% 1H-NMR (CDCl3) δ = 7.30 (d, 1 H), 7.06 (s, 1 H), 7.03 (d, 1 H).


 


24








64% [MH]+ = 173









Preparative Example 25




Step A

A mixture of the title compound from the Preparative Example 18, Step A (2.55 g), Zn(CN)2 (1.0 g) and Pd(PPh3)4 (653 mg) in dry DMF (10 mL) was degassed and heated at 85° C. under an argon atmosphere for 40 h. The mixture was concentrated, diluted with EtOAc, washed subsequently with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO4), concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as colorless crystals (1.05 g, 54%). 1H-NMR (CDCl3) δ=7.72 (s, 1H), 7.35-7.50 (m, 2H), 2.40 (s, 3H), 2.18 (s, 3H).
Preparative Examples 26-30
Following a similar procedure as described in the Preparative Example 25, except using the intermediates indicated in Table I-2 below, the following compounds were prepared.










TABLE I-2





Prep. Ex. #
intermediate
product
yield







26








>99% [MNa]+ = 261


 


27








94% [MH]+ = 173


 


28








86% [MH]+ = 173


 


29








98% 1H-NMR (CDCl3) δ = 7.10-7.75 (m, 8 H), 5.22 (br s, 1 H), 5.13 (s, 2 H), 4.42 (d, 2 H).


 


30








56% [MH]+ = 271









Preparative Example 31




Step A

A solution of commercially available 3-cyano-benzenesulfonyl chloride (1.07 g) in a 33% solution of NH3 in H2O (40 mL) was stirred at room temperature for 1 h, then concentrated to  ̃20 mL and placed in an ice bath. The formed precipitate was separated by filtration, washed with H2O and dried in vacuo to afford the title compound as a colorless solid (722 mg, 75%). [MH]+=183.
Preparative Example 32




Step A

Commercially available 2-trifluoromethyl-pyrimidine-4-carboxylic acid methyl ester (1.0 g) was dissolved in a 7M solution of NH3 in MeOH and heated in a sealed pressure tube to 50° C. for 16 h. Cooling to room temperature and concentration afforded the title compound (941 mg, >99%). [MH]+=192.
Step B
A 2M solution of oxalyl chloride in CH2Cl2 (520 μL) was diluted in DMF (3 mL) and then cooled to 0° C. Pyridine (1684) and a solution of the title compound from Step A above (100 mg) in DMF (1 mL) were added and the mixture was stirred at 0° C. for 3 h and then at room temperature overnight. The mixture was concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and concentrated to afford the title compound (60 mg, 65%). 1H-NMR (CDCl3) δ=9.20 (d, 1H), 7.85 (d, 1H).
Preparative Example 33




Step A

A solution of commercially available 7-cyano-1,2,3,4-tetrahydroisoquinoline (103 mg) and sulfamide (69 mg) in dry 1,2-dimethoxyethane (10 mL) was heated to reflux overnight, concentrated, diluted with EtOAc, washed subsequently with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to give the title compound as a colorless solid (165 mg, >99%). [MH]+=238.
Preparative Example 34




Step A

To an ice cooled solution of the title compound from the Preparative Example 33, Step A (165 mg) in dry MeOH (20 mL) were added di-tert-butyl dicarbonate (300 mg) and NiCl2.6H2O (20 mg), followed by the careful portionwise addition of NaBH4 (220 mg). The resulting black mixture was stirred for 20 min at 0-5° C. (ice bath), then the ice bath was removed and stirring at room temperature was continued overnight. Then diethylenetriamine was added and the mixture was concentrated to dryness. The remaining residue was suspended in EtOAc washed subsequently with 10% aqueous citric acid, saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a colorless solid (109 mg, 46%). [MNa]+=364.
Preparative Example 35




Step A

A solution of commercially available 7-cyano-1,2,3,4-tetrahydroisoquinoline (407 mg) in dry CH2Cl2 (10 mL) was added iodosobenzene (1.13 g). The reaction mixture was stirred at room temperature overnight, diluted with CH2Cl2, washed subsequently with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO4), filtered, absorbed on silica and purified by chromatography (silica, CH2Cl2/MeOH). The obtained intermediate (240 mg) was dissolved in dry DMF (7 mL) and cooled to 0° C. An excess of NaH and methyl iodide were added subsequently and the mixture was stirred for 2 h while warming to room temperature. The mixture was diluted with EtOAc, washed subsequently with 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to give the title compound as a slowly crystallizing oil (104 mg, 22%). [MH]+=187.
Preparative Example 36




Step A

To a solution of commercially available 7-Cyano-1,2,3,4-tetrahydroisoquinoline (158 mg) in acetic anhydride (5 mL) was added pyridine (0.2 mL). The mixture was stirred overnight and then concentrated to afford the crude title compound. [MNa]+=223.
Preparative Example 37




Step A

The title compound from the Preparative Example 20, Step A (549 mg) was dissolved in dry DMF (7 mL) and cooled to 0° C. An excess of NaH and methyl iodide were added subsequently and the mixture was stirred for 2 h while warming to room temperature. The mixture was diluted with EtOAc, washed subsequently with 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO4), filtered, absorbed on silica and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as colorless needles (311 mg, 52%). [MH]+=189.
Preparative Example 38




Step A

Under an argon atmosphere a mixture of commercially available 4-fluoro-3-methoxybenzonitrile (5.0 g), AlCl3 (8.8 g) and NaCl (1.94 g) was heated (melted) to 190° C. for 45 min, cooled, poured on ice (200 mL) and extracted with CHCl3 (3×). The combined organic phases were washed with H2O, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexanefEtOAc) to afford the title compound as colorless needles (3.45 g, 76%). [MH]+=138.
Step B
A suspension of the title compound from Step A above (883 mg) and K2CO3 (980 mg) in dry DMF (15 mL) was heated to 50° C. for 10 min and then cooled to −40° C. Chlorodifluoromethane (50 g) was condensed into the mixture and the resulting slurry was stirred at 80° C. with a dry ice condenser for 6 h and then at room temperature overnight without condenser. The mixture was concentrated, diluted with EtOAc, washed subsequently with 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated. Purification by chromatography (silica, cyclohexandEtOAc) afforded the crude title compound as a colorless oil (1.31 g). [MH]+=188.
Preparative Example 39




Step A

To a cooled (−30° C.) solution of iPr2NH (16.9 mL) in THF (140 mL) was dropwise added a 2.5M solution of BuLi in hexane (43.2 mL). The mixture was stirred between −20° C. and −30° C. for 20 min and then cooled to −78° C. To this solution dry HMPA (72 mL) was added dropwise not allowing the temperature of the mixture to exceed −70° C. The resultant mixture was cooled again to −78° C. and a solution of commercially available dimethylcyclohexane-1,4-dicarboxylate (20 g) in THF (20 mL) was added dropwise over a period of −10 min. Stirring at −78° C. was continued for 40 min, then 1-bromo-2-chloroethane (10 mL) was added over a period of 5 min, the cooling bath was removed and the mixture was allowed to warm to room temperature. The mixture was then quenched with saturated aqueous NH4Cl, the volatiles were removed by evaporation and the mixture was diluted with cyclohexane and H2O. The aqueous phase was separated and extracted with cyclohexane (2×). The combined organic phases were washed with H2O and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated. The remaining residue was distilled (10−2 mbar, 100° C.) to give the title compound as a pale yellow oil (17 g, 65%). [MH]+=263.
Step B
To a cooled (−30° C.) solution of iPr2NH (18.7 mL) in THF (180 mL) was dropwise added a 2.5M solution of BuLi in hexane (53.6 mL). The mixture was stirred between −20° C. and −30° C. for 20 min and then cooled to −78° C. This solution was canulated over a period of 30 min into a cooled (−78° C.) mixture of the title compound from Step A above (32 g) and HMPA (90 mL) in THF (440 mL) not allowing the temperature of the mixture to exceed −70° C. Stirring at −78° C. was continued for 25 min and then the mixture was allowed to warm to room temperature over a period of 11⁄2 h. The mixture was kept at room temperature for 1 h and then quenched with saturated aqueous NH4Cl. The volatiles were removed by evaporation and the mixture was diluted with cyclohexane and H2O. The aqueous phase was separated and extracted with cyclohexane (3×). The combined organic phases were washed with H2O and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated. The remaining residue was recrystallized from cyclohexane to give the title compound (13.8 g, 50%). [MH]+=227.
Step C
A mixture of the title compound from Step B above (20 g) and KOH (5.5 g) in MeOH/H2O (10:1, 106 mL) was heated to reflux overnight, cooled to room temperature and concentrated. The residue was diluted with EtOAc and extracted with 1N aqueous NaOH (2×100 mL). The organic phase was dried (MgSO4), filtered and concentrated to give the starting material as a white solid. The combined aqueous phases were adjusted with 2N aqueous HCl to pH 1-2 and extracted with EtOAc (4×250 mL). The combined turbid organic phases were filtered through a fluted filter, washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to give the title compound as a colorless solid (13.1 g, 70%). [MH]+=213.
Step D
To a cooled (−40° C.) solution of the title compound from Step C above (500 mg) and NEt3 (1.23 mL) in THF (50 mL) was slowly added ethyl chloroformate (0.67 mL). The mixture was allowed to warm to −25° C. and stirred at this temperature for 1 h. A 7N solution of NH3 in MeOH (10 mL) was added and the mixture was stirred at −20° C. for 30 min. The cooling bath was removed and the mixture was stirred at room temperature for 15 min before it was concentrated. To the remaining residue were added H2O (10 mL) and CH2Cl2 (20 mL), the organic phase was separated and the aqueous phase was extracted with CH2Cl2 (2×10 mL). The combined organic phases were washed with 1N aqueous KOH (10 mL), dried (MgSO4), filtered and concentrated to afford the title compound (458 mg, 92%). [MH]+=212.
Preparative Example 40




Step A

To a cooled (0° C.) mixture of the title compound from the Preparative Example 39, Step A (228 mg) and imidazole (147 mg) in pyridine (10 mL) was slowly added POCl3 (0.40 mL). The mixture was stirred at 0° C. for 1 h and then added to a mixture of ice, NaCl and EtOAc. The organic phase was separated and washed with 1N aqueous HCl until the aqueous phase remained acidic. Drying (MgSO4), filtration and concentration afforded the title compound (137 mg, 72%). [MH]+=194.
Preparative Example 41




Step A

The title compound from the Preparative Example 40, Step A (137 mg) was treated similarly as described in the Preparative Example 34, Step A to afford the title compound (163 mg, 77%). [MNa]+=320.
Preparative Example 42




Step A

To a solution of the title compound from the Preparative Example 41, Step A (2.0 g) in MeOH (10 mL) was added a solution of KOH (753 mg) in H2O (2 mL). The mixture was heated to reflux for 15 h, concentrated to approximately half of its volume and diluted with H2O (50 mL). EtOAc (100 mL) was added and the organic phase was separated. The aqueous phase was acidified to pH 4.5 and extracted with EtOAc (3×40 mL). The combined organic phases were washed with saturated aqueous NaCl (50 mL), dried (MgSO4), filtered and concentrated to afford the title compound (1.1 g, 56%). [MNa]+=306.
Preparative Example 43




Step A

A mixture of commercially available norbonene (15 g) and RuCl3 (0.3 g) in CHCl3 (100 mL) was stirred at room temperature for 5 min. Then a solution of NaIO4 (163 g) in H2O (1200 mL) was added and the mixture was stirred at room temperature for 2 d. The mixture was filtered through a pad of Celite® and the organic phase was separated. The aqueous phase was saturated with NaCl and extracted with EtOAc (3×500 mL). The combined organic phases were treated with MgSO4 and charcoal, filtered and concentrated to afford the crude title compound as thick slightly purple liquid (13.5 g, 53%). [MH]+=159.
Step B
To a solution of the title compound from Step A above (11.2 g) in MeOH (250 mL) was added concentrated H2SO4 (0.5 mL) at room temperature. The mixture was heated to reflux for 15 h, cooled to room temperature, filtrated and concentrated. The remaining residue was diluted with EtOAc (100 mL), washed with saturated aqueous NaHCO3 (3×50 mL) and saturated aqueous NaCl (50 mL), dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a colorless solid (8.43 g, 64%). [MH]+=187.
Step C
To a cooled (−20° C.) solution of iPr2NH (17.3 mL) in THF (230 mL) was dropwise added a 2.5M solution of BuLi in hexane (45.3 mL). The mixture was stirred between −20° C. and −30° C. for 20 min and then cooled to −78° C. To this solution dry HMPA (63.2 mL) was added dropwise not allowing the temperature of the mixture to exceed −70° C. The resultant mixture was cooled again to −78° C. and a solution of the title compound from Step B above (8.43 g) in THF (40 mL) was added dropwise over a period of 20 min. Then the mixture was stirred at 0° C. for 20 min and cooled again to −78° C. 1-Bromo-2-chloroethane (6.32 mL) was added over a period of 40 min, the cooling bath was removed and the mixture was allowed to warm to room temperature over a period of 2 h. The mixture was then quenched with saturated aqueous NH4Cl (60 mL), concentrated to 1⁄5 volume and diluted with H2O (120 mL). The aqueous phase was separated and extracted with cyclohexane (3×100 mL). The combined organic phases were washed with H2O (100 mL) and saturated aqueous NaCl (100 mL), dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a colorless solid (7.86 g, 82%). [MH]+=213.
Step D
To a solution of the title compound from Step C above (3.5 g) in MeOH (15 mL) was added a solution of KOH (1.6 g) in H2O (1.75 mL). Using a microwave, the mixture was heated to 140° C. for 25 min before H2O (30 mL) was added. The aqueous mixture was washed with cyclohexane (2×30 mL), adjusted to pH 1 with 1N aqueous HCl and extracted with CH2Cl2 (2×30 mL). The combined organic phases were washed with saturated aqueous NaCl (15 mL), dried (MgSO4), filtered, concentrated and purified by flash chromatography (silica, CH2Cl2/MeOH) to afford the title compound (2.3 g, 70%). [MH]+=199.
Preparative Example 44




Step A

To a solution of commercially available trans-4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid (262 mg) in dry THF (5 mL) was added 1,1′-carbonyldiimidazole (243 mg). The resulting clear colorless solution was stirred at room temperature for 1 h, then a 0.5M solution of NH3 in 1,4-dioxane (20 mL) was added and stirring at room temperature was continued for 5 h. The mixture was concentrated and purified by flash chromatography (silica, CH2Cl2/MeOH) to afford the title compound (250 mg, 97%). [MNa]+=279.
Preparative Example 45




Step A

To a solution of title compound from the Preparative Example 7, Step B (35 mg) in DMF (3 mL) were added HATU (60 mg), HOAt (20 mg) and a 2M solution of MeNH2 in THF (150 μL). The mixture was stirred for 16 h, concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/acetone) to afford the title compound (35 mg, 95%). [MH]+=291.
Preparative Examples 46-53
Following similar procedures as described in the Preparative Examples 39 (method A), 44 (method B) or 45 (method C), except using the acids and amines indicated in Table I-3 below, the following compounds were prepared.










TABLE I-3





Prep. Ex. #
acid, amine
product
method, yield







46








A, 79% [MH]+ = 297


 


47








B, 90% [MH]+ = 311


 


48








B, 44% [MH]+ = 353


 


49








A, 51% [MH]+ = 283


 


50








A, 37% [MH]+ = 198


 


51








B, 99% [MNa]+ = 293


 


52








B, 98% [MNa]+ = 307


 


53








C, 60% [MH]+ = 305









Preparative Example 54




Step A

The title compound from the Preparative Example 50 (300 mg) was treated similarly as described in the Preparative Example 40, Step A to afford the title compound (250 mg, 92%). [MH]+=180.
Preparative Example 55




Step A

To a suspension of the title compound from the Preparative Example 39, Step C (1.0 g) in acetone (7.5 mL) was added phenolphthaleine (1 crystal). To this mixture was added 1M aqueous NaOH until the color of the solution changed to red (pH −8.5). Then a solution of AgNO3 (850 mg) in H2O (1.25 mL) was added. The formed precipitate (Ag-salt) was collected by filtration, washed with H2O, acetone and Et2O and dried in vacuo at room temperature for 6 h and at 100° C. for 18 h. The obtained solid (1.28 g) was suspended in hexane (15 mL), bromine (643 mg) was added dropwise and the mixture was stirred at room temperature for 30 min. Then the mixture was placed in a preheated oil bath (80° C.) and stirred at the temperature for another 30 min. The mixture was filtered and the filter cake was washed with Et2O (2×30 mL). The combined filtrates were washed with saturated aqueous NaHCO3 (2×25 mL), dried (MgSO4), filtered and concentrated to afford the title compound (817 mg, 70%). [MH]+=247/249.
Preparative Example 56




Step A

To the title compound from the Preparative Example 55, Step A (600 mg) was added 1% aqueous NaOH (65 mL). The mixture was stirred at 100° C. (temperature of the oil bath) for 18 h, concentrated to 15 mL and diluted with 1N aqueous HCl (20 mL). The resulting mixture was acidified to pH 1 with 12N aqueous HCl and extracted with EtOAc (2×75 mL). The combined organic phases were dried (MgSO4), filtered and concentrated to afford the crude title compound, which was not further purified (340 mg, 82%). [M-CO2]+=188/190.
Preparative Example 57




Step A

To a cooled (−30° C.) solution of the title compound from the Preparative Example 56, Step A (540 mg) and NEt3 (375 mL) in THF (25 mL) was added ethyl chloroformate (200 μL). The mixture was stirred at −30° C. for 1 h and then filtered. The precipitated salts were washed with THF (15 mL). The combined filtrates were cooled to −20° C. and a 33% solution of NH3 in H2O (7 mL) was added. The mixture was stirred at −20° C. for 20 min, then the cooling bath was removed and the mixture was stirred at room temperature for 40 min. Then the mixture was concentrated and dissolved in THF (12 mL). Pyridine (6904) was added and the mixture was cooled to 0° C. Trifluoroacetic anhydride (600 μL) was added and the mixture was stirred at 0° C. for 2 h. Then the mixture was concentrated to 5 mL, diluted with MeOH (10 mL) and 10% aqueous K2CO3 (5 mL) and stirred at room temperature for 21⁄2 h. The MeOH was evaporated and Et2O/EtOAc (9:1, 80 mL), H2O (10 mL), saturated aqueous NaCl (10 mL) and saturated aqueous NH4Cl (15 mL) were added. The organic phase was separated, washed with 0.1N aqueous HCl (30 mL), dried (MgSO4), filtered and concentrated to afford the crude title compound, which was not further purified (222 mg, 86%). [MH]+=214/216.
Preparative Examples 58-80
Following a similar procedure as described in the Preparative Example 34, except using the nitriles indicated in Table I-4 below, the following compounds were prepared.










TABLE I-4





Prep.





Ex.





#
nitrile
product
yield







58








68% [MNa]+ = 310


 


59








73% [MNa]+ = 285


 


60








68% [MNa]+ = 298


 


61








69% [MNa]+ = 313


 


62








41% [MNa]+ = 301


 


63








51% [MNa]+ = 315


 


64








62% [MNa]+ = 315


 


65








n.d. [MNa]+ = 314


 


66








98% [MH]+ = 307


 


67








67% [MH]+ = 277


 


68








18% 1H-NMR (CDCl3) δ = 8.80 (d, 1 H), 7.50 (d, 1 H), 5.40 (br s, 1 H), 4.50 (br d, 2 H), 1.40 (s, 9 H) 


 


69








n.d. [MNa]+ = 309


 


70








67% [MH]+ = 292


 


71








74% [MH]+ = 243


 


72








38% [M- isobu- tene]+ = 282


 


73








24% [M- isobu- tene]+ = 262


 


74








57% [MH]+ = 284


 


75








61% [MH]+ = 226


 


76








n.d. [MNa]+ = 305


 


77








75% [MNa]+ = 299


 


78








79% [MH]+ = 277


 


79








>99% [MNa]+ = 411


 


80








89% [MNa]+ = 397









Preparative Example 81




Step A

To the title compound from the Preparative Example 55, Step A (677 mg) was added 10% aqueous NaOH (65 mL). The mixture was stirred at 100° C. (temperature of the oil bath) for 42 h, concentrated to 15 mL and diluted with 1N aqueous HCl (30 mL). The resulting mixture was acidified to pH 1 with 12N aqueous HCl and extracted with EtOAc (5×70 mL). The combined organic phases were dried (MgSO4), filtered and concentrated to afford the title compound (540 mg, 89%). [MH]+=171.
Preparative Example 82




Step A

To a cooled (−30° C.) solution of the title compound from the Preparative Example 81, Step A (540 mg) and NEt3 (590 μL) in THF (35 mL) was added ethyl chloroformate (320 μL). The mixture was stirred at −30° C. for 1 h and then filtered. The precipitated salts were washed with THF (20 mL). The combined filtrates were cooled to −20° C. and a 33% solution of NH3 in H2O (10 mL) was added. The mixture was stirred at −20° C. for 20 min, then the cooling bath was removed and the mixture was stirred at room temperature for 40 min. The mixture was concentrated and dissolved in THF/CH3CN (4:1, 25 mL). Pyridine (1.26 mL) was added and the mixture was cooled to 0° C. Trifluoroacetic anhydride (1.10 mL) was added and the mixture was stirred at 0° C. for 2 h. Then the mixture was concentrated to 5 mL, diluted with MeOH (18 mL) and 10% aqueous K2CO3 (9 mL), stirred at room temperature overnight, concentrated to 10 mL, acidified to pH 1 with 1N aqueous HCl and extracted with CH2Cl2 (4×75 mL). The combined organic phases were dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound (433 mg, 90%). [MH]+=152.
Preparative Example 83




Step A

To a suspension of LiAlH4 (219 mg) in THF (12 mL) was added a solution of the title compound from the Preparative Example 82, Step A (433 mg) in THF (35 mL) over a period of 20 min. The mixture was heated to reflux for 36 h and then cooled to 0° C. 1N aqueous NaOH (1 mL) was added and the mixture was stirred overnight while warming to room temperature. The mixture was filtered through a pad of Celite® and the filter cake was washed with Et2O (250 mL). The combined filtrates were concentrated to afford the title compound (410 mg, 92%). [MH]+=156.
Preparative Example 84




Step A

To a solution of the title compound from the Preparative Example 83, Step A (390 mg) in THF (80 mL) were successively added iPr2NEt (0.66 mL) and di-tert-butyl dicarbonate (740 mg). The mixture was stirred at room temperature for 3 d, concentrated, diluted with EtOAc (100 mL), washed subsequently with H2O (15 mL), 0.1N aqueous HCl and saturated aqueous NaCl, dried (MgSO4), concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound (196 mg, 30%). [MNa]+=278.
Step B
To a cooled (−78° C.) solution of the title compound from Step A above (85 mg) in CH2Cl2 (4 mL) was added a solution of diethylaminosulfur trifluoride (73 μL) in CH2Cl2 (4 mL). The mixture was stirred at −78° C. for 15 min and then poured on saturated aqueous NaHCO3 (40 mL). The organic phase was separated and the aqueous phase was extracted with CH2Cl2 (3×40 mL). The combined organic phases were washed with saturated aqueous NaCl (30 mL), dried over MgSO4, filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (28 mg, 32%). [MNa]+=280.
Preparative Example 85




Step A

To a solution of the title compound from the Preparative Example 42, Step A (50 mg) in DMF (1.6 mL) were added HATU (67 mg), iPr2NEt (68 μL) and N-hydroxyacetamidine (−60%, 22 mg). Using a microwave, the mixture was heated in a sealed tube to 130° C. for 30 min. Additional HATU (130 mg) and N-hydroxyacetamidine (50 mg) were added and the mixture was again heated to 130° C. (microwave) for 30 min. Additional HATU (130 mg) and N-hydroxyacetamidine (59 mg) were added and the mixture was heated to 140° C. (microwave) for 30 min. The mixture was concentrated and purified by flash chromatography (silica, cyclohexane/EtOAc) to afford the title compound (18 mg, 32%). [MNa]+=322.
Preparative Example 86




Step A

To a solution of the title compound from the Preparative Example 49 (150 mg) in THF (6 mL) was added methyl N-(triethylammoniosulfonyl) carbamate [“Burgess reagent”] (316 mg). The mixture was stirred at room temperature for 15 h, diluted with EtOAc (15 mL), filtered, concentrated and purified by flash chromatography (silica, CH2Cl2/MeOH) to afford the title compound (77 mg, 55%). [MH]+=265.
Preparative Example 87




Step A

To a cooled (−40° C.) solution of the title compound from the Preparative Example 42, Step A (60 mg) and NEt3 (40 μL) in THF (5 mL) was added ethyl chloroformate (24 μL). The mixture was stirred at −40° C. for 1 h and then filtered. The precipitated salts were washed with THF (30 mL). The combined filtrates were cooled to 0° C. and a solution of NaBH4 (24 mg) in H2O (430 μL) was added. The mixture was stirred at 0° C. for 1 h, then the cooling bath was removed and the mixture was stirred at room temperature for 1 h. The mixture was diluted with saturated aqueous NaHCO3 (5 mL) and saturated aqueous NaCl (5 mL) and extracted with EtOAc (3×20 mL). The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound (22 mg, 39%). [MH]+=292.
Preparative Example 88




Step A

To a ice cooled solution of the title compound from the Preparative Example 42, Step A (95 mg) in CH2Cl2 (5 mL) were successively added DMAP (61 mg), EDCI (96 mg) and methane sulfonamide (32 mg). The cooling bath was removed and the mixture was stirred at room temperature for 24 h. The mixture was diluted with CH2Cl2 (20 mL), washed with 1M aqueous citric acid (15 mL) and saturated aqueous NaCl (15 mL), dried (MgSO4), filtered, concentrated and purified by flash chromatography (silica, CH2Cl2/MeOH) to afford the title compound (63 mg, 51%). [MNa]+=383.
Preparative Example 89




Step A

The title compound from the Preparative Example 42, Step A (95 mg) was treated similarly as described in the Preparative Example 88, Step A, except using 4-methoxy-phenyl sulfonamide (64 mg) to afford the title compound (58 mg, 38%). [MH]+=453.
Preparative Example 90




Step A

To a solution of commercially available (4-amino-benzyl)-carbamic acid tert-butyl ester (229 mg) in dry CH2Cl2 (1 mL) were successively added iPrOH (100 μL) and trimethylsilyl isocyanate (154 mL). The resulting reaction mixture was stirred at room temperature for 171⁄2 h. Additional trimethylsilyl isocyanate (154 μL) was added and stirring at room temperature was continued for 75 h. The resulting reaction mixture was diluted with MeOH (5 mL), concentrated and purified by flash chromatography (silica, CH2Cl2/MeOH) to afford the title compound (263 mg, 99%). [MH]+=266.
Preparative Example 91




Step A

To a solution of commercially available (4-amino-benzyl)-carbamic acid tert-butyl ester (229 mg) in dry CH2Cl2 (1 mL) were successively added iPr2NEt (349 μL) and N-succinimidyl N-methylcarbamate (355 mg). The resulting reaction mixture was stirred at room temperature for 72 h, diluted with EtOAc (20 mL), washed with 0.1M aqueous NaOH (3×10 mL), dried (MgSO4), filtered and concentrated to afford the title compound (269 mg, 96%). [MH]+=280.
Preparative Example 92




Step A

To a solution of commercially available (4-amino-benzyl)-carbamic acid tert-butyl ester (222 mg) in dry pyridine (1 mL) was added N,N-dimethylcarbamoyl chloride (103 μL). The resulting dark red reaction mixture was stirred at room temperature for 171⁄2 h and then diluted with H2O (10 mL) and EtOAc (20 mL). The organic phase was separated and washed with 1M aqueous NH4Cl (2×10 mL). The aqueous phases were combined and extracted with EtOAc (2×10 mL). The combined organic phases were dried (MgSO4), filtered and concentrated to afford the title compound (284 mg, 97%). [MH]+=294.
Preparative Example 93




Step A

To a solution of commercially available (3-aminomethyl-benzyl)-carbamic acid tert-butyl ester (236 mg) in DMF (3 mL) was added dimethyl-N-cyano-dithioiminocarbonate (146 mg). The mixture was stirred at room temperature overnight, a 7M solution of NH3 in MeOH (5 mL) and HgCl2 (300 mg) were added and stirring at room temperature was continued for 2 d. Concentration and purification by chromatography (silica, CHCl3/MeOH) afforded the title compound as a white solid (260 mg, 85%). [MH]+=304.
Preparative Example 94




Step A

To a solution of commercially available (3-amino-benzyl)-carbamic acid tert-butyl ester (97 mg) in DMF (5 mL) were added N-cyano-methylthioiminocarbonate (50 mg) and HgCl2 (120 mg). The reaction mixture was stirred at room temperature overnight, concentrated and purified by chromatography (silica, CHCl3/MeOH) to afford the title compound as a pale yellow solid (53 mg, 43%). [MH]+=290.
Preparative Example 95




Step A

A solution of commercially available 7-cyano-1,2,3,4-tetrahydroisoquinoline (2.75 g), K2CO3 (3.60 g) and benzylchloroformate (2.7 mL) in THF/H2O was stirred overnight and then concentrated. The residue was diluted with EtOAc, washed with 10% aqueous citric acid, saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4) and concentrated. The residue was dissolved in MeOH (100 mL) and di-tert-butyl dicarbonate (7.60 g) and NiCl2.6H2O (400 mg) was added. The solution was cooled to 0° C. and NaBH4 (2.60 g) was added in portions. The mixture was allowed to reach room temperature and then vigorously stirred overnight. After the addition of diethylenetriamine (2 mL) the mixture was concentrated, diluted with EtOAc, washed subsequently with 10% aqueous citric acid, saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a colorless oil (1.81 g, 26%). [MH]+=397.
Preparative Example 96




Step A

A mixture of the title compound from the Preparative Example 95, Step A (1.4 g) and Pd/C (10 wt %, 200 mg) in MeOH (40 mL) was hydrogenated at atmospheric pressure overnight, filtered and concentrated to afford the title compound as an off-white solid (960 mg, >99%.) [MH]+=263.
Preparative Example 97




Step A

To a solution of the title compound from the Preparative Example 96, Step A (100 mg) in dry CH2Cl2 (5 mL) were successively added iPrOH (500 μL) and trimethylsilyl isocyanate (100 μL). The resulting mixture was stirred at room temperature for 70 h, diluted with MeOH (5 mL), concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a colorless solid (80 mg, 69%). [MNa]+=328.
Preparative Example 98




Step A

To a solution of the title compound from the Preparative Example 96, Step A (100 mg) in dry CH2Cl2 (5 mL) were successively added iPr2NEt (132 μL) and N-succinimidyl N-methylcarbamate (131 mg). The resulting mixture was stirred at room temperature for 72 h, diluted with EtOAc (5 mL), washed with 0.1M aqueous NaOH (3×10 mL), dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound (92 mg, 76%). [MNa]+=342.
Preparative Example 99




Step A

To a solution of the title compound from the Preparative Example 96, Step A (100 mg) in dry pyridine (2 mL) was added N,N-dimethylcarbamoyl chloride (38 μL). The resulting mixture was stirred at room temperature for 70 h, diluted with MeOH (5 mL), concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a white solid (40 mg, 32%). [MNa]+=356.
Preparative Example 100




Step A

To a suspension of the title compound from the Preparative Example 96, Step A (100 mg) and N-methylmorpholine (145 μL) in dry CH2Cl2/THF (5:1, 12 mL) was added methanesulfonyl chloride (88 μL). The mixture was stirred for 2 h, diluted with CH2Cl2, washed subsequently with 10% aqueous citric acid, saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a colorless solid (96.3 mg, 74%). [MNa]+=363.
Preparative Example 101




Step A

To a suspension of the title compound from the Preparative Example 96, Step A (84 mg) and iPr2NEt (70 μL) in dry THF (10 mL) was added trifluoromethanesulfonyl chloride (50 μL) at −20° C. under an argon atmosphere. The cooling bath was removed and the mixture was stirred for 4 h, diluted with EtOAc, washed subsequently with 10% aqueous citric acid, saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as colorless crystals (47 mg, 37%). [MNa]+=417.
Preparative Example 102




Step A

To a solution of the title compound from the Preparative Example 26 (242 mg) in MeOH/H2O (2:1, 30 mL) was added sodium perborate tetrahydrate (470 mg). The mixture was heated to 50° C. overnight, concentrated, diluted with EtOAc, washed subsequently with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to give the title compound as colorless crystals (220 mg, 85%). [MNa]+=279.
Preparative Example 103




Step A

Commercially available tert-butyl-N-[(5-bromo-2-thienyl)methyl]carbamate (2.0 g), Pd(OAc)2 (76 mg), dppp (282 mg) and NEt3 (2.9 mL) were dissolved in dry DMSO/MeOH (3:1, 60 mL) and stirred at 80° C. under a carbon monoxide atmosphere at 7 bar over the weekend. The mixture was concentrated, diluted with EtOAc, washed subsequently with 1N aqueous HCl, H2O and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated. Purification by chromatography (silica, cyclohexane/EtOAc) afforded the title compound as colorless crystals (1.73 g, 94%). [MNa]+=294.
Preparative Example 104




Step A

To an ice cooled solution of commercially available 5-ethyl-thiophene-3-carboxylic acid (3.0 g) in CH2Cl2 (50 mL) were subsequently added oxalyl chloride (2.3 mL) and DMF (0.4 mL). The mixture was stirred at 0° C. for 1 h and then at room temperature for 3 h. The mixture was concentrated, diluted with CH2Cl2 (3 mL) and then slowly added to condensed NH3 ( ̃30 mL) at  ̃−40° C. The resulting mixture was stirred at  ̃−30° C. for 1 h, slowly warmed to room temperature over a period of −10 h and then concentrated to give the title compound as a tan solid (2.0 g, 68%). [MH]+=156.
Step B
A vigorously stirred mixture of the title compound from Step A above (1.0 g) and Bu4NBH4 (4.9 g) in dry CH2Cl2 (30 mL) was heated at 55-62° C. for 24 h and then concentrated. The remaining oil was cooled to 0° C. and 1N aqueous HCl (15 mL) was slowly added over a period of 1 h. Then the mixture was heated to 100° C. for 1 h, cooled to room temperature, washed with Et2O (100 mL), adjusted to pH  ̃10 with concentrated aqueous KOH and extracted with Et2O (100 mL). The organic extract was dried (MgSO4), filtered and concentrated to give the title compound as an oil (0.25 g, 27%). [MH]+=142.
Preparative Example 105




Step A

To an ice cooled mixture of commercially available 5-bromo-1-indanone (29.84 g) in MeOH (300 mL) was added NaBH4 (2.67 g). After 10 min the mixture was allowed to warm to room temperature. The mixture was stirred for 11⁄2 h and then concentrated. The resulting oil was brought up in EtOAc (300 mL), washed with 1N aqueous NaOH (200 mL) and saturated aqueous NaCl (200 mL), dried (MgSO4), filtered and concentrated to give a white solid (30.11 g, >99%). [M-OH]+=195.
Step B
A solution of the title compound from Step A above (9.03 g) and 4-toluenesulfonic acid monohydrate (150 mg) in benzene (300 mL) was heated to reflux for 1 h using a Dean Starks trap. Once cooled the reaction solution was washed with H2O, dried (MgSO4), filtered and concentrated to give a clear oil (7.86 g, 95%). 1H-NMR (CDCl3) δ=7.60 (s, 1H), 7.40 (dd, J=8.0, 1.7 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 6.83 (dtd, J=5.7, 2.1, 1.1 Hz, 1H), 6.55 (dt, J=5.5, 2.1 Hz, 1H), 3.39 (br s, 2H).
Preparative Example 106




Step A

To an ice cooled vigorously stirred mixture of the title compound from the Preparative Example 105, Step B (9.99 g), (S,S)-(+)-N,N′-bis(3,5-di-tert-butyl-salicylindene)-1,2-cyclohexane-diaminomanganese(III) chloride (390 mg) and 4-phenylpyridine N-oxide (526 mg) in CH2Cl2 (6.2 mL) was added a solution of NaOH (425 mg) in 1.25M aqueous NaClO (53.2 mL) by an addition funnel over 21⁄2 h. After the addition was complete, stirring at 0° C. was continued for another 3 h. Hexanes (30 mL) was added, the resulting biphasic mixture was filtered through Celite® and the filter cake was washed with CH2Cl2 (3×20 mL). The supernatant was placed in a separatory funnel, the aqueous layer was removed and the organic layer was washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated. The resulting solid was dissolved in EtOH (100 mL) and a 28% solution of NH3 in H2O (200 mL) was added. The solution was stirred at 110° C. for 30 min, cooled to room temperature and washed with CH2Cl2 (4×200 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give a dark brown solid (7.50 g). [M-NH2]+=211. This solid was dissolved in CH2Cl2 (150 mL) and NEt3 (5.5 mL) and di-tert-butyl-dicarbonate (7.87 g) were added subsequently. The resulting solution was stirred for 4 h at room temperature, then absorbed on silica and purified by chromatography (silica, hexanes/EtOAc) to give an off-white solid (6.87 g, 41%), [MNa]+=350.
Step B
A solution of the title compound from Step A above (6.87 g), Pd(PPh3)4 (1.20 g) in MeOH (100 mL), DMSO (100 mL) and NEt3 (14 mL) was stirred at 80° C. under an atmosphere of carbon monoxide (1 atm) for 18 h. Once the mixture was cooled to room temperature, it was placed in a separatory funnel and EtOAc (200 mL) and 1N aqueous HCl (200 mL) were added. The layers were separated and the aqueous layer was washed with EtOAc (200 mL). The organic layers were combined, washed with 1N aqueous HCl (200 mL), saturated aqueous NaHCO3 (200 mL) and saturated aqueous NaCl (200 mL), dried (MgSO4), filtered and absorbed on silica. Purification by chromatography (silica, hexanes/EtOAc) afforded an off-white solid (1.45 g, 23%). [MNa]+=330.
Preparative Example 107




Step A

To an ice cooled vigorously stirred mixture of the title compound from the Preparative Example 105, Step B (3.92 g), (R,R)—(−)—N,N′-bis(3,5-di-tert-butyl-salicylindene)-1,2-cyclohexane-diaminomanganese(III) chloride (76.2 mg) and 4-phenylpyridine N-oxide (103 mg) in CH2Cl2 (2.4 mL) was added a solution of NaOH (122 mg) in 1.25M aqueous NaClO (15.3 mL) by an addition funnel over 21⁄2 h. After the addition was complete, stirring at 0° C. was continued for another 3 h. Hexanes (20 mL) was added, the resulting biphasic mixture was filtered through Celite® and the filter cake was washed with CH2Cl2 (3×20 mL). The supernatant was placed in a separatory funnel, the aqueous layer was removed and the organic layer was washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated. The remaining brown solid was suspended in CH3CN (10 mL) at −40° C., trifluoromethane sulfonic acid (1.2 mL) was added and the resulting mixture was stirred at −40° C. for 11⁄2 h. H2O (20 mL) was added and the mixture was stirred at 110° C. for 5 h, while distilling off the CH3CN. Once the reaction mixture was cooled to room temperature, the aqueous layer was washed with CH2Cl2 (2×50 mL). The organic layers were discarded and the aqueous layer was basified with 3N aqueous NaOH and washed with EtOAc (3×50 mL). The EtOAc phases were combined, dried (MgSO4), filtered and concentrated. [M-NH2]+=211. The remaining solid residue was dissolved in CH2Cl2 (30 mL) and NEt3 (515 μL) and di-tert-butyl-dicarbonate (707 g) were added subsequently. The resulting solution was stirred for 6 h at room temperature, then absorbed on silica and purified by chromatography (silica, hexanes/EtOAc) to give an off-white solid (774 mg, 12%). [MNa]+=350.
Step B
A solution of the title compound from Step A above (774 mg), Pd(PPh3)4 (136 mg) in MeOH (10 mL), DMSO (10 mL) and NEt3 (1.6 mL) was stirred at 80° C. under an atmosphere of carbon monoxide (1 atm) for 18 h. Once the mixture was cooled to room temperature, it was placed in a separatory funnel and EtOAc (30 mL) and 1N aqueous HCl (30 mL) were added. The layers were separated and the aqueous layer was washed with EtOAc (30 mL). The organic layers were combined, washed with 1N aqueous HCl (30 mL), saturated aqueous NaHCO3 (30 mL) and saturated aqueous NaCl (30 mL), dried (MgSO4), filtered and absorbed on silica. Purification by chromatography (silica, hexanes/EtOAc) afforded an off-white solid (333 mg, 46%). [MNa]+=330.
Preparative Example 108




Step A

The title compound from the Preparative Example 107, Step A above (406 mg) was treated similarly as described in the Preparative Example 107, Step B, except using EtOH (10 mL) as the solvent to afford the title compound (353 mg, 89%). [MNa]+=344.
Preparative Example 109




Step A

To a solution of commercially available trans-4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid (262 mg) in dry THF (5 mL) was added 1,1′-carbonyldiimidazole (243 mg). The resulting clear colorless solution was stirred at room temperature for 1 h, then hydrazine monohydrate (219 μL) was added and stirring at room temperature was continued for 17 h. The mixture was concentrated and purified by flash chromatography (silica, CH2Cl2/MeOH). The isolated white solid was dissolved in EtOAc (50 mL) and washed with 0.01 M aqueous HCl (2×50 mL) and saturated aqueous NaCl (50 mL). The combined HCl layers were saturated with NaCl and extracted with EtOAc (2×100 mL). The combined EtOAc layers were dried (MgSO4), filtered and concentrated to afford the title compound (264 mg, 97%). [MNa]+=294.
Preparative Example 110




Step A

To a solution of the title compound from the Preparative Example 109, Step A (136 mg) in dry MeOH (12.5 mL) were successively added trifluoroacetic anhydride (104 μL) and iPr2NEt (130 μL). The resulting reaction mixture was stirred at room temperature for 23 h, concentrated and purified by flash chromatography (silica, CH2Cl2/MeOH) to afford the title compound (66 mg, 43%). [MNa]+=390.
Step B
To a solution of the title compound from Step A above (66 mg) in dry THF (3.6 mL) was added methyl N-(triethylammoniosulfonyl) carbamate [“Burgess reagent”] (88 mg). The resulting reaction mixture was heated in a sealed tube to 150° C. (microwave) for 15 min, concentrated and purified by flash chromatography (silica, CH2Cl2/MeOH) to afford the title compound (52 mg, 83%). [MNa]+=372.
Preparative Example 111




Step A

To a suspension of the title compound from the Preparative Example 109, Step A (54.3 mg) in trimethyl orthoformate (2 mL) was added dry MeOH (200 μL). The resulting clear solution was heated in a sealed tube to 150° C. (microwave) for 24 h, concentrated and purified by flash chromatography (silica, CH2Cl2/MeOH) to afford the title compound (45.6 mg, 81%). [MNa]+=304.
Preparative Example 112




Step A

To a solution of commercially available trans-4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid (262 mg) and N-hydroxyacetamidine (19 mg) in DMF/CH2Cl2 (9:1, 2 mL) were added N,N′-diisopropylcarbodiimide (33 mg) and HOBt (36 mg). The resulting mixture was stirred at room temperature for 2 h, concentrated, dissolved in EtOAc, washed subsequently with saturated aqueous NaHCO3, 0.5N aqueous HCl and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to afford the title compound (255 mg, 80%). [MH]+=314.
Step B
To a solution of the title compound from Step A above (55 mg) in EtOH (3 mL) was added a solution of NaOAc (12 mg) in H2O (270 μL). Using a microwave, the mixture was heated in a sealed vial at 120° C. for 50 min. Concentration and purification by chromatography (silica, cyclohexane/EtOAc) afforded the title compound as a colorless oil (24 mg, 46%). [MH]+=296.
Preparative Example 113




Step A

To a solution of commercially available trans-4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid (520 mg) and acetic acid hydrazide (178 mg) in DMF (10 mL) were added N,N′-diisopropylcarbodiimide (303 mg) and HOBt (326 mg). The resulting mixture was stirred at room temperature for 2 h, concentrated, dissolved in EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound (400 mg, 64%). [MH]+=314.
Step B
To a solution of the title compound from Step A above (216 mg) in dry THF (10 mL) was added methyl N-(triethylammoniosulfonyl) carbamate [“Burgess reagent”] (300 mg). Using a microwave, the mixture was heated in a sealed vial at 150° C. for 15 min. Concentration and purification by chromatography (silica, CH2Cl2/MeOH) afforded the title compound as a colorless oil (143 mg, 70%). [MH]+=296.
Preparative Example 114




Step A

To a suspension of the title compound from the Preparative Example 44, Step A (552 mg) in dry THF (11 mL) was added methyl N-(triethylammoniosulfonyl) carbamate [“Burgess reagent”] (375 mg). The mixture was stirred at room temperature for 30 min, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a colorless solid (160 mg, 31%). [MH]+=239.
Step B
To a solution of hydroxyl amine hydrochloride in dry MeOH (1 mL) were successively added a 30 wt % solution of NaOMe in MeOH (250 μL) and a solution of the title compound from Step A above (160 mg) in dry MeOH (3 mL). The mixture was heated to reflux for 24 h and then concentrated to afford the crude title compound, which was used without further purification (170 mg, 93%). [MH]+=272.
Step C
To a solution of the title compound from Step B above (170 mg) in toluene (5 mL) were successively added iPr2NEt (132 μL) and trifluoroacetic anhydride (280 μL). The mixture was heated to reflux for 21⁄2 h, concentrated, dissolved in EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (46 mg, 20%). [MH]+=350.
Preparative Example 115




Step A

To a suspension of the title compound from the Preparative Example 44, Step A (266 mg) in THF (5 mL) was added 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide [“Lawesson reagent”] (311 mg). The mixture was stirred at room temperature for 1 h, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a pale yellow solid (190 mg, 67%). [MH]+=273.
Step B
To a solution of the title compound from Step A above (190 mg) in DMF (5 mL) were added a 4M solution of HCl in 1,4-dioxane (6 μL) and 2-bromo-1,1-diethoxy-ethane (323 μL). Using a microwave, the mixture was heated in a sealed vial at 100° C. for 25 min. The mixture was concentrated, dissolved in EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (50 mg, 24%). [MH]+=297.
Preparative Example 116




Step A

To a solution of commercially available N-(tert-butoxycarbonyl) alanine (227 mg) in DMF (3 mL) were successively added ethyl 2-oximinooxamate (158 mg) and HATU (684 mg). The mixture was stirred at room temperature for 2 h, concentrated, dissolved in EtOAc, washed with saturated aqueous NaHCO3, 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to afford the title compound as a colorless solid (163 mg, 45%). [MH]+=304.
Step B
To a solution of the title compound from Step A above (163 mg) in EtOH (15 mL) was added a solution of NaOAc (78 mg) in H2O (1 mL). Using a microwave, the mixture was heated in a sealed vial at 120° C. for 50 min. Concentration and purification by chromatography (silica, cyclohexane/EtOAc) afforded the title compound as a colorless oil (46 mg, 30%). NM+=286.
Preparative Example 117




Step A

A mixture of commercially available 3-chloro-5-trifluoromethoxy-benzonitrile (263 mg) and Bu4NBH4 in CH2Cl2 (2 mL) was heated to reflux for 12 h. The reaction was quenched with 1M aqueous NaOH, extracted with CH2Cl2, dried (MgSO4), filtered and concentrated to afford the title compound. [MH]+=226.
Preparative Example 118




Step A

Commercially available 4-chloro-3-trifluoromethoxy-benzonitrile (227 mg) was treated similarly as described in the Preparative Example 117, Step A to afford the title compound. [MH]+=226.
Preparative Example 119




Step A

A mixture of commercially available 3-cyanobenzaldehyde (263 mg), KCN (130 mg) and (NH4)2CO3 (769 mg) in EtOH/H2O (1:1, 12 mL) was heated to 55° C. overnight, cooled, filtered and concentrated. The remaining aqueous mixture was extracted with Et2O (3×10 mL). The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, hexanes/EtOAc) to give the title compound as a colorless solid (347 mg, 86%). [MH]+=202.
Preparative Examples 120-121
Following a similar procedure as described in the Preparative Example 119, except using the nitriles indicated in Table I-5 below, the following compounds were prepared.










TABLE I-5





Prep. Ex. #
protected amine
product
yield







120








90% [MH]+ = 202


 


121








n.d. [MH]+ = 216









Preparative Example 122




Step A

A mixture of commercially available 3-cyanobenzaldehyde (262 mg), hydantoin (220 mg) and KOAc (380 mg) in AcOH (2 mL) was heated to reflux for 3 h and then poured on ice (20 g). The colorless precipitate was collected by filtration, washed with ice water and dried to give the title compound as a yellow solid. [MH]+=216.
Preparative Example 123




Step A

A mixture of the title compound from the Preparative Example 119, Step A above (347 mg), 50% aqueous AcOH (2 mL) and Pd/C (10 wt %, 200 mg) in EtOH was hydrogenated at 50 psi overnight, filtered and concentrated to give the title compound as colorless solid (458 mg, >99%). [M-OAc]+=206.
Preparative Examples 124-126
Following a similar procedure as described in the Preparative Example 123, except using the nitriles indicated in Table I-6 below, the following compounds were prepared.










TABLE I-6





Prep. Ex. #
protected amine
product
yield







124








50% (over 2 steps) [M-OAc]+ = 220


 


125








n.d. [M-OAc]+ = 220


 


126








76% [M-OAc]+ = 206









Preparative Example 127




Step A

To the solution of commercially available 2-N-(tert-butoxycarbonylamino)acetaldehyde (250 mg) in MeOH/H2O (1:1, 10 mL) were added KCN (130 mg) and (NH4)2CO3 (650 mg). The mixture was stirred at 55° C. overnight, then cooled to room temperature, acidified (pH 2) with 3N aqueous HCl and extracted with EtOAc (2×10 mL). The combined organic layers were washed with saturated aqueous NaCl, dried (MgSO4) and concentrated to give a white solid (75 mg, 21%). [MH]+=230.
Preparative Example 128




Step A

To a solution of the title compound from the Preparative Example 7, Step B (100 mg), N-methyl-N-methoxyamine hydrochloride (42.2 mg) in CH2Cl2 (3 mL) and DMF (1 mL) were added EDCI (84.3 mg), HOBt (58 mg) and NaHCO3 (121 mg). The mixture was stirred at room temperature overnight, washed with saturated aqueous Na2CO3 (5 mL) and 1N aqueous HCl (5 mL) and concentrated to give the desired product, which was used without further purification (97 mg, 84%). [MH]+=321.
Step B
To the title compound from Step A above (256 mg) in anhydrous Et2O (10 mL) was added a 1M solution of LiAlH4 in Et2O (4 mL). The mixture was stirred for 20 min and then cooled to 0° C. 1M aqueous NaOH (5 mL) was added dropwise, followed by the addition of Et2O (10 mL). The organic phase was separated and the aqueous phase was extracted with Et2O (2×5 mL). The combined organic layers were washed with saturated aqueous NaCl (5 mL), dried (MgSO4), concentrated and purified by chromatography (silica, hexanes/EtOAc) to give a white solid (178 mg, 85%). [MH]+=262.
Step C
To the title compound from Step B above (178 mg) in MeOH/H2O (1:1, 10 mL) were added KCN (67 mg) and (NH4)2CO3 (262 mg). The mixture was stirred at 55° C. overnight, then cooled to room temperature, acidified (pH 2) with 3N aqueous HCl and extracted with EtOAc (2×10 mL). The combined organic layers were washed with saturated aqueous NaCl, dried (MgSO4) and concentrated to give a white solid (170 mg, 73%). [MH]+=346.
Preparative Example 129




Step A

To the solution of commercially available 4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid (515 mg), N-methyl-N-methoxyamine hydrochloride (390 mg) in CH2Cl2 (20 mL) were added PyBOP (1.04 g) and NEt3 (0.84 mL). The mixture was stirred for 2 h at room temperature, washed with saturated aqueous Na2CO3 (5 mL) and 1N aqueous HCl (5 mL), concentrated and purified by chromatography (silica, hexanes/EtOAc) to give a white solid (544 mg, 91%). [MH]+=323.
Step B
To the title compound from Step A above (544 mg) in anhydrous Et2O (10 mL) was added a 1M solution of LiAlH4 in Et2O (1.8 mL). The mixture was stirred for 20 min and then cooled to 0° C. 1M aqueous NaOH (5 mL) was added dropwise, followed by the addition of Et2O (10 mL). The organic phase was separated and the aqueous phase was extracted with Et2O (2×5 mL). The combined organic layers were washed with saturated aqueous NaCl (5 mL), dried (MgSO4), concentrated and purified by chromatography (silica, hexanes/EtOAc) to give a white solid (440 mg, >99%). [MH]+=242.
Step C
To the title compound from Step B above (440 mg) in MeOH/H2O (1:1, 12 mL) was added were added KCN (178 mg) and (NH4)2CO3 (670 mg). The mixture was stirred at 55° C. overnight, then cooled to room temperature, acidified (pH 2) with 3N aqueous HCl and extracted with EtOAc (2×10 mL). The combined organic layers were washed with saturated aqueous NaCl, dried (MgSO4) and concentrated to give a white solid (454 mg, 81%). [MH]+=312.
Preparative Example 130




Step A

To a solution of commercially available 4-N-(tert-butoxycarbonylamino-methyl)-cyclohexanone (0.26 g) in EtOH/H2O (1:1, 20 mL) were added NaCN (0.10 g) and (NH4)2CO3 (0.56 g). The resulting mixture was heated to reflux overnight, partially concentrated, diluted with H2O and filtered to give a white solid (0.19 g, 56%). [MNa]+=320.
Preparative Example 131




Step A

To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (1.3 mL) in EtOH (40 mL) was added commercially available (3-aminomethyl-benzyl)-carbamic acid tert-butyl ester (1.39 g). The mixture was stirred for 2 h, a 28% solution of NH3 in H2O (40 mL) was added and stirring was continued for 2 h. Then the mixture was concentrated and slurried in MeOH (20 mL). The formed precipitate was collected by filtration to give the title compound (1.6 g, 82%). [MNa]+=354.
Preparative Example 132




Step A

To a solution of commercially available (3-amino-benzyl)-carbamic acid tert-butyl ester (1.11 g) in EtOH (20 mL) was added 3,4-diethoxy-3-cyclobutene-1,2-dione (1.30 g). The mixture was heated to reflux for 21⁄2 h, cooled to room temperature filtered and concentrated. The remaining solid residue was crystallized from refluxing EtOH to afford the title compound (687 mg, 40%). [MNa]+=369.
Step B
The title compound from Step A above (346 mg) was dissolved in a −7N solution of NH3 in MeOH (14.3 mL). The reaction mixture was stirred at room temperature for 3 h and then concentrated to afford the title compound (316 mg, >99%). [MNa]+=340.
Preparative Example 133




Step A

To a suspension of the title compound from the Preparative Example 110, Step B (52 mg) in EtOAc (600 ML) was added a 4M solution of HCl in 1,4-dioxane (600 μL). The reaction mixture was stirred at room temperature for 11⁄2 h and concentrated to afford the title compound (43 mg, 99%). [M-Cl]+=250.
Preparative Examples 134-207
Following a similar procedure as described in the Preparative Example 133, except using the protected amines indicated in Table I-7 below, the following compounds were prepared.










TABLE I-7





Prep.





Ex. #
protected amine
product
yield







134








>99% [M- NH3Cl]+ = 156


 


135








>99% [M-Cl]+ = 159


 


136








99% [M-Cl]+ = 218


 


137








>99% [M-Cl]+ = 232


 


138








>99% [M- NH3Cl]+ = 215


 


139








>99% [M- NH3Cl]+ = 201


 


140








>99% [M-Cl]+ = 198


 


141








99% [M-Cl]+ = 207


 


142








64% [M-Cl]+ = 177


 


143








>99% [M-Cl]+ = 178


 


144








>99% [M- NH3Cl]+ = 195/197


 


145








67% (over 2 steps) [M-Cl]+ = 187


 


146








>99% [M-Cl]+ = 192


 


147








n.d. [M- NH3Cl]+ = 210/212


 


148








81% [M-Cl]+ = 222


 


149








77% [M- NH3Cl]+ = 253


 


150








>99% [M-Cl]+ = 143


 


151








>99% [M-Cl]+ = 238


 


152








>99% [M-Cl]+ = 191


 


153








>99% [M-Cl]+ = 205


 


154








>99% [M- NH3Cl]+ = 188


 


155








>99% [M-Cl]+ = 163


 


156








>99% [M- NH3Cl]+ = 159


 


157








>99% [M-Cl]+ = 241


 


158








>99% [M-Cl]+ = 295


 


159








>99% [M-Cl]+ = 242


 


160








>99% [M-Cl]+ = 191


 


161








>99% [M- NH3Cl]+ = 162


 


162








>99% [M- NH3Cl]+ = 176


 


163








>99% [M-Cl]+ = 193


 


164








96% [M-Cl]+ = 139


 


165








>99% [M-Cl]+ = 157


 


166








>99% [M- NH3Cl]+ = 155


 


167








>99% [M-Cl]+ = 192


 


168








95% [M-Cl]+ = 196


 


169








>99% [M-Cl]+ = 182


 


170








99% [M-Cl]+ = 157


 


171








99% [M-Cl]+ = 171


 


172








98% [M-Cl]+ = 185


 


173








93% [M-Cl]+ = 130


 


174








>99% [M-Cl]+ = 246


 


175








>99% [M-Cl]+ = 212


 


176








>99% [M- NH3Cl]+ = 191


 


177








>99% [M- NH3Cl]+ = 191


 


178








>99% [M-Cl]+ = 198


 


179








>99% [M-Cl]+ = 197


 


180








>99% [M-Cl]+ = 211


 


181








>99% [M-Cl]+ = 253


 


182








>99% [M-Cl]+ = 223


 


183








>99% [M-Cl]+ = 183


 


184








>99% [M-Cl]+ = 165


 


185








>99% [M-Cl]+ = 170


 


186








>99% [M-Cl]+ = 261


 


187








>99% [M-Cl]+ = 353


 


188








>99% [M-Cl]+ = 184


 


189








n.d. [M-Cl]+ = 196


 


190








n.d. [M-Cl]+ = 250


 


191








n.d. [M-Cl]+ = 197


 


192








n.d. [M-Cl]+ = 139


 


193








n.d. [M-Cl]+ = 286


 


194








n.d. [M-Cl]+ = 286


 


195








>99% [M- HCl2]+ = 204


 


196








94% [M- HCl2]+ = 190


 


197








99% [M-Cl]+ = 206


 


198








99% [M-Cl]+ = 220


 


199








99% [M-Cl]+ = 134


 


200








99% [M-Cl]+ = 205


 


201








92% [M- HCl2]+ = 177


 


202








>99% [M- HCl2]+ = 177


 


203








99% [M-Cl]+ = 166


 


204








99% [M-Cl]+ = 180


 


205








99% [M-Cl]+ = 194


 


206








98% [M-Cl]+ = 232


 


207








>99% [M- NH3Cl]+ = 218









Preparative Example 208




Step A

To a ice cooled solution of the title compound from the Preparative Example 73 (89 mg) in CHCl3 (3 mL) was added a solution of trifluoroacetic acid (1.5 mL) in CHCl3 (1.5 mL). The mixture was stirred at 0° C. for 5 min, then the cooling bath was removed and the mixture was stirred at room temperature for 11⁄2 h. The mixture was concentrated, dissolved in CH3CN (5 mL), again concentrated and dried in vacuo to afford the title compound (93 mg, >99%). [M-TFA]+=218/220.
Preparative Examples 209-210
Following a similar procedure as described in the Preparative Example 208, except using the protected amines indicated in Table I-8 below, the following compounds were prepared.










TABLE I-8





Prep. Ex. #
protected amine
product
yield







209








>99% [M-TFA]+ = 158


 


210








93% [M-(NH2•TFA)]+ = 160









Preparative Example 211




Step A

Commercially available 3-aminomethyl-benzoic acid methyl ester hydrochloride (500 mg) was dissolved in a 33% solution of NH3 in H2O (50 mL) and heated in a sealed pressure tube to 90° C. for 20 h. Cooling to room temperature and concentration afforded the title compound (469 mg, >99%). [M-Cl]+=151.
Preparative Example 212




Step A

Commercially available 3-aminomethyl-benzoic acid methyl ester hydrochloride (100 mg) was dissolved in a 40% solution of MeNH2 in H2O (20 mL) and heated in a sealed pressure tube to 90° C. for 20 h. Cooling to room temperature and concentration afforded the title compound (107 mg, >99%). [M-Cl]+=165.
Preparative Example 213




Step A

A mixture of commercially available 2-hydroxy-5-methylaniline (5.2 g) and N,N′-carbonyldiimidazole (6.85 g) in dry THF (60 mL) was heated to reflux for 6 h, cooled to room temperature, poured on ice and adjusted to pH 4 with 6N aqueous HCl. The formed precipitate was isolated by filtration, dried and recrystallized from toluene to afford the title compound as a grey solid (4.09 g, 65%).
Step B
The title compound from Step A above (1.5 g), K2CO3 (1.7 g) and methyl iodide (6 mL) were dissolved in dry DMF (15 mL). The mixture was stirred at 50° C. for 2 h, concentrated and acidified to pH 4 with 1N HCl. The precipitate was isolated by filtration and dried to afford the title compound as an off-white solid (1.48 g, 90%). 1H-NMR (CDCl3) δ=7.05 (s, 1H), 6.90 (d, 1H), 6.77 (s, 1H), 3.38 (s, 3H), 2.40 (s, 3H).
Step C
The title compound from Step B above (1.1 g), N-bromosuccinimide (1.45 g) and α,α′-azoisobutyronitrile (150 mg) were suspended in CCl4 (50 mL), degassed with argon and heated to reflux for 1 h. The mixture was cooled, filtered, concentrated and dissolved in dry DMF (20 mL). Then NaN3 (1 g) was added and the mixture was vigorously stirred for 3 h, diluted with EtOAc, washed subsequently with H2O and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as colorless needles (963 mg, 70%). 1H-NMR (CDCl3) δ=7.07 (s, 1H), 6.98 (d, 1H), 6.88 (s, 1H), 4.25 (s, 2H), 3.36 (s, 3H).
Step D
A mixture of he title compound from Step C above (963 mg) and PPh3 (1.36 g) in THF (30 mL) were stirred for 14 h, then H2O was added and stirring was continued for 2 h. The mixture was concentrated and coevaporated twice with toluene. The remaining residue was diluted with dry dioxane and a 4M solution of HCl in 1,4-dioxane (1.5 mL) was added. The formed precipitate was isolated by filtration and dried to afford the title compound as a colorless solid (529 mg, 52%). [M-Cl]+=179.
Preparative Example 214




Step A

A mixture of the title compound from the Preparative Example 95, Step A (1.81 g) and Pd/C (10 wt %, 200 mg) in EtOH (50 mL) was hydrogenated at atmospheric pressure overnight, filtered and concentrated to a volume of −20 mL. 3,4-Diethoxy-3-cyclobutene-1,2-dione (0.68 mL) and NEt3 (0.5 mL) were added and the mixture was heated to reflux for 4 h. Concentration and purification by chromatography (silica, cyclohexane/EtOAc) afforded a slowly crystallizing colorless oil. This oil was dissolved in EtOH (20 mL) and a 28% solution of NH3 in H2O (100 mL) was added. The mixture was stirred for 3 h, concentrated, slurried in H2O, filtered and dried under reduced pressure. The remaining residue was dissolved in a 4M solution of HCl in 1,4-dioxane (20 mL), stirred for 14 h, concentrated, suspended in Et2O, filtered and dried to afford the title compound as an off-white solid (1.08 g, 92%). [M-Cl]+=258.
Preparative Examples 215-216
Following a similar procedure as described in the Preparative Example 214, except using the intermediates indicated in Table I-9 below, the following compounds were prepared.










TABLE I-9





Ex.





#
intermediate
product
yield







215








n.d. [M-Cl]+ = 250


 


216








67% [M- NH3Cl]+ = 236









Preparative Example 217




Step A

Commercially available 5-acetyl-thiophene-2-carbonitrile (2.5 g) was stirred with hydroxylamine hydrochloride (0.6 g) and NaOAc (0.6 g) in dry MeOH (30 mL) for 11⁄2 h. The mixture was concentrated, diluted with EtOAc, washed subsequently with H2O and saturated aqueous NaCl dried (MgSO4), filtered and absorbed on silica. Purification by chromatography (silica, cyclohexane/EtOAc) afforded the title compound as a colorless solid (844 mg, 31%). [MH]+=167.
Step B
To a solution of the title compound from Step A above (844 mg) in AcOH (30 mL) was added zinc dust (1.7 g). The mixture was stirred for 5 h, filtered, concentrated, diluted with CHCl3, washed with saturated aqueous NaHCO3, dried (MgSO4) and filtered. Treatment with a 4M solution of HCl in 1,4-dioxane (2 mL) and concentration afforded the title compound as an off-white solid (617 mg, 64%). [M-NH3Cl]+=136.
Preparative Example 218




Step A

A suspension of commercially available 2,5-dibromobenzenesulfonyl chloride (1.0 g), Na2SO3 (0.46 g) and NaOH (0.27 g) in H2O (10 mL) was heated to 70° C. for 5 h. To the cooled solution was added methyl iodide (4 mL) and MeOH. The biphasic system was stirred vigorously at 50° C. overnight, concentrated and suspended in H2O. Filtration afforded the title compound as colorless needles (933 mg, 99%). [MH]+=313/315/317.
Step B
Under an argon atmosphere in a sealed tube was heated a mixture of the title compound from Step A above (8.36 g) and CuCN (7.7 g) in degassed N-methylpyrrolidone (30 mL) to 160° C. overnight. Concentration, absorbtion on silica and purification by chromatography (silica, cyclohexane/EtOAc) afforded the title compound as beige crystals (1.08 g, 20%).
Step C
A mixture of the title compound from Step B above (980 mg) and 1,8-diazabicyclo-[5.4.0]undec-7-ene (0.72 mL) in degassed DMSO was heated to 50° C. for 45 min under an argon atmosphere. The solution was diluted with EtOAc, washed subsequently with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO4), concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a bright yellow solid (694 mg, 71%). 1H-NMR (CD3CN) δ=8.00-8.10 (m, 2H), 7.72 (d, 1H), 5.75 (br s, 2H), 5.70 (s, 1H).
Step D
A mixture of the title compound from Step C above (892 mg) and Pd/C (10 wt %, 140 mg) in DMF (10 mL) was hydrogenated at atmospheric pressure for 2 h and then filtered. Di-tert-butyl dicarbonate (440 mg) was added and the mixture was stirred overnight. The mixture was concentrated, diluted with EtOAc, washed subsequently with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO4), and concentrated. Purification by chromatography (silica, cyclohexane/EtOAc) afforded a colorless solid, which was stirred in a 4M solution of HCl in 1,4-dioxane (20 mL) overnight and then concentrated to give the title compound as colorless crystals (69 mg, 8%). [M-Cl]+=209.
Preparative Example 219




Step A

A solution of commercially available 4-bromobenzoic acid (24 g) in chlorosulfonic acid (50 mL) was stirred at room temperature for 2 h and then heated to 150° C. for 3 h. The mixture was cooled to room temperature and poured on ice (600 mL). The formed precipitate was collected by filtration and washed with H2O. To the obtained solid material were added H2O (300 mL), Na2SO3 (20 g) and NaOH (17 g) and the resulting mixture was stirred at 80° C. for 5 h. Then the mixture was cooled to room temperature and diluted with MeOH (250 mL). Iodomethane (100 mL) was slowly added and the mixture was heated to reflux overnight. Concentration, acidification, cooling and filtration afforded the title compound as a white powder (28.0 g, 84%). [MH]+=279/281.
Step B
To a solution of the title compound from Step A above (5.0 g) in dry MeOH (120 mL) was slowly added SOCl2 (4 mL). The resulting mixture was heated to reflux for 4 h, concentrated and diluted with NMP (20 mL). CuCN (1.78 g) was added and the resulting mixture was heated in a sealed tube under an argon atmosphere to 160° C. overnight. The mixture was concentrated, absorbed on silica and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as colorless needles (976 mg, 23%). [MH]+=240.
Step C
To a solution of the title compound from Step B above (1.89 g) in MeOH (40 mL) and was added NaOMe (1.3 g). The mixture was heated to reflux for 90 min, cooled to room temperature, diluted with concentrated HCl (2 mL) and H2O (10 mL) and heated again to reflux for 30 min. The mixture was concentrated, diluted with EtOAc, washed with saturated aqueous NaCl, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as colorless crystals (682 mg, 36%). [MH]+=241.
Step D
A solution the title compound from Step C above (286 mg), NaOAc (490 mg) and hydroxylamine hydrochloride (490 mg) in dry MeOH (20 mL) was heated to reflux for 2% h. The mixture was concentrated, dissolved in EtOAc, washed with saturated aqueous NaCl and concentrated to afford the title compound as an off-white solid (302 mg, 99%). 1H-NMR (DMSO): δ=12.62 (s, 1H), 8.25-8.28 (m, 2H), 8.04 (d, 1H), 4.57 (s, 2H), 3.90 (s, 3H).
Step E
The title compound from Step D above (170 mg) was dissolved in MeOH (50 mL) and heated to 60° C. Then zinc dust (500 mg) and 6N aqueous HCl (5 mL) were added in portions over a period of 30 min. The mixture was cooled, filtered, concentrated, diluted with EtOAc, washed subsequently with a saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to afford the title compound as a yellow oil (128 mg, 80%). [MH]+=242.
Preparative Example 220




Step A

To a solution of commercially available 2-[(3-chloro-2-methylphenyl)thio]acetic acid (2.1 g) in DMF (3 drops) was added dropwise oxalyl chloride (5 mL). After 1.5 h the mixture was concentrated, redissolved in 1,2-dichloroethane (20 mL) and cooled to −10° C. AlCl3 (1.6 g) was added and the cooling bath was removed. The mixture was stirred for 1 h, poured on ice and extracted with CH2Cl2 to afford the crude title compound as a brown solid (2.01 g). [MH]+=199.
Step B
To a solution of the title compound from Step A above (1.01 g) in CH2Cl2 (40 mL) was added mCPBA (70-75%, 1.14 g) at room temperature. The mixture was stirred for 1 h, diluted with CH2Cl2, washed subsequently with 1N aqueous HCl, saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated. Purification by chromatography (silica, cyclohexane/EtOAc) afforded the title compound as a colorless solid (668 mg). [MH]+=231.
Step C
A mixture of the title compound from Step B above (430 mg), NaOAc (800 mg) and hydroxylamine hydrochloride (800 mg) in dry MeOH (20 mL) was heated to reflux for 2 h. The mixture was concentrated, dissolved in EtOAc, washed with saturated aqueous NaCl and concentrated to afford the title compound as colorless crystals (426 mg, 93%). [MH]+=246.
Step D
The title compound from Step C above (426 mg) was dissolved in MeOH (50 mL) and heated to 60° C. Then zinc dust (1.3 g) and 6N aqueous HCl (20 mL) were added in portions over a period of 30 min. The mixture was cooled, filtered, concentrated, diluted with CHCl3, washed subsequently with a saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to afford the title compound as an off-white solid (313 mg, 78%). [MH]+=232.
Preparative Example 221




Step A

A mixture of commercially available 1-aza-bicyclo[2.2.2]octane-4-carbonitrile (0.5 g), AcOH (1 mL) and Pd/C (10 wt %, 200 mg) in THF (20 mL) was hydrogenated at atmospheric pressure overnight, filtered and concentrated to afford the crude title compound as a brown solid. [M-OAc]+=141.
Preparative Example 222




Step A

Commercially available 5-fluoroindanone (1.0 g) was treated similarly as described in the Preparative Example 220, Step C to afford the title compound as a colorless solid (1.3 g, >99%). [MH]+=166.
Step B
The title compound from Step A above (1.35 g) was treated similarly as described in the Preparative Example 217, Step B to afford the title compound as a colorless solid (36.5 mg). [M-NH3Cl]+=135.
Preparative Example 223




Step A

To an ice cooled solution of commercially available cis-4-hydroxymethyl-cyclohexanecarboxylic acid methyl ester (330 mg) in CH2Cl2/pyridine (3:1, 4 mL) was added 4-toluenesulfonic acid chloride (0.49 g). The mixture was stirred at room temperature overnight, cooled to 0° C., quenched with 2N aqueous HCl (35 mL) and extracted with CH2Cl2 (3×40 mL). The combined organic phases were dried (MgSO4), filtered and concentrated to afford the title compound (643 mg, >99%). [MH]+=327.
Step B
A mixture of the title compound from Step A above (643 mg) and NaN3 (636 mg) in DMA (5 mL) was stirred at 70° C. overnight. The mixture was concentrated and diluted with EtOAc (25 mL), H2O (5 mL) and saturated aqueous NaCl (5 mL). The organic phase was separated, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (299 mg, 77%). [MNa]+=220.
Step C
A mixture of the title compound from Step B above (299 mg) and Pd/C (10 wt %, 50 mg) in MeOH (10 mL) was hydrogenated at atmospheric pressure for 4 h, filtered and concentrated. The remaining residue was taken up in MeOH (7 mL), treated with 1N HCl in Et2O (6 mL) and concentrated to afford the crude title compound (248 mg, 95%). [MH]+=172.
Preparative Example 224




Step A

Commercially available cis-3-hydroxymethyl-cyclohexanecarboxylic acid methyl ester (330 mg) was treated similarly as described in the Preparative Example 223, Step A to afford the title compound (606 mg, 97%). [MH]+=327.
Step B
The title compound from Step A above (606 mg) was treated similarly as described in the Preparative Example 223, Step B to afford the title compound (318 mg, 87%). [MNa]+=220.
Step C
The title compound from Step B above (318 mg) was treated similarly as described in the Preparative Example 223, Step C to afford the crude title compound (345 mg, >99%). [MH]+=172.
Preparative Example 225




Step A

To a suspension of commercially available (3-cyano-benzyl)-carbamic acid tert-butyl ester (50 mg) in CHCl3 (2 mL) were successively added triethylsilane (0.5 mL) and trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 2 h and then concentrated to afford the crude title compound. [M-TFA]+=134.
Preparative Example 226




Step A

To a stirred solution of KOH (1.2 g) in EtOH (10 mL) was added commercially available bis(tert-butyldicarbonyl) amine (4.5 g). The mixture was stirred at room temperature for 1 h and then diluted with Et2O. The formed precipitate was collected by filtration and washed with Et2O (3×10 mL) to afford the title compound (3.4 g, 64%).
Preparative Example 227




Step A

To a stirred solution of the title compound from the Preparative Example 226, Step A (160 mg) in DMF (2 mL) was added a solution of commercially available 5-bromomethyl-benzo[1,2,5]thiadiazole (115 mg) in DMF (1 mL). The mixture was stirred at 50° C. for 2 h, concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and concentrated to afford the crude title compound (180 mg, 71%). [MH]+=366.
Step B
A solution of the title compound from Step A above (180 mg) in trifluoroacetic acid (2 mL) was stirred at room temperature for 1 h at room temperature and then concentrated to afford the title compound (140 mg, >99%). [M-TFA]+=166.
Preparative Example 228




Step A

Commercially available 5-bromomethyl-benzo[1,2,5]oxadiazole was treated similarly as described in the Preparative Example 227 to afford the title compound. [M-TFA]+=150.
Preparative Example 229




Step A

Commercially available (S)-(−)-1-(4-bromophenyl)ethylamine (2.0 g) was treated similarly as described in the Preparative Example 3, Step D to afford the title compound as a white solid (2.5 g, 92%). 1H-NMR (CDCl3) δ=7.43 (d, 2H), 7.17 (d, 2H), 4.72 (br s, 2H), 1.35 (br s, 12H).
Step B
The title compound from Step A above (4.0 g) was treated similarly as described in the Preparative Example 3, Step E to afford the title compound (2.0 g, 60%). [MH]+=247.
Step C
The title compound from Step B above (2.0 g) was treated similarly as described in the Preparative Example 2, Step A to afford the title compound (1.8 g, >99%). [M-Cl]+=166.
Step D
The title compound from Step C above (1.0 g) was treated similarly as described in the Preparative Example 2, Step B to afford the title compound (310 mg, 35%). [MH]+=180.
Preparative Example 230




Step A

If one were to follow a similar procedure as described in the Preparative Example 229, except using commercially available (R)-(+)-1-(4-bromophenyl)ethylamine instead of (S)-(−)-1-(4-bromophenyl)ethyl amine, one would obtain the title compound.
Preparative Example 231




Step A

To a solution of commercially available 4-bromo-2-methyl-benzoic acid (1.5 g) in anhydrous CH2Cl2 (10 mL) was added tert-butyl 2,2,2-trichloroacetimidate (3.0 mL). The resulting mixture was heated to reflux for 24 h, cooled to room temperature, concentrated and purified by chromatography (silica, CH2Cl2) to give the desired title compound (1.0 g, 52%). [MH]+=271.
Step B
A mixture of the title compound from Step A above (1.0 g), Zn(CN)2 (1.0 g) and Pd(PPh3)4 (1.0 g) in anhydrous DMF (15 mL) was heated at 110° C. under a nitrogen atmosphere for 18 h, concentrated and purified by chromatography (silica, hexane/CH2Cl2) to give the desired title compound (0.6 g, 75%). [MH]+=218.
Step C
To a solution of the title compound from Step B above (0.55 g), in anhydrous CH2Cl2 (30 mL) was added Bu4NBH4 (1.30 g). The mixture was heated to reflux under a nitrogen atmosphere for 12 h and then cooled to room temperature. 1N aqueous NaOH (5 mL) was added and the mixture was stirred for 20 min before it was concentrated. The remaining residue was then taken up in Et2O (150 mL), washed with 1N aqueous NaOH (25 mL) and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to give the title compound (0.50 g, 89%). [MH]+=222.
Preparative Example 232




Step A

A solution of commercially available (R)-amino-thiophen-3-yl-acetic acid (0.50 g), 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.86 g) and NEt3 (0.65 mL) in 1,4-dioxane/H2O (3:2, 7 mL) was stirred for 24 h, concentrated to 1⁄3 volume and diluted with H2O (100 mL). The resulting aqueous mixture was extracted with Et2O (100 mL), acidified with 1N aqueous HCl and extracted with Et2O (2×80 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give the desired title compound (0.7 g, 86%). [MH]+=258.
Step B
To a stirred mixture of the title compound from Step A above (0.43 g) and (NH4)2CO3 (0.48 g) in 1,4-dioxane/DMF (6:1, 3.5 mL) were added pyridine (0.4 mL) and di-tert-butyl dicarbonate (0.50 g). The mixture was stirred for 48 h, diluted with EtOAc (40 mL), washed with 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to give the desired title compound, which was not further purified (0.35 g, 86%). [MH]+=257.
Step C
The title compound from Step B above (0.35 g) was taken up in a 4M solution of HCl in 1,4-dioxane (10 mL). The mixture was stirred overnight and concentrated to give the title compound (0.15 g, n.d.). [MH]+=157.
Preparative Examples 233-235
Following a similar procedure as described in the Preparative Example 232, except using the amino acids indicated in Table I-10 below, the following compounds were prepared.










TABLE I-10





Prep. Ex. #
amino acid
product
yield







233








n.d. [M-Cl]+ = 194


 


234








n.d. [M-Cl]+ = 157


 


235








n.d. [M-Cl]+ = 113









Preparative Example 236




Step A

Commercially available (R)-2-amino-4,4-dimethyl-pentanoic acid (250 mg) was treated similarly as described in the Preparative Example 232, Step A to afford the title compound (370 mg, 87%). [MNa]+=268.
Step B
The title compound from Step A above (370 mg) was treated similarly as described in the Preparative Example 232, Step B to afford the title compound. [MNa]+=267.
Step C
The title compound from Step B above was treated similarly as described in the Preparative Example 208, Step A to afford the title compound (30 mg, 14% over 2 steps). [M-TFA]+=145.
Preparative Example 237




Step A

If one were to follow a similar procedure as described in the Preparative Example 232, Step A and Step B, except using commercially available (R)-amino-(4-bromo-phenyl)-acetic acid instead of (R)-amino-thiophen-3-yl-acetic acid in Step A, one would obtain the title compound.
Preparative Example 238




Step A

If one were to follow a similar procedure as described in the Preparative Example 229, Step B to Step D, except using the title compound from the Preparative Example 237, Step A instead of (R)-amino-thiophen-3-yl-acetic acid, one would obtain the title compound.
Preparative Example 239




Step A

To a solution of commercially available 1H-pyrazol-5-amine (86.4 g) in MeOH (1.80 L) was added commercially available methyl acetopyruvate (50.0 g). The mixture was heated to reflux for 5 h and then cooled to room temperature overnight. The precipitated yellow needles were collected by filtration and the supernatant was concentrated at 40° C. under reduced pressure to  ̃2⁄3 volume until more precipitate began to form. The mixture was cooled to room temperature and the precipitate was collected by filtration. This concentration/precipitation/filtration procedure was repeated to give 3 batches. This material was combined and recrystallized from MeOH to give the major isomer of the title compound (81.7 g, 72%). [MH]+=192.
The remaining supernatants were combined, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the minor isomer of title compound (6.8 g, 6%). [MH]+=192.
Preparative Example 240




Step A

To a solution of the major isomer of the title compound from the Preparative Example 239, Step A (2.0 g) in CH2Cl2 (20 mL) were added acetyl chloride (3.0 mL) and SnCl4 (10.9 g). The resulting mixture was heated to reflux overnight, cooled and quenched with H2O (10 mL). The aqueous phase was separated and extracted with CH2Cl2 (2×). The combined organic phases were concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (1.2 g, 49%). [MH]+=234.
Step B
Trifluoroacetic anhydride (4.6 mL) was added dropwise to an ice cooled suspension of urea hydrogen peroxide (5.8 g) in CH2Cl2 (40 mL). The mixture was stirred for 30 min, then a solution of the title compound from Step A above (1.8 g) in CH2Cl2 (20 mL) was added and the mixture was stirred at room temperature overnight. NaHSO3 (1.0 g) was added and the resulting mixture was diluted with saturated aqueous NaHCO3 (40 mL). The aqueous phase was separated and extracted with CH2Cl2. The combined organic phases were concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (500 mg, 26%). 1H-NMR (CDCl3) δ=8.40 (s, 1H), 7.47 (d, 1H), 4.03 (s, 3H), 2.84 (d, 3H), 2.42 (s, 3H).
Preparative Example 241




Step A

A mixture of commercially available 5-amino-3-methylpyrazole (1.44 g) and methyl acetopyruvate (0.97 g) in MeOH (20 mL) was heated to reflux for 2 h and then cooled to 0° C. The formed precipitate was collected by filtration to give the desired ester (1.78 g, 87%). [MH]+=206.
Preparative Example 242




Step A

A mixture of commercially available 5-aminopyrazolone (5 g) and POCl3 (50 mL) was heated to 210° C. for 5 h, concentrated and quenched with MeOH (10 mL) at 0° C. Purification by chromatography (silica, hexanes/EtOAc) afforded the desired product (293 mg, 5%). [MH]+=118.
Step B
A mixture of the title compound from Step A above (117 mg) and methyl acetopyruvate (144 mg) in MeOH (5 mL) was heated to reflux for 2 h and then cooled to 0° C. The formed precipitate was collected by filtration to give the desired ester (200 mg, 89%). [MH]+=226.
Preparative Example 243




Step A

Under a nitrogen atmosphere at 0° C. was slowly added 1,4-dioxane (350 mL) to NaH (60% in mineral oil, 9.6 g) followed by the slow addition of CH3CN (12.6 mL). The mixture was allowed to warm to room temperature before ethyl trifluoroacetate (23.8 mL) was added. The mixture was stirred at room temperature for 30 min, heated at 100° C. for 5 h, cooled to room temperature and concentrated. The remaining solid was taken up in H2O (400 mL), washed with Et2O (300 mL), adjusted to pH  ̃2 with concentrated HCl and extracted with CH2Cl2 (300 mL). The CH2Cl2 extract was dried (MgSO4), filtered and concentrated to give a brown liquid, which was not further purified (12.5 g, 74%). [M-H]′=136.
Step B
A mixture of the title compound from Step A above (12.5 g) and hydrazine monohydrate (6.0 g) in absolute EtOH (300 mL) was heated to reflux under a nitrogen atmosphere for 8 h, cooled to room temperature and concentrated. The remaining oil was taken up in CH2Cl2 (150 mL), washed with saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to give the title compound (0.25 g, 2%). [MH]+=152.
Step C
Using a microwave, a mixture of the title compound from Step B above (150 mg) and commercially available methyl acetopyruvate (150 mg) in MeOH (1 mL) in a sealed vial was heated at 120° C. for 12 min, concentrated and purified by chromatography (silica, CH2Cl2) to give the title compound (0.15 g, 58%). [MH]+=260.
Preparative Example 244




Step A

To a suspension of selenium dioxide (9 g) in 1,4-dioxane (35 mL) was added commercially available 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (3 g). The mixture was heated to reflux for 24 h, cooled to room temperature, filtered through a plug of Celite® and concentrated. The remaining solid residue was taken up in MeOH (50 mL), ozone (7 g) was added and the mixture was heated to reflux for 24 h, cooled to room temperature, diluted with CH2Cl2 (50 mL), filtered through a plug of Celite® and concentrated. The remaining residue was dissolved in a saturated solution of HCl in MeOH (150 mL), heated to reflux under a nitrogen atmosphere for 24 h, filtered through a medium porosity fritted glass funnel, concentrated and partially purified by chromatography (silica, CH2Cl2/MeOH) to give the title compound, which was not further purified (0.2 g, 4%). [MH]+=238.
Preparative Example 245




Step A

A solution of methyl pyruvate (13.6 mL) in tBuOMe (100 mL) was added dropwise to a cooled (−10° C.) solution of pyrrolidine (12.6 mL) in tBuOMe (100 mL) over a period of 30 min. The mixture was stirred at −10° C. for 15 min, then trimethylborate (8.0 mL) was added dropwise over a period of 2 min and stirring at −10° C. was continued for 2 h. NEt3 (55 mL) was added, followed by the dropwise addition of a solution of methyl oxalylchloride (24.6 mL) in tBuOMe (100 mL) over a period of 30 min. The resulting thick slurry was stirred for 30 min and then diluted with saturated aqueous NaHCO3 (250 mL) and CH2Cl2 (200 mL). The aqueous phase was separated and extracted with CH2Cl2 (2×100 mL). The combined organic phases were concentrated to give an oil, which was triturated with tBuOMe to afford the title compound as a yellowish solid (15.75 g, 45%). [MH]+=242.
Step B
To mixture of the title compound from Step A above (6 g) and commercially available 2-aminopyrazole (2.1 g) in MeOH (10 mL) was added 3N aqueous HCl (3 mL). The mixture was heated to reflux overnight and cooled. The precipitated title compound was collected by filtration. The supernatant was concentrated and purified by chromatography (silica, hexane/EtOAc) to afford additional solid material, which was combined with the collected precipitate to give title compound (3.7 g, 60%). [MH]+=250.
Preparative Example 246




Step A

A mixture of commercially available 5-amino-1H-[1,2,4]triazole-3-carboxylic acid (20.3 g) and methyl acetopyruvate (20.0 g) in glacial AcOH (250 mL) was heated to 95° C. for 3 h. The mixture was concentrated and diluted with saturated aqueous NaHCO3 (200 mL) and CH2Cl2 (500 mL). The organic phase was separated, dried (MgSO4), filtered and concentrated to give a pale orange mixture of regioisomers (80:20, 21.3 g, 80%). Recrystallization of the crude material from hot THF (110 mL) afforded the major isomer of the title compound (13.0 g, 49%). [MH]+=193.
The supernatant was concentrated and purified by chromatography (silica, hexanes/EtOAc) to afford the minor isomer of title compound. [MH]+=193.
Preparative Examples 247-248
Following a similar procedure as described in the Preparative Example 246, except using the amines indicated in Table I-11 below, the following compounds were prepared.










TABLE I-11





Prep. Ex. #
amine
product
yield







247








96% [MH]+ = 208


 


248








92% [MH]+ = 236









Preparative Example 249




Step A

To a solution of the minor isomer of the title compound from the Preparative Example 239, Step A (500 mg) in CH3CN (10 mL) were added AcOH (2 mL) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) [Selectfluor®] (551 mg). The resulting mixture was stirred at 70° C. for 7 h, cooled to room temperature, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (149 mg, 27%). [MH]+=210.
Preparative Example 250




Step A

To a suspension of the major isomer of the title compound from the Preparative Example 239, Step A (10.0 g) in H2O (1.0 L) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) [Selectfluor®] (18.6 g). The resulting mixture was stirred at 50° C. for 18 h, cooled to room temperature and extracted with CH2Cl2 (3×350 mL). The combined organic phases were dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/acetone) to afford the title compound (4.25 g, 39%). [MH]+=210.
Preparative Example 251




Step A

To a stirred solution of Bu4N(NO3) (1.39 g) in CH2Cl2 (10 mL) was added trifluoroacetic acid (579 μL). The resulting mixture was cooled to 0° C. and added to an ice cooled solution of the major isomer of the title compound from the Preparative Example 239, Step A (796 mg) in CH2Cl2 (10 mL). The mixture was allowed to reach room temperature overnight, diluted with CHCl3, washed with saturated aqueous NaHCO3, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (200 mg, 20%). [MH]+=237.
Preparative Example 252




Step A

To a suspension of the minor isomer of the title compound from the Preparative Example 239, Step A (500 mg) in CHCl3 (10 mL) was added N-bromosuccinimide (465 mg). The resulting mixture was heated to reflux for 1 h, cooled to room temperature, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (599 mg, 85%). [MI-1]+=270/272.
Preparative Example 253




Step A

A mixture of the minor isomer of title compound from the Preparative Example 239, Step A (100 mg) and N-chlorosuccinimide (77 mg) in CCl4 (5 mL) was heated to reflux for 24 h, cooled, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (98 mg, 83%). [MH]+=226.
Preparative Example 254




Step A

A mixture of commercially available 2H-pyrazol-3-ylamine (2.0 g) and 2-fluoro-3-oxo-butyric acid methyl ester (4.4 g) in MeOH (15 mL) was heated at 80° C. for 16 h and then cooled to room temperature. The formed precipitate was isolated by filtration and dried to afford the title compound (4.2 g, 84%). [MH]+=168.
Step B
To a mixture of the title compound from Step A above (1.67 g) in CH3CN (150 mL) were added K2CO3 (4.15 g) and POBr3 (8.58 g). The mixture was heated to reflux for 16 h, concentrated, diluted with CHCl3, washed with saturated aqueous NaHCO3, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a colorless solid (690 mg, 30%). [MH]+=230/232.
Step C
The title compound from Step B above (28 mg) was treated similarly as described in the Preparative Example 103, Step A to afford the title compound (295 mg, 70%). [MH]+=210.
Preparative Example 255




Step A

A mixture of the major isomer of title compound from the Preparative Example 246, Step A (1.34 g) and selenium dioxide (1.78 g) in 1,4-dioxane (20 mL) was heated to 120° C. under closed atmosphere for 12 h, cooled and filtered through Celite®. To the filtrate were added ozone (1.70 g) and H2O (400 μL) and the resulting suspension was stirred at room temperature overnight. Concentration and purification by chromatography (silica, CH2Cl2/MeOH) afforded the title compound (1 g, 64%). [MH]+=223.
Preparative Examples 256-270
Following a similar procedure as described in the Preparative Example 255, except using the intermediates indicated in Table I-12 below, the following compounds were prepared.










TABLE I-12





Prep. Ex. #
intermediate
product
yield







256








69% [MH]+ = 223


 


257








70% [MH]+ = 238


 


258








77% [MH]+ = 266


 


259








34% [MH]+ = 222


 


260








24% [MH]+ = 222


 


261








60% [MH]+ = 240


 


262








71% [MH]+ = 240


 


263








87% [MH]+ = 280


 


264








46% [MH]+ = 267


 


265








n.d. [MH]+ = 300/302


 


266








80% [MH]+ = 256


 


267








55% [MH]+ = 236


 


268








82% [MH]+ = 256


 


269








68% [MH]+ = 290


 


270








80% [MH]+ = 240









Preparative Example 271




Step A

A suspension of commercially available methyl acetopyruvate (3.60 g) in H2O (10 mL) was heated to 40° C., then a mixture of commercially available 1H-tetrazol-5-amine (2.10 g) and concentrated HCl (2 mL) in H2O (4 mL) was added and the mixture was heated to reflux for 1 h, before it was cooled to 0° C. The formed precipitate was filtered off, washed with H2O, dried in vacuo and purified by flash chromatography (silica, CH2Cl2/acetone) to afford the title compound as a mixture of regioisomers ( ̃91:9, 2.15 g, 45%). [MH]+=194.
Step B
To a mixture of selenium dioxide (780 mg) in 1,4-dioxane (10 mL) was added dropwise a 5.5M solution of tert-butyl hydroperoxide in hexanes (5 mL). The mixture was stirred at room temperature for 30 min, then the title compound from Step A above (600 mg) was added and the mixture was heated to reflux for 24 h. The mixture was filtered through a plug of Celite®, concentrated, diluted with H2O (10 mL) and extracted with CHCl3. The combined organic phases were dried (MgSO4), filtered and concentrated to afford the crude title compound, which was used without further purification. [MH]+=224.
Preparative Example 272




Step A

Commercially available 1H-tetrazol-5-amine (2.15 g) was treated similarly as described in the Preparative Example 271, Step A, except using ethyl acetopyruvate (4.00 g) to afford the title compound as a pale orange mixture of regioisomers ( ̃75:25, 4.20 g, 80%). [MH]+=208.
Step B
The title compound from Step B above (4.00 g) was treated similarly as described in the Preparative Example 271, Step B to afford the title compound as a orange red solid (1.30 g, 28%). [MH]+=238
Preparative Example 273




Step A

To an ice cooled solution of commercially available 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester (20.05 g) in MeOH (500 mL) was added NaBH4 (8.10 g) in small portions over a period of 3 h. The cooling bath was removed and the mixture was stirred at room temperature for 10 h. The mixture was poured into saturated aqueous NH4Cl and extracted with EtOAc (3×100 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to afford the title compound as an off-white solid (17.26 g, >99%). [MH]+=159.
Step B
To an ice cooled suspension of the title compound from Step A above (17.08 g) in CH2C12 (300 mL) were subsequently added iPr2NEt (30 mL) and (2-methoxyethoxy)methyl chloride (13.5 mL). The mixture was stirred at room temperature for 12 h, additional iPr2NEt (11 mL) and (2-methoxyethoxy)methyl chloride (6.1 mL) were added and stirring at room temperature was continued for 6 h. Then the mixture was concentrated and purified by chromatography (silica, hexane/EtOAc) to afford the title compound as a yellow oil (10.75 g, 42%). [MH]+=247.
Step C
Under a nitrogen atmosphere a solution of the title compound from Step B above (10.75 g) in MeOH (60 mL) was added dropwise to a stirred solution of hydrazine hydrate (10.60 mL) in MeOH (300 mL) at 70° C. The mixture was stirred at 70° C. for 14 h, cooled and concentrated. The remaining residue was diluted with CH2Cl2 (200 mL), filtered and concentrated to afford the title compound as a yellow oil (10.00 g, 95%). [MH]+=243.
Step D
A suspension of the title compound from Step C above (9.50 g) in (EtO)3CH (200 mL) was heated to reflux for 6 h. Then AcOH (5 mL) was added at heating to reflux was continued for 6 h. The mixture was cooled, concentrated and purified by chromatography (silica) to afford major isomer (7.05 g, 71%) and the minor isomer (2.35 g, 24%) of the title compound. [MH]+=253.
Preparative Example 274




Step A

To a solution of the major isomer of title compound from the Preparative Example 273, Step D (9.40 g) in THF (200 mL) was added a 4M solution of HCl in 1,4-dioxane (37 mL). The mixture was stirred at room temperature for 2 h and then concentrated to afford the title compound (8.53 g, >99%). [MH]+=165.
Step B
The title compound from Step A above (8.53 g) and Na2CO3 (4.26 g) were dissolved in H2O (250 mL). The suspension was heated to 50° C. and KMnO4 (8.13 g) was added in small portions over a period of 30 min. The mixture was stirred at 50° C. for 2 h, cooled to room temperature, filtered through a pad of Celite® and concentrated to afford the crude title compound, which was used without further purification (13.42 g). [MH]+=179.
Step C
SOCl2 (10.9 mL) was added dropwise to an ice cooled suspension of the title compound from Step B above (13.4 g) in MeOH (400 mL). The cooling bath was removed and the mixture was stirred at room temperature for 12 h. Concentration and purification by chromatography (silica, CH2Cl2/MeOH) afforded the title compound as an orange solid (2.23 g, 16%). [MH]+=193.
Step D
A mixture of the title compound from Step C above (1.21 g) and selenium dioxide (1.40 g) in 1,4-dioxane (20 mL) was heated to 70° C. for 4 h. Cooling to room temperature, filtration through a pad of Celite® and concentration afforded the crude title compound as a red solid, which was used without further purification (1.4 g). [MH]+=223.
Preparative Example 275




Step A

The minor isomer of title compound from the Preparative Example 273, Step D (2.35 g) was treated similarly as described in the Preparative Example 274, Step A to afford the title compound (1.53 g, >99%). [MH]+=165.
Step B
The title compound from Step A above (1.53 g) was treated similarly as described in the Preparative Example 274, Step B to afford the title compound. [MH]+=179.
Step C
The title compound from Step B above was treated similarly as described in the Preparative Example 274, Step C to afford the title compound. [MH]+=193.
Step D
The title compound from Step C above was treated similarly as described in the Preparative Example 274, Step D to afford the title compound. [MH]+=223.
Preparative Example 276




Step A

A suspension of the title compound from the Preparative Example 255, Step A (2.22 g) in dry toluene (15 mL) was placed in a preheated oil bath ( ̃80° C.). Then N,N-dimethylformamide di-tert-butyl acetal (9.60 mL) was added carefully over a period of  ̃10 min and the resulting black/brown mixture was stirred at  ̃80° C. for 1 h. The mixture was cooled to room temperature, diluted with EtOAc (150 mL), washed with H2O (2×150 mL) and saturated aqueous NaCl (150 mL), dried (MgSO4), filtered, concentrated and purified by flash chromatography (silica, cyclohexane/EtOAc) to afford the title compound (1.39 g, 50%). [MH]+=279.
Step B
To a solution of the title compound from Step A above (1.39 g) in dry 1,2-dichloroethane (50 mL) was added trimethyltin hydroxide (1.01 g). The resulting yellow suspension was placed in a preheated oil bath ( ̃80° C.) and stirred at this temperature for 2 h. The mixture was cooled to room temperature, diluted with EtOAc (250 mL), washed with 5% aqueous HCl (2×250 mL) and saturated aqueous NaCl (250 mL), dried (MgSO4), filtered, concentrated and vacuum dried for  ̃15 h to afford a beige solid, which was used without further purification (756 mg, 57%). [MH]+=265.
Preparative Example 277




Step A

The title compound from the Preparative Example 272, Step B (2.37 g) was treated similarly as described in the Preparative Example 276, Step A to afford the title compound (1.68 g, 57%). [MH]+=294.
Step B
The title compound from Step A above (1.36 g) was treated similarly as described in the Preparative Example 276, Step B to afford the title compound as a beige solid (1.20 g, 97%). [MH]+=266.
Preparative Example 278




Step A

To a solution of the title compound from the Preparative Example 259 (94 mg) in DMF (3 mL) were added the title compound from the Preparative Example 7, Step D (94 mg), PyBrOP (216 mg) and iPr2NEt (123 mL). The mixture was stirred at room temperature for 2 h, concentrated and purified by chromatography (silica, CH2Cl2/acetone) to afford the title compound (60 mg, 37%). [MH]+=451.
Preparative Example 279




Step A

To an ice cooled solution of the title compound from the Preparative Example 255, Step A (250 mg) and the title compound from the Preparative Example 214, Step A (329 mg) in DMF (10 mL) were added N-methylmorpholine (170 μL), HATU (570 mg) and HOAt (204 mg). The mixture was stirred overnight while warming to room temperature and then concentrated. The remaining residue was dissolved in CHCl3, washed with saturated aqueous NaHCO3, 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO4), filtered, absorbed on silica and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a yellow/brown gummy solid (177 mg, 35%). [MH]+=462.
Preparative Example 280




Step A

To a solution of the title compound from the Preparative Example 267 (236 mg) in anhydrous CH2Cl2 (5 mL) was added oxalyl chloride (0.32 mL) at 0° C., followed by the addition of anhydrous DMF (0.1 mL). The mixture was allowed to warm to room temperature, stirred for 1 h and concentrated. To the remaining reddish solid residue was added anhydrous CH2Cl2 (5 mL) at 0° C., followed by the addition of a solution of the title compound from the Preparative Example 138 (231 mg) and NEt3 (0.42 mL) in anhydrous CH2Cl2 (5 mL). The mixture was allowed to warm to room temperature, stirred overnight, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to give the desired product (150 mg, 34%). [MH]+=449.
Preparative Example 281




Step A

A solution of the title compound from the Preparative Example 271, Step B (−670 mg), PyBOP (2.35 g) and iPr2NEt (780 μL) in DMF (5 mL) was stirred at room temperature for 1 h. Commercially available 4-fluoro-3-methyl benzylamine (500 mg) and iPr2NEt (780 μL) were added and stirring at room temperature was continued overnight. The mixture was concentrated, diluted with EtOAc, washed with H2O and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/acetone) to afford the title compound as a single regioisomer (200 mg, 19% over two steps). [MH]+=345.
Preparative Example 282




Step A

To a solution of the title compound from the Preparative Example 260 (506 mg) and the title compound from the Preparative Example 161 (555 mg) in DMF (15 mL) were added N-methylmorpholine (250 NL), EDCI (530 mg) and HOAt (327 mg). The mixture was stirred overnight and then concentrated. The remaining residue was dissolved in CHCl3, washed with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO4), filtered, absorbed on silica and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as an orange solid (208 mg, 24%). [MH]+=382.
Preparative Examples 283-320
Following similar procedures as described in the Preparative Examples 279 (method A), 280 (method B), 281 (method C), 278 (method D) or 282 (method E), except using the acids and amines indicated in Table I-13 below, the following compounds were prepared.










TABLE I-13





Prep.





Ex.


method,


#
acid, amine
product
yield







283








B, 36% [MH]+ = 431


 


284








C, 47% [MH]+ = 388


 


285








C, n.d. [MH]+ = 421/423


 


286








C, 33% [MH]+ = 440


 


287








A, 41% [MH]+ = 347


 


288








A, 44% [MH]+ = 347


 


289








A, 76% [MH]+ = 458/460


 


290








D, 11% [MH]+ = 343


 


291








A, 83% [MH]+ = 381


 


292








A, 73% [MH]+ = 414


 


293








A, 32% [MH]+ = 491


 


294








B, 76% [MH]+ = 452


 


295








A, 7% (over 2 steps), [MH]+ = 410


 


296








A, n.d. [MH]+ = 344


 


297








B, 34% [MH]+ = 364


 


298








B, 72% [MH]+ = 363


 


299








A, 37% [MH]+ = 395


 


300








A, 79% [MH]+ = 381


 


301








A, 71% [MH]+ = 364


 


302








A, 43% [MH]+ = 435


 


303








E, 82% [MH]+ = 400


 


304








A, 67% [MH]+ = 500


 


305








A, 73% [MNa]+ = 475


 


306








B, 34% [MH]+ = 449


 


307








B, 34% [MNa]+ = 491


 


308








B, 73% [M-H]− = 501


 


309








A, 20% [MH]+ = 342


 


310








A, 21% [MH]+ = 401


 


311








A, 10% [MH]+ = 453


 


312








A, 73% [MH]+ = 414


 


313








A, 71% [MH]+ = 453


 


314








A, >99% [MH]+ = 397


 


315








A, 70% [MH]+ = 344


 


316








A, 33% [MH]+ = 359


 


317








A, 54% [MH]+ = 411


 


318








A, 60% [MH]+ = 387


 


319








A, 47% [MH]+ = 419


 


320








A, 29% [MH]+ = 401









Preparative Example 321




Step A

To an ice cooled solution of the title compound from the Preparative Example 278, Step A (75 mg) in dry THF (10 mL) were successively added NaH (95%, 10 mg) and methyl iodide (250 μL). The cooling bath was removed and the resulting mixture was stirred at room temperature for 2 h. Concentration and purification by chromatography (silica, CHCl3/MeOH) afforded the title compound as a colorless solid (52 mg, 69%). [MNa]+=473.
Preparative Example 322




Step A

A mixture of commercially available 2-aminoimidazole sulfate (1.0 g), NH4OAc (1.2 g) and methyl acetopyruvate (1.1 g) in AcOH (10 mL) was stirred at 120° C. for 3 h, then absorbed on silica and purified by chromatography (silica, EtOAc/MeOH) to give an off-white solid (396 mg, 14%). [MH]+=192.
Step B
A solution of the title compound from Step A above (14 mg) in THF (100 μL), MeOH (100 μL), and 1N aqueous LiOH (80 μL) was stirred at 0° C. for 2 h and then concentrated to give a yellow residue. [MH]+=178. A mixture of this residue, PyBOP (42 mg), 4-fluoro-3-methyl-benzylamine (11 mg), and NEt3 (20 μL) in DMF (200 μL) and THF (400 μL) was stirred for 4 h, then absorbed on silica and purified by chromatography (silica, EtOAc/MeOH) to give an off-white solid (12 mg, 55%). [MH]+=299.
Step C
A mixture of the title compound from Step B above (100 mg) and selenium dioxide (93 mg) in dioxane (1.5 mL) was stirred at 80° C. for 2 h. The mixture was cooled to room temperature and filtered through Celite®. The filter cake was washed with dioxane (3×1 mL). To the supernatant were added oxone (206 mg) and H2O (100 μL) and the resulting mixture was stirred for 4 h and then filtered. The supernatant was concentrated and then stirred in a premixed solution of acetyl chloride (100 μL) in MeOH (2 mL) in a sealed vial for 3 h at 65° C. The solution was absorbed on silica and purified by chromatography (silica, hexanes/EtOAc) to give a yellow solid (40 mg, 35%). [MH]+=343.
Preparative Example 323




Step A

A mixture of commercially available 4-nitroimidazole (5 g) and Pd/C (10 wt %, 500 mg) in a premixed solution of acetyl chloride (4 mL) in MeOH (100 mL) was hydrogenated in a Parr shaker at 35 psi for 5 h. The mixture was filtered through Celite® and concentrated to give a black oil. [MH]+=115. This oil and methyl acetylpyruvate (6.4 g) were stirred in AcOH (70 mL) and MeOH (70 mL) at 65° C. for 18 h. The resulting mixture was absorbed on silica and purified by chromatography (silica, CH2Cl2/MeOH). Further purification of the resulting residue by chromatography (silica, EtOAc) afforded an orange solid (120 mg, 1.4%). [MH]+=192.
Step B
A mixture of the title compound from Step A above (50 mg) and selenium dioxide (116 mg) in dioxane (1 mL) was heated to 130° C. in a sealed tube for 6 h, cooled and filtered through Celite®. The supernatant was concentrated to give a orange residue. [MH]+=222. This residue was stirred with 4-fluoro-3-methyl-benzylamine (27 μL), PyBOP (150 mg), and NEt3 (73 μL) in THF (2 mL) for 3 h, absorbed on silica and purified by chromatography (silica, hexanes/EtOAc) to give a yellow solid (22 mg, 24%). [MH]+=343.
Preparative Example 324




Step A

A solution of the title compound from the Preparative Example 262 (0.5 g) and 4-fluoro-3-trifluoromethylbenzyl amine (1.6 g) in DMF (2.5 mL) was stirred at 48° C. for 10 h and then concentrated to an oil. The oil was taken up in EtOAc (120 mL), washed with 1N aqueous HCl (2×70 mL) and saturated aqueous NaCl (70 mL), dried (MgSO4), filtered and concentrated. The remaining solid was washed with hexanes/Et2O (1:1) and MeOH to give a yellow solid (0.31 g, 35%). [MH]+=401.
Preparative Examples 325-327
Following a similar procedure as described in the Preparative Example 324, except using the acids and amines indicated in Table I-14 below, the following compounds were prepared.










TABLE I-14





Prep. 





Ex. #
acid, amine
product
yield







325



 




n.d. [MNa]+ = 355


 


326



 




33% [MH]+ = 344


 


327



 




65% [MH]+ = 381









Preparative Example 328




Step A

A mixture of the title compound from the Preparative Example 245, Step B (10 mg), commercially available 4-fluorobenzylamine (5.3 mg) and scandium triflate (1 mg) in anhydrous DMF (1 mL) was heated to 60° C. for 12 h, concentrated and purified by chromatography (silica) to afford the title compound as a yellow solid (11.5 mg, 83%). [α]+=329.
Preparative Example 329




Step A

The title compound from the Preparative Example 245, Step B (10 mg) was treated similarly as described in the Preparative Example 328, Step A, except using commercially available 3-chloro-4-fluorobenzylamine instead of 4-fluorobenzylamine to afford the title compound as a yellow solid (11.5 mg, 79%). [MH]+=363.
Preparative Example 330




Step A

Under an argon atmosphere a solution of commercially available [1,3,5]triazine-2,4,6-tricarboxylic acid triethyl ester (818 mg) and 3-aminopyrazole (460 mg) in dry DMF (8 mL) was heated to 100° C. overnight and then concentrated. The remaining residue was dissolved in CHCl3, washed with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a colorless solid (409 mg, 56%). [MH]+=265.
Step B
A mixture of the title compound from Step A above (203 mg) and commercially available 3-chloro-4-fluorobenzylamine (160 mg) in dry DMF (3 mL) was heated to 70° C. overnight and concentrated. The remaining residue was dissolved in CHCl3, washed with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by preparative thin layer chromatography (silica, CH2Cl2/MeOH) to afford the title compound from the Example 286 and the separated regioisomers of the title compound. [MH]+=378.
Preparative Example 331




Step A

To a solution of NaOH (24 mg) in dry MeOH (3.2 mL) was added the title compound from the Preparative Example 315 (170 mg). The resulting suspension was stirred at room temperature for 1 h, acidified with 1N aqueous HCl and concentrated. The remaining residue was dissolved in EtOAc, washed with 1N aqueous HCl, dried (MgSO4), filtered and concentrated to afford the title compound (130 mg, 80%). [MH]+=330.
Preparative Example 332




Step A

To a solution of the title compound from the Preparative Example 280, Step A (45 mg) in dioxane (3 mL) was added 1M aqueous LiOH (0.12 mL). The resulting mixture was stirred at room temperature for 2 h, adjusted to pH 2 and concentrated to give a red solid, which was used without further purification (43 mg, 99%). [MH]+=435.
Preparative Example 333




Step A

A mixture of the title compound from the Preparative Example 281, Step A (23 mg) and trimethyltin hydroxide (30 mg) in 1,2-dichloroethane (2 mL) was heated at 80° C. for 3 h, concentrated, diluted with EtOAc (5 mL), washed with 10% aqueous KHSO4 (5 mL) and saturated aqueous NaCl (5 mL), dried (MgSO4), filtered and concentrated to afford the crude title compound (22 mg, 95%). [MH]+=331.
Preparative Examples 334-372
Following similar procedures as described in the Preparative Examples 331 (method A), 332 (method B) or 333 (method C), except using the esters indicated in Table I-15 below, the following compounds were prepared.










TABLE I-15





Prep. 


method,


Ex. #
ester
product
yield







334








B,  >99%  [MH]+ = 415


 


335








C, 97%  [MH]+ = 374


 


336








C, 95% [MNa]+ = 462


 


337








A, 98%  [MH]+ = 437


 


338








A, 78%  [MH]+ = 333


 


339








A, 93%  [MH]+ = 333


 


340








A, n.d.  [MH]+ = 407/ 409


 


341








A, 98%  [MH]+ = 329


 


342








A, 96%  [MH]+ = 367


 


343








B, 61%  [MH]+ = 400


 


344








A, 96% [MNa]+ = 477


 


345








C, n.d.  [MH]+ = 396


 


346








B, 83% [MH]+ = 350


 


347








B, 97%  [MH]+ = 349


 


348








B, n.d.  [MH]+ = 330


 


349








A, 67%  [MH]+ = 448


 


350








A, 91%  [MH]+ = 381


 


351








A, >99%  [MH]+ = 367


 


352








B, 85%  [MH]+ = 350


 


353








A, 93%  [MH]+ = 421


 


354








B, 96% [MH]+ = 368


 


355








B, 82%  [MH]+ = 386


 


356








B, 98%  [MH]+ = 455


 


357








B,  >99%  [MH]+ = 330


 


358








B,  >99%  [MH]+ = 489


 


359








A, n.d. [MH]+ = 315


 


360








A, 18%  [MH]+ = 349


 


361








B, n.d. [MH]+ = 345


 


362








C, n.d.  [MH]+ = 397


 


363








B, 61%  [MH]+ = 414


 


364








B,  >99%  [MH]+ = 439


 


365








B, n.d.  [MH]+ = 329


 


366








B, n.d.  [MH]+ = 329


 


367








A,  >99%  [MH]+ = 383


 


368








A, n.d.  [MH]+ = 345


 


369








A, n.d.  [MH]+ = 397


 


370








A, n.d.  [MH]+ = 373


 


371








A, 95% [MH]+ = 405


 


372








A, 95% [MH]+ = 387









Preparative Example 373




Step A

The title compound from the Preparative Example 304 (142 mg) was dissolved in trifluoroacetic acid/H2O (9:1, 1.5 mL), stirred at room temperature for 1 h and concentrated by co-evaporation with toluene (3×10 mL) to yield a citreous/white solid, which was used without further purification (114 mg, 91%). [MNa]+=445.
Preparative Examples 374-375
Following a similar procedure as described in the Preparative Example 373, except using the esters indicated in Table I-16 below, the following compounds were prepared.










TABLE I-16





Prep. 





Ex. #
ester
product
yield







374








>99%  [MH]+ =  402/404


 


375








 97%  [MH]+ = 419









Preparative Example 376




Step A

A mixture of NaOMe (5.40 g), thiourea (5.35 g) and commercially available 2-fluoro-3-oxo-butyric acid ethyl ester (6.27 mL) in anhydrous MeOH (50 mL) was stirred at 100° C. (temperature of the oil bath) for 51⁄2 h and then allowed to cool to room temperature. The obtained beige suspension was concentrated and diluted with H2O (50 mL). To the resulting aqueous solution was added concentrated HCl (9 mL). The formed precipitate was collected by filtration and washed with H2O (100 mL) to afford the title compound as a pale beige solid (5.6 g, 70%). [MH]+=161.
Step B
A suspension of the title compound from Step A above (5.6 g) and Raney®-nickel (50% slurry in H2O, 8 mL) in H2O (84 mL) was heated to reflux for 16 h. The mixture was allowed to cool to room temperature and then filtered. The filter cake was washed successively with MeOH and EtOAc and the combined filtrates were concentrated. The obtained viscous oily residue was diluted with EtOAc and concentrated to afford the title compound as a reddish solid (3.6 g, 80%). [MH]+=129.
Step C
A mixture of the title compound from Step B above (3.6 g), K2CO3 (11.6 g) and POBr3 (24.0 g) in anhydrous CH3CN (200 mL) was heated to reflux for 19 h, cooled to room temperature and concentrated. A mixture of ice (180 g) and H2O (30 mL) was added and the mixture was stirred for 30 min. The aqueous mixture was extracted with CHCl3 (2×150 mL) and EtOAc (2×150 mL) and the combined organic extracts were washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to afford the title compound as a yellow liquid (3.15 g, 58%). [α]+=191/193.
Step D
Under a carbon monoxide atmosphere (7 bar) a mixture of the title compound from Step C above (2.91 g), Pd(OAc)2 (142 mg), 1,1′-bis-(diphenylphosphino)ferrocene (284 mg) and Et3N (4.2 mL) in anhydrous DMA/MeOH (1:1, 150 mL) was heated at 80° C. for 17 h. The mixture was cooled to room temperature, concentrated, absorbed on silica (500 mg) and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a beige solid (1.53 g, 59%). [MH]+=171.
Step E
The title compound from Step D above (473 mg) was treated similarly as described in the Preparative Example 255, Step A to afford the title compound (514 mg, 92%). [MH]+=201.
Preparative Example 377




Step A

The title compound from the Preparative Example 376, Step E (360 mg) was treated similarly as described in the Preparative Example 279, Step A, except using commercially available 3-chloro-4-fluoro-benzylamine instead of the title compound from the Preparative Example 214, Step A to afford the title compound (195 mg, 32%). [MH]+=342.
Step B
The title compound from Step A above (195 mg) was treated similarly as described in the Preparative Example 331, Step A to afford the title compound (175 mg, 93%). [MH]+=328.
Step C
The title compound from Step B above (175 mg) was treated similarly as described in the Preparative Example 280, Step A, except using a commercially available 0.5M solution of NH3 in 1,4-dioxane instead of the title compound from the Preparative Example 138 to afford the title compound (160 mg, 92%). [W]+=327.
Step D
A 2M solution of oxalyl chloride in CH2Cl2 (450 μL) was diluted in DMF (8 mL) and then cooled to 0° C. Pyridine (144 μL) and a solution of the title compound from Step C above (146 mg) in DMF (2 mL) were added and the mixture was stirred at 0° C. for 3 h and then at room temperature overnight. The mixture was concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and concentrated to afford the title compound (57 mg, 41%). [MH]+=309.
Step E
To a stirring solution of the title compound from Step D above (9 mg) in 1,4-dioxane (3 mL) was added a 1M solution of hydrazine hydrate in 1,4-dioxane (45 μL). The mixture was stirred at room temperature for 3 h and then concentrated to afford the title compound (10 mg, >99%). [MH]+=321.
Preparative Example 378




Step A

A suspension of commercially available 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride (5.06 g) and formamidine acetate (4.20 g) in EtOH (35 mL) was heated to reflux overnight and cooled to room temperature. The formed precipitate was collected by filtration, washed with EtOH and dried to afford the title compound as colorless needles (3.65 g, >99%). [MH]+=136.
Step B
A mixture of the title compound from Step A above (491 mg) and POBr3 (4 g) was heated to 80° C. for 2 h. The mixture was cooled to room temperature, poured into saturated aqueous NaHCO3 and extracted with CHCl3. The organic extracts were concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as an off-white solid (276 mg, 38%). [MH]+=198/200.
Step C
Under a carbon monoxide atmosphere (7 bar) a mixture of the title compound from Step B above (276 mg), Pd(OAc)2 (13 mg), 1,1′-bis-(diphenylphosphino)ferrocene (31 mg) and Et3N (370 μL) in anhydrous DMA/MeOH (1:2, 15 mL) was heated at 80° C. for 3 d. The mixture was cooled to room temperature, concentrated, absorbed on silica and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a brown solid (260 mg, >99%). [MH]+=178.
Step D
To the ice cooled title compound from Step C above (120 mg) was added concentrated HNO3 (ρ=1.5, 1 mL). The mixture was stirred at 0° C. (ice bath) for 30 min, the cooling bath was removed and stirring was continued for 30 min. Ice was added and the formed precipitate was collected by filtration and dried to afford the title compound as a brown solid (87 mg, 58%). [MH]+=223.
Step E
To the title compound from Step D above (87 mg) was added a solution of LiOH (47 mg) in H2O. The resulting mixture was stirred for 2 h and then acidified with 1N aqueous HCl. The formed precipitate was collected by filtration and dried to afford the title compound as a brown solid (93 mg, >99%). [MH]+=209.
Preparative Example 379




Step A

To a solution of the title compound from the Preparative 378, Step E above (93 mg) and the title compound from the Preparative Example 161 (110 mg) in DMF (5 mL) were added N-methylmorpholine (40 μL), EDCI (120 mg) and HOAt (60 mg). The mixture was stirred overnight and then concentrated. 10% aqueous citric acid was added and the formed precipitate was collected by filtration and dried to afford the title compound as a brown solid (91.5 mg, 63%). [MH]+=369.
Step B
A mixture of the title compound from Step A above (91 mg), AcOH (200 μL) and Pd/C (10 wt %, 55 mg) in THF/MeOH was hydrogenated at atmospheric pressure overnight, filtered, concentrated and diluted with saturated aqueous NaHCO3. The formed precipitate was collected by filtration and purified by preparative thin layer chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a brown solid (12 mg, 9%). [MH]+=339.
Preparative Example 380




Step A

Commercially available 4-bromo-3-hydroxy-benzoic acid methyl ester (500 mg) was treated similarly as described in the Preparative Example 32, Step A to afford the title compound (475 mg, >99%). [MH]+=216.
Step B
The title compound from Step A above (475 mg) was treated similarly as described in the Preparative Example 32, Step B to afford the title compound as a colorless solid (316 mg, 73%). [MH]+=298.
Preparative Example 381




Step A

Commercially available 5-bromo-2-fluoro-benzamide (500 mg) was treated similarly as described in the Preparative Example 25, Step A to afford the title compound as colorless needles (196 mg, 52%). [MH]+=165.
Preparative Example 382




Step A

At room temperature commercially available 4-trifluoromethyl benzoic acid (4.90 g) was slowly added to a 90% solution of HNO3 (10 mL). H2SO4 (12 mL) was added and the mixture was stirred at room temperature for 20 h. The mixture was poured on a mixture of ice (250 g) and H2O (50 mL). After 30 min the precipitate was collected by filtration, washed with H2O and air dried. Purification by chromatography (CH2Cl2/cyclohexane/AcOH) afforded the title compound as regioisomer A (2.30 g, 38%) and regioisomer B (1.44 g, 23%). 1H-NMR (acetone-d6) regioisomer A: S=8.36 (s, 1H), 8.13-8.25 (m, 2H), regioisomer B: S=8.58 (s, 1H), 8.50 (m, 1H), 8.20 (d, 1H).
Step B
A mixture of the regioisomer A from Step A above (1.44 g) and Pd/C (10 wt %, 400 mg) in MeOH (150 mL) was hydrogenated at atmospheric pressure for 1 h and filtered. The filter cake was washed with MeOH (50 mL) and the combined filtrates were concentrated to afford the title compound (1.20 g, 95%). [MH]+=206.
Step C
To a cooled to (0-5° C.) mixture of the title compound from Step B above (1.2 g) and concentrated H2SO4 (6 mL) in H2O (34 mL) was slowly added a solution of NaNO3 (420 mg) in H2O (6 mL). The mixture was stirred at 0-5° C. for 45 min and then added to a mixture of H2O (48 mL) and concentrated H2SO4 (6 mL), which was kept at 135° C. (temperature of the oil bath). The resulting mixture was stirred at 135° C. (temperature of the oil bath) for 21⁄2 h, cooled to room temperature, diluted with ice water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed with saturated aqueous NaCl (50 mL), dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/cyclohexane/AcOH) to afford the title compound (797 mg, 66%). [MH]+=207.
Step D
To a cooled (−30° C.) solution of the title compound from Step C above (790 mg) and NEt3 (1.4 mL) in THF (45 mL) was added ethyl chloroformate (790 μL). The mixture was stirred at −30° C. to −20° C. for 1 h and then filtered. The precipitated salts were washed with THF (20 mL). The combined filtrates were cooled to −20° C. and a 33% solution of NH3 in H2O (20 mL) was added. The mixture was stirred at −20° C. for 20 min, then the cooling bath was removed and the mixture was stirred at room temperature for 40 min. Then the mixture was concentrated and dissolved in THF (25 mL) and CH3CN (6 mL). Pyridine (3.15 mL) was added and the mixture was cooled to 0° C. Trifluoroacetic anhydride (2.73 mL) was added and the mixture was stirred at 0° C. for 3 h. Then the mixture was concentrated in vacuo, diluted with MeOH (22 mL) and 10% aqueous K2CO3 (22 mL) and stirred at room temperature for 48 h. The mixture was concentrated to −20 mL, acidified (pH  ̃1) with 1N aqueous HCl and extracted with EtOAc (2×100 mL). The combined organic phases were dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound (490 mg, 67%). [MH]+=188.
Preparative Examples 383-386
Following a similar procedure as described in the Preparative Example 34, except using the nitriles indicated in Table I-17 below, the following compounds were prepared.










TABLE I-17





Prep. 





Ex. #
nitrile
product
yield







383








51%  1H-NMR (DMSO-d6) δ = 7.78 (d, 1 H),  7.58 (t, 1 H), 7.38 (d, 1 H), 7.32 (s, 1 H),  4.25 (d, 2 H), 1.52 (s, 9 H), 1.40 (s, 9 H)


 


384








53% [MNa]+ = 324/326


 


385








n.d. [MNa]+ = 291


 


386








n.d. [MH]+ = 292









Preparative Examples 387-389
Following a similar procedure as described in the Preparative Example 133, except using the protected amines indicated in Table I-18 below, the following compounds were prepared.










TABLE I-18





Prep. 





Ex. #
protected amine
product
yield







387








>99% [M − Cl]+ = 201/203


 


388








n.d. [M − Cl]+ = 169


 


389








>99% [M − Cl]+ = 192









Preparative Example 390




Step A

The title compound from the Preparative Example 383 (42 mg) was treated similarly as described in the Preparative Example 208, Step A to afford the title compound (32 mg, 98%). [M-TFA]+=165.
Preparative Example 391




Step A

A solution of title compound from the Preparative Example 39, Step C (1.0 g) in SOCl2 (5 mL) was heated to reflux for 3 h, concentrated and coevaporated several times with cyclohexane to afford the corresponding acid chloride. A mixture of magnesium turnings (127 mg) and EtOH (100 μL) in dry benzene (2 mL) was heated to reflux until the dissolution of the magnesium started. A mixture of diethyl malonate (810 μl) and EtOH (700 μL) in benzene (3 mL) was added over a period of 30 min and heating to reflux was continued for 3 h (complete dissolution of the magnesium). The EtOH was then removed by azeotropic distillation with fresh portions of benzene and the volume was brought to  ̃5 mL by addition of benzene. The mixture was heated to reflux, a solution of the acid chloride in benzene (5 mL) was added over a period of 30 min and heating to reflux was continued for 31⁄2 h. The resulting viscous mixture was poured on a mixture of ice and 6N aqueous HCl. The organic phase was separated and the aqueous phase was extracted was benzene (2×10 mL). The combined organic phases were washed with H2O, dried (MgSO4), filtered and concentrated. The remaining residue was diluted with AcOH (25 mL) and concentrated HCl (25 mL), heated to reflux for 16 h, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (665 mg, 76%). [MH]+=197.
Step B
A mixture of hydroxylamine hydrochloride (807 mg) and pyridine (4.5 mL) in EtOH (4.5 mL) was heated to reflux for 5 min, the title compound from Step A above (759 mg) was added and heating to reflux was continued for 3 h. The mixture was cooled, concentrated and diluted with cold 3N aqueous HCl (30 mL). The formed precipitate was collected by filtration, washed with H2O and air dried to afford the title compound (590 mg, 72%). [MH]+=212.
Step C
A mixture of the title compound from Step B above (440 mg), 6N aqueous HCl (5 mL) and PtO2 (95 mg) in 90% aqueous EtOH (40 mL) was hydrogenated at atmospheric pressure for 36 h, filtered and concentrated to afford the crude title compound as a colorless solid (436 mg, 80%). [M-Cl]+=226.
Preparative Examples 392-393
Following similar procedures as described in the Preparative Examples 280, except using the acids and amines indicated in Table I-19 below, the following compounds were prepared.










TABLE I-19





Prep.





Ex. #
acid, amine
product
yield







392



 







69% [MH]+ = 330


 


393



 







41%  [MH]+ = 429









Preparative Examples 394-395
Following similar procedures as described in the Preparative Examples 331, except using the esters indicated in Table I-20 below, the following compounds were prepared.










TABLE I-20





Prep.





Ex. #
ester
product
yield







394








95%  [MH]+ =  316


 


395








95% [MH]+ =  415









The Preparative Example numbers 396 to 804 were intentionally excluded.

Preparative Example 805




Step A

To a cooled (−40° C.) solution of the title compound from the Preparative Example 39, Step C (1.0 g) and NEt3 (890 μL) in THF (50 mL) was slowly added ethyl chloroformate (490 μL). The mixture was stirred at −25° C. for 1 h and then filtered. The precipitated salts were washed with THF (40 mL). The combined filtrates were cooled to 0° C. and a solution of NaBH4 (528 mg) in H2O (9.4 mL) was added carefully. The mixture was stirred at 0° C. for 45 min, the cooling bath was removed and stirring was continued at room temperature for 45 min. Then the mixture was diluted with saturated aqueous NaHCO3 (40 mL) and saturated aqueous NaCl (40 mL). The organic phase was separated, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/acetone) to afford the title compound (910 mg, 97%). [MH]+=199.
Step B
To a mixture of the title compound from Step A above (20 mg) in CH2Cl2 (2 ml) was added IBX-polystyrene (500 mg) and the mixture was stirred at room temperature for 5 h, filtered and concentrated to afford the title compound (19 mg, 97%). [MH]+=197.
The Preparative Example numbers 806 to 835 and the Table numbers 1-21 to 11-30 were intentionally excluded.
Preparative Example 836




Step A

To a mixture of the commercial available 1-chloro-3-iodo-2-methylbenzene (2 52 g), tert.-butyl acrylate (4.35 mL) and NaOAc (1.65 g) in DMF (10 mL) was added Ru/Al2O3 (5 wt %, 1.00 g). The reaction mixture was stirred at 150° C. for 12 h, extracted with EtOAc and Et2O, washed with H2O, dried (MgSO4), filtered and concentrated. The remaining residue was purified by short pad filtration (silica, cyclohexane/EtOAc) to afford the title compound as a liquid (2.40 g, 95%). [MH]+=253.
Step B
A mixture of the title compound from Step A above (2.4 g) and Pt/C (10 wt %, 200 mg) in MeOH (10 mL) was hydrogenated at 1.5 bar overnight, filtered and concentrated. The remaining residue was purified by short pad filtration (silica, CH2Cl2/MeOH) to afford the title compound as a liquid (2.39 g, 95%). [MH]+=255.
Step C
To a solution of the title compound from Step B above (2.1 g) in CH2Cl2 (300 mL) was added dropwise pure CSA (2.5 mL) The resulting mixture was stirred at room temperature for 3 h, concentrated, diluted with EtOAc and Et2O and carefully added to ice water. The organic phase was separated, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to afford the title compound as a white solid (1.26 g, 85%). [NH]+=181.
Step D
Under an argon atmosphere a pressure reactor was charged with the title compound from Step C above (1.0 g), Na2CO3 (1.1 g), Pd(OAc)2 (120 mg), H2O (2 mL), dppp (410 mg) and DMA (20 mL). The reactor was purged with carbon monoxide, the reactor pressure was adjusted to 1 bar and placed in a preheated oil bath (135° C.). The reactor vessel was pressurized with carbon monoxide (6 bar) and heating to 135° C. was continued overnight. The resulting mixture was cooled to room temperature, purged with argon, diluted with H2O (15 mL) and hexane (15 mL) and stirred at room temperature for 15 min. Activated carbon was added and stirring at room temperature was continued for 20 min. The mixture was filtered through a pad Celite®, adjusted to pH=1-2 and extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered, concentrated and slurried in Et2O. Filtration and drying in vacuo afforded the title compound (840 mg, 80%). [MH]+=191.
Step E
A mixture of the title compound from Step D above (100 g) and Na2CO3 (55.7 g) in DMF (500 mL) was stirred at room temperature for 18 h and then quenched at 0-5° C. (ice bath) with H2O (600 mL). The formed precipitate was collected by filtration, washed with H2O (2×200 mL), dissolved in CH2Cl2, washed with H2O, dried (MgSO4), filtered and concentrated to afford the title compound (91 mg, 85%). [MH]+=205.
Step F
A solution of the title compound from Step E above (21.7 g) in CH2Cl2 (50 mL) was added over a 10 h period to a cooled (−20° C.) mixture of a 1M solution of (S)-(−)-2-methyl-CBS-oxazaborolidine in toluene (21.2 mL) and a 1M solution of BH3.Me2S complex in CH2Cl2 (107 mL) in CH2Cl2 (150 mL). The mixture was then quenched at −20° C. by addition of MeOH (210 mL), warmed to room temperature and concentrated. The obtained solid residue was dissolved in CH2Cl2 (210 mL), washed with 1M aqueous H3PO4 (2×100 mL), saturated aqueous NaHCO3 (100 mL) and saturated aqueous NaCl (100 mL), dried (MgSO4), filtered and concentrated to afford the title compound (21 g, 96%,  ̃99% ee). [MH]+=207.
Step G
To an cooled (0° C.) mixture of the title compound from Step F above (50 g) and diphenylphosphoryl azide (70 mL) in toluene was added DBU (55 mL). The resulting mixture was stirred at 0° C. for 2 h and then at 20° C. for 16 h. The resulting biphasic mixture was washed with H2O (750 mL), 1M aqueous H3PO4 (650 mL), saturated aqueous NaHCO3 (650 mL) and saturated aqueous NaCl (650 mL), dried (MgSO4) and filtered. The obtained filtrate was agitated with charcoal (25 g), filtered and concentrated to afford the crude title compound. [MH]+=232.
Step H
A mixture of the title compound from Step G above (2.5 g) and Pt/C (10 wt %, 250 mg) in toluene (78 mL) was hydrogenated at 200 psi for 21 h, filtered through Celite® and extracted with 1M aqueous HCl. The aqueous phase was washed with EtOAc, basified with 1M aqueous K3PO4 (400 ml), extracted with CH2Cl2 (2×50 mL), dried (MgSO4), filtered and concentrated to afford the title compound (1.8 g, 81%, 98.8% ee). [MH]+=206.
Preparative Example 837




Step A

A suspension of commercially available 3,4-dihydroxybenzonitrile (2.00 g) and Na2CO3 (4.91 g) in dry DMF (50 mL) was stirred at room temperature for 16 h. Into this mixture was condensed commercially available chlorodifluoromethane (−50 g) using a dry ice condenser. The resulting slurry was stirred at 160° C. (temperature of the oil bath) for 5 h, cooled and stirred at room temperature overnight without condenser. The mixture was concentrated, diluted with EtOAc, washed with 5% aqueous NaOH, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as an oil (49 mg, 1%). [MH]+=236.
Preparative Example 838




Step A

To a suspension of commercially available 3-(2-oxopyrrolidin-1-yl)benzoic acid (500 mg) in CH2Cl2 (10 mL) was added a 2M solution of oxalyl chloride in CH2Cl2 (1.83 mL). The resulting mixture was stirred at room temperature for 4 h and then concentrated to dryness. A 0.5M solution of NH3 in 1,4-dioxane (20 mL) was added and stirring at room temperature was continued for 16 h. The resulting mixture was diluted with 1,4-dioxane (20 mL), filtered and concentrated to afford the title compound (374 mg, 75%). [MH]+=205.
Step B
To a suspension of the title compound from Step A above (376 mg) in CH2Cl2 (8 mL) was added trifluoroacetic anhydride (566 μL). The resulting mixture was stirred at room temperature for 2 d, an additional portion of trifluoroacetic anhydride (566 μL) was added and stirring at room temperature was continued for 1 d. The mixture was concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound (63.1 mg, 18%). [MH]+=187.
Preparative Example 839




Step A

In a sealed pressure tube a mixture of commercially available 2-chloropyridine-4-carbonitrile (1.00 g) in morpholine (30 mL) was heated to 130° C. for 13 h. The resulting mixture was concentrated and purified by chromatography (silica, CHCl3/MeOH) to afford the title compound (256 mg, 19%). [MH]+=190.
Preparative Example 840




Step A

A mixture of commercially available 4-fluoro-3-nitro-benzonitrile (1.5 g) and Pd/C (10 wt %, 400 mg) in EtOH (10 mL) was hydrogenated at atmospheric pressure overnight, filtered and concentrated to afford the title compound (1.2 g, >99%.) [MH]+=137.
Preparative Example 841




Step A

A mixture of the title compound from the Preparative Example 840, Step A (566 mg), iPr2NEt (2.15 mL) and commercially available 1-(2-bromoethoxy)-2-bromoethane (627 μL) was stirred at 100° C. for 16 h and at 140° C. for 6 h. An additional portion of 1-(2-bromoethoxy)-2-bromoethane (627 μL) was added and stirring was continued at 160° C. for 6 h. The resulting mixture was concentrated and purified by chromatography (silica, CHCl3/MeOH) to afford the title compound. [MH]+=207.
Preparative Example 842




Step A

A mixture of the commercially available cubane-1,4-dicarboxylic acid dimethyl ester (1.65 g) and KOH (300 mg) in MeOH/H2O (10:1, 11 mL) was heated to reflux overnight, cooled to room temperature, concentrated, diluted with EtOAc and extracted with 1N aqueous NaOH (2×10 mL). The combined aqueous phases were adjusted to pH 1-2 with 2N aqueous HCl and extracted with EtOAc (4×25 mL). The combined turbid organic phases were filtered through a fluted filter, washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to give the title compound as a colorless solid (500 mg, 32%). [MH]+=207.
Step B
To a cooled (−40° C.) solution of the title compound from Step A above (490 mg) and NEt3 (400 μL) in THF (20 mL) was slowly added ethyl chloroformate (240 μL). The mixture was allowed to warm to −25° C. and stirred at this temperature for h. A 0.5N solution of NH3 in 1,4-dioxane (5.5 mL) was added and the mixture was stirred at −20° C. for 30 min. The cooling bath was removed and stirring was continued for 15 min. The mixture was concentrated diluted H2O (10 mL) and extracted with CH2Cl2 (1×20 mL, 2×10 mL). The combined organic phases were washed with saturated aqueous NaCl (10 mL), dried (MgSO4), filtered and concentrated to afford the title compound (208 mg, 42%). [MH]+=206.
Step C
DMF (10 mL) was cooled to 0-5° C. (ice bath) and a 2M solution of oxalyl chloride in CH2Cl2 (650 μL) was added followed by a solution of the title compound from Step B above (208 mg) in DMF (10 mL). The resulting mixture was stirred at 0-5° C. (ice bath) for 5 h, diluted with EtOAc, washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and concentrated to afford the title compound (140 mg, 75%). [MH]+=188.
Preparative Example 843




Step A

To an ice cooled (0-5° C.) suspension of commercially available 4-amino-3-hydroxybenzoic acid (5 g) in MeOH (50 mL) was dropwise added thionyl chloride (10.9 mL). The ice bath was removed and the mixture was stirred at room temperature for 12 h, before it was concentrated to afford the title compound as a solid (5.34 g, >99%). [MH]+=168.
Step B
To a mixture of the title compound from Step A above (5.34 g) and NaHCO3 (10 g) in acetone/H2O (1:1, 120 mL) was slowly added 2-bromopropionyl bromide (3 mL). The resulting mixture was heated to reflux for 2 h, cooled and stirred at 25° C. overnight. The formed precipitate was collected by filtration and washed several times with H2O to afford the title compound (3.6 g, 50%). [MH]+=208.
Step C
To a solution of the title compound from Step B above (3.55 g) in THF/MeOH (2:1, 120 mL) was added 1M aqueous LiOH (50 mL). The resulting mixture was stirred at room temperature for 24 h, adjusted to pH 2 with 1M aqueous HCl and concentrated. The formed precipitate was collected by filtration and washed with H2O to afford the crude title compound, which used without further purification (3.0 g, 90%). [MH]+=194.
Step D
To an ice cooled (0-5° C.) solution of the title compound from Step C above (1.00 g) in DMF (10 mL) was added 1,1′-carbonyldiimidazole (1.44 g). The resulting solution was stirred at 0-5° C. (ice bath) for 50 min, then a 0.5M solution of NH3 in 1,4-dioxane (20 mL) was added, the ice bath was removed and the mixture was stirred at room temperature overnight. The formed precipitate was collected by filtration and washed with H2O and dried in vacuo to afford the title compound (795 mg, 80%). [MH]+=193.
Step E
DMF (10 mL) was cooled to 0-5° C. (ice bath) and a 2M solution of oxalyl chloride in CH2Cl2 (2.5 mL) was added followed by a solution of the title compound from Step D above (795 mg) in DMF (10 mL). The resulting mixture was stirred at 0-5° C. (ice bath) for 5 h, diluted with EtOAc, washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and concentrated to afford the title compound (140 mg, 90%). [MH]+=175.
Preparative Example 844




Step A

At room temperature dimethylformamide dimethyl acetal (3 5 mL) was added to a solution of the commercially available 2-amino-5-cyanopyridine (2.4 g) in iPrOH (10 mL). The resulting mixture was heated to reflux for 3 h and then cooled to 50° C. Hydroxylamine hydrochloride (1.8 g) was added and the mixture was aged under sonication at 50° C. for 6 h. All volatile components were evaporated and the remaining residue was purified by chromatography (silica, EtOAc/MeOH) to afford the title compound (2.6 g, 80%). [MH]+=163.
Step B
To an ice cooled (0-5° C.) solution of the title compound from Step A above (2.6 g) in 1,4-dioxane/DMF (1:1, 60 mL) trifluoroacetic anhydride (2.5 mL) was slowly added over a period of 10 min, keeping the internal temperature below 20° C. After the complete addition the ice bath was removed and the mixture was heated to 90° C. for 48 h. The mixture was cooled, concentrated and purified by chromatography (silica, EtOAc/MeOH) to afford the title compound (322 mg, 11%). [MH]+=145.
Preparative Example 845




Step A

To a cooled (−78° C.) solution of the commercial available 2-hydroxy-isonicotinonitrile (1.08 g) in THF/DMF (1:1, 40 mL) was added NaH (260 mg) in portions. The mixture was stirred at −25° C. for 2 h and then cooled to −78° C. again. Iodomethane (680 μL) was added, the cooling bath was removed and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with 10% aqueous KHSO4 (10 mL) and saturated aqueous NaCl (20 mL), dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/acetone) to afford the title compound (600 mg, 49%). [MH]+=135.
Preparative Example 846




Step A

Commercially available chlorodifluoromethane was passed through a cooled (−78° C.) suspension of the commercial available 2-hydroxy-isonicotinonitrile (230 mg) and Cs2CO3 (650 mg) in 1,2-dichloroethane/DMA (10:1, 11 mL) for 30 min. The reaction vessel was sealed and—using a microwave—the chlorodifluoromethane saturated mixture was heated at 150° C. for 5 h. Then the mixture was cooled to room temperature, diluted with CHCl3 (20 mL), washed with H2O (10 mL) and saturated aqueous NaCl (20 mL), dried (MgSO4), filtered and concentrated to afford the crude title compound (200 mg, 55%). [MH]+=171.
Preparative Example 847




Step A

A mixture of commercially available 4-bromomethyl-benzoic acid methyl ester (500 mg) and KCN (354 mg) in DMA (9 mL) was stirred at 60-70° C. (temperature of the oil bath) overnight, concentrated and diluted with Et2O (200 mL) and H2O (80 mL). The organic phase was separated, washed with H2O (2×80 mL), dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (273 mg, 71%). [MH]+=176.
Preparative Examples 848-854
Following a similar procedure as described in the Preparative Example 25, except using the intermediates indicated in Table I-31 below, the following compounds were prepared.










TABLE I-31





Prep.





Ex. #
intermediate
product
yield







848








n.d. [MH]+ = 144


 


849








[MH]+ = 144


 


850








67% [MH]+ = 175


 


851








n.d. 


 


852








61% [MH]+ = 161


 


853








n.d.


 


854








93% [MH]+ = 175









Preparative Examples 855-859
Following a similar procedure as described in the Preparative Example 37, except using the intermediates and reagents indicated in Table I-32 below, the following compounds were prepared.










TABLE I-32





Prep.





Ex. #
intermediate, reagent
product
yield







855



 







99% [MH]+ = 175


 


856



 







73% [MH]+ = 189


 


857



 







22% [MH]+ = 203


 


858



 







80% [MH]+ = 203


 


859



 







n.d. [MH]+ = 217









Preparative Example 860




Step A

A solution of the title compound from the Preparative Example 840, Step A (100 mg) in acetic anhydride (3 mL) was stirred at room temperature for 2 h, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a white solid (77.6 mg, 60%). [MH]+=179.
Preparative Example 861




Step A

To an ice cooled (0-5° C.) solution of the title compound from the Preparative Example 840, Step A (100 mg) in pyridine (2 mL) was added methanesulfonyl chloride (67.8 μL). The resulting mixture was stirred overnight while warming to room temperature, cooled to 0-5° C. (ice bath) again, neutralized with 1M aqueous HCl, diluted with H2O and extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a colorless solid (47.4 mg, 30%). [MH]+=215.
Preparative Example 862




Step A

To a mixture of morpholinomethyl polystyrene (295 mg) in 1,2-dichlorethane (1 mL) were added commercially available 4-cyanobenzene-1-sulfonylchloride (50 mg) and commercially available 2-amino-3-methyl-butyric acid tert.-butyl ester hydrochloride (52 mg). The mixture was agitated at room temperature overnight, filtered and concentrated to afford the title compound as pale yellow solid, which was used without further purification. (75 mg, 90%). [MH]+=339.
Preparative Examples 863-867
Following a similar procedure as described in the Preparative Example 862, except using the acids and acid chlorides indicated in Table I-33 below, the following compounds were prepared.










TABLE I-33





Prep.





Ex. #
amine, acid chloride
product
yield







863



 







92% [MH]+ = 339


 


864



 







88% [MH]+ = 339


 


865



 







88% [MH]+ = 339


 


866



 







88% [MH]+ = 339


 


867



 







87% [MH]+ = 339









Preparative Example 868




Step A

Commercially available 3,4-diamino-benzonitrile (1.02 g) was treated similarly as described in the Preparative Example 213, Step A to afford the title compound as a brown solid (1.18 g, 97%). [MH]+=160.
Step B
Title compound from Step A above (1.18 g) was treated similarly as described in the Preparative Example 213, Step B to afford the title compound as an off-white solid (1.14 g, 80%). [MH]+=188.
Step C
The title compound from Step A above (1.32 g) was treated similarly as described in the Preparative Example 213, Step C to afford the title compound as a white solid (496 mg, 38%). [MH]+=191.
Step D
The title compound from Step C above (1.32 g) was treated similarly as described in the Preparative Example 213, Step D to afford the title compound as white crystals (264 mg, >99%). [M-Cl]+=165.
Preparative Example 869




Step A

To an ice cooled (0-5° C.) solution of the title compound from the Preparative Example 29 (1.10 g) in DMF (8 mL) were added NaH (102 mg) and iodomethane (500 μL). The ice bath was removed and the resulting mixture was stirred at room temperature overnight, concentrated and diluted with H2O and extracted with EtOAc. The organic phase was separated, dried (MgSO4), filtered and concentrated to afford the title compound (1.02 g, 88%). [MH]+=299
Preparative Examples 870-901
Following a similar procedure as described in the Preparative Example 34, except using the nitriles indicated in Table I-34 below, the following compounds were prepared.










TABLE I-34





Prep.





Ex. #
nitrile
product
yield







870








 69% (over 2  steps)  [MH]+ =  248


 


871








n.d.  [MH]+ =  248


 


872








 25%  [MNa]+ =  362


 


873








 66% [MNa]+ =  313


 


874








n.d.  [MH]+ =  294


 


875








 53%  [MH]+ =  311


 


876








 42% [MH]+ =  279


 


877








 50%  [MH]+ =  292


 


878








 35% [MH]+ =  301


 


879








 50%  [MH]+ =  271


 


880








 70%  [MH]+ =  278


 


881








n.d.  [MNa]+ =  261


 


882








n.d.  [MNa]+ =  297


 


883








 50%  (over 2  steps)  [MNa]+ =  298


 


884








 40%  1H-NMR (CDCl3)  δ = 7.96  (d, 2 H),  7.24  (d, 2 H), 4.98  (br s, 1 H),  3.90 (s, 3 H),  3.30- 3.40  (m, 2 H),  2.82 (t, 2 H), 1.40 (s, 9 H).


 


885








 99%  [MNa]+ = 274


 


886








 45%  [MH]+ = 443


 


887








 62%  [MH]+ = 443


 


888








 49%  [MH]+ = 443


 


889








 68%  [MH]+ = 443


 


890








 62%  [MH]+ = 443


 


891








 64%  [MH]+ = 443


 


892








 89%  [MH]+ = 279


 


893








 52%  [MH]+ = 293


 


894








>99%  [MH]+ = 307


 


895








 53%  [MNa]+ = 329


 


896








 81%  [MNa]+ =  343


 


897








n.d.  [MNa]+ = 300


 


898








n.d.  [MNa]+ =  301


 


899








n.d.  [MNa]+ =  425


 


900








 8%  [MNa]+ =  286


 


901








80%  [MNa]+ =  314









Preparative Example 902




Step A

A mixture of The title compound from the Preparative Example 885 (507 mg), iPr2NEt (6.5 mL) and iodomethane (700 μL) in DMF (8 mL) was stirred at room temperature over the weekend, concentrated and diluted with EtOAc (60 mL) and H2O (20 mL). The organic phase was separated, washed with 0.1M aqueous HCl (15 mL) and saturated aqueous NaCl (15 mL), dried (MgSO4), filtered and concentrated to afford the title compound (430 mg, 80%). 1H-NMR (CDCl3) δ=7.95 (d, 1H), 7.45-7.49 (m, 2H) 7.29-7.37 (m, 1H), 5.55 (br s, 1H), 4.49 (d, 2H), 3.90 (s, 3H), 1.40 (s, 9H).
Preparative Example 903




Step A

A mixture of commercially available N-(tert-butoxycarbonyl)-L-methionine (2.50 g), tert-butylamine (1.06 mL), EDCI (2.02 g), HOBt (1.99 g) and iPr2NEt (7.62 mL) in CH2Cl2 (100 mL) was stirred at room temperature overnight and then diluted with H2O. The aqueous phase was separated and extracted with CH2Cl2 (2×). The combined organic phases were washed with saturated aqueous NaHCO3 and 1M aqueous HCl, dried (MgSO4), filtered and concentrated to afford the title compound as a colorless solid (2.89 g, 95%). [MH]+=305.
Preparative Example 904




Step A

Commercially available N-(tert-butoxycarbonyl)-L-alanine (1.00 g) was treated similarly as described in the Preparative Example 903, Step A to afford the title compound as a white solid (1.38 g, >99%). [MNa]+=267.
Preparative Example 905




Step A

A solution of the title compound from the Preparative Example 903, Step A (1.89 g) in iodomethane (10 mL) was stirred at room temperature overnight and then concentrated to afford the title compound as a yellow solid (2.67 g, 97%). [M-S(CH3)2I]+=257.
Step B
Under an argon atmosphere NaH (166 mg, 60% in mineral oil) was added at once to an ice cooled (0-5° C.) solution of the title compound from Step A above (1.85 g) in DMF (25 mL). The resulting mixture was stirred at 0-5° C. (ice bath) for 15 min and at room temperature for 2 h, diluted with H2O and saturated aqueous NH4Cl and extracted with EtOAc (3×). The combined organic phases were washed with H2O and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a colorless oil (800 mg, 75%). [MNa]+=279.
Preparative Example 906




Step A

The title compound from the Preparative Example 79 (2.50 g) was treated similarly as described in the Preparative Example 96, Step A to afford the title compound as an oil (1.63 g, >99%). [MNa]+=277.
Step B
The title compound from Step A above (1.63 g) was treated similarly as described in the Preparative Example 97, Step A to afford the title compound as a white solid (1.43 g, 68%). [MNa]+=320.
Preparative Example 907




Step A

To an ice cooled (0-5° C.) solution of commercially available (3-amino-benzyl)-carbamic acid tert-butyl ester (400 mg) in pyridine (5 mL) was added methanesulfonyl chloride (1704) before the stirring mixture was allowed to warm to room temperature overnight. The resulting mixture was cooled to 0-5° C. (ice bath), carefully neutralized with 1M aqueous HCl, diluted with H2O and extracted with CH2Cl2. The organic phase was washed H2O and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as colorless crystals (407 mg, 75%). [MNa]+=323.
Preparative Example 908




Step A

To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (790 μL) in MeOH (20 mL) was added commercially available (3-aminomethyl-benzyl)-carbamic acid tert-butyl ester (840 mg). The mixture was stirred for 2 h, 30% aqueous solution of methylamine (30 mL) was added and stirring was continued for 2 h. The formed precipitate was collected by filtration to afford the title compound as a white solid (1.17 g, 95%). [MNa]+=368.
Preparative Example 909




Step A

Commercially available (3-aminomethyl-benzyl)-carbamic acid tert-butyl ester (1.39 g) was treated similarly as described in the Preparative Example 907, Step A, except using a 2M solution of dimethylamine in THF instead of 30% aqueous methylamine to afford the title compound as black needles (632 mg, 88%). [MNa]+=382.
Preparative Examples 910-911
Following a similar procedure as described in the Preparative Example 7, Step C, except using the acids indicated in Table I-35 below, the following compounds were prepared.










TABLE I-35





Prep.





Ex. #
acid
product
yield







910








>99% [MH]+ = 308


 


911








 35% [MNa]+ = 356









Preparative Example 912




Step A

The title compound from the Preparative Example 39, Step C (500 mg) was treated similarly as described in the Preparative Example 17, Step A to afford the title compound (460 mg, 60%). [MNa]+=306.
Preparative Example 913




Step A

To a solution of the title compound from the Preparative Example 805, Step B (339 mg), 30% aqueous NH4OH (240 μL) and KCN (124 mg) in MeOH/H2O (2:1, 15 mL) was added NH4Cl (104 mg). The resulting mixture was stirred at 70° C. overnight, diluted with H2O and extracted with EtOAc (2×). The combined organic phases were washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to afford the crude title compound (330 mg, 86%). [MH]+=223.
Step B
To a solution of the title compound from Step A above (330 mg) in THF (10 mL) were subsequently added di-tert-butyl dicarbonate (487 mg) and NaHCO3 (249 mg). The resulting mixture was stirred at room temperature overnight, concentrated, diluted with EtOAc, washed with saturated aqueous NH4Cl and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to afford the title compound (385 mg, 85%). [MNa]+=345.
Step C
To a solution of the title compound from Step B above (385 mg) in MeOH/H2O (2:1, 15 mL) was added sodium perborate tetrahydrate (552 mg). The resulting mixture was stirred at 50° C. overnight, concentrated and diluted with EtOAc and saturated aqueous NH4Cl. The organic phase was separated, washed with H2O and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to afford the title compound (393 mg, 97%). [MNa]+=363.
Preparative Examples 914-946
Following a similar procedure as described in the Preparative Example 133, except using the protected amines indicated in Table I-36 below, the following compounds were prepared.










TABLE I-36





Prep.





Ex. #
protected amine
product
yield







914








>99% [M − Cl]+ =  148


 


915








>99% (over 3 steps) [M − Cl]+ = 148


 


916








>99%  [M − Cl]+ =  240


 


917








>99%  [M − Cl]+ =  191


 


918








>99%  [M − HCl2]+ =  194


 


919








>99%  [M − Cl]+ =  211


 


920








>99%  [M − NH3Cl]+ = 162


 


921








>99% [M − Cl]+ =  158


 


922








>99%  [M − Cl]+ =  156


 


923








 99% [M − Cl]+ =  192


 


924








 99%  [M − Cl]+ =  179


 


925








 99% [M − Cl]+ =  149


 


926








>99%  [M − Cl]+ =  156


 


927








n.d. [M − Cl]+ =  139


 


928








n.d. [M − Cl]+ =  175


 


929








 95% [M − Cl]+ =  176


 


930








>99%  [M − NH3Cl]+ =  162


 


931








>99%  [M − NH3Cl]+ = 176


 


932








>99%  [M − NH3Cl]+ =  190


 


933








>99%  [M − Cl]+ =  157


 


934








>99% [M − Cl]+ =  145


 


935








>99%  [M − Cl]+ =  207


 


936








>99% [M − Cl]+ =  221


 


937








>99% [M − Cl]+ = 184


 


938








>99% [M − Cl]+ =  241


 


939








 57% (over 3 steps) [M − NH3Cl]+ =  161


 


940








 37%  (over 2 steps) [M − NH3Cl]+ =  162


 


941








>99%  [M − Cl]+ =  198


 


942








>99%  [M − NH3Cl]+ =  184


 


943








>99%  [M − Cl]+ =  164


 


944








>99%  [M − Cl]+ =  192


 


945








>99%  [M − Cl]+ = 246


 


946








 88% [M − Cl]+ =  260









Preparative Example 947




A mixture of the title compound from the Preparative Example 852 (127 mg), Pd/C (10 wt %, 93 mg) and 50% aqueous AcOH (1 mL) in EtOH (5 mL) was hydrogenated at atmospheric pressure overnight, filtered and concentrated. The remaining residue was diluted with a 4M solution of HCl in 1,4-dioxane (3 mL), stirred at room temperature for 1 h and concentrated to afford the title compound as a white solid (148 mg, 93%). [M-NH3C1]+=148.
Preparative Examples 948-949
Following a similar procedure as described in the Preparative Example 947, except using the nitriles indicated in Table I-37 below, the following compounds were prepared.










TABLE I-37





Prep.





Ex. #
nitrile
product
yield







948








>99% [M − NH3Cl]+ = 156


 


949








 27% [M − NH3Cl]+ = 202









Preparative Examples 950-951
Following a similar procedure as described in the Preparative Example 214, except using the intermediates and amines indicated in Table I-38 below instead of the title compound from the Preparative Example 95, Step A and NH3, the following compounds were prepared.










TABLE I-38





Prep.





Ex. #
intermediate, amine
product
yield







950








n.d.  [M − Cl]+ =  264


 


951








50%  (over 3 steps) [M − Cl]+ =  264









Preparative Example 952




Step A

Commercially available 4-aminomethyl-benzoic acid methyl ester hydrochloride (500 mg) was dissolved in a 33% solution of NH3 in H2O (50 mL) and heated in a sealed pressure tube to 90° C. for 20 h. Cooling to room temperature and concentration afforded the title compound. [M-Cl]+=151.
Preparative Example 953




Step A

Commercially available 6-acetyl-4H-benzo[1,4]oxazin-3-one (2.36 g) was treated similarly as described in the Preparative Example 217, Step A to afford the title compound as a colorless fluffy needles (2.19 g, 86%). [MH]+=207.
Step B
The title compound from Step B above (888 mg) was treated similarly as described in the Preparative Example 217, Step B to afford the title compound as a colorless solid (163 mg, 32%). [MH]+=193.
Preparative Example 954




Step A

Commercially available 2-hydroxy-4-methylaniline (4.64 g) was treated similarly as described in the Preparative Example 213, Step A to afford the title compound as black needles (5.00 g, 89%).
Step B
A mixture of the title compound from Step A above (1.03 g) in acetic anhydride (20 mL) was heated to 80° C. for 2 h, concentrated, diluted with toluene (2×), concentrated (2×) and dried in vacuo to afford the title compound as brown crystals (1.32 g, >99%).
Step C
The title compound from Step A above (1.32 g) was treated similarly as described in the Preparative Example 213, Step C to afford the title compound as a white solid (496 mg, 38%). [MH]+=191.
Step D
The title compound from Step C above (1.32 g) was treated similarly as described in the Preparative Example 213, Step D to afford the title compound as white crystals (264 mg, >99%). [M-Cl]+=165.
Preparative Example 955




Step A

The title compound from Preparative Example 954, Step C (240 mg) was treated similarly as described in the Preparative Example 213, Step B to afford the title compound as a white solid (243 mg, 94%). [MI-1]+=205.
Step B
The title compound from Step A above (243 mg) was treated similarly as described in the Preparative Example 213, Step D to afford the title compound as a white solid (118 mg, 44%). [M-Cl]+=179.
Preparative Examples 956-957
Following a similar procedure as described in the Preparative Example 208, except using the protected amines indicated in Table I-39 below, the following compounds were prepared.










TABLE I-39





Prep. Ex. #
protected amine
product
yield







 


956








>99% [M − TFA]+ = 180


 


957








>99% [M − TFA]+ = 164









Preparative Examples 958-965
Following a similar procedure as described in the Preparative Example 7, Step D, except using the protected amines indicated in Table I-40 below, the following compounds were prepared.










TABLE I-40





Prep. Ex. #
protected amine
product
yield







958








58% [MH]+ = 208


 


959








20% [M − NH2]+ = 217


 


960








84% [MH]+ = 343


 


961








63% [MH]+ = 343


 


962








55% [MH]+ = 343


 


963








51% [MH]+ = 343


 


964








50% [MH]+ = 343


 


965








50% [MH]+ = 343









Preparative Example 966




Step A

A mixture of commercially available 4-bromomethyl-benzoic acid methyl ester (500 mg) and NaN3 (666 mg) in DMA (9 mL) was stirred at 60-70° C. (temperature of the oil bath) overnight, concentrated and diluted with Et2O (200 mL) and H2O (80 mL). The organic phase was separated, washed with H2O (2×80 mL), dried (MgSO4), filtered and concentrated to afford the title compound (375 mg, 90%). 1H-NMR (CDCl3) δ=8.03 (d, 2H), 7.39 (d, 2H), 4.40 (s, 2H), 3.90 (s, 3H).
Step B
A mixture of the title compound from Step A above (375 mg) and Pd/C (10 wt %, 150 mg) in MeOH (100 mL) was hydrogenated at atmospheric pressure for 1 h, filtered and concentrated to afford the title compound (291 mg, 90%). [MH]+=166.
Preparative Examples 967-968
Following a similar procedure as described in the Preparative Example 245, Step B, except using the aminopyrazoles indicated in Table I-41 below instead of 2-aminopyrazole, the following compounds were prepared.










TABLE I-41





Prep. Ex. #
aminopyrazole
product
yield







967








 6% [MH]+ = 312


 


968








13% [MH]+ = 318









Preparative Example 969




Step A

A mixture of title compound from the Preparative Example 262 (100 mg), di-tert.-butyl dicarbonate (182 mg) and DMAP (15 mg) in THF (2 mL) was stirred at room temperature for 3 h, concentrated and purified by chromatography (silica, hexanes/EtOAc) to afford title compound as yellow solid (84 mg, 68%). [MNa]+=318.
Step B
To a solution of the title compound from Step A (77 mg) in THF/MeOH (1:1, 2 mL) was added 1M aqueous LiOH (340 μL). The resulting mixture was stirred at room temperature for 2 h and then concentrated to afford the crude title compound, which was used without further purification (85 mg). [(M-Li)HNa]+=304.
Preparative Example 970




Step A

The title compound from the Preparative Example 262 (50 mg) was treated similarly as described in the Preparative Example 969, Step B to afford the title compound. [(M−]′=224.
Preparative Example 971




Step A

To the title compound from the Preparative Example 278, Step A (462 mg) in CHCl3 (5 mL) was added N-iodosuccinimide (277 mg). The resulting mixture was heated to reflux for 16 h, concentrated and purified by chromatography (silica, hexanes/EtOAc) to afford the title compound (587 mg, >99%). [MNa]+=599.
Preparative Example 972




Step A

The title compound from the Preparative Example 971, Step A (520 mg), Pd(OAc)2 (20 mg), dppf (200 mg) and KOAc (354 mg) were dissolved in dry DMSO (5.4 mL) and stirred at 60° C. under a carbon monoxide atmosphere at 1 atm for 16 h. The mixture was diluted with EtOAc, washed subsequently with 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated. Purification by chromatography (silica, CH2Cl2/MeOH) afforded the title compound as a yellow solid (391 mg, 88%). [M-H]−=588.
Preparative Example 973




Step A

The title compound from the Preparative Example 288 (210 mg) in CHCl3 (5 mL) was added N-iodosuccinimide (167 mg). The resulting mixture was stirred at 70° C. for 1 h, absorbed onto silica and purified by chromatography (silica, hexanes/EtOAc) to afford the title compound (365 mg, 97%). [MH]+=473.
Preparative Example 974




Step A

The title compound from the Preparative Example 973, Step A (95 mg), Pd(OAc)2 (4.5 mg), dppf (45 mg) and KOAc (79 mg) were dissolved in dry DMSO (1.5 mL) and stirred at 60° C. under a carbon monoxide atmosphere at 1 atm for 4 h. The mixture was diluted with EtOAc, washed subsequently with 1N aqueous HCl (2×) and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to afford the crude title compound, which was use with out further purification (92 mg). [MH]+=391.
Preparative Example 975




Step A

A mixture of commercially available 5-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.45 g) and Pd/C (10 wt %, 106 mg) in MeOH (25 mL) was hydrogenated at 25 psi for 2 h, filtered through Celite® and concentrated to afford the title compound (1.25 g, 88%). [MH]+=142.
Step B
A mixture of the title compound from Step A above (325 mg) and methyl acetopyruvate (330 mg) in MeOH (10 mL) was heated to reflux for 2 h and then cooled to room temperature. The formed precipitate was collected by filtration and dried to afford the title compound as a white solid (356 mg, 62%). [MH]+=250.
Step C
To a solution of the title compound from Step B above (229 mg) in 1,4-dioxane/MeOH (5:1, 12 mL) was added 1M aqueous NaOH (1 mL). The resulting mixture was stirred at room temperature overnight and then acidified. The formed precipitate was collected by filtration to afford the crude title compound as a white solid. (177 mg, 38%). [MH]+=236.
Step D
The title compound from Step C above (172 mg) was treated similarly as described in the Preparative Example 280, Step A to afford the title compound (171 mg, 65%). [MH]+=361.
Step E
The title compound from Step D above (151 mg) was treated similarly as described in the Preparative Example 274, Step D to afford the title compound. [MH]+=391.
Preparative Examples 976-982
Following similar procedures as described in the Preparative Examples 279 (method A), 280 (method B), 281 (method C), 278 (method D) or 282 (method E), except using the acids and amines indicated in Table I-42 below, the following compounds were prepared.










TABLE I-42





Prep. 


method, 


Ex. #
acid, amine
product
yield







976








E, 68% [MNa]+ =  435


 


977








E, 67% [M − H]− = 602


 


978








E, 95% [MH]+ =  382


 


979








E, 84% [MH]+ =  221


 


980








B, 42% (over 2 steps) [M − H]− = 500


 


981








A, n.d. [MH]+ =  387


 


982








A, n.d. [MH]+ = 444









Preparative Examples 983-986
Following a similar procedure as described in the Preparative Example 328, Step A, except using the esters and nucleophiles indicated in Table I-43 below, the following compounds were prepared.










TABLE I-43





Prep. Ex. #
ester, nucleophile
product
yield







983








39% [MH]+ = 423


 


984








32% [MH]+ = 429


 


985








80% [MH]+ = 298


 


986








94% [MH]+ = 304









Preparative Examples 987-993
Following similar procedures as described in the Preparative Examples 331 (method A), 332 (method B) or 333 (method C), except using the esters indicated in Table I-44 below, the following compounds were prepared.










TABLE I-44





Prep. 


method, 


Ex. #
ester
product
yield







987








A, >99% [MH]+ = 207


 


988








B, n.d. [MH]+ = 376


 


989








B, 99% [MH]+ = 486


 


990








C, 70% [MH]+ = 409


 


991








C, 67% [MH]+ = 415


 


992








A, n.d. [MH]+ = 373


 


993








A, n.d. [MH]+ = 430









Preparative Example 994




Step A

The title compound from the Preparative Example 976 was treated similarly as described in the Preparative Example 373 to afford the title compound (>99%). [MH]+=357
Preparative Examples 995-996
Following a similar procedures as described in the Preparative Example 324, Step A, except using the esters and amines indicated in Table I-45 below, the following compounds were prepared.










TABLE I-45





Prep. Ex. #
ester, amine
product
yield







995








74% [MH]+ = 409


 


996








87% [MH]+ = 415









Preparative Example 997




Step A

A mixture of the title compound from the Preparative Example 339 (50 mg) and HSO3Cl (500 μL) was stirred at 90° C. for 1 h, cooled and the cautiously poured onto ice (5 g). The formed precipitate was collected by filtration, dried in vacuo and then added to a premixed solution of acetyl chloride (100 μL) in MeOH (1 mL). The resulting mixture was stirred at 40° C. for 1 h and concentrated to afford the title compound (42 mg, 65%). [M-H]−=425.
Preparative Example 998




Step A

A mixture of the title compound from the Preparative Example 339 (168 mg) and HSO3Cl (2 mL) was stirred at 90° C. for 2 h, cooled and the cautiously poured onto ice (15 g). The formed precipitate was collected by filtration, dried in vacuo and then added to solution of commercially available 2-chloroaniline (100 μL) in CHCl3 (5 mL). The resulting mixture was stirred at 70° C. for 18 h, concentrated and purified by chromatography (silica) to afford a residue containing the title compound (9 mg). [M-H]−=519.
Preparative Example 999




Step A

At 100° C. N,N-dimethylformamide di-tert-butyl acetal (3.6 mL) was added to a solution of commercial available pyridine-2,5-dicarboxylic acid 5-methyl ester (1.36 g) in dry toluene (10 mL). The mixture was stirred at 100° C. for 3 h, cooled to room temperature, concentrated, diluted with EtOAc (20 mL), washed with water (20 mL) and saturated aqueous NaCl (10 mL), dried (MgSO4), filtered and concentrated to afford the crude title compound (726 mg, 40%). [MH]+=238.
Step B
Using a microwave, a mixture of the title compound from Step A above (600 mg) and trimethyltin hydroxide (1.35 mg) in 1,2-dichloroethane (20 mL) was heated at 100° C. for 1 h. The mixture was cooled to room temperature, diluted with CHCl3 (30 mL), washed with 10% aqueous KHSO4 (20 mL) and saturated aqueous NaCl (20 mL), dried (MgSO4), filtered and concentrated to afford the crude title compound (307 mg, 55%). [MH]+=224.
Preparative Example 1000




Step A

A mixture of the commercial available trans-dimethylcyclohexane-1,4-dicarboxylate (1 g) and KOH (300 mg) in THF/H2O (10:1, 30 mL) was stirred at 100° C. overnight, cooled to room temperature and concentrated. The residue was diluted with EtOAc and adjusted to pH 1-2 with 1N aqueous HCl and extracted with EtOAc (3×50 mL). The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound (820 mg, 88%). [MH]+=187.
Preparative Example 1001




Step A

Using a microwave, a suspension of commercially available 4-bromo-3-methyl-benzoic acid methyl ester (1.5 g) and CuCN (490 mg) in dry N-methyl-pyrrolidin-2-one (10 mL) was heated at 230° C. for 10 h. The mixture was cooled to room temperature, diluted with 35% aqueous NH3 (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated aqueous NaCl (200 mL), dried (MgSO4), filtered and concentrated to afford the title compound as a solid (590 mg, 67%). [MH]+=176.
Step B
To a solution of the title compound from Step A above (590 mg) in THF/MeOH (2:1, 60 mL) was added 1M aqueous LiOH (10 mL). The resulting mixture was stirred at room temperature for 2 h, adjusted to pH 2 and concentrated to afford the crude title compound as a solid, which was used without further purification (540 mg, 99%). [MH]+=162.
Preparative Examples 1002-1007
Following a similar procedure as described in the Preparative Example 805, Step A, except using the intermediates indicated in Table I-46 below, the following compounds were prepared.










TABLE 1-46





Prep. Ex. #
intermediate
product
yield







1002








52% [MH]+ = 210


 


1003








57% [MH]+ = 168


 


1004








51% [MH]+ = 199


 


1005








52% [MH]+ = 173


 


1006








61% [MH]+ = 148


 


1007








18% [MH]+ = 188









Preparative Examples 1008-1013
Following a similar procedure as described in the Preparative Example 805, Step B, except using the intermediates indicated in Table I-47 below, the following compounds were prepared.










TABLE I-47





Prep. Ex. #
intermediate
product
yield







1008








99% [MH]+ = 208


 


1009








99% [MH]+ = 166


 


1010








92% [MH]+ = 197


 


1011








95% [MH]+ = 171


 


1012








95% [MH]+ = 146


 


1013








87% [MH]+ = 186









Preparative Example 1014




Step A

To an ice cooled (0-5° C.) suspension of commercially available 4-bromo-2-methylbenzoic acid (3.22 g) in MeOH (60 mL) was dropwise added thionyl chloride (3.2 mL). The ice bath was removed and the mixture was stirred at room temperature for 12 h. The mixture was concentrated, diluted with EtOAc (20 mL), washed with H2O (20 mL) and saturated aqueous NaCl (10 mL), dried (MgSO4), filtered and concentrated to afford the title compound as a solid (2.94 g, 86%). [MH]+=230.
Step B
Using a microwave, a mixture of the title compound from Step A above (1.37 g), Pd(PPh3)4 (135 mg) and tributyl(vinyl)tin (2.1 mL) in 1,4-dioxane (15 mL) was heated at 120° C. for 5 h. The mixture was cooled to room temperature and Florisil® was added. The resulting mixture was allowed to stand for 2 h and then filtered. The filter cake was washed with H2O and EtOAc. The combined filtrates were washed with H2O (20 mL) and saturated aqueous NaCl (20 mL), dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/acetone) to afford the title compound (800 mg, 75%). [MH]+=177.
Step C
A slow flow of ozone was passed through a cooled (−78° C.) solution of the title compound from Step B above (627 mg) in CHCl3 (50 mL) over a period of 20 min. The mixture was purged with nitrogen and dimethylsulfide (1 mL) was added. The resulting mixture was stirred at −78° C. for 1 h, allowed to warm to room temperature, concentrated and purified by chromatography (silica, CH2Cl2/acetone) to afford the title compound (570 mg, 90%). [MH]+=179.
Preparative Example 1015




Step A

To an ice cooled (0-5° C.) mixture of commercially available L-prolinamide (25 g), NEt3 (30 mL) and DMAP (1.9 g) in CH2Cl2 (1.2 L) was added fumaryl chloride (11.7 ml). The ice bath was removed and the resulting dark mixture was stirred at room temperature for 16 h. The mixture was cooled again to 0-5° C. (ice bath), trifluoroacetic anhydride (77 mL) was dropwise added and the resulting mixture was stirred for 2 d while warming to room temperature. Ice (500 g) was added followed by cautious addition of saturated aqueous NaHCO3 (600 mL). After the evolution of gas had ceased, the organic phase was separated and washed with saturated aqueous NaHCO3 (350 mL), H2O (350 mL) and saturated aqueous NaCl (200 mL), dried (MgSO4), filtered and concentrated to afford the title compound (28.6 g, 98%). 1H-NMR (CDCl3) δ=7.26 (s, 2H), 4.72-4.83 (m, 2H), 3.73-3.89 (m, 2H), 3.58-3.69 (m, 2H), 2.12-2.30 (m, 8H).
Step B
A slow flow of ozone was passed through a cooled (−78° C.) solution of the title compound from Step A above (9.6 g) in CHCl3/MeOH (1:1, 180 mL) over a period of 3 h. The mixture was purged with nitrogen and dimethylsulfide (6 mL) was added. The resulting mixture was stirred at −78° C. for 1 h, allowed to warm to room temperature, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a −9:1 mixture of the corresponding methoxy hemiacetal and the free aldehyde (8.9 g, 69%). 1H-NMR (D2O) δ=7.90 (s, 1/10H), 5.50 (s, 9/10H), 4.72-4.81 (m, 1H), 3.60-3.84 (m, 2H), 3.32 (s, 3H), 2.10-2.38 (m, 4H).
Preparative Example 1016




Step A

To an ice cooled (0-5° C.) mixture of commercially available thiazolidine (1 g), NEt3 (780 μL) and DMAP (136 mg) in CH2Cl2 (56 mL) was added fumaryl chloride (604 μl). The ice bath was removed and the resulting dark mixture was stirred at room temperature overnight, filtered and concentrated to afford the crude title compound (2.69 g, 98%). [MH]+=259.
Step B
A slow flow of ozone was passed through a cooled (−78° C.) solution of the title compound from Step A above (833 mg) in CH2Cl2/MeOH (1:1, 16 mL) over a period of 45 min. The mixture was purged with nitrogen and dimethylsulfide (1.2 mL) was added. The resulting mixture was stirred at −78° C. for 1 h, allowed to warm to room temperature, concentrated and purified by chromatography (silica, EtOAc/MeOH) to afford the title compound (293 mg, 23%).
Preparative Example 1017




Step A

Commercially available 4-formyl-benzenesulfonyl chloride (70 mg) was suspended in 1M aqueous HCl (3 mL) and stirred at room temperature for 2 h and then concentrated to afford the title compound, which was used without further purification.
Preparative Example 1018




Step A

To a solution of commercially available trans-cyclobutane-1,2-dicarboxylic acid (1.5 g) in MeOH (50 mL) was added thionyl chloride (2.3 mL). The resulting mixture was heated to reflux for 2 h and then concentrated to afford the title compound as a yellow liquid (1.79 g, >99%). 1H-NMR (CDCl3) δ=3.67 (s, 6H), 3.33-3.43 (m, 2H), 2.11-2.19 (m, 4H).
Preparative Example 1019




Step A

To a solution of commercially available trans-cyclopropane-1,2-dicarboxylic acid (1.0 g) in MeOH/H2O (10:1, 7.7 mL) was added KOH (354 mg). The resulting mixture was stirred at room temperature for 6 h, diluted with H2O (40 mL), washed with cyclohexane (2×30 mL), acidified to pH ̃1 with a 1M aqueous HCl and extracted with EtOAc (3×40 mL). The combined organic phases were dried (MgSO4), filtered and concentrated to afford the title compound as a colorless oil (685 mg, 75%). 1H-NMR (CDCl3) δ=3.70 (s, 3H), 2.11-2.27 (m, 2H), 1.43-1.52 (m, 2H).
Preparative Examples 1020-1021
Following a similar procedure as described in the Preparative Example 1019, except using the bisesters indicated in Table I-48 below, the following compounds were prepared.










TABLE I-48





Prep. Ex. #
bisester
product
yield







1020








80% 1H-NMR (CDCl3) δ = 3.70 (s, 3 H), 2.06-2.15 (m, 2 H), 1.63-1.73 (m, 1 H), 1.30-1.40 (m, 1 H).


 


1021








69% 1H-NMR (CDCl3) δ = 3.70 (s, 3 H), 3.38-3.48 (m, 2 H), 2.15-2.23 (m, 4 H).









Preparative Example 1022




Step A

To a suspension of commercially available phthalic acid monomethyl ester (900 mg) in toluene (6 mL) were added DMF (1 drop) and thionyl chloride (2.3 mL). The resulting mixture was heated at 95° C. (temperature of the oil bath) for 11⁄2 h, concentrated and dried in vacuo to afford the title compound as a pale yellow oil (964 mg, 97%). 1H-NMR (CDCl3) δ=7.81-7.87 (m, 1H), 7.72-7.76 (m, 1H), 7.58-7.64 (m, 2H), 3.91 (s, 3H).
Preparative Examples 1023-1026
Following a similar procedure as described in the Preparative Example 1022, except using the acids indicated in Table I-49 below, the following compounds were prepared.










TABLE I-49





Prep. Ex. #
acid
product
yield







1023








92% 1H-NMR (CDCl3) δ = 8.73 (t, 1 H), 8.32 (dt, 1 H), 8.27 (dt, 1 H), 7.60 (t, 1 H), 3.92 (s, 3 H).


 


1024








87% 1H-NMR (CDCl3) δ = 3.74 (s, 3 H), 2.58-2.68 (m, 1 H), 2.38-2.48 (m, 1 H), 1.54-1.70 (m, 2 H).


 


1025








91% 1H-NMR (CDCl3) δ = 3.75 (s, 3 H), 2.58-2.68 (m, 1 H), 2.27-2.37 (m, 1 H), 1.85-1.95 (m, 1 H), 1.40-1.50 (m, 1 H).


 


1026








91% 1H-NMR (CDCl3) δ = 3.84 (q, 1 H), 3.72 (s, 3 H), 3.84 (q, 1 H), 2.10-2.38 (m, 4 H).









Preparative Example 1027




Step A

To a solution of commercially available tert-butylamine (66 μL) in pyridine (3 mL) was added the title compound from the Preparative Example 1024 (100 mg). The resulting mixture was stirred at room temperature overnight, concentrated and diluted with EtOAc (40 mL) and H2O (15 mL). The organic phase was separated, washed with 1M aqueous HCl (15 mL) and H2O (15 mL), dried (MgSO4), filtered and concentrated to afford the title compound as a yellow oil (67.6 mg, 55%). [MH]+=200.
Step B
The title compound from Step A above (67.6 mg) in THF/H2O (1:1, 6 mL) was added a 1M aqueous KOH (680 μL). The mixture was stirred at room temperature overnight. Additional 1M aqueous KOH (680 μL) was added and stirring at room temperature was continued for 4 h. The mixture was concentrated, acidified to pH ̃1 with a 1M aqueous HCl and extracted with EtOAc (3×20 mL). The combined organic phases were dried (MgSO4), filtered and concentrated to afford the title compound as a white solid (60 mg, 95%). [α]+=186.
Preparative Examples 1028-1029
Following a similar procedure as described in the Preparative Example 1027, except using the acids indicated in Table I-50 below, the following compounds were prepared.










TABLE I-50





Prep. Ex. #
acid
product
yield







1028








59% [MH]+ = 174


 


1029








37% [MH]+ = 186









Preparative Example 1030




Step A

To a solution of potassium 1,1,1,3,3,3-hexamethyl-disilazane (3.29 g) in DMF (40 mL) was added a solution of commercially available (4-bromo-phenyl)-acetic acid ethyl ester (3.6 g) in DMF (10 mL). The resulting mixture was stirred at room temperature for 10 min, before bromoacetaldehyde diethylacetal (3.25 g) was added dropwise. After complete addition the mixture was heated at 45° C. for 1 h, cooled (ice bath), diluted with saturated aqueous NH4Cl (5 mL) and ice water (45 mL) and extracted with cyclohexane (3×50 mL). The combined organic phases were concentrated, suspended in H2O (7.5 mL) and cooled to 0-5° C. (ice bath). A 1:1 mixture of trifluoroacetic acid and CHCl3 (45 mL) was added and the mixture was stirred for 2 h. The mixture was poured into a mixture of 1M aqueous K2CO3 (115 mL) and CH2Cl2 (200 mL) and the pH was adjusted to pH ̃7.5 by addition of solid K2CO3. The organic phase was separated and the aqueous phase was extracted with CH2Cl2 (120 mL). The combined organic phases were washed with H2O (200 mL) and saturated aqueous NaCl (200 mL), dried (MgSO4), filtered, concentrated and purified by chromatography (silica, petroleum ether/EtOAc) to afford the title compound (3.35 g, 79%). 1H-NMR (CDCl3) δ=9.77 (s, 1H), 7.43-7.51 (m, 2H), 7.13-7.22 (m, 2H), 4.02-4.25 (m, 3H), 3.36 (dd, 1H), 2.78 (dd, 1H), 1.20 (t, 3H).
Preparative Example 1031




Step A

Commercially available phenyl-acetic acid ethyl ester was treated similarly as described in the Preparative Example 1030, Step A to afford the title compound (88%). 1H-NMR (CDCl3)=9.78 (s, 1H), 7.21-7.38 (m, 5H), 4.02-4.25 (m, 3H), 3.39 (dd, 1H), 2.80 (dd, 1H), 1.20 (t, 3H).
Preparative Example 1032




Step A

The title compound from the Preparative Example 378, Step A (4 g) was added in portions to an ice cooled mixture of 90% HNO3 (8 mL) and 65% HNO3 (4 mL). After complete addition, conc. H2SO4 (13.6 mL) was added slowly keeping the reaction temperature below 12° C. After the complete addition, the mixture was stirred at 0-5° C. (ice bath) for 2 h. The obtained clear yellow solution was then poured onto a mixture of ice (30 g) and H2O (60 mL). The formed precipitate was collected by filtration, washed with H2O (160 mL) and dried in vacuo to afford the title compound as a yellow solid (4.78 g, 89%). 1H-NMR (DMSO-d6) δ=13.50 (s, 1H), 12.58 (s, 1H), 8.52 (d, 1H), 8.10 (s, 1H).
Step B
The title compound from Step A above (4.78 g) was grinded in a mortar and added at 110-115° C. in portions to neat POBr3 (40 g). The obtained mixture was stirred at 110-115° C. overnight, cooled to 0-5° C. (ice bath) and hydrolyzed by careful addition with ice water (450 mL). The mixture was adjusted to pH-8 by careful addition of solid NaHCO3 and then extracted with EtOAc (6×400 mL). The combined organic phase was dried (MgSO4), filtered and concentrated to afford the title compound (1.30 g, 20%). [MH]+=243/245. The remaining aqueous phase was acidified (pH  ̃1) by addition of 37% HCl. The formed precipitate was collected by filtration, washed with H2O and dried in vacuo to afford a solid residue (2.7 g) containing a mixture of the title compound (70%) and the unreacted title compound from Step A (30%).
Step C
To a slurry of a mixture (2.7 g) of the title compound from Step B above (70%) and the title compound from Step A (30%) in MeOH/DMA (60:40, 125 mL) and MeOH (75 ml) was added NEt3 (3.5 mL). The resulting mixture was sonicated for 25 min while a stream of N2 was passed through the mixture. Pd(OAc)2 (130 mg) and dppf (252 mg) were added and the mixture was stirred at 80° C. under a carbon monoxide atmosphere at 6.5 bar until the bromo starting material was consumed. The mixture was filtered and the filter cake was washed with MeOH. The combined filtrate concentrated in vacuo, coated on silica and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as an orange solid (1 g, 41%). [MH]+=223.
Preparative Example 1033




Step A

A mixture of the title compound from the Preparative Example 1032, Step C (832 mg) and Pd/C (10 wt %, 300 mg) in MeOH (80 mL) was hydrogenated at atmospheric pressure for 30 min, filtered and concentrated to afford the title compound as a red solid residue (719 mg, >99%). [MH]+=193.
Preparative Example 1034




Step A

A mixture of the title compound from the Preparative Example 1033, Step A (540 mg), di-tert-butyl dicarbonate (590 mg) and NEt3 (400 μL) in THF/ACN (1:1, 24 mL) was stirred at room temperature overnight, concentrated, coated on silica and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a yellow solid (300 mg, 32%). [MH]+=293.
Preparative Example 1035




Step A

A mixture of the title compound from the Preparative Example 1033, Step A (100 mg), acetyl chloride (32 μL) and NEt3 (67 μL) in THF/ACN (1:1, 100 mL) was stirred at room temperature overnight, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as an orange solid (58.5 mg, 55%). [MH]+=235.
Preparative Examples 1036-1039
Following a similar procedure as described in the Preparative Example 1035, except using the acid chlorides indicated in Table I-51 below, the following compounds were prepared.










TABLE I-51





Prep. Ex. #
acid chloride
product
yield







1036








n.d. [MH]+ = 297


 


1037








n.d. [MH]+ = 355


 


1038








n.d. [MH]+ = 355


 


1039








n.d. [MH]+ = 355









Preparative Example 1040




Step A

A mixture of the title compound from the Preparative Example 1034, Step A (50 mg) in a 4M solution of HCl in 1,4-dioxane (1 mL) was stirred at room temperature for 1 h and then concentrated. The remaining residue was added to solution of NaBH3CN (25 mg) in THF/MeOH (1:1, 1 mL). To the resulting solution was slowly added a solution of the title compound from the Preparative Example 1030, Step A (50 mg) in THF/MeOH (1:1, 1 mL) over a period of 2 h. Then the mixture was concentrated, diluted with saturated aqueous NaHCO3 and extracted with EtOAc (3×). The combined organic phases were dried (MgSO4), filtered, absorbed onto silica and purified by chromatography (silica) to afford the title compound (23 mg, 28%). [MH]+=461/463.
Step B
To an ice cooled (0-5° C.) solution of the title compound from Step A above (13 mg) in THF (1 mL) was added a 1M solution of tert.-butyl magnesium chloride (60 μL). The resulting mixture was stirred at 0-5° C. (ice bath) for 11⁄2 h, diluted with saturated aqueous NaHCO3 and extracted with EtOAc (3×). The combined organic phases were dried (MgSO4), filtered, concentrated and purified by preparative thin layer chromatography (silica, EtOAc) to afford the title compound as a brown solid (7 mg, 60%). [MH]+=429/431.
Preparative Example 1041




Step A

To a solution of the title compound from the Preparative Example 1034, Step A (150 mg) in THF/ACN/H2O (1:1:1, 12.9 mL) was added a 1M aqueous KOH (770 μL). The mixture was stirred at room temperature for 1 h, concentrated and dried in vacuo to afford the title compound (162 mg, >99%). [(M-K)H2]+=279.
Preparative Examples 1042-1046
Following a similar procedure as described in the Preparative Example 1041, except using the esters indicated in Table I-52 below, the following compounds were prepared.










TABLE I-52





Prep. 





Ex. #
ester
product
yield







1042








n.d. [(M − K)H2]+ =  221.


 


1043








n.d. [(M − K)H2]+ =  283


 


1044








n.d. [(M − K)H2]+ =  341


 


1045








n.d. [(M − K)H2]+ = 341


 


1046








n.d. [(M − K)H2]+ = 401/403









Preparative Example 1047




Step A

To a solution of the title compound from the Preparative Example 1038 (24.6 mg) in THF/ACN/H2O (1:1:1, 1.8 mL) was added a 1M aqueous KOH (69 μL). The mixture was stirred at room temperature for 1 h, concentrated and dried in vacuo to afford a −1:1 mixture of the carboxylate I ([(M-K)H2]+=341) and the carboxylate II ([(M-K2)H3]+=327).
Preparative Example 1048




Step A

The title compound from the Preparative Example 376, Step E (400 mg) was treated similarly as described in the Preparative Example 279, Step A, except using the title compound from the Preparative Example 7, Step D (500 mg) instead of the title compound from the Preparative Example 214, Step A to afford the title compound (287 mg, 33%). [MH]+=430.
Step B
The title compound from Step A above (287 mg) was treated similarly as described in the Preparative Example 331, Step A to afford the title compound (260 mg, 94%). [α]+=416.
Step C
The title compound from Step B above (260 mg) was treated similarly as described in the Preparative Example 280, Step A, except using a commercially available 0.5M solution of NH3 in 1,4-dioxane instead of the title compound from the Preparative Example 138 to afford the title compound (196 mg, 76%). [MH]+=415.
Step D
The title compound from Step C above (196 mg) was treated similarly as described in the Preparative Example 377, Step D to afford the title compound (113 mg, 61%). [MH]+=397.
Step E
The title compound from Step D above (113 mg) was treated similarly as described in the Preparative Example 377, Step E to afford the title compound (110 mg, 98%). [MH]+=409.
Preparative Example 1049




Step A

The title compound from the Preparative Example 376, Step E (2.93 g) was treated similarly as described in the Preparative Example 279, Step A, except using the title compound from the Preparative Example 161 (3.35 g) instead of the title compound from the Preparative Example 214, Step A to afford the title compound (1.89 g, 36%). (MH)+=361.
Step B
The title compound from Step A above (1.89 g) was treated similarly as described in the Preparative Example 331, Step A to afford the crude title compound (2.0 g). [MH]+=347.
Step C
The crude title compound from Step B above (2.0 g) was treated similarly as described in the Preparative Example 280, Step A, except using a commercially available 0.5M solution of NH3 in 1,4-dioxane instead of the title compound from the Preparative Example 138 to afford the crude title compound (5.0 g). [MH]+=346.
Step D
The crude title compound from Step C above (4.6 g) was treated similarly as described in the Preparative Example 377, Step D to afford the title compound (233 mg, 5% over 3 steps). [MH]+=328.
Step E
The title compound from Step D above (233 mg) was treated similarly as described in the Preparative Example 377, Step E to afford the title compound (245 mg, 96%). [MH]+=340.
Preparative Example 1050




Step A

The title compound from the Preparative Example 376, Step E (1.19 g) was treated similarly as described in the Preparative Example 279, Step A, except using commercially available 4-fluoro-3-trifluoromethyl-benzylamine instead of the title compound from the Preparative Example 214, Step A to afford the title compound (1.42 g, 64%). [MH]+=376.
Step B
The title compound from Step A above (1.42 g) was treated similarly as described in the Preparative Example 331, Step A to afford the crude title compound (1.36 g, 99%). [MH]+=347.
Step C
The title compound from Step B above (1.36 g) was treated similarly as described in the Preparative Example 280, Step A, except using a commercially available 0.5M solution of NH3 in 1,4-dioxane instead of the title compound from the Preparative Example 138 to afford the crude title compound (969 mg, >99%). [MH]+=361.
Step D
The crude title compound from Step C above (969 mg) was treated similarly as described in the Preparative Example 377, Step D to afford the title compound (152 mg, 24%). [MH]+=343.
Step E
The title compound from Step D above (110 mg) was treated similarly as described in the Preparative Example 377, Step E to afford the title compound (123 mg, >99%). [MH]+=355.
Preparative Example 1051




Step A

The title compound from Preparative Example 377, Step D (22 mg) was treated similarly as described in the Preparative Example 377, Step E, except using commercially available methylhydrazine instead of hydrazine to afford the title compound (26 mg, >99%). [MH]+=335.
Example 1




Step A

To a solution of the title compound from the Preparative Example 335 (40 mg) in DMF (2 mL) were added the title compound from the Preparative Example 4, Step B (34 mg), PyBOP (84 mg) and iPr2NEt (46 μL). The mixture was stirred overnight, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (23 mg, 40%). 1H-NMR (CDCl3) δ=10.50 (br d, 1H), 9.00 (s, 1H), 8.85 (s, 1H), 8.30 (br t, 1H), 7.95 (s, 1H), 7.90 (d, 2H), 7.40 (d, 2H), 7.25-7.10 (m, 2H), 6.95 (m, 1H), 5.80 (m, 1H), 4.65 (d, 2H), 3.90 (s, 3H), 3.20-2.70 (m, 3H), 2.25 (s, 3H), 2.20-2.00 (m, 1H).
Example 2




Step A

To a solution of the title compound from the Preparative Example 373, Step A (30 mg) and the title compound from the Preparative Example 228, Step A (30 mg) in DMF (3 mL) were added N-methylmorpholine (40 μL), EDCI (25 mg) and HOAt (13 mg). The mixture was stirred overnight and then concentrated. The remaining residue was dissolved in EtOAc, washed with saturated NaHCO3, 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a colorless solid (35 mg, 90%). [MH]+=553.
Example 3




Step A

To a solution of the title compound from the Preparative Example 331, Step A (31 mg) and the title compound from the Preparative Example 218, Step D (27 mg) in DMF (5 mL) were added N-methylmorpholine (13 μL), HATU (57 mg) and HOAt (16 mg). The mixture was stirred overnight and then concentrated. The remaining residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3, 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a colorless solid (57 mg, >99%). [MH]+=520.
Example 4




Step A

To a solution of the title compound from the Preparative Example 349 (21.5 mg) in DMF (3 mL) were added cyclohexanemethylamine (30 μL), PyBrOP (29 mg) and HOAt (8 mg). The mixture was stirred over the weekend and then concentrated. The remaining residue was dissolved in CHCl3, washed with saturated aqueous NaI-1CO3, 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by preparative thin layer chromatography (silica, CH2Cl2/MeOH) to afford the title compound as an off-white solid (11.9 mg, 46%). [MH]+=543.
Example 5




Step A

To a mixture of the title compound from the Preparative Example 324, Step A (106 mg), DMF (20 mL) and CH2Cl2 (2.5 mL) at 0° C. was added oxalyl chloride (116 μL). The ice bath was removed and the mixture was stirred for 45 min and concentrated. The resulting residue was brought up in CH2Cl2 (1.5 mL) and cannulated into a mixture of the title compound from the Preparative Example 176, Step A (75 mg) and NEt3 (122 μL) in CH2Cl2 (1 mL). The resulting mixture was stirred for 16 h and concentrated. The remaining solid was washed with MeOH (10 mL). The supernatant was concentrated and the resulting solid was washed with MeOH (10 mL). The yellow solids were combined to give the title compound (51 mg, 33%). [M-H]′=588.
Example 6




Step A

To a mixture of N-cyclohexyl-carbodiimide-N′-methyl-polystyrene (43 mg) in DMF (100 μL) were added a 0.2M solution of the title compound from the Preparative Example 331, Step A in DMF (150 μL) and a 0.5M solution of HOBt in DMF (60 μL). The mixture was agitated for 30 min, then a 0.5M solution of (1,1-dioxidotetrahydrothien-3-yl)-methylamine in DMF (54 μL) was added and agitation at room temperature was continued for 12 h. The mixture was filtered, concentrated and dissolved in 1,2-dichloroethane (200 μL). (Polystyrylmethyl)-trimethylammonium bicarbonate (16 mg) was added and the mixture was agitated at room temperature for 2 h. Filtration and concentration afforded the title compound (13.1 mg, 95%). [MH]+=461.
Example 7




Step A

To a mixture of polystyrene-IIDQ (131 mg) in DMF (800 μL) were added the title compound from the Preparative Example 331, Step A (39 mg) and a 0.5M solution of commercially available 4-aminomethyl-benzoic acid (40 mg). The mixture was agitated for 24 h, filtered and concentrated to afford the title compound (40 mg, 73%). [MH]+=463.
Examples 8-277
Following similar procedures as described in the Examples 1 (method A), 2 (method B), 3 (method C), 4 (method D), 5 (method E), 6 (method F) or 7 (method G), except using the acids and amines indicated in Table II-1 below, the following compounds were prepared.










TABLE II-1





Ex. #
acid, amine
product
method, yield







 8








B, 90% [MH]+ = 579


 


 9








B, 80% [MH]+ = 644


 


 10








B, 86% [MH]+ = 698


 


 11








B, >99% [MH]+ = 645


 


 12








B, 98% [MH]+ = 542


 


 13








B, >99% [MH]+ = 594


 


 14








B, 95% [MH]+ = 582


 


 15








B, >99% [MH]+ = 596


 


 16








B, n.d. [MH]+ = 577


 


 17








B, n.d. [MH]+ = 560


 


 18








B, n.d. [MH]+ = 566


 


 19








B, n.d. [MH]+ = 536


 


 20








B, n.d. [MH]+ = 536


 


 21








B, n.d. [MH]+ = 591


 


 22








B, n.d. [MH]+ = 556


 


 23








B, n.d. [MH]+ = 596


 


 24








B, 92% [MH]+ = 483


 


 25








B, 85% [MH]+ = 502


 


 26








B, 79% [MH]+ = 606


 


 27








B, 88% [MH]+ = 592


 


 28








B, 95% [MH]+ = 599


 


 29








B, 18% [MH]+ = 489


 


 30








B, 95% [MH]+ = 595


 


 31








B, 41% [MH]+ = 385


 


 32








B, 87% [MH]+ = 539


 


 33








B, 45% [MH]+ = 507


 


 34








B, 77% [MH]+ = 481


 


 35








B, 65% [MH]+ = 399


 


 36








B, 35% [MH]+ = 413


 


 37








B, 97% [MH]+ = 547


 


 38








B, 84% [MH]+ = 581


 


 39








B, 81% [MH]+ = 612


 


 40








B, 85% [MH]+ = 578


 


 41








B, n.d. % [MH]+ = 554


 


 42








B, 68% [MH]+ = 560


 


 43








C, 95% [MH]+ = 543


 


 44








C, 56% [MH]+ = 468


 


 45








D, >99% [MH]+ = 557


 


 46








D, 47% [MH]+ = 590


 


 47








D, >99% [MH]+ = 521


 


 48








D, >99% [MH]+ = 507


 


 49








D, 76% [MH]+ = 501


 


 50








D, >99% [MH]+ = 519


 


 51








D, 30% [MH]+ = 501


 


 52








D, 77% [MH]+ = 594


 


 53








C, 62% [MNa]+ = 661


 


 54








C, 76% [MH]+ = 636


 


 55








C, 85% [MH]+ = 582


 


 56








C, 77% [MH]+ = 557


 


 57








C, 91% [MNa]+ = 562


 


 58








C, 85% [M − Boc]+ = 412


 


 59








C, 98% [M − Boc]+ = 412


 


 60








C, 92% [MH]+ = 468


 


 61








C, 71% [MH]+ = 482


 


 62








C, 86% [MH]+ = 496


 


 63








C, 75% [MH]+ = 483


 


 64








C, 81% [MH]+ = 566


 


 65








C, 97% [MH]+ = 580


 


 66








C, 87% [MH]+ = 544


 


 67








C, 88% [MH]+ = 598


 


 68








C, 71% [MH]+ = 530


 


 69








E, 23% [MH]+ = 517


 


 70








E, 39% [MH]+ = 517


 


 71








E, 82% [MH]+ = 441


 


 72








E, 59% [MH]+ = 557


 


 73








E, 21% [MH]+ = 523


 


 74








E, 73% [MH]+ = 576


 


 75








E, 73% [MH]+ = 576


 


 76








E, 38% [MH]+ = 596


 


 77








E, 33% [M − H]− = 588


 


 78








E, 40% [M − H]− = 588


 


 79








E, 30% [M − H]− = 568


 


 80








E, 42% [M − H]− = 568


 


 81








E, 42% [M − H]− = 588


 


 82








E, 26% [M − H]− = 554


 


 83








E, 60% (over 2 steps), [M − H]− = 556


 


 84








E, 11% (over 2 steps), [M − H]− = 556


 


 85








C, 77% [MH]+ = 483


 


 86








C, 66% [MH]+ = 483


 


 87








C, >99% [MH]+ = 614


 


 88








C, >99% [MH]+ = 612


 


 89








C, 48% [MNa]+ = 634


 


 90








C, 54% [MH]+ = 410


 


 91








F, 87% [MH]+ = 397


 


 92








F, >99% [MH]+ = 399


 


 93








F, 61% [MH]+ = 441


 


 94








F, 67% [MH]+ = 409


 


 95








F, 40% [MH]+ = 437


 


 96








F, 36% [MH]+ = 433


 


 97








F, 54% [MH]+ = 463


 


 98








F, 52% [MH]+ = 437


 


 99








F, 48% [MH]+ = 437


 


100








F, 51% [MH]+ = 420


 


101








F, 56% [MH]+ = 459


 


102








F, 56% [MH]+ = 518


 


103








F, 23% [MH]+ = 504


 


104








F, 68% [MH]+ = 439


 


105








F, 56% [MH]+ = 439


 


106








F, 95% [MH]+ = 465


 


107








F, 93% [MH]+ = 447


 


108








G, 87% [MH]+ = 451


 


109








G, >99% [MH]+ = 462


 


110








G, 99% [MH]+ = 425


 


111








G, 85% [MH]+ = 426


 


112








F, 64% [MH]+ = 439


 


113








F, 97% [MH]+ = 447


 


114








G, 94% [MH]+ = 427


 


115








G, 26% [MH]+ = 491


 


116








G, 40% [MH]+ = 505


 


117








C, 54% [MH]+ = 411


 


118








C, 86% [MH]+ = 437


 


119








C, 21% [MH]+ = 477


 


120








C, 57% [MH]+ = 454


 


121








C, 31% [MH]+ = 544


 


122








C, 66% [MH]+ = 544


 


123








C, 26% [MH]+ = 518


 


124








C, 14% [MH]+ = 494


 


125








C, 41% [MH]+ = 483


 


126








C, 75% [MH]+ = 450


 


127








C, 78% [MH]+ = 507


 


128








C, 61% [MH]+ = 507


 


129








C, 75% [MH]+ = 483


 


130








C, 59% [MH]+ = 497


 


131








C, 52% [MH]+ = 503


 


132








C, 31% [MH]+ = 527


 


133








C, 77% [MH]+ = 527


 


134








C, 26% [MH]+ = 544


 


135








C, 51% [MH]+ = 598


 


136








C, 33% [MH]+ = 546


 


137








C, 80% [MH]+ = 483


 


138








C, 72% [MH]+ = 483


 


139








C, 48% [MH]+ = 532


 


140








C, 83% [MH]+ = 608


 


141








C, 94% [MH]+ = 609


 


142








C, 80% [MH]+ = 623


 


143








C, 78% [MH]+ = 637


 


144








C, 90% [MH]+ = 593


 


145








C, 59% [MH]+ = 607


 


146








C, 30% [MH]+ = 564


 


147








C, 76% [MH]+ = 554


 


148








C, 64% [MH]+ = 597


 


149








C, 84% [MH]+ = 597


 


150








C, 78% [MH]+ = 597


 


151








C, 49% [MH]+ = 566


 


152








C, 75% [M −  “indene”]+ = 362


 


153








C, 82% [MH]+ = 495


 


154








C, 29% [MH]+ = 553


 


155








C, 26% [MH]+ = 496


 


156








C, 56% [MH]+ = 518


 


157








C, 5% [MH]+ = 514


 


158








C, 52% [MH]+ = 506


 


159








C, 38% [MH]+ = 610


 


160








C, 19% [MH]+ = 702


 


161








C, 25% [MH]+ =  549/551


 


162








C, 48% [MH]+ = 504


 


163








C, 41% [MH]+ = 546


 


164








C, 48% [MH]+ = 509


 


165








C, 55% [MH]+ = 528


 


166








C, 20% [MH]+ = 528


 


167








C, 71% [MH]+ = 508


 


168








C, 72% [MH]+ = 526


 


169








C, 41% [MH]+ = 565


 


170








C, 68% [MH]+ = 512


 


171








C, 72% [MH]+ = 530


 


172








C, 78% [MH]+ = 580


 


173








C, 79% [MH]+ = 512


 


174








C, 75% [MH]+ = 596


 


175








C, 83% [MH]+ = 560


 


176








C, 82% [MH]+ = 578


 


177








C, 21% [MH]+ = 546


 


178








C, 15% [MH]+ = 580


 


179








E, 21% [M − H]− = 515


 


180








E, 23% [M − H]− = 529


 


181








E, 24% [M − H]− = 529


 


182








E, 11% [M − H]− = 526


 


183








E, 34% [MH]+ = 507


 


184








E, 52% [MH]+ = 563


 


185








E, n.d. [MH]+ = 644


 


186








E, n.d. [MH]+ = 644


 


187








E, 57% [M − H]− = 628


 


188








B, n.d. [MH]+ = 627


 


189








B, n.d. [MH]+ = 597


 


190








D, 72% [MH]+ = 628


 


191








A, 54% [MH]+ = 612


 


192








A, 27% [MH]+ = 578


 


193








A, 28% [MH]+ = 612


 


194








A, 33% 1H-NMR (CDCl3) δ = 10.50 (br d, 1 H), 9.00 (s, 1 H), 8.85 (s, 1 H), 8.35 (br t, 1 H), 8.00 (s, 1 H), 7.95 (d, 1 H), 7.40 (d, 1 H), 7.25-7.00 (m, 2 H), 7.00-6.90 (m, 1 H), 5.80 (m, 1 H), 4.65 (br d, 2 H), 3.90 (s, 3 H), 3.20-2.70 (m, 3 H), 2.25  (s, 3 H), 2.20- 2.00 (m, 1 H).


 


195








A, n.d. [MH]+ = 594/596


 


196








A, n.d. MH]+ = 528/530


 


197








A, 43% [MH]+ = 558


 


198








C, 66% [MH]+ = 562


 


199








C, 44% [MH]+ = 562


 


200








C, 48% [MH]+ = 613


 


201








C, n.d. [MH]+ = 550


 


202








C, 65% [MH]+ = 523/525


 


203








C, 52% [MH]+ = 543/545


 


204








C, 54% 1H-NMR (CDCl3) δ = 10.25 (br d, 1 H), 8.60 (s, 1 H), 8.10 (m, 1 H), 8.00 (d, 1 H), 7.60 (d, 1 H), 7.30 (d, 1 H), 7.20-7.10 (m, 2 H), 7.10-7.00 (m, 1 H), 5.70 (m, 1 H), 4.55 (d, 2 H), 3.10-2.60 (m, 3 H), 2.40 (s, 9 H), 2.00-1.90 (m, 1 H).


 


205








C, 70% [MH]+ = 595


 


206








C, 79% [MH]+ = 599


 


207








C, 55% [MH]+ = 522


 


208








C, 59% [MH]+ = 536


 


209








C, 63% [MH]+ = 598


 


210








C, 32% [M − “indene”]+ = 398


 


211








C, 66% [MH]+ = 623


 


212








C, 61% [MH]+ = 571


 


213








C, 86% [MH]+ = 585


 


214








E, 60% [M − H]− = 520


 


215








E, 65% [M − H]− = 520


 


216








E, 49% [MH]+ = 539/541


 


217








E, 90% [MH]+ = 533


 


218








E, 80% [MH]+ = 550


 


219








C, 45% [MH]+ = 452


 


220








C, 43% [MH]+ = 461


 


221








C, 46% [MH]+ = 572


 


222








C, 47% [MH]+ = 586


 


223








C, n.d. [MH]+ = 569


 


224








C, n.d. [MH]+ = 517


 


225








C, n.d. [MH]+ = 459


 


226








C, n.d. [MH]+ = 546


 


227








C, n.d. [MNa]+ = 584


 


228








C, n.d. [MNa]+ = 669


 


229








C, n.d. [MNa]+ = 696


 


230








C, n.d. [MNa]+ = 624


 


231








C, 60% (over 2 steps), [MH]+ = 517


 


232








A, 51% [MH]+ = 530


 


233








A, 7% (over 2 steps), [MH]+ = 451


 


234








A, 20% (over 2 steps), [MH]+ = 451


 


235








E, 35% [M − H]− = 502


 


236








E, 29% [M − H]− = 488


 


237








A, 98% [MH]+ = 471


 


238








A, 16% [MH]+ = 517


 


239








E, 52% [MNa]+ = 566


 


240








E, 31% [M − H]− = 576


 


241








A, n.d. [MH]+ = 599


 


242








E, 51% [MH]+ = 533


 


243








E, 50% [MH]+ = 462


 


244








E, 40% [MH]+ = 428


 


245








E, 30% [MH]+ = 469


 


246








E, 10% [MH]+ = 426


 


247








E, 34% [MH]+ = 442


 


248








E, 20% [MH]+ = 468


 


249








E, 30% [MH]+ = 456


 


250








E, 25% [MH]+ = 424


 


251








E, 30% [MH]+ = 468


 


252








E, 34% [MH]+ = 525


 


253








E, 18% [MH]+ = 516


 


254








E, n.d. [MH]+ = 579


 


255








E, 42% [MH]+ = 444


 


256








E, 70% [MH]+ = 630


 


257








C, 10% [MH]+ = 518


 


258








C, 29% [MH]+ = 518


 


259








C, 96% [MH]+ = 564


 


260








C, 91% [MH]+ = 547


 


261








C, n.d. [MH]+ = 597


 


262








C, 93% [MH]+ = 547


 


263








C, 81% [MH]+ = 529


 


264








C, 86% [MH]+ = 529


 


265








C, 76% [MH]+ = 545


 


266








C, n.d. [MH]+ = 543


 


267








C, n.d. [MH]+ = 543


 


268








C, n.d. [MH]+ = 537


 


269








C, n.d. [MH]+ = 537


 


270








C, n.d. [MH]+ = 557


 


271








C, n.d. [MH]+ = 595


 


272








C, 38% [MH]+ = 540


 


273








C, n.d. [MH]+ = 537


 


274








C, n.d. [MNa]+ = 584


 


275








C, n.d. [MNa]+ = 602


 


276








C, n.d. [MH]+ = 594


 


277








C, n.d. [MH]+ = 614









Example 278




Step A

To a solution of the title compound from the Preparative Example 315 (67 mg) in anhydrous DMF (500 μL) was added a solution of the title compound from the Preparative Example 229, Step D (75 mg). The resulting mixture was heated at 60° C. for 15 h, concentrated and purified by preparative thin layer chromatography (silica, CH2Cl2/MeOH) to give the desired title compound (39 mg, 41%). [MH]+=491.
Examples 279-284
Following a similar procedure as described in the Example 278, except using the esters and amines indicated in Table II-2 below, the following compounds were prepared.










TABLE II-2





Ex. #
ester, amine
product
yield







279








47% [MH]+ = 477


 











 


280








48% [MH]+ = 462


 











 


281








43% [MH]+ = 439


 











 


282








60% [MH]+ = 552


 











 


283








50% [MH]+ = 458


 











 


284








53% [MH]+ = 442


 
















Example 285




Step A

To a solution of the title compound from the Preparative Example 244, Step A (200 mg) in anhydrous DMF (2 mL) was added commercially available 4-fluoro-3-methyl-benzylamine (120 mg). The resulting mixture was heated at 60° C. for 24 h, concentrated and purified by preparative thin layer chromatography (silica, CH2Cl2/MeOH) to give the title compound (30 mg, 8%). [MH]+=452.
Example 286




Step A

A mixture of the title compound Preparative Example 330, Step A (203 mg) and commercially available 3-chloro-4-fluorobenzylamine (160 mg) in dry DMF (3 mL) was heated to 70° C. overnight and concentrated. The remaining residue was dissolved in CHCl3, washed with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by preparative thin layer chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a colorless solid (111 mg, 29%). [MH]+=492.
Example 287




Step A

A solution of the title compound from the Preparative Example 331, Step A (26 mg) in a 7M solution of NH3 in MeOH (1 mL) was heated at 90° C. for 2 h. The formed precipitate was isolated by filtration to afford the title compound as a colorless solid (8.6 mg, 34%). [MH]+=329.
Example 288




Step A

The title compound from the Preparative Example 294 (9.7 mg) and commercially available 4-aminomethyl-phenylamine (10 mg) were dissolved in N-methylpyrrolidin-2-one (0.5 mL). The mixture was heated in a sealed tube at 160° C. (microwave) for 15 min, diluted with EtOAc, washed with aqueous LiCl, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound (9.6 mg, 84%). [M-H]′=540.
Example 289




Step A

The title compound from the Preparative Example 294 (154 mg) and commercially available 3-aminomethyl-phenylamine (57 mg) were dissolved in N-methylpyrrolidin-2-one (3 mL). The mixture was heated in a sealed tube at 160° C. (microwave) for 55 min, diluted with EtOAc, washed with aqueous LiCl, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound (110 mg, 84%). [M-H]−=540.
Example 290




Step A

To a solution of the title compound from the Example 289, Step A (19.1 mg) in CH2Cl2 (1 mL) were successively added pyridine (0.1 mL) and methanesulfonyl chloride (8.1 mg). The mixture was stirred for 1d, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound (13.1 mg, 60%). [M-H]′=618.
Example 291




Step A

To a solution of the title compound from the Preparative Example 342 (51 mg) in THF (5 mL) were added the title compound from the Preparative Example 149, EDCI (53 mg), HOBt (38 mg) and K2CO3 (44 mg). The mixture was stirred for 16 h, absorbed on silica (500 mg) and purified by chromatography (silica, hexanes/EtOAc) to afford the title compound as a solid (79.3 mg, 92%). [M-H]′=616.
Example 292




Step A

To a solution of the title compound from the Example 291, Step A (50 mg) in MeOH/CH2Cl2 (1:1, 2 mL) was added hydrazine (26 mg). The resulting mixture was stirred for 1 d, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a yellow solid. (37.1 mg, 74%). [M-H]′=615.
Example 293




Step A

To a solution of the title compound from the Example 179 (2.5 mg) in toluene/MeOH (3:1, 2 mL) was added a 2M solution of (trimethylsilyl)diazomethane in Et2O (portions à 10 μL) until complete consumption of the starting material. The mixture was concentrated and then triturated with Et2O (4×) to give the title compound as a yellow solid (1.0 mg, 40%). [M-H]′=529.
Example 294




Step A

A mixture of the title compound from the Example 196 (52 mg) and Pd/C (10 wt %, 20 mg) in MeOH/EtOAc (1:1, 4 mL) was hydrogenated at atmospheric pressure for 18 h, filtered, concentrated and purified by chromatography (silica, CH2Cl2/acetone) to afford the title compound (19 mg, 43%). [MH]+=450.
Example 295




Step A

Under an argon atmosphere a mixture of commercially available 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester (9.38 g) and selenium dioxide (8.93 g) in 1,4-dioxane (50 mL) was stirred at 105° C. for 12 h. The mixture was filtered twice through Celite®, the filter cake was rinsed with 1,4-dioxane (2×100 mL) and the combined filtrates were concentrated to afford the title compound as viscous orange oil (8.0 g, 74%). [MH]+=217.
Step B
To an ice cooled solution of the title compound from Step A above (900 mg) in anhydrous CH2Cl2 (20 mL) were subsequently and slowly added oxalyl chloride (870 μL) and DMF (3 drops). The cooling bath was removed and the mixture was stirred at room temperature until gas evolution ceased. The mixture was then concentrated and diluted with CH2Cl2. Pyridine (340 μL) and commercially available 4-fluoro-3-methylbenzylamine (530 μL) were added subsequently and the mixture was stirred at room temperature for 30 min. Filtration, absorption onto silica and purification by chromatography (silica, hexane/EtOAc) afforded the title compound as a yellow solid (670 mg, 48%). [MH]+=338.
Step C
To an ice cooled solution of the title compound from Step B above (670 mg) in THF (20 mL) was slowly added 1M aqueous LiOH (3.98 mL). The mixture was stirred at 0° C. for 2 h, quenched with 1M aqueous HCl (4.0 mL), warmed to room temperature and concentrated. The remaining residue was triturated with THF, filtered and concentrated to afford the title compound as an orange solid. [MH]+=324.
Step D
The title compound from Step C above (256 mg), commercially available 4-aminomethyl-benzoic acid methyl ester hydrochloride (160 mg), PyBOP (800 mg) and NEt3 (202 μL) were dissolved in THF/DMF (2:1, 15 mL). The mixture was stirred at room temperature for 2 h, concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/acetone) to afford the title compound (196 mg, 44%). [MH]+=570.
Step E
To a stirred solution of the title compound from Step D above (50 mg) in anhydrous THF (5 mL) was added hydrazine hydrate (40 μL). The mixture was stirred at room temperature for 2 h and then concentrated. The residue was dissolved in anhydrous 1,2-dichloroethane (2 mL) and cooled to 0° C. A 20% solution of phosgene in toluene (500 μL) was added, the cooling bath was removed and the mixture was stirred at room temperature for 2 h. Concentration afforded the crude title compound as a mixture of two isomers, which was used without further purification. [MH]+=493.
Step F
To a solution of the title compound from Step E above (30 mg) in THF/MeOH (2:1, 1.5 mL) was added 1N aqueous LiOH (0.2 mL). The mixture was stirred at room temperature overnight, adjusted to pH 4.5 with 2N aqueous HCl and extracted with EtOAc. The organic phase was washed with saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by preparative thin layer chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a mixture of two isomers (3 mg, 8% over 2 steps). [MH]+=479.
Example 296




Step A

To a solution of the title compound from the Preparative Example 331, Step A (329 mg) in DMF (10 mL) were successively added HATU (427 mg), HOAt (153 mg), commercially available trans-(4-aminomethyl-cyclohexyl)-carbamic acid tert-butyl ester (291 mg) and iPr2NEt (191 μL) and the mixture was stirred at room temperature for 5 h. Additional HATU (427 mg), trans-(4-aminomethyl-cyclohexyl)-carbamic acid tert-butyl ester (291 mg) and iPr2NEt (191 μL) were successively added and stirring at room temperature was continued for 2 h. The mixture was diluted with EtOAc (100 mL), washed with 0.01N aqueous HCl (3×100 mL) and saturated aqueous NaCl (100 mL), dried (MgSO4) and filtered. The filter cake was rinsed with CH2Cl2/MeOH (95:5, 500 mL) and the combined filtrates were concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a colorless solid (493 mg, 91%). [MNa]+=562.
Step B
To a suspension of the title compound from Step A above (436 mg) in EtOAc (3.22 mL) was added a 4M solution of HCl in 1,4-dioxane (3.22 mL). The reaction mixture was stirred at room temperature for 21⁄2 h, diluted with MeOH (10 mL), concentrated, suspended in CH3CN/MeOH (4:1, 20 mL) and concentrated again to afford the title compound (384 mg, 99%). [M-Cl]+=440.
Examples 297-299
Following a similar procedure as described in the Example 296, Step B, except using the protected amines indicated in Table II-3 below, the following compounds were prepared.










TABLE II-3





Ex. #
protected amine
product
yield







297








>99% [M − Cl]+ = 426


 


298








98% [M − Cl]+ = 412


 


298








98% [M − Cl]+ = 412









Example 299




Step A

To a suspension of the title compound from the Example 296, Step B (23.8 mg) in dry CH2Cl2 (1 mL) were added a 1M solution of acetyl chloride in dry CH2Cl2 (50 μL) and iPr2NEt (26.1 μL). The reaction mixture was stirred at room temperature for 1 h, concentrated and purified by flash chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a beige/white solid (24.1 mg, >99%). [MH]+=482.
Examples 300-309
Following a similar procedure as described in the Example 299, except using the amines and the acid chlorides indicated in Table II-4 below, the following compounds were prepared.










TABLE II-4





Ex. #
amine, acid chloride
product
yield







300








92% [MH]+ = 524


 











 


301








99% [MH]+ = 518


 











 


302








73% [MH]+ = 468


 











 


303








75% [MH]+ = 504


 











 


304








97% [MH]+ = 454


 











 


305








94% [MH]+ = 490


 











 


306








89% [MH]+ = 454


 











 


307








95% [MH]+ = 490


 











 


308








71% [MH]+ = 544


 











 


309








83% [MH]+ = 519


 
















Example 310




Step A

To a solution of the title compound from the Example 298 (22.4 mg) in dry CH2Cl2 (500 μL) were added iPr2NEt (17.4 μL) and sulfamide (10.8 mg). The resulting reaction mixture was heated in a sealed tube to 140° C. (microwave) for 2 h, concentrated and purified by flash chromatography (silica, CH2Cl2/MeOH) to afford the title compound (11.7 mg, 48%). [MH]+=491.
Example 311




Step A

To a suspension of the title compound from the Example 296, Step B (23.8 mg) in dry CH2Cl2 (500 μL) was added KOtBu (6.4 mg). The resulting reaction mixture was stirred at room temperature for 5 min, then iPrOH (50 μL) and trimethylsilyl isocyanate (13.9 μL) were added and stirring at room temperature was continued for 19 h. The mixture was diluted with MeOH (5 mL), concentrated and purified by flash chromatography (silica, CH2Cl2/MeOH) to afford the title compound (15 mg, 62%). [MH]+=483.
Example 312




Step A

To a solution of the title compound from the Example 296, Step B (20 mg) in DMF (2.5 mL) were successively added iPr2NEt (15 μL) and 2-iodoethanol (3.5 μL). Using a microwave, the mixture was heated in a sealed vial at 100° C. for 10 min. The mixture was concentrated and dissolved in dry THF (1 mL). Methyl N-(triethylammoniosulfonyl) carbamate [“Burgess reagent”] (27 mg) was added and using a microwave, the mixture was heated in a sealed vial at 130° C. for 7 min. Concentration and purification by chromatography (silica, CH2Cl2/MeOH) afforded the title compound as a colorless solid (1.7 mg, 6%). [MH]+=603.
Example 313




Step A

To a suspension of the title compound from the Example 297 (23.1 mg) in dry CH2Cl2 (500 μL) was added KO′Bu (6.4 mg). The resulting reaction mixture was stirred at room temperature for 5 min, then iPrOH (50 μL) and trimethylsilyl isocyanate (13.9 μL) were added and stirring at room temperature was continued for 16 h. The mixture was diluted with MeOH (5 mL), concentrated and purified by flash chromatography (silica, CH2Cl2/MeOH) to afford the title compound (10 mg, 43%). [α]+=469.
Example 314




Step A

To a solution of the title compound from the Example 25 (43.9 mg) in THF (10 mL) was added a solution of LiOH (18 mg) in H2O (10 mL). The solution was stirred for 5 h, acidified, concentrated and purified by preparative thin layer chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a bright yellow solid (16.4 mg, 38%). [MH]+=488.
Example 315




Step A

Using a microwave, a mixture of the title compound from the Example 5 (51 mg) and trimethyltin hydroxide (236 mg) in 1,2-dichloroethane (2 mL) in a sealed vial was stirred at 160° C. for 1 h. The contents were loaded onto a silica and purified by chromatography (silica, CH2Cl2/MeOH) to give a yellow solid (18 mg, 35%). [MH]′=574.
Examples 316-361
Following similar procedures as described in the Examples 314 (method A) or 315 (method B), except using the esters indicated in Table II-5 below, the following compounds were prepared.










TABLE II-5








method,


Ex. #
ester
product
yield







316








A, 60% [MH]+ = 576


 


317








A, 8% [MH]+ = 525


 


318








B, 40% [MH]+ = 533


 


319








B, 54% [MH]+ = 564


 


320








B, 40% [MH]+ = 546


 


321








A, 40% 1H-NMR (CDCl3) δ = 10.50 (br d, 1 H), 9.00 (s, 1 H), 8.90 (s, 1 H), 8.25 (d, 1 H), 7.95 (s, 1 H), 7.90 (d, 1 H), 7.35 (d, 1 H), 7.25-7.10 (m, 2 H), 7.00 (m, 1 H), 5.75 (m, 1 H), 4.70 (d, 2 H), 3.20-2.80 (m, 3 H), 2.25 (s, 3 H), 2.25-2.00 (m, 1 H).


 


322








A, 31% [MH]+ = 488


 


323








A, 37% [MH]+ = 533


 


324








B, 66% [M − H]− = 506


 


325








B, 71% [M − H]− = 506


 


326








B, 70% [M − H]− = 531


 


327








B, 82% [M − H]− = 522


 


328








B, 45% [MH]+ = 503


 


329








B, 18% [MH]+ = 622


 


330








B, 15% [MH]+ = 543


 


331








B, 14% [M − H]− = 501


 


332








B, 50% [MH]+ = 477


 


333








B, 32% [MH]+ = 463


 


334








A, 86% [MH]+ = 504


 


335








A, 51% [MH]+ = 504


 


336








B, 34% [M − H]− = 574


 


337








B, 46% [M − H]− = 554


 


338








B, 29% [M − H]− = 554


 


339








B, 45% [M − H]− = 540


 


340








B, 44% [M − H]− = 540


 


341








B, 52% [MH]+ = 532


 


342








B, 42% [MH]+ = 495


 


343








B, 40% [MH]+ = 514


 


344








B, 35% [MH]+ = 494


 


345








B, 43 % [MH]+ = 512


 


346








B, 39% [MH]+ = 551


 


347








B, 21% [MH]+ = 481


 


348








B, 41% [MH]+ = 498


 


349








B, 39% [MH]+ = 516


 


350








B, 32% [MH]+ = 566


 


351








B, 37% [MH]+ = 498


 


352








B, 44% [MH]+ = 582


 


353








B, 42% [MH]+ = 546


 


354








B, 46% [MH]+ = 564


 


355








B, 15% [MH]+ = 532


 


356








A, 11% [MH]+ = 504


 


357








B, 10% [MH]+ = 504


 


358








B, 68% [MH]+ = 489


 


359








B, 66% [MH]+ = 469 


 


360








B, 94% [MH]+ = 469


 


361








B, 95% [MH]+ = 469









Example 362




Step A

To a solution of the title compound from the Example 184 (109 mg) in THF (4 mL) were added morpholine (0.17 mL) and Pd(PPh3)4 (23.8 mg). The mixture was stirred at room temperature for 31⁄2 h, diluted with a 4M solution of HCl in 1,4-dioxane (490 μL) and concentrated. The remaining residue was purified by chromatography (silica, CH2Cl2/MeOH) and preparative thin layer chromatography (silica, CH2Cl2/MeOH) to give the title compound as a yellow solid (39.4 mg, 39%). [M-H]−=521.
Examples 363-435
Following a similar procedure as described in the Example 362, except using the esters indicated in Table II-6 below, the following compounds were prepared.










TABLE II-6





Ex. #
ester
product
yield







363








  53% [M − H]− = 588


 


364








n.d. [MH]+ = 609


 


365








n.d. [MH]+ = 557


 


366








  42% [MH]+ = 573


 


367








  42% (over 2 steps) [MH]+ = 550


 


368








  37% [MH]+ = 555


 


369








  48% [MH]+ = 558


 


370








  90% [MH]+ = 572


 


371








  49% [MH]+ = 583


 


372








  59% [MNa]+ = 553


 


373








  40% [MNa]+ = 567


 


374








  37% (over 2 steps) [MH]+ = 529


 


375








  20% (over 2 steps) [MH]+ = 477


 


376








  34% (over 2 steps) [MH]+ = 419


 


377








  29% (over 2 steps) [MH]+ = 506


 


378








  90% [MH]+ = 579


 


379








  90% [MH]+ = 579


 


380








  41% [MH]+ = 604


 


381








  77% [MH]+ = 658


 


382








  71% [MH]+ = 605


 


383








  67% [MH]+ = 502


 


384








  75% [MH]+ = 554


 


385








  18% [MH]+ = 542


 


386








  62% [MH]+ = 556


 


387








  33% [MH]+ = 537


 


388








  69% [MH]+ = 520


 


389








  22% [MH]+ = 526


 


390








   8% [MH]+ = 496


 


391








  77% [MH]+ = 496


 


392








  71% [MH]+ = 551


 


393








  65% [MH]+ = 516


 


394








  46% [MH]+ = 556


 


395








  98% [MH]+ = 559


 


396








  80% [MH]+ = 554


 


397








  58% [MH]+ = 541


 


398








  90% [MH]+ = 572


 


399








  95% [MH]+ = 554


 


400








  77% [MH]+ = 621


 


401








  68% [MH]+ = 542


 


402








  86% [MH]+ = 536


 


403








  87% [MH]+ = 556


 


404








  50% [MH]+ = 524


 


405








  45% [MH]+ = 507


 


406








  30% (over 2 steps) [MH]+ = 557


 


407








n.d. [MH]+ = 507


 


408








  90% [MH]+ = 489


 


409








  78% [MH]+ = 489


 


410








  86% [MH]+ = 505


 


411








  57% (over 2 steps) [MH]+ = 503


 


412








  57% (over 2 steps) [MH]+ = 503


 


413








  20% (over 2 steps) [MH]+ = 497


 


414








  29% (over 2 steps) [MH]+ = 497


 


415








  36% (over 2 steps) [MH]+ = 517


 


416








  19% [MH]+ = 555


 


417








   7% (over 2 steps) [MH]+ = 497


 


418








  82% (over 2 steps) [MH]+ = 554


 


419








  82% (over 2 steps) [MH]+ = 614


 


420








  40% [M − H]− = 588 


 


421








  60% [MH]+ = 540


 


422








  94% [MH]+ = 574


 


423








  98% [MH]+ = 572


 


424








  45% [MH]+ = 568


 


425








20% [MH]+ = 569


 


426








51% [MH]+ = 583


 


427








15% [MH]+ = 597


 


428








  24% [MH]+ = 553


 


429








  31% [MH]+ = 567


 


430








>99% [MH]+ = 524


 


431








  46% [MH]+ = 514


 


432








  64% [MH]+ = 557


 


433








  78% [MH]+ = 557


 


434








  65% [MH]+ = 557


 


435








  71% [MH]+ = 526









Example 436




Step A

A solution of the title compound from the Example 83 (20 mg) in a mixture of trifluoroacetic acid (100 μL) and CH2Cl2 (100 μL) was stirred for 30 min and then concentrated. The remaining residue was washed with Et2O (200 μL) to give a yellow solid (17 mg, 92%). [MH]+=502.
Examples 437-464
Following a similar procedure as described in the Example 436, except using the esters as indicated in Table II-7 below, the following compounds were prepared.










TABLE II-7





Ex. #
ester
product
yield







437








n.d. [M − H]− = 586


 


438








n.d. [M − H]− = 586


 


439








  95% [MH]+ = 572


 


440








  89% [MH]+ = 522


 


441








  98% [MH]+ = 556


 


442








  35% [MH]+ = 506


 


443








  98% [MH]+ = 506


 


444








  96% [MH]+ = 540


 


445








  74% [MH]+ = 502


 


446








  96% [MH]+ = 486


 


447








  79% [M − H]− = 562


 


448








  56% (over 2 steps) [MH]+ = 506


 


449








  63% (over 2 steps) [MH]+ = 590


 


450








  32% (over 2 steps) [MH]+ = 618


 


451








  10% (over 2 steps) [MH]+ = 546


 


452








  90% [MH]+ = 550


 


453








  90% [MH]+ = 536


 


454








  73% [M − H]− = 488


 


455








  53% [M − H]− = 501


 


456








  36% [MH]+ = 477


 


457








  50% [MH]+ = 523


 


458








  50% [MH]+ = 496


 


459








  67% (over 2 steps) [MH]+ = 506


 


460








  65% [MH]+ = 524


 


461








  56% [MH]+ = 502


 


462








  83% [M − H]− = 520


 


463








>99% [MH]+ = 556


 


464








>99% [M − “indene”]+ = 362









Example 465




Step A

To a solution of the title compound from the Example 360 (50 mg) in THF (1.5 mL) was added N,N′-carbonyldiimidazole (26 mg). The mixture was stirred at room temperature for 2 h, then a 0.5M solution of NH3 in 1,4-dioxane (5 mL) was added and stirring at room temperature was continued for 2 h. Concentration and purification by chromatography (silica, CH2Cl2/MeOH) afforded the title compound as a colorless solid (29 mg, 60%). [MH]+=468.
Example 466




Step A

The title compound from the Example 361 (45 mg) was treated similarly as described in the Example 465, Step A to afford the title compound (21 mg, 48%). [MH]+=468.
Example 467




Step A

A mixture of the title compound from the Example 321 (10 mg) and Pd/C (10 wt %, 5 mg) in EtOH was hydrogenated at atmospheric pressure for 5 h, filtered, concentrated and purified by preparative thin layer chromatography (silica, CHCl3/MeOH) to afford the title compound (1 mg, 10%). [MH]+=503.
Example 468




Step A

To a solution of the title compound from the Example 381 (26 mg) in DMF (3 mL) was added morpholine (80 μL), EDCI (10 mg) and HOAt (5 mg). The mixture was stirred overnight and then concentrated. The remaining residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3, 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a colorless solid (9.9 mg, 34%). [MH]+=727.
Example 469




Step A

In a sealed vial was a mixture of the title compound from the Example 3, Step A (54 mg), dibutyltin oxide (15 mg) and azidotrimethylsilane (400 μL) in toluene (10 mL) under an argon atmosphere heated at 110° C. for 18 h. The reaction mixture was then diluted with MeOH, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to give the title compound as an off-white solid (8.6 mg, 15%). [Mi]+=563.
Examples 470-477
Following a similar procedure as described in the Example 469, except using the nitriles indicated in Table II-8 below, the following compounds were prepared.










TABLE II-8





Ex. #
nitrile
product
yield







470








74% [MH]+ = 526


 


471








34% [MH]+ = 600


 


472








38% [MH]+ = 564


 


473








40% [MH]+ = 550


 


474








55% [MH]+ = 514


 


475








27% [MH]+ = 487


 


476








46% [MH]+ = 485


 


477








53% [MH]+ = 583









Example 478




Step A

To a solution of the title compound from the Example 477 (80 mg) in DMF (3 mL) were added iodomethane (9 μL) and K2CO3 (19 mg) and the mixture was stirred at room temperature overnight. Additional iodomethane (8 μL) was added and stirring at room temperature was continued for 2 h. The mixture was concentrated and purified by preparative thin layer chromatography (silica, EtOAc) to afford the major isomer (30 mg, 37%) and the minor isomer (15 mg, 18%) of the title compound. [MH]+=597.
Example 479




Step A

To a stirring solution of the title compound from the Preparative Example 377, Step E (9 mg) in MeOH (3 mL) were added AcOH (a few drops), a 1M solution of commercially available 4-fluorobenzaldehyde in MeOH (30 μL) and NaBH(OAc)3 (5 mg). The mixture was stirred at room temperature overnight, concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by preparative thin layer chromatography (silica, cyclohexane/EtOAc) to afford the title compound as an off-white solid (5 mg, 42%). [MH]+=429.
Example 480-482
Following similar procedures as described in the Example 479, except using the aldehydes indicated in Table II-9 below, the following compounds were prepared.










TABLE II-9





Ex. #
aldehyde
product
yield







480








>99% [MH]+ = 455


 


481








  63% [MH]+ = 455


 


482








n.d. [MH]+ = 417









Example 483




Step A

To a solution of the title compound from the Preparative Example 379, Step G (7 mg) in anhydrous pyridine (1 mL) was added Ac2O (1 mL). The mixture was stirred at room temperature for 5 h, concentrated and slurried in MeOH. The formed precipitate was collected by filtration and dried to afford the title compound as a brown solid (5.1 mg, 64%). NM+=381.
Example 484




Step A

A stirring solution of the title compound from the Preparative Example 377, Step G (9 mg) in MeOH/H2O/THF (3:2:1, 6 mL) was adjusted to pH 6 with 3M aqueous NaOAc. 4-Formylbenzoic acid (6 mg) was added and the mixture was stirred at room temperature for 30 min. NaBH3CN (5 mg) was added and stirring at room temperature was continued overnight. The mixture was concentrated and diluted with 0.1N aqueous HCl (5 mL). The formed precipitate was collected by filtration, washed with 0.1N aqueous HCl (8 mL) and dried to afford the title compound as an orange solid (7.8 mg, 61%). [MH]+=473.
Example 485




Step A

The title compound from the Preparative Example 377, Step G (9 mg) was treated similarly as described in the Preparative Example 484, except using cyclohexanecarbaldehyde (0.04 mL) instead of 4-formylbenzoic acid to afford the title compound as a reddish glass (6.5 mg, 45%). [MH]+=531.
Examples 486-504
Following similar procedures as described in the Examples 1 (method A), 2 (method B), 3 (method C), 4 (method D), 5 (method E), 6 (method F) or 7 (method G), except using the acids and amines indicated in Table II-10 below, the following compounds were prepared.










TABLE II-10





Ex. #
acid, amine
product
method, yield







486








B, n.d. [MH]+ = 526 


 


487








B, 34% [MH]+ = 739 


 


488








B, 75% [MH]+ = 738 


 


489








B, n.d. [MH]+ = 1015


 


490








B, 31% [MH]+ = 491 


 


491








C, 77% [MH]+ = 562 


 


492








C, 69% [MH]+ = 494 


 


493








C, 71% [MH]+ = 542 


 


494








C, 69% [MH]+ = 560 


 


495








C, 54% [MH]+ = 545 


 


496








C, 55% [MH]+ = 563 


 


497








C, 90% [MH]+ = 529 


 


498








C, 90% [MH]+ = 495 


 


499








C, n.d. [MH]+ = 522 


 


500








C, 33% [M − “indene”]+ = 408


 


501








C, n.d. [MH]+ = 571 


 


502








C, n.d. [MH]+ = 612 


 


503








C, 40% [MNa]+ = 618


 


504








C, 40% 1H-NMR (CDCl3) δ = 10.34 (d, 1 H),  8.69 (s, 1 H), 8.08 (t, 1 H), 8.06 (d, 1 H), 7.78 (d, 1 H), 7.47 (d, 1 H), 7.20-7.24 (m, 1 H), 6.95-7.02 (m, 2 H), 5.93-6.08 (m, 2 H), 5.72-5.82 (m, 1 H),  5.37 (dd, 1 H), 5.25 (dd, 1 H), 4.78 (d, 2 H),  4.67 (d, 2 H), 3.00-3.16 (m, 1 H), 2.71-2.95 (m, 2 H),  2.50 (s, 3 H), 1.96-2.10 (m, 1 H)









Examples 505-513
Following similar procedures as described in the Examples 314 (method A) or 315 (method B), except using the esters indicated in Table H-11 below, the following compounds were prepared.










TABLE II-11








method,


Ex. #
ester
product
yield







505








A, 41% [MH]+ = 548


 


506








A, 49% [MH]+ = 480


 


507








A, 39% [MH]+ = 528


 


508








A, 49% [MH]+ = 546


 


509








A, n.d. [MH]+ = 531


 


510








A, n.d. [MH]+ = 549


 


511








B, n.d. [MH]+ = 515


 


512








B, n.d. [MH]+ = 481


 


513








A, n.d. [MH]+ = 508









Examples 514-518
Following a similar procedure as described in the Example 362, except using the esters indicated in Table II-12 below, the following compounds were prepared.










TABLE II-12





Ex. #
ester
product
yield







514








n.d. % [MH]+ = 486


 


515








17% [M − “indene”]+ = 408


 


516








n.d. [MH]+ = 549


 


517








n.d. [MH]+ = 572


 


517








>99% [MH]+ = 556


 


518








69% 1H-NMR (CDCl3) δ = 12.20-13.20 (br s, 1 H), 10.40-10.70 (br s, 1 H),  10.06 (d, 1 H),  9.73 (t, 1 H), 8.68 (d, 1 H), 8.07 (s, 1 H), 7.72 (d, 1 H), 7.49 (d, 1 H), 7.32 (d, 1 H), 7.04 (s, 1 H), 6.93 (d, 1 H), 5.61-5.71 (m, 1 H),  4.52 (d, 2 H), 2.80-3.11 (m, 2 H), 2.61-2.72 (m, 1 H),  2.50 (s, 3 H), 1.96-2.10 (m, 1 H)









Example 519




Step A

The title compound from the Example 487 (42 mg) was treated similarly as described in the Example 296, Step B to afford the title compound (44 mg, >99%). [M-Cl]+=639.
The Example numbers 520 to 1699 and the Table numbers 11-13 to 11-38 were intentionally excluded.
Example 1700
Assay for Determining MMP-13 Inhibition
The typical assay for MMP-13 activity is carried out in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl2 and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 50 nM stock solution of catalytic domain of MMP-13 enzyme (produced by Alantos) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed and incubated for 10 min at room temperature. Upon the completion of incubation, the assay is started by addition of 40 μL of a 12.5 μM stock solution of MMP-13 fluorescent substrate (Calbiochem, Cat. No. 444235). The time-dependent increase in fluorescence is measured at the 320 nm excitation and 390 nm emission by automatic plate multireader. The IC50 values are calculated from the initial reaction rates.
Example 1701
Assay for Determining MMP-3 Inhibition
The typical assay for MMP-3 activity is carried out in assay buffer comprised of 50 mM MES, pH 6.0, 10 mM CaCl2 and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 100 nM stock solution of the catalytic domain of MMP-3 enzyme (Biomol, Cat. No. SE-109) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed and incubated for 10 min at room temperature. Upon the completion of incubation, the assay is started by addition of 40 μL of a 12.5 μM stock solution of NFF-3 fluorescent substrate (Calbiochem, Cat. No. 480455). The time-dependent increase in fluorescence is measured at the 330 nm excitation and 390 nm emission by an automatic plate multireader. The IC50 values are calculated from the initial reaction rates.
Example 1702
Assay for Determining MMP-8 Inhibition
The typical assay for MMP-8 activity is carried out in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl2 and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 50 nM stock solution of activated MMP-8 enzyme (Calbiochem, Cat. No. 444229) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed and incubated for 10 min at 37° C. Upon the completion of incubation, the assay is started by addition of 40 μL of a 10 μM stock solution of OmniMMP fluorescent substrate (Biomol, Cat. No. P-126). The time-dependent increase in fluorescence is measured at the 320 nm excitation and 390 nm emission by an automatic plate multireader at 37° C. The IC50 values are calculated from the initial reaction rates.
Example 1703
Assay for Determining MMP-12 Inhibition
The typical assay for MMP-12 activity is carried out in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl2 and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 50 nM stock solution of the catalytic domain of MMP-12 enzyme (Biomol, Cat. No. SE-138) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed and incubated for 10 min at room temperature. Upon the completion of incubation, the assay is started by addition of 40 μL of a 12.5 μM stock solution of OmniMMP fluorescent substrate (Biomol, Cat. No. P-126). The time-dependent increase in fluorescence is measured at the 320 nm excitation and 390 nm emission by automatic plate multireader at 37° C. The IC50 values are calculated from the initial reaction rates.
Example 1704
Assay for Determining Aggrecanase-1 Inhibition
The typical assay for aggrecanase-1 activity is carried out in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl2 and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 75 nM stock solution of aggrecanase-1 (Invitek) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed. The reaction is started by addition of 40 μL of a 250 nM stock solution of aggrecan-IGD substrate (Invitek) and incubation at 37° C. for exact 15 min. The reaction is stopped by addition of EDTA and the samples are analysed by using aggrecanase ELISA (Invitek, InviLISA, Cat. No. 30510111) according to the protocol of the supplier. Shortly: 100 μL of each proteolytic reaction are incubated in a pre-coated micro plate for 90 min at room temperature. After 3 times washing, antibody-peroxidase conjugate is added for 90 min at room temperature. After 5 times washing, the plate is incubated with TMB solution for 3 min at room temperature. The peroxidase reaction is stopped with sulfurous acid and the absorbance is red at 450 nm. The IC50 values are calculated from the absorbance signal corresponding to residual aggrecanase activity.
Example 1705
Assay for Determining Inhibition of MMP-3 Mediated Proteoglycan Degradation
The assay for MMP-3 activity is carried out in assay buffer comprised of 50 mM MES, pH 6.0, 10 mM CaCl2 and 0.05% Brij-35. Articular cartilage is isolated fresh from the first phalanges of adult cows and cut into pieces (−3 mg). Bovine cartilage is incubated with 50 nM human MMP-3 (Chemikon, cat.#25020461) in presence or absence of inhibitor for 24 h at 37° C. Sulfated glycosaminoglycan (aggrecan) degradation products (sGAG) are detected in supernatant, using a modification of the colorimetric DMMB (1,9-dimethylmethylene blue dye) assay (Billinghurst et al., 2000, Arthritis & Rheumatism, 43 (3), 664). 10 μL of the samples or standard are added to 190 μL of the dye reagent in microtiter plate wells, and the absorbance is measured at 525 nm immediately. All data points are performed in triplicates.
Example 1706
Assay for Determining Inhibition of MMP-3 mediated Pro-Collagenase 3 Activation
The assay for MMP-3 mediated activation of pro-collagenase 3 (pro-MMP-13) is carried out in assay buffer comprised of 50 mM MES, pH 6.0, 10 mM CaCl2 and 0.05% Brij-35 (Nagase; J. Biol. Chem.1994 Aug. 19; 269(33):20952-7).
Different concentrations of tested compounds are prepared in assay buffer in 5 μL aliquots. 10 μL of a 100 nM stock solution of trypsin-activated (Knauper V., et al., 1996 J. Biol. Chem. 271 1544-1550) human pro-MMP-3 (Chemicon; CC1035) is added to the compound solution. To this mixture, 35 μL of a 286 nM stock solution of pro-collagenase 3 (Invitek; 30100803) is added to the mixture of enzyme and compound. The mixture is thoroughly mixed and incubated for 5 h at 37° C. Upon the completion of incubation, 10 μL of the incubation mixture is added to 50 μL assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl2 and 0.05% Brij-35 and the mixture is thoroughly mixed.
The assay to determine the MMP-13 activity is started by addition of 40 μL of a 10 μM stock solution of MMP-13 fluorogenic substrate (Calbiochem, Cat. No. 444235) in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl2 and 0.05% Brij-35 (Knauper, V., et al., 1996. J. Biol. Chem. 271, 1544-1550). The time-dependent increase in fluorescence is measured at 320 nm excitation and 390 nm emission by an automatic plate multireader at room temperature. The IC50 values are calculated from the initial reaction rates.
Example 1707




Step A

A mixture of the title compound from the Example 418 (130 mg), NEt3 (71 μL) and diphenylphosphoryl azide (104 μL) in (BuOH (4 mL) was heated to 70° C. overnight, concentrated and purified by chromatography (silica, cyclohexancfEtOAc) to afford the title compound (43 mg, 30%). [MH]+=645.
Step B
A solution of the title compound from Step A above (43 mg) in a mixture of trifluoroacetic acid (1 mL) and CH2Cl2 (6 mL) was stirred at room temperature for 2 h, diluted with CH3CN (3 mL) and then concentrated. The remaining residue was diluted with 0.1M aqueous HCl, concentrated, again diluted with 0.1M aqueous HCl and concentrated to afford the title compound (39 mg, >99%). [M-Cl]+=581.
Example 1708




Step A

A mixture of the title compound from the Example 418 (40 mg), 2-chloro-N,N-dimethylacetamide (7.9 mL), NaI (11 mg) and NEt3 (10.5 μL) in EtOAc (3 mL) was heated to reflux for 3 h, cooled, filtered, washed with saturated aqueous NaS2O3, half saturated aqueous NaHCO3 and saturated aqueous NaCl (200 mL), dried (MgSO4), filtered, concentrated and purified by preparative thin layer chromatography (silica, CH2Cl2/acetone) to afford the title compound (25 mg, 72%). [MH]+=659.
Example 1709




Step A

The title compound from the Preparative Example 968 (109 mg) was treated similarly as described in the Preparative Example 328, Step A, except using commercially available 3,4-difluorobenzylamine instead of 4-fluorobenzylamine to afford title compound from the Preparative Example 984 (47 mg, 32%, [MH]+=429) and the title compound (4.1 mg, 3%). [M-H]′=538.
Example 1710




Step A

To a solution of the title compound from the Preparative Example 355 (50 mg) in MeOH (5 mL) was added thionyl chloride (150 μL). The resulting mixture was heated to reflux for 2 h and then concentrated. The remaining residue was dissolved in EtOH (10 mL), hydrazine monohydrate (100 μL) was added and the resulting mixture was heated to reflux for 2 h and then cooled to room temperature. The formed precipitate was collected by filtration to afford the title compound (69 mg, >99%). [MH]+=400.
Example 1711




Step A

To a solution of the title compound from the Example 1710, Step A (35 mg) in CHCl3 (2 mL) was added trifluoroacetic anhydride (1 mL). The resulting mixture was heated to 50° C. for 3 h, concentrated and dried in vacuo to afford the title compound (47 mg, >99%). [MH]+=496.
Examples 1712-1829
Following similar procedures as described in the Examples 1 (method A), 2 (method B), 3 (method C), 4 (method D), 5 (method E), 6 (method F) or 7 (method G), except using the acids and amines indicated in Table II-39 below, the following compounds were prepared.










TABLE II-39





Ex. #
acid, amine
product
method, yield







1712








C, 53% [MH]+ = 482


 


1713








B, 83% [MH]+ = 630


 


1714








E, 29% [MH]+ = 506


 


1715








E, 45% [MH]+ = 448


 


1716








E, 30% [MH]+ = 448


 


1717








E, 35% [MH]+ = 448


 


1718








E, 55% [MH]+ = 436


 


1719








E, 55% [MH]+ = 436


 


1720








E, 40% [MH]+ = 462


 


1721








E, 26% [MH]+ = 536


 


1722








E, 25% [MH]+ = 487


 


1723








E, 55% [MH]+ = 446


 


1724








E, 40% [MH]+ = 456


 


1725








E, n.d. [MH]+ = 522


 


1726








E, 25% [MH]+ = 506


 


1727








C, 76% [MNa]+ = 632


 


1728








C, 76% [MH]+ = 584


 


1729








C, 67% [MH]+ = 584


 


1730








C, 47% [MNa]+ = 698


 


1731








B, 91% [M − tBu]+ = 555


 


1732








C, 48% [MNa]+ = 594


 


1733








C, 90% [MNa]+ = 611


 


1734








C, 77% [MNa]+ = 614


 


1735








C, 53% [MNa]+ = 631


 


1736








C, n.d. [MH]+ = 565


 


1737








C, 20% [MH]+ = 615


 


1738








C, n.d. [MH]+ = 467


 


1739








C, n.d. [MH]+ = 518


 


1740








C, 58% [MH]+ = 550


 


1741








C, 36% [MH]+ = 518


 


1742








C, 19% [MH]+ = 564


 


1743








C, 86% [MH]+ = 507


 


1744








C, 89% [MH]+ = 493


 


1745








C, >99% [MH]+ = 525


 


1746








C, 95% [MH]+ = 523


 


1747








C, 72% [MH]+ = 533


 


1748








C, 26% [MH]+ = 423


 


1749








C, 32% [MH]+ = 439


 


1750








C, 25% [MH]+ = 475


 


1751








C, 51% [MH]+ = 493


 


1752








C, n.d. [MH]+ = 547


 


1753








B, 70% [MH]+ = 462 


 


1754








E, n.d. [MH]+ = 488


 


1755








G, 70% [MH]+ = 561


 


1756








G, 83% [MH]+ = 574 


 


1757








G, 66% [MH]+ = 554


 


1758








G, 97% [MH]+ = 559


 


1759








G, 79% [MH]+ = 516


 


1760








G, 90% [MNa]+ = 619


 


1761








G, 87% [MNa]+ = 596


 


1762








G, 89% [MH]+ = 567


 


1763








G, n.d. [MNa]+ = 614


 


1764








G, n.d. [MNa]+ = 633


 


1765








B, 91% [MH]+ = 637


 


1766








B, 50% [MH]+ = 456


 


1767








B, >99% [MNa]+ = 549


 


1768








B, 83% [MNa]+ = 521


 


1769








B, 82% [MNa]+ = 535


 


1770








B, 86% [MNa]+ = 535


 


1771








B, 87% [MNa]+ = 535


 


1772








B, 55% [MH]+ = 457


 


1773








B, 87% [MH]+ = 568


 


1774








B, 84% [MH]+ = 468


 


1775








B, 94% [MNa]+ = 563


 


1776








B, 91% [MH]+ = 456


 


1777








B, 98% [M − Boc]+ = 471


 


1778








B, 93% [M − Boc]+ = 473


 


1779








B, 78% [MH]+ = 509


 


1780








B, 77% [MH]+ = 482


 


1781








B, n.d. [MNa]+ = 652


 


1782








B, 82% [MH]+ = 485


 


1783








B, 68% [MH]+ = 491/493


 


1784








B, n.d. [MNa]+ = 634


 


1785








B, n.d. [MNa]+ = 636


 


1786








B, n.d. [MNa]+ = 646


 


1787








B, 88% [MH]+ = 524


 


1788








B, 72% [MH]+ = 581


 


1789








B, n.d. [MH]+ = 595


 


1790








B, 88% [MH]+ = 367


 


1791








E, 23% [MNa]+ = 642


 


1792








C, 59% [MH]+ = 533


 


1793








C, 79% [MH]+ = 533


 


1794








C, 44% [MH]+ = 533


 


1795








C, 59% [MH]+ = 547


 


1796








C, 75% [MH]+ = 539


 


1797








E, 67% [M − H]− = 636


 


1798








E, 85% [M − H]− = 642


 


1799








E, 55% [M − H]− = 520


 


1800








E, 65% [M − H]− = 636


 


1801








E, 44% [M − H]− = 642


 


1802








E, 81% [M − H]− = 560


 


1803








E, 31% [MH]+ = 411


 


1804








E, n.d. [M − H]− = 749


 


1805








C, 17% [MH]+ = 452


 


1806








C, 7% [(M − iPr2NEt)H]+ = 453


 


1807








F, 74% [MH]+ = 761


 


1808








F, 73% [MH]+ = 761


 


1809








F, 74% [MH]+ = 761


 


1810








F, 58% [MH]+ = 761


 


1811








F, 58% [MH]+ = 761


 


1812








F, 68% [MH]+ = 761


 


1813








C, 43% [MNa]+ = 623


 


1814








C, 50% [MNa]+ = 637


 


1815








C, 99% [MNa]+ = 651


 


1816








C, 85% [MH]+ = 665


 


1817








C, 50% [MNa]+ = 641


 


1818








C, 47% [MNa]+ = 677


 


1819








B, 19% [MH]+ = 456


 


1820








B, 64% [MH]+ = 512


 


1821








B, 74% [MH]+ = 524


 


1822








C, n.d. [MH]+ = 529


 


1823








C, 70% [MH]+ = 480


 


1824








C, >99% [MH]+ = 579


 


1825








C, 63% [MH]+ = 593


 


1826








C, n.d. [MNa]+ = 607


 


1827








C, n.d. [MH]+ = 538


 


1828








C, 42% [MH]+ = 538


 


1829








C, 17% [MH]+ = 537









Example 1830




Step A

To the title compound from the Example 1799 (500 mg) in CHCl3 (10 mL) was added N-iodosuccinimide (259 mg). The resulting mixture was stirred at 70° C. for 1 h, absorbed onto silica and purified by chromatography (silica) to afford the title compound (485 mg, 78%). [M-H]′=644.
Example 1831




Step A

The title compound from the Example 1802 (309 mg) was treated similarly as described in the Example 1830, Step A to afford the title compound (365 mg, 97%). [M-H]−=686.
Example 1832




Step A

A mixture of the title compound from the Example 1830, Step A (30 mg), Pd(PPh3)4 (5 mg) and NEt3 (50 μL) in DMSO/MeOH (1:1, 400 μL) was stirred at 80° C. under a carbon monoxide atmosphere at 1 atm for 18 h, diluted with 1N aqueous HCl and extracted with EtOAc (3×). The combined organic phases were washed with 1N aqueous HCl (2×) and saturated aqueous NaCl, dried (MgSO4), filtered, absorbed onto silica and purified by chromatography (silica) to afford the title compound (27 mg, 99%). [M-H]−=576.
Example 1833




Step A

The title compound from the Example 1831, Step A (393 mg) was treated similarly as described in the Example 1832, Step A to afford the title compound (195 mg, 55%). [M-H]−=618.
Example 1834




Step A

The title compound from the Example 1831, Step A (188 mg), Pd(OAc)2 (4.6 mg), dppf (32.2 mg) and KOAc (110 mg) were dissolved in dry DMSO (1.5 mL) and stirred at 60° C. under a carbon monoxide atmosphere at 1 atm for 18 h. The mixture was diluted with EtOAc, washed subsequently with 1N aqueous HCl (2×) and saturated aqueous NaCl, dried (MgSO4), filtered, absorbed onto silica and purified by chromatography (silica) to afford the title compound (150 mg, 85%). [M-H]−=604.
Example 1835




Step A

A mixture of the title compound from the Example 1830, Step A (30 mg), Pd(PPh3)4 (3 mg) and commercially available trimethyl(phenyl)tin (5 μL) in THF (250 μL) was stirred at 80° C. under an argon atmosphere for 2 d, absorbed onto silica and purified by chromatography (silica) to afford the title compound (9 mg, 66%). [M-H]′=594.
Example 1836




Step A

The title compound from the Example 1830, Step A (15 mg) was treated similarly as described in the Example 1835, Step A, except using commercially available (tributylstannyl)thiophene instead of trimethyl(phenyl)tin to afford the title compound (14 mg, 99%). [M-H]′=600.
Example 1837




Step A

A mixture of the title compound from the Example 1753 (7.8 mg) and Pd/C (10 wt %, 10 mg) in MeOH (5 mL) was hydrogenated at 30 psi for 12 h, filtered through Celite® and concentrated to afford the title compound (6.0 mg, 95%). [MH]+=356.
Examples 1838-1853
Following a similar procedure as described in the Examples 288, except using the esters and amines indicated in Table II-40 below, the following compounds were prepared.








TABLE II-40







Ex. #
ester, amine





1838






 


1839






 


1840






 


1841






 


1842






 


1843






 


1844






 


1845






 


1846






 


1847






 


1848






 


1849






 


1850






 


1851






 


1852



   7M NH3 in MeOH


 


1853
















Ex. #
product
yield





1838




18% [MH]+ = 570


 


1839




65% [M − H]− = 721


 


1840




>99% [M − H]− = 601


 


1841




48% [M − H]− = 601


 


1842




37% [M − H]− = 678


 


1843




40% [M − H]− = 748


 


1844




67% [M − H]− = 641


 


1845




73% [M − H]− = 669


 


1846




63% [M − H]− = 683


 


1847




68% [M − H]− = 681


 


1848




62% [M − H]− = 677


 


1849




70% [M − H]− = 677


 


1850




47% [M − H]− = 705


 


1851




42% [M − H]− = 732


 


1852




50% [MH]+ = 367


 


1853




n.d. [MNa]+ = 755









Example 1854




Step A

To an ice cooled (0-5° C.) mixture of the title compound from the Example 1834, Step A (150 mg) and DMF (2 μL) in CH2Cl2 (2.5 mL) was added oxalyl chloride (108 μL). The ice bath was removed and the mixture was stirred for 2 h and then concentrated. The resulting residue was brought up in acetone (1.5 mL) and cooled to 0-5° C. (ice bath). A solution of NaN3 (100 mg) in H2O (500 μL) was added and the ice bath was removed. The mixture was stirred at room temperature for 1 h, diluted with H2O (5 mL) and extracted with toluene (3×5 mL). The combined organic phases were dried (MgSO4), filtered, concentrated and diluted with toluene/tert-butanol (1:1, 2 mL). Molecular sieves 4 Å (100 mg) were added and the resulting mixture was heated to 100° C. for 11⁄2 h. Filtration, absorption onto silica and purification by chromatography (silica) to afforded the title compound (88 mg, 52%). [M-H]−=675.
Step B
To a solution of the title compound from Step a above (88 mg) in tBuOAc (1 mL) was added concentrated H2SO4 (35 mL). The resulting mixture was stirred at room temperature for 1 h and then diluted with saturated aqueous NaHCO3 (4 mL) and EtOAc (2 mL). The aqueous phase was separated and extracted with EtOAc (2×) and CH2Cl2 (2×). The combined organic phases were dried (MgSO4), filtered, absorbed onto silica and purified by chromatography (silica) to afford the title compound (36 mg, 50%). [MH]+=577.
Example 1855




Step A

To an ice cooled (0-5° C.) solution of commercially available benzenesulfonyl chloride (3.5 μL) in CH2Cl2 (100 μL) were added NEt3 (6 μL) and a solution of the title compound from the Example 1854, Step B (12 mg) in CH2Cl2 (100 μL). The ice bath was removed and the mixture was stirred at room temperature for 18 h and then concentrated. The remaining residue was purified by preparative thin layer chromatography (silica) to afford the title compound (3.1 mg, 21%). [M-H]′=715.
Example 1856




Step A

A mixture of the title compound from the Example 1854, Step B (12 mg) and commercially available phenyl isocyanate (3 μL) in CH2Cl2 (200 μL) was stirred at room temperature for 3 d, concentrated and purified by chromatography (silica) to afford the title compound (11 mg, 76%). [M-H]−=694.
Example 1857




Step A

To an ice cooled (0-5° C.) solution of commercially available benzoyl chloride (3 μL) in CH2Cl2 (100 μL) were added NEt3 (6 μL) and a solution of the title compound from the Example 1854, Step B (12 mg) in CH2Cl2 (100 μL). The ice bath was removed and the mixture was stirred at room temperature for 18 h and then concentrated. The remaining residue was purified by preparative thin layer chromatography (silica) to afford the title compound (11.2 mg, 79%). [M-H]−=679.
Example 1858




Step A

To a solution of the title compound from the Example HK119 (36 mg) in THF/H2O (3:1, 2.4 mL) was added a 1M aqueous KOH (210 μL). The mixture was stirred at room temperature for 3 h, concentrated and diluted with EtOAc (150 mL) and 10% aqueous citric acid (40 mL). The organic phase was separated, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a yellow solid (20.9 mg, 56%). [MH]+=525.
Example 1859




Step A

A solution of the title compound from the Example 1835, Step A (6 mg) and AlBr3 (7 mg) in tetrahydrothiophene was stirred at room temperature for 16 h, absorbed onto silica and purified by chromatography (silica) to afford the title compound (3 mg, 52%). [M-H]−=580.
Examples 1860-1879
Following similar procedures as described in the Examples 314 (method A), 315 (method B), 1858 (method C) or 1859 (method D), except using the esters indicated in Table II-41 below, the following compounds were prepared.








TABLE II-41







Ex. #
ester





1860






 


1861






 


1862






 


1863






 


1864






 


1865






 


1866






 


1867






 


1868






 


1869






 


1870






 


1871






 


1872






 


1873






 


1874






 


1875






 


1876






 


1877






 


1878






 


1879


















method,


Ex. #
product
yield





1860




B, 50% [M − H]− = 490


 


1861




A, n.d. [MH]+ = 533


 


1862




B, 90% [MH]+ = 570


 


1863




B, 43% [MH]+ = 560


 


1864




B, 66% [MH]+ = 554


 


1865




B, 20% [MH]+ = 545


 


1866




B, 86% [MNa]+ = 628


 


1867




C, 21% [MH]+ = 519


 


1868




C, 56% [MH]+ = 519


 


1869




C, 6% [MH]+ = 519


 


1870




C, 15% [MH]+ = 533


 


1871




D, 43% [M − H]− = 562


 


1872




D, 28% [M − H]− = 586


 


1873




B, 17% [MH]+ = 515


 


1874




A, 21% [MH]+ = 466


 


1875




A, 12% [MH]+ = 565


 


1876




A, 34% [MH]+ = 579


 


1877




A, 19% [MH]+ = 593


 


1878




A, n.d. [MH]+ = 524


 


1879




A, 29% [MH]+ = 523









Examples 1880-1884
Following a similar procedure as described in the Example 362, except using the esters indicated in Table II-42 below, the following compounds were prepared.








TABLE II-42







Ex. #
ester





1880






 


1881






 


1882






 


1883






 


1884
















Ex. #
product
yield





1880




75% [MH]+ = 532


 


1881




43% [MH]+ = 571


 


1882




43% [MH]+ = 574


 


1883




19% [MH]+ = 591


 


1884




28% (over 2 steps) [MH]+ = 555









Example 1885




Step A

The title compound from the Example 1767 (27.5 mg) was stirred in formic acid (4 mL) at room temperature for 2 h and then concentrated to afford the title compound as a yellow solid (15.5 mg; 63%). [MH]+=471.
Examples 1886-1954
Following similar procedures as described in the Examples 436 (method A) or 1885 (method B), except using the esters as indicated in Table II-43 below, the following compounds were prepared.








TABLE II-43







Ex. #
ester





1886






 


1887






 


1888






 


1889






 


1890






 


1891






 


1892






 


1893






 


1894






 


1895






 


1896






 


1897






 


1898






 


1899






 


1900






 


1901






 


1902






 


1903






 


1904






 


1905






 


1906






 


1907






 


1908






 


1909






 


1910






 


1911






 


1912






 


1913






 


1914






 


1915






 


1916






 


1917






 


1918






 


1919






 


1920






 


1921






 


1922






 


1923






 


1924






 


1925






 


1926






 


1927






 


1928






 


1929






 


1930






 


1931






 


1932






 


1933






 


1934






 


1935






 


1936






 


1937






 


1938






 


1939






 


1940






 


1941






 


1942






 


1943






 


1944






 


1945






 


1946






 


1947






 


1948






 


1949






 


1950






 


1951






 


1952






 


1953






 


1954


















method,


Ex. #
product
yield





1886




A, 95% [M − H]− = 478


 


1887




A, 77% [M − H]− = 388


 


1888




A, 16% (over 2 steps) [M − H]− = 464


 


1889




A, 62% [M − H]− = 450


 


1890




A, >99% [MH]+ = 554


 


1891




A, >99% [MH]+ = 528


 


1892




A, >99% [MH]+ = 528


 


1893




A, >99% [MH]+ = 620


 


1894




A, >99% [MH]+ = 555


 


1895




A, 6% (over 2 steps) [MH]+ = 509


 


1896




A, >99% [MH]+ = 559


 


1897




A, 99% [MH]+ = 514


 


1898




A, 94% [M − H]− = 665


 


1899




A, >99% [M − H]− = 601


 


1900




A, >99% [M − (TFA + H)]− = 636


 


1901




A, >99% [M − (TFA + H)]− = 622


 


1902




A, >99% [M − H]− = 692


 


1903




A, >99% [M − H]− = 585


 


1904




A, >99% [M − H]− = 613


 


1905




A, 94% [M − H]− = 627


 


1906




A, >99% [M − H]− = 625


 


1907




A, 86% [M − H]− = 621


 


1908




A, 79% [M − H]− = 653


 


1909




A, 68% [M − H]− = 649


 


1910




A, >99% [M − (TFA + H)]− = 676


 


1911




A, 98% [MH]+ = 541


 


1912




A, 89% [MH]+ = 518


 


1913




A, 13% [MH]+ = 511


 


1914




A, 12% (over 2 steps) [MH]+ = 536


 


1915




A, 18% (over 2 steps) [MH]+ = 555


 


1916




B, 73% [MH]+ = 443


 


1917




B, 87% [MH]+ = 457


 


1918




B, 59% [MH]+ = 457


 


1919




B, 80% [MH]+ = 457


 


1920




B, 74% [MH]+ = 512


 


1921




B, 59% (over 2 steps) [MH]+ = 574


 


1922




B, 56% (over 2 steps) [MH]+ = 556


 


1923




B, 34% (over 2 steps) [MH]+ = 558


 


1924




B, 53% (over 2 steps) [MH]+ = 568


 


1925




A, 99% [MH]+ = 564


 


1926




A, n.d. [MH]+ = 675


 


1927




A, 78% [M − H]− = 580


 


1928




A, 78% [M − H]− = 586


 


1929




A, 68% [M − H]− = 580


 


1930




A, 62% [M − H]− = 586


 


1931




A, 25% [M − H]− = 693


 


1932




A, 99% [M − H]− = 561


 


1933




A, 82% [M − H]− = 617


 


1934




A, 99% [M − H]− = 637


 


1935




A, 99% [M − H]− = 657


 


1936




A, 99% [M − H]− = 548


 


1937




A, 99% [M − H]− = 562


 


1938




A, 99% [M − H]− = 547


 


1939




A, 63% [M − H]− = 659


 


1940




A, 94% [M − H]− = 638


 


1941




A, n.d. [M − H]− = 623


 


1942




B, 46% [MH]+ = 649


 


1943




B, 53% [MH]+ = 649


 


1944




B, 39% [MH]+ = 649


 


1945




B, 52% [MH]+ = 649


 


1946




B, 62% [MH]+ = 649


 


1947




B, 57% [MH]+ = 649


 


1948




A, 99% [MH]+ = 545


 


1949




A, 90% [MH]+ = 559


 


1950




A, 48% [MH]+ = 573


 


1951




A, 34% [MH]+ = 587


 


1952




A, 90% [MH]+ = 563


 


1953




A, 99% [MH]+ = 599


 


1954




B, n.d. [MH]+ = 587









Example 1955




Step A

To a mixture of N-cyclohexyl-carbodiimide-N′-methyl-polystyrene (30 mg) in DMA (340 μL) were added a 0.2M solution of the title compound from the Preparative Example 337 in DMA (85 μL) and a 0.5M solution of HOBt in DMA (45 μL). The mixture was agitated for 15 min, then a 0.5M solution of morpholine in DMA (30 μL) was added and the mixture was heated in a sealed tube at 100° C. (microwave) for 5 min. (Plystyrylmethyl)-trimethylammonium bicarbonate (20 mg) was added and the mixture was agitated at room temperature for 3 h. Then the mixture was filtered, concentrated, diluted with formic acid (100 μL) and stirred at room temperature for 5 h. Concentration afforded the title compound as a pale yellow solid, which was used without further purification. [MH]+=450.
Examples 1956-2138
Following a similar procedure as described in the Example 1955, except using amines indicated in Table II-44 below, the following compounds were prepared.










TABLE II-44





Ex. #
amine
product
yield







1956








n.d. [MH]+ =  438


 


1957








n.d. [MH]+ =  514


 


1958








n.d. [MH]+ =  550


 


1959








n.d. [MH]+ =  460


 


1960








n.d. [MH]+ =  500


 


1961








n.d. [MH]+ =  488


 


1962








n.d. [MH]+ =  434


 


1963








n.d. [MH]+ = 488


 


1964








n.d. [MH]+ =  544


 


1965








n.d. [MH]+ =  448


 


1966








n.d. [MH]+ =  450


 


1967








n.d. [MH]+ =  422


 


1968








n.d. [MH]+ =  448


 


1969








n.d. [MH]+ =  470


 


1970








n.d. [MH]+ =  476


 


1971








n.d. [MH]+ = 478


 


1972








n.d. [MH]+ =  408


 


1973








n.d. [MH]+ =  462


 


1974








n.d. [MH]+ =  451


 


1975








n.d. [MH]+ =  492


 


1976








n.d. [MH]+ =  548


 


1977








n.d. [MH]+ =  394


 


1978








n.d. [MH]+ =  464


 


1979








n.d. [MH]+ =  590


 


1980








n.d. [MH]+ =  500


 


1981








n.d. [MH]+ =  500


 


1982








n.d. [MH]+ =  484


 


1983








n.d. [MH]+ =  464


 


1984








n.d. [MH]+ =  464


 


1985








n.d. [MH]+ =  498


 


1986








n.d. [MH]+ =  461


 


1987








n.d. [MH]+ =  452


 


1988








n.d. [MH]+ =  508


 


1989








n.d. [MH]+ =  502


 


1990








n.d. [MH]+ =  463


 


1991








n.d. [MH]+ =  520


 


1992








n.d. [MH]+ =  568


 


1993








n.d. [MH]+ =  481


 


1994








n.d. [MH]+ =  512


 


1995








n.d. [MH]+ =  510


 


1996








n.d. [MH]+ =  437


 


1997








n.d. [MH]+ =  471


 


1998








n.d. [MH]+ =  484


 


1999








n.d. [MH]+ =  484


 


2000








n.d. [MH]+ =  463


 


2001








n.d. [MH]+ =  549


 


2002








n.d. [MH]+ =  480


 


2003








n.d. [MH]+ =  466


 


2004








n.d. [MH]+ =  502


 


2005








n.d. [MH]+ =  551


 


2006








n.d. [MH]+ =  460


 


2007








n.d. [MH]+ =  465


 


2008








n.d. [MH]+ =  418


 


2009








n.d. [MH]+ =  549


 


2010








n.d. [MH]+ =  554


 


2011








n.d. [MH]+ =  528


 


2012








n.d. [MH]+ =  482


 


2013








n.d. [MH]+ =  651


 


2014








n.d. [MH]+ = 527.622


 


2015








n.d. [MH]+ =  502


 


2016








n.d. [MH]+ =  502


 


2017








n.d. [MH]+ =  530


 


2018








n.d. [MH]+ =  546


 


2019








n.d. [MH]+ =  500


 


2020








n.d. [MH]+ =  500


 


2021








n.d. [MH]+ =  528


 


2022








n.d. [MH]+ =  528


 


2023








n.d. [MH]+ =  528


 


2024








n.d. [MH]+ =  510


 


2025








n.d. [MH]+ =  491


 


2026








n.d. [MH]+ =  510


 


2027








n.d. [MH]+ =  596


 


2028








n.d. [MH]+ =  496


 


2029








n.d. [MH]+ =  496


 


2030








n.d. [MH]+ =  610


 


2031








n.d. [MH]+ =  500


 


2032








n.d. [MH]+ =  547


 


2033








n.d. [MH]+ =  464


 


2034








n.d. [MH]+ =  555


 


2035








n.d. [MH]+ =  555


 


2036








n.d. [MH]+ =  511


 


2037








n.d. [MH]+ =  545


 


2038








n.d. [MH]+ =  516


 


2039








n.d. [MH]+ =  534


 


2040








n.d. [MH]+ =  492


 


2041








n.d. [MH]+ =  459


 


2042








n.d. [MH]+ =  477


 


2043








n.d. [MH]+ =  436


 


2044








n.d. [MH]+ =  528


 


2045








n.d. [MH]+ =  528


 


2046








n.d. [MH]+ =  521


 


2047








n.d. [MH]+ =  572


 


2048








n.d. [MH]+ =  526


 


2049








n.d. [MH]+ =  538


 


2050








n.d. [MH]+ =  544


 


2051








n.d. [MH]+ =  538


 


2052








n.d. [MH]+ =  484


 


2053








n.d. [MH]+ =  513


 


2054








n.d. [MH]+ =  520


 


2055








n.d. [MH]+ =  484


 


2056








n.d. [MH]+ =  538


 


2057








n.d. [MH]+ =  488


 


2058








n.d. [MH]+ =  490


 


2059








n.d. [MH]+ =  490


 


2060








n.d. [MH]+ =  464


 


2061








n.d. [MH]+ =  450


 


2062








n.d. [MH]+ =  476


 


2063








n.d. [MH]+ =  555


 


2064








n.d. [MH]+ =  501


 


2065








n.d. [MH]+ =  550


 


2066








n.d. [MH]+ =  526


 


2067








n.d. [MH]+ =  540


 


2068








n.d. [MH]+ =  527


 


2069








n.d. [MH]+ =  541


 


2070








n.d. [MH]+ =  541


 


2071








n.d. [MH]+ =  541


 


2072








n.d. [MH]+ =  554


 


2073








n.d. [MH]+ =  594


 


2074








n.d. [MH]+ =  549


 


2075








n.d. [MH]+ =  622


 


2076








n.d. [MH]+ =  538


 


2077








n.d. [MH]+ =  608


 


2078








n.d. [MH]+ =  612


 


2079








n.d. [MH]+ =  626


 


2080








n.d. [MH]+ =  626


 


2081








n.d. [MH]+ =  620


 


2082








n.d. [MH]+ =  560


 


2083








n.d. [MH]+ =  512


 


2084








n.d. [MH]+ =  498


 


2085








n.d. [MH]+ =  498


 


2086








n.d. [MH]+ =  498


 


2087








n.d. [MH]+ =  450


 


2088








n.d. [MH]+ =  468


 


2089








n.d. [MH]+ =  436


 


2090








n.d. [MH]+ =  436


 


2091








n.d. [MH]+ =  490


 


2092








n.d. [MH]+ =  464


 


2093








n.d. [MH]+ =  526


 


2094








n.d. [MH]+ =  555


 


2095








n.d. [MH]+ =  510


 


2096








n.d. [MH]+ =  569


 


2097








n.d. [MH]+ =  554


 


2098








n.d. [MH]+ =  471


 


2099








n.d. [MH]+ =  485


 


2100








n.d. [MH]+ =  555


 


2101








n.d. [MH]+ =  568


 


2102








n.d. [MH]+ =  554


 


2103








n.d. [MH]+ =  517


 


2104








n.d. [MH]+ =  478


 


2105








n.d. [MH]+ =  519


 


2106








n.d. [MH]+ =  512


 


2107








n.d. [MH]+ =  534


 


2108








n.d. [MH]+ =  567


 


2109








n.d. [MH]+ =  495


 


2110








n.d. [MH]+ =  460


 


2111








n.d. [MH]+ =  476


 


2112








n.d. [MH]+ =  462


 


2113








n.d. [MH]+ =  512


 


2114








n.d. [MH]+ =  534


 


2115








n.d. [MH]+ =  556


 


2116








n.d. [MH]+ =  556


 


2117








n.d. [MH]+ =  528


 


2118








n.d. [MH]+ =  544


 


2119








n.d. [MH]+ =  544


 


2120








n.d. [MH]+ =  555


 


2121








n.d. [MH]+ =  532


 


2122








n.d. [MH]+ =  539


 


2123








n.d. [MH]+ =  512


 


2124








n.d. [MH]+ =  477


 


2125








n.d. [MH]+ =  486


 


2126








n.d. [MH]+ =  480


 


2127








n.d. [MH]+ =  519


 


2128








n.d. [MH]+ =  519


 


2129








n.d. [MH]+ =  569


 


2130








n.d. [MH]+ =  539


 


2131








n.d. [MH]+ =  528


 


2132








n.d. [MH]+ =  501


 


2133








n.d. [MH]+ =  484


 


2134








n.d. [MH]+ =  563


 


2135








n.d. [MH]+ =  438


 


2136








n.d. [MH]+ =  438


 


2137








n.d. [MH]+ =  513


 


2138








n.d. [MH]+ =  513









Example 2139




Step A

The title compound from the Example 1925 (3.6 mg) was treated similarly as described in the Example 314, except using NaOH instead of LiOH to afford the title compound as a yellow solid (2.2 mg, 60%). [MH]+=550.
Example 2140




Step A

A solution of the title compound from the Example 1791 (5 mg) in a 7M solution of NH3 in MeOH (1 mL) was heated to reflux overnight, concentrated and purified by chromatography (silica) to afford the title compound as a yellow solid (4.5 mg, 90%). [MH]+=605.
Example 2141




Step A

The title compound from the Preparative Example 974, Step A (6.4 mg) was treated similarly as described in the Example 2140, Step A to afford the title compound as a yellow solid (5.6 mg, 90%). [MH]+=485.
Example 2142




Step A

The title compound from the Example 1833, Step A (15 mg) was treated similarly as described in the Example 2140, Step A to afford the title compound (2.5 mg, 17%). [M-H]′=603.
Examples 2143-2213
Following similar procedures as described in the Examples 1 (method A), 2 (method B), 3 (method C), 4 (method D), 5 (method E), 6 (method F) or 7 (method G), except using the acids and amines or alcohols indicated in Table II-45 below, the following compounds were prepared.










TABLE II-45









Ex. #
acid, amine or alcohol







2143







 



2144







 



2145







 



2146







 



2147







 



2148







 



2149







 



2150







 



2151







 



2152







 



2153







2154







 



2155







 



2156







 



2157







 



2158







 



2159







 



2160







 



2161







 



2162







 



2163







 



2164







 



2165







 



2166







 



2167







 



2168







 



2169







 



2170







 



2171







 



2172







 



2173







 



2174







 



2175







 



2176







 



2177







 



2178







 



2179







 



2180







 



2181







 



2182







 



2183







 



2184







 



2185







 



2186







 



2187







 



2188







 



2189







 



2190







 



2191







 



2192







 



2193







 



2194







 



2195







 



2196







 



2197







 



2198







 



2199







 



2200







 



2201







 



2202







 



2203







 



2204







 



2205







 



2206







 



2207







 



2208







 



2209







 



2210







 



2211







 



2212







 



2213



















Ex. #
product
method, yield







2143




B, 74% [MH]+ = 629



 



2144




B, 79% [MH]+ = 685



 



2145




B, 77% [MH]+ = 741



 



2146




B, 54% [MH]+ = 686



 



2147




B, 95% [MH]+ = 624



 



2148




B, 92% [MH]+ = 654



 



2149




B, 94% [MH]+ = 727



 



2150




B, >99% [MH]+ = 572



 



2151




B, 78% [MH]+ = 743



 



2152




E, 68% [(MH2)/2]+ = 399



 



2153




E, n.d. [M − H]− = 679



 



2154




E, n.d. [M − H]− = 714



 



2155




E, n.d. [M − H]− = 709



 



2156




E, 40% [M − H]− = 686



 



2157




E, 39% [M − H]− = 693



 



2158




E, 25% [M − H]− = 714



 



2159




E, 35% [M − H]− = 714



 



2160




E, 41% [M − H]− = 669



 



2161




E, 12% [M − H]− = 737



 



2162




E, 76% [M − H]− = 705



 



2163




E, 40% [MNa]+ = 610



 



2164




E, 41% [MNa]+ = 624



 



2165




E, 9% [MH]+ = 687



 



2166




E, 62% [M − H]− = 671



 



2167




E, 87% [M − H]− = 651



 



2168




E, 99% [M − H]− = 655



 



2169




E, 78% [M − H]− = 667



 



2170




E, 65% [M − H]− = 667



 



2171




E, 99% [M − H]− = 685



 



2172




E, 83% [M − H]− = 697



 



2173




E, 80% [M − H]− = 747



 



2174




E, 77% [M − H]− = 697



 



2175




E, 59% [M − H]− = 747



 



2176




E, 76% [M − H]− = 693



 



2177




E, 85% [M − H]− = 680



 



2178




E, 65% [M − H]− = 695



 



2179




E, 70% [M − H]− = 695



 



2180




B, 39% [MH]+ = 498



 



2181




B, 35% [MH]+ = 484



 



2182




D, 40% [MH]+ = 590



 



2183




B, 11% [MH]+ = 601



 



2184




B, 22% [MH]+ = 671



 



2185




B, 10% [MNa]+ = 713



 



2186




B, 92% [MH]+ = 687



 



2187




B, 76% [MH]+ = 568



 



2188




B, 4% [MH]+ = 598



 



2189




E, 4% 1H-NMR (DMSO-d6) δ = 10.07 (t, 1 H), 9.73 (t, 1 H), 8.60 (d, 1 H), 8.11 (s, 1 H), 7.58 (d, 1 H), 7.39 (d, 2 H),7.15 (d, 1 H), 4.52 (d, 2 H), 4.00 (t, 1 H), 3.29 (d, 2 H), 2.31-2.12 (m, 4 H), 1.75-1.12 (m, 20 H).



 



2190




E, 73% [MNA]+ = 710.



 



2191




A, 99% [MH]+ = 695



 



2192




E, 99% [MH]+ = 659



 



2193




E, n.d. [MNa]+ = 681



 



2194




A, 67% [MNa]+ = 671



 



2195




E, 20% [MH]+ = 595



 



2196




E, 20% [MH]+ = 633



 



2197




E, 17% [MH]+ = 599



 



2198




E, 75% [MH]+ = 701



 



2199




E, 35% [MH]+ = 689



 



2200




E, n.d. [MH]+ = 619



 



2201




E, 66% [M − H]− = 617



 



2202




E, 73% [M − H]− = 673



 



2203




E, 72% [M − H]− = 693



 



2204




E, 65% [M − H]− = 713



 



2205




E, 23% [MNa]+ = 710



 



2206




C, 30% [MH]+ = 524



 



2207




C, 12% [MH]+ = 578 



 



2208




C, n.d. [MNa]+ = 604



 



2209




C, 77% [MH]+ = 476



 



2210




C, 46% [MH]+ = 526



 



2211




C, 34% [MH]+ = 564



 



2212




C, 40% [MH]+ = 539



 



2213




C, 91% [MH]+ = 524










Example 2214




Step A

The title compound from the Example 2208 was treated similarly as described in the Example 296, Step B to afford the title compound. [M-Cl]+=482.
Example 2215




Step A

To an ice cooled (0-5° C.) solution of the title compound from the Example 1834 (25 mg) in THF (1 mL) was added BH3.THF complex (120 μL). The resulting mixture was stirred for 24 h while warming to room temperature, cooled to 0-5° C. (ice bath), hydrolyzed with 1M aqueous HCl (2 mL) and extracted with CH2Cl2 (3×5 mL). The combined organic phases were dried (MgSO4), filtered, concentrated and purified by chromatography (silica, hexanes/EtOAc) to afford the title compound as a yellow solid (5 mg, 23%). [MH]+=592.
Step B
To a solution of the title compound from Step A above (5 mg) in CH2Cl2 (1 mL) were sequentially added molecular sieves 4A (100 mg), N-methylmorpholine N-oxide (2 mg) and TPAP (0.5 mg). The resulting black mixture was stirred at room temperature for 3 h, filtered through Celite® and concentrated to afford the title compound (5 mg, 98%). [MH]+=590.
Step C
To a solution of the title compound from Step B above (5 mg) in MeOH (2 mL) were added NaBH3CN (1.6 mg) and AcOH (50 μL). The resulting mixture was stirred at room temperature overnight, concentrated and purified by preparative thin layer chromatography (silica, hexanes/EtOAc) to afford the title compound as a yellow solid (2 mg, 35%). [MNa]+=723.
Examples 2216-2220
Following a similar procedure as described in the Example 1859, except using the esters indicated in Table II-46 below, the following compounds were prepared.








TABLE II-46







Ex. #
ester





2216






 


2217






 


2218






 


2219






 


2220
















Ex. #
product
yield





2216




40% [M − H]− = 657


 


2217




34% [M − H]− = 653


 


2218




55% [M − H]− = 637


 


2219




40% [M − H]− = 637


 


2220




B, 35% [MH]+ = 619









Examples 2221-2255
Following similar procedures as described in the Example 436 (method A) and the Example 1885 (method B), except using the esters as indicated in Table H-47 below, the following compounds were prepared.








TABLE II-47







Ex. #
ester





2221






 


2222






 


2223






 


2224






 


2225






 


2226






 


2227






 


2228






 


2229






 


2230






 


2231






 


2232






 


2233






 


2234






 


2235






 


2236






 


2237






 


2238






 


2239






 


2240






 


2241






 


2242






 


2243






 


2244






 


2245






 


2246






 


2247






 


2248






 


2249






 


2250






 


2251






 


2252






 


2253






 


2254






 


2255
















Ex. #
product
method, yield





2221




B, 92% [MH]+ = 598


 


2222




B, 96% [MH]+ = 671


 


2223




B, >99% [MH]+ = 671


 


2224




B, 93% [MH]+ = 687


 


2225




A, 17% (over 2 steps) [M − H]− = 623


 


2226




A, 42% (over 2 steps) [M − H]− = 658


 


2227




A, 45% (over 2 steps) [M − H]− = 653


 


2228




A, 91% [M − H]− = 630


 


2229




A, 82% [M − H]− = 637


 


2230




A, 50% [M − H]− = 658


 


2231




A, 50% [M − H]− = 658


 


2232




A, 95% [M − H]− = 613


 


2233




A, 70% [M − H]− = 681


 


2234




A, 97% [M − H]− = 649


 


2235




A, 85% [M − H]− = 629


 


2236




A, >99% [M − H]− = 641


 


2237




A, >99% [M − H]− = 691


 


2238




A, 69% [M − H]− = 641


 


2239




A, 59% [M − H]− = 691


 


2240




A, >99% [M − H]− = 637


 


2241




A, 79% [M − (TFA + H)]− = 624


 


2242




A, >99% [M − H]− = 639


 


2243




A, >99% [M − H]− = 639


 


2244




B, 68% [MH]+ = 631


 


2245




B, 83% [MH]+ = 632


 


2246




A, 99% [MH]+ = 549


 


2247




A, 99% [MH]+ = 639


 


2248




A, 99% [MH]+ = 603


 


2249




A, 99% [MH]+ = 625


 


2250




A, 99% [M H]+ = 593


 


2251




A, 99% [MH]+ = 654


 


2252




A, 99% [MH]+ = 643


 


2253




A, 99% [MH]+ = 645


 


2254




A, 99% [MH]+ = 633


 


2255




A, n.d. [M − H]− = 561









Example 2256




Step A

To a solution of the title compound from the Example 2205 (11 mg) in CH2Cl2 (1 mL) was added a 50% aqueous solution of trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for 6 h, diluted with CH2Cl2 (30 mL), washed with saturated aqueous NaHCO3, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound (8.5 mg, 81%). [MNa]+=670.
Example 2257




Step A

To a degassed solution of the title compound from the Preparative Example 377, Step E (30 mg) and the title compound from the Preparative Example 19, Step B (25 mg) in DMF (2 mL) were added Pd(OAc)2 (1 mg), BINAP (3 mg) and KOtBu (10 mg). The resulting mixture was heated to 180° C. (microwave) for 30 min, cooled, concentrated, diluted with EtOAc, washed with 0.1M aqueous HCl and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (6.5 mg, 15%). [MH]+=466.
Examples 2258-2296
Following a similar procedure as described in the Example 479, except using the amines and carbonyl compounds indicated in Table II-48 below, the following compounds were prepared.










TABLE II-48






amine,




Ex. #
carbonyl compound
product
yield







2258



   







13% [MH]+ = 428


 


2259



   







53% [MH]+ = 501


 


2260



   







14% [MH]+ = 461


 


2261



   







46% [MH]+ = 482


 


2262



   







51% [MH]+ = 475


 


2263



   







42% [MH]+ = 485


 


2264



   







50% [MH]+ = 479


 


2265



   







27% [MH]+ = 441


 


2266



   







22% [MH]+ = 450


 


2267



   







32% [MH]+ = 496


 


2268



   







95% [MH]+ = 490


 


2269



   







54% [MH]+ = 547


 


2270



   







n.d. [MH]+ = 483


 


2271



   







n.d. [MH]+ = 469


 


2272



   







n.d. [MH]+ = 534


 


2273



   







n.d. [MNa]+ = 573


 


2274



   







n.d. [MNa]+ = 607


 


2275



   







n.d. [MNa]+ = 557


 


2276



   







n.d. [MNa]+ = 592


 


2277



   







73% [MH]+ = 474


 


2278



   







24% [MH]+ = 494


 


2279



   







n.d. [MH]+ = 520


 


2280



   







14% [MH]+ = 519


 


2281



   







10% [MH]+ = 493


 


2282



   







89% [MH]+ = 489


 


2283



   







86% [MH]+ = 497


 


2284



   







15% [MH]+ = 535


 


2285



   







80% [MH]+ = 491


 


2286



   







52% [MH]+ = 413


 


2287



   







82% [MH]+ = 463


 


2288



   







58% [MH]+ = 466


 


2289



   







82% [MH]+ = 379


 


2290



 







78% [MH]+ = 469


 


2291



   







40% [MH]+ = 412


 


2292



   







38% [MH]+ = 461


 


2293



   







67% [MH]+ = 433


 


2294



 







5% [MH]+ = 491


 


2295



   







7% [MH]+ = 377


 


2296



   







52% [MH]+ = 363









Example 2297




Step A
To a solution of the title compound from Example 2268 (10 mg) in anhydrous CH3CN (1.5 mL) was added trimethylsilyl bromide (2.6 μL) at 25° C. The resulting mixture was stirred at room temperature for 24 h, concentrated and purified by HPLC (RP-C18, AcCN/H2O) to afford the title compound (1.0 mg, 11%). [MH]+=491.
Example 2298




Step A

The crude  ̃1:1 mixture of the carboxylate I and the carboxylate II from the Preparative Example 1047 was treated similarly as described in the Example 2 to afford the title compound I (5.3 mg, 16%, [MH]+=468) and the title compound II (4.8 mg, 11%, [MH]+=647).
Examples 2299-2312
Following similar procedures as described in the Examples 1 (method A), 2 (method B), 3 (method C), 4 (method D), 5 (method E), 6 (method F) or 7 (method G), except using the acids and amines indicated in Table II-49 below, the following compounds were prepared.










TABLE II-49





Ex.


method,


#
acid, amine
product
yield







2299



   







B, 50% (over 2  steps) [MH]+ = 460


 


2300



   







B, 34% (over 2  steps) [MH]+ =  354


 


2301



   







B, 31% (over 2  steps) [MH]+ =  368


 


2302



   







B, 46% (over 2  steps) [MH]+ =  352


 


2303



   







B, 47% (over 2  steps) [MH]+ =  390


 


2304



   







B, 40% (over 2  steps) [MH]+ =  350


 


2305



   







B, 32% (over 2  steps) [MH]+ = 310


 


2306



   







B, 24% (over 2  steps) [MH]+ =  323


 


2307



   







B, 30% (over 2  steps) [MH]+ =  323


 


2308



   







B, 8.8% (over 2  steps) [MH]+ = 297


 


2309



   







B, 20% (over 2  steps) [MH]+ =  335


 


2310



   







B, 37% (over 2  steps) [MH]+ =  335


 


2311



   







B, 88% [MH]+ = 439


 


2312



   







B, 95% (over 2  steps) [MH]+ =  561/563









Example 2313




Step A

A mixture of the title compound from the Example 2311 (53 mg) in a 4M solution of HCl in 1,4-dioxane (3 mL) was stirred at room temperature for 3 h and then concentrated. The remaining residue was added to solution of NaBH3CN (16 mg) in MeOH (2 mL). To the resulting solution was slowly added a solution of the title compound from the Preparative Example 1031, Step A (25 mg) in THF/MeOH (1:1, 1 mL) over a period of 7 h. Then the mixture was concentrated, diluted with saturated aqueous NaHCO3 and extracted with EtOAc (3×). The combined organic phases were dried (MgSO4), filtered, absorbed onto silica and purified by chromatography (silica) to afford the title compound (23 mg, 36%). [MH]+=529.
Step B
To an ice cooled (0-5° C.) solution of the title compound from Step A above (9 mg) in THF (2 mL) was added a 1M solution of tert.-butyl magnesium chloride (60 μL). The resulting mixture was stirred at 0-5° C. (ice bath) for 11⁄2 h, diluted with saturated aqueous NaHCO3 and extracted with EtOAc (3×). The combined organic phases were dried (MgSO4), filtered, concentrated and purified by preparative thin layer chromatography (silica, EtOAc) to afford the title compound as a light yellow solid (1.7 mg, 20%). [MH]+=483.
Example 2314




Step A

To the title compound from the Example 2311 (23.2 mg) was added a 4M solution of HCl in 1,4-dioxane (940 μL). The resulting mixture was stirred at room temperature for 3 h and then concentrated. The obtained residue was suspended in pyridine (800 μL), the title compound from Preparative Example 1022 (10.5 μL) was added and the resulting mixture was stirred at room temperature for 3 h. The mixture was concentrated, diluted with 10% aqueous citric acid (5 mL), sonicated for  ̃1 min and allowed to stand at room temperature for 30 min. The formed precipitate was collected by filtration, washed with H2O (5 mL) and dried in vacuo to afford the title compound as yellow solid (16.8 mg, 63%). [MH]+=501.
Examples 2315-2322
Following a similar procedure as described in the Example 2314, except using the acid chlorides indicated in Table II-50 below, the following compounds were prepared.










TABLE II-50





Ex. #
acid chloride
Product
yield







2315








96% [MH]+ = 407


 


2316








14% [MH]+ = 439


 


2317








24% [MH]+ = 453


 


2318








52% [MH]+ = 467


 


2319








45% [MH]+ = 465


 


2320








47% [MH]+ = 465


 


2321








35% [MH]+ = 423


 


2322








50% [MH]+ = 479









Example 2323




Step A

To a solution of the title compound from the Example 2314, Step A (13 mg) in THF/H2O (1:1, 2 mL) was added a 1M aqueous KOH (140 μL). The mixture was stirred at room temperature for 2 h, concentrated, diluted with a 0.1M aqueous HCl (3 mL), sonicated for  ̃1 min and allowed to stand at room temperature for 30 min. The formed precipitate was collected by filtration, washed with H2O (5 mL) and dried in vacuo to afford the title compound (11.7 mg, 92%). [MH]+=487.
Examples 2324-2336
Following similar procedures as described in the Examples 314 (method A), 315 (method B) or 2314 (method C), except using the esters indicated in Table II-51 below, the following compounds were prepared.










TABLE II-51





Ex.


method,


#
ester
product
yield







2324








A, 57% (over 2 step) [MH]+ = 456


 


2325








A, 32% (over 2 step) [MH]+ = 469


 


2326








A, 100% [MH]+ = 487


 


2327








B, 78% [MH]+ = 487


 


2328








A, 98% [MH]+ = 480


 


2329








A, 18% (over 2 step) [MH]+ = 506,


 


2330








C, 29% [MH]+ = 487


 


2331








C, 9% [MH]+ = 487


 


2332








C, 98% [MH]+ = 439


 


2333








C, 69% [MH]+ = 453


 


2334








C, 91% [MH]+ = 451


 


2335








C, 92% [MH]+ = 465


 


2336








A, >99% [MH]+ = 521









Examples 2337-2341
Following a similar procedure as described in the Example 436, except using the esters indicated in Table II-52 below, the following compounds were prepared.










TABLE II-52





Ex. 





#
ester
Product
yield







2337








66% (over 2 steps) [MH]+ = 456


 


2338








23% (over 2 steps) [MH]+ = 495


 


2339








18% (over 2 steps) [MH]+ =  529


 


2340








52% (over 2 steps) [MH]+ = 479


 


2341








32% (over 2 steps) [MH]+ = 514









Example 2342




Step A

To a suspension of the title compound from the Example 2311 (939 mg) in EtOAc (17.1 mL) was added a 4M solution of HCl in 1,4-dioxane (17.1 mL). The reaction mixture was stirred at room temperature for 20 h and concentrated to afford the title compound (850 mg, >99%). [M-Cl]+=339.
Example 2343




Step A

To a solution of the title compound from the Example 2311 (22.5 mg) in CHCl3 (500 μL) was added and a 1:1 mixture of trifluoroacetic acid and CHCl3 (500 μL). The mixture was stirred at room temperature for 3 h, concentrated and dried in vacuo. The obtained residue was dissolved in DMF (500 μL) and iPr2NEt (10.2 μL) was added. The mixture was stirred at room temperature overnight, concentrated and diluted with EtOAc and 10% aqueous citric acid. The organic phase was separated, washed with 10% aqueous citric acid, saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by preparative thin layer chromatography (silica, CH2Cl2/MeOH) to afford the title compound as pale yellow solid (12.5 mg; 56%). [MH]+=435.
Example 2344




Step A

To a solution of the title compound from the Preparative Example 1028 (4.5 mg) in THF (1 mL) was added 1,1′-carbonyldiimidazole (5.4 mg). The resulting solution was stirred at room temperature for 90 min, then a solution of the title compound from the Example 2342, Step A (8.1 mg) in DMF (1 mL) and iPr2NEt (5 μL) were added and stirring at room temperature was continued overnight. Additional 1,1′-carbonyldiimidazole (5.4 mg) was added and stirring at room temperature was continued for 8 h. The mixture was concentrated, diluted with a 0.1M aqueous HCl (3 mL) and H2O (15 mL) and extracted with EtOAc (3×30 mL). The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by preparative thin layer chromatography (silica, CH2Cl2/MeOH) to afford the title compound (1.1 mg; 9%). [MH]+=494.
Example 2345




Step A

The title compound from the Example 2342, Step A (10.2 mg) was treated similarly as described in the Example 2344, Step A, except using the title compound from the Preparative Example 1029 instead of the title compound from the Preparative Example 1028 to afford the title compound (1.1 mg, 7.9%). [MH]+=506.
Example 2346




Step A

Using a microwave, a mixture of the title compound from Preparative Example 1049, Step E (3 mg), CsCO3 (9 mg) and acetyl chloride (3 μL) in 1,4-dioxane/CH3CN (1:1, 1 ml) was heated at 110° C. for 20 min and then cooled to room temperature. The formed precipitate was collected by filtration, washed with MeOH/H2O (1:1) and then dried in vacuo to afford the title compound as orange solid (1.6 mg, 47%). [MH]+=382.
Example 2347




Step A

To a suspension of the title compound from the Example 2342, Step A (2.8 mg) in dry pyridine (75 μL) was added a 0.1M solution of thiophene-2-carbonyl chloride in 1,2-dichlorethane (75 μL). The resulting mixture was agitated (−800 rpm) at room temperature for 15 h, concentrated and dried in vacuo for 12 h to afford the crude title compound. [MH]+=449.
Examples 2348-2387
Following similar procedures as described in the Example 2346 (method A) or 2347 (method B), except using the amines and acid chlorides indicated in Table II-53 below, the following compounds were prepared.










TABLE II-53





Ex. #
amine, acid chloride
product
yield







2348



   







A, 31% [MH]+ =  469 


 


2349



   







A, 61% [MH]+ =  363 


 


2350



   







B, n.d. [MH]+ =  533 


 


2351



   







B, n.d. [MH]+ =  493 


 


2352



   







B, n.d. [MH]+ =  409 


 


2353



   







B, n.d. [MH]+ =  471 


 


2354



   







B, n.d. [MH]+ =  457 


 


2355



   







B, n.d. [MH]+ =  487 


 


2356



   







B, n.d. [MH]+ =  473 


 


2357



   







B, n.d. [MH]+ =  487 


 


2358



   







B, n.d. [MH]+ =  468 


 


2359



   







B, n.d. [MH]+ =  527 


 


2360



   







B, n.d. [MH]+ =  489 


 


2361



   







B, n.d. [MH]+ =  486 


 


2362



   







B, n.d. [MH]+ =  395 


 


2363



   







B, n.d. [MH]+ =  461 


 


2364



   







B, n.d. [MH]+ =  475 


 


2365



   







B, n.d. [MH]+ =  491 


 


2366



   







B, n.d. [MH]+ =  463 


 


2367



   







B, n.d. [MH]+ =  425 


 


2368



   







B, n.d. [MH]+ =  519 


 


2369



   







B, n.d. [MH]+ =  449 


 


2370



   







B, n.d. [MH]+ =  461 


 


2371



    







B, n.d. [MH]+ =  421 


 


2372



   







B, n.d. [MH]+ =  463 


 


2373



   







B, n.d. [MH]+ =  467 


 


2374



   







B, n.d. [MH]+ =  483 


 


2375



   







B, n.d. [MH]+ =  473 


 


2376



   







B, n.d. [MH]+ =  435 


 


2377



   







B, n.d. [MH]+ =  449 


 


2378



   







B, n.d. [MH]+ =  478 


 


2379



   







B, n.d. [MH]+ =  499 


 


2380



   







B, n.d. [MH]+ =  449 


 


2381



   







B, n.d. [MH]+ =  462 


 


2382



   







B, n.d. [MH]+ =  487 


 


2383



   







B, n.d. [MH]+ =  468 


 


2384



   







B, n.d. [MH]+ =  465 


 


2385



   







B, n.d. [MH]+ =  499 


 


2386



   







B, n.d. [MH]+ =  478 


 


2387



   







B, n.d. [MH]+ =  445 









Example 2388




Step A

The title compound from the Example 2286 (4.5 mg) was treated similarly as described in the Example 2, Step A, except using commercially available tert-butylamine instead of the title compound from the Preparative Example 228, Step A to afford the title compound (1.9 mg, 37%). [MH]+=468.
Example 2389




Step A

To a solution of the title compound from the Example 2289 (20 mg) in anhydrous THF (2 mL) was added 1,1′-carbonyldiimidazole (35 mg). The resulting mixture was stirred at room temperature for 1 h and then cooled to 0-5° C. (ice bath). A 2M solution of methylamine in THF (1 mL) was added and the ice bath was removed. The mixture was stirred at room temperature for 3 h, concentrated, diluted with H2O and 10% aqueous citric acid and extracted with EtOAc (3×). The combined organic phases were washed saturated aqueous NaCl (200 mL), dried (MgSO4), filtered, concentrated and purified by preparative thin layer chromatography (silica, CH2Cl2/MeOH) to afford the title compound (14 mg, 85%). [α]+=392.
Example 2390




Step A

The title compound from the Example 2289 (20 mg) was treated similarly as described in the Example 2389, Step A, except using a 2M solution of dimethylamine in THF instead of a 2M solution of methylamine in THF to afford the title compound (17.9 mg, 83%). [MH]+=406.
Example 2391




Step A

A mixture of the title compound from the Example 2285 (8.5 mg) and conc. HCl (4.5 mL) in THF (3 mL) was stirred at room temperature for 6 h, concentrated, absorbed on silica and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound I (1.3 mg, 15%, [MH]+=509) and title compound II (4 mg, 47%, [MH]+=492).
Example 2392




Step A

To a suspension of the Preparative Example 377, Step E (30 mg) in cyclohexane (5 mL) were added tert-butyl 2,2,2-trichloroacetimidate (44 mg) and BF3.Et2O (2 drops). The resulting mixture was stirred at room temperature overnight, concentrated, absorbed on silica and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound (10.2 mg, 34%). [MH]+=377.

## Claims

1. A compound having Formula




wherein:
R1 is selected from the group consisting of cycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, arylalkyl, and 5- to 10-membered heteroarylalkyl,
wherein R1 is optionally substituted by one R16 group and by one or more R9 groups;
R2 is hydrogen;
R4 in each occurrence is independently selected from the group consisting of R10, hydrogen, alkyl, cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, 5- to 10-membered heteroaryl, halo, haloalkyl, CF3, (C0-C6)-alkyl-COR10, (C0-C6)-alkyl-OR10, (C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NO2, (C0-C6)-alkyl-CN, (C0-C6)-alkyl-S(O)yOR10, (C0-C6)-alkyl-S(O)yNR10R11, (C0-C6)-alkyl-NR10CONR11SO2R30, (C0-C6)-alkyl-S(O)xR10, (C0-C6)-alkyl-OC(O)R10, (C0-C6)-alkyl-OC(O)NR10R11, (C0-C6)-alkyl-C(═NR10)NR10R11, (C0-C6)-alkyl-NR10C(═NR11)NR10R11, (C0-C6)-alkyl-C(O)OR10, (C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10SO2R11, (C0-C6)-alkyl-C(O)—NR11—CN, O—(C0-C6)-alkyl-C(O)NR10R11, S(O)x—(C0-C6)-alkyl-C(O)OR10, S(O)x—(C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10—(C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NR10—C(O)R10, (C0-C6)-alkyl-NR10—C(O)OR10, (C0-C6)-alkyl-NR10—C(O)—NR10R11, (C0-C6)-alkyl-NR10—S(O)yNR10R11, (C0-C6)-alkyl-NR10—S(O)yR10, O—(C0-C6)-alkyl-aryl and O—(C0-C6)-alkyl-5- to 10-membered heteroaryl,
wherein each R4 group is optionally substituted by one or more R14 groups;
R9 in each occurrence is independently selected from the group consisting of R10, hydrogen, alkyl, cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, 5- to 10-membered heteroaryl, halo, CHF2, CF3, OR10, SR10, COOR10, CH(CH3)CO2H, (C0-C6)-alkyl-COR10, (C0-C6)-alkyl-OR10, (C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NO2, (C0-C6)-alkyl-CN, (C0-C6)-alkyl-S(O)yOR10, (C0-C6)-alkyl-P(O)2OH, (C0-C6)-alkyl-S(O)yNR10R11, (C0-C6)-alkyl-NR10CONR11SO2R30, (C0-C6)-alkyl-S(O)xR10, (C0-C6)-alkyl-OC(O)R10, (C0-C6)-alkyl-OC(O)NR10R11, (C0-C6)-alkyl-C(═NR10)NR10R11, (C0-C6)-alkyl-NR10C(═NR11)NR10R11, (C0-C6)-alkyl-NR10C(═N—CN)NR10R11, (C0-C6)-alkyl-C(═N—CN)NR10R11, (C0-C6)-alkyl-NR10C(═N—NO2)NR10R11, (C0-C6)-alkyl-C(═N—NO2)NR10R11, (C0-C6)-alkyl-C(O)OR10, (C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10SO2R11, C(O)NR10—(C0-C6)-alkyl-5- to 10-membered heteroaryl, C(O)NR10—(C0-C6)-alkyl-aryl, S(O)2NR10—(C0-C6)-alkyl-aryl, S(O)2NR10—(C0-C6)-alkyl-5- to 10-membered heteroaryl, S(O)2NR10-alkyl, S(O)2—(C0-C6)-alkyl-aryl, S(O)2—(C0-C6)-alkyl-5- to 10-membered heteroaryl, (C0-C6)-alkyl-C(O)—NR11—CN, O—(C0-C6)-alkyl-C(O)NR10R11, S(O)x—(C0-C6)-alkyl-C(O)OR10, S(O)x—(C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10—(C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NR10—C(O)R10, (C0-C6)-alkyl-NR10—C(O)OR10, (C0-C6)-alkyl-NR10—C(O)—NR10R11, (C0-C6)-alkyl-NR10—S(O)yNR10R11, (C0-C6)-alkyl-NR10—S(O)yR11, O—(C0-C6)-alkyl-aryl and O—(C0-C6)-alkyl-5- to 10-membered heteroaryl,
wherein each R9 group is optionally substituted by one or more R14 groups;
R10 and R11 in each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, 3- to 10-membered heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, fluoroalkyl, 3- to 10-membered heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, 5- to 10-membered heteroaryl, arylalkyl, 5- to 10-membered heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, 3- to 10-membered heterocycloalkyl, fluoroalkyl, 3- to 10-membered heterocycloalkylalkyl, alkenyl, alkynyl, aryl, 5- to 10-membered heteroaryl, arylalkyl, 5- to 10-membered heteroarylalkyl and aminoalkyl are optionally substituted one or more times, or R10 and R11 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O)x, or NR50 and which is optionally substituted one or more times;
R14 is independently selected from the group consisting of hydrogen, alkyl, arylalkyl, cycloalkylalkyl, 5- to 10-membered heteroarylalkyl, heterocyclylalkyl and halo, wherein alkyl, arylalkyl, cycloalkylalkyl, 5- to 10-membered heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times;
R16 is selected from the group consisting of cycloalkyl, 3- to 10-membered heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, 5- to 10-membered heteroaryl, cycloalkyl fused aryl, 3- to 10-membered heterocycloalkyl fused aryl, cycloalkyl fused 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl fused 5- to 10-membered heteroaryl, cycloalkylalkyl, 3- to 10-membered heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, 5- to 10-membered heteroarylalkyl, cycloalkyl fused arylalkyl, 3- to 10-membered heterocycloalkyl fused arylalkyl, cycloalkyl fused 5- to 10-membered heteroarylalkyl, 3- to 10-membered heterocycloalkyl fused 5- to 10-membered heteroarylalkyl,
wherein said cycloalkyl, 3- to 10-membered heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, 5- to 10-membered heteroaryl, cycloalkyl fused aryl, 3- to 10-membered heterocycloalkyl fused aryl, cycloalkyl fused 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl fused 5- to 10-membered heteroaryl, cycloalkylalkyl, 3- to 10-membered heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, 5- to 10-membered heteroarylalkyl, cycloalkyl fused arylalkyl, 3- to 10-membered heterocycloalkyl fused arylalkyl, cycloalkyl fused 5- to 10-membered heteroarylalkyl, and 3- to 10-membered heterocycloalkyl fused 5- to 10-membered heteroarylalkyl are optionally substituted one or more times;
R22 is hydrogen;
R30 is selected from the group consisting of alkyl and (C0-C6)-alkyl-aryl, wherein alkyl and aryl are optionally substituted;
R50 in each occurrence is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, C(O)R80, C(O)NR80R81, SO2R80 and SO2NR80R81, wherein alkyl, aryl, and heteroaryl are optionally substituted one or more times;
R80 and R81 in each occurrence are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, 3- to 10-membered heterocycloalkyl, fluoroalkyl, 3- to 10-membered heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, 5- to 10-membered heteroaryl, arylalkyl, 5- to 10-membered heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, 3- to 10-membered heterocycloalkyl, fluoroalkyl, 3- to 10-membered heterocycloalkylalkyl, alkenyl, alkynyl, aryl, 5- to 10-membered heteroaryl, arylalkyl, 5- to 10-membered heteroarylalkyl and aminoalkyl are optionally substituted, or R80 and R81 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally a heteroatom selected from O, S(O)x, —NH, and —N(alkyl) and which is optionally substituted one or more times;
R51 is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and haloalkyl, wherein alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and haloalkyl are optionally substituted one or more time;
x is selected from 0 to 2;
y is selected from 1 and 2; and
wherein each of said optional substitution is selected from the group consisting of C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; CF3; halo; OH; O—(C1-C4 alkyl); OCH2F; OCHF2; OCF3; ONO2; OC(O)—(C1-C4 alkyl); OC(O)—(C1-C4 alkyl); OC(O)NH—(C1-C4 alkyl); OC(O)N(C1-C4 alkyl)2; OC(S)NH—(C1-C4 alkyl); OC(S)N(C1-C4 alkyl)2; SH; S—(C1-C4 alkyl); S(O)—(C1-C4 alkyl); S(O)2—(C1-C4 alkyl); SC(O)—(C1-C4 alkyl); SC(O)O—(C1-C4 alkyl); NH2; N(H)—(C1-C4 alkyl); N(C1-C4 alkyl)2; N(H)C(O)—(C1-C4 alkyl); (CH3)C(O)—(C1-C4 alkyl); N(H)C(O)—CF3; N(CH3)C(O)—CF3; N(H)C(S)—(C1-C4 alkyl); N(CH3)C(S)—(C1-C4 alkyl); N(H)S(O)2—(C1-C4 alkyl); N(H)C(O)NH2; N(H)C(O)NH—(C1-C4 alkyl); N(CH3)C(O)NH—(C1-C4 alkyl); N(H)C(O)N(C1-C4 alkyl)2; N(CH3)C(O)N(C1-C4 alkyl)2; N(H)S(O)2NH2); N(H)S(O)2NH—(C1-C4 alkyl); N(CH3)S(O)2NH—(C1-C4 alkyl); N(H)S(O)2N(C1-C4 alkyl)2; N(CH3)S(O)2N(C1-C4 alkyl)2; N(H)C(O)O—(C1-C4 alkyl); N(CH3)C(O)O—(C1-C4 alkyl); N(H)S(O)2O—(C1-C4 alkyl); N(CH3)S(O)2O—(C1-C4 alkyl); N(CH3)C(S)NH—(C1-C4 alkyl); N(CH3)C(S)N(C1-C4 alkyl)2; N(CH3)C(S)O—(C1-C4 alkyl); N(H)C(S)NH2; NO2; CO2H; CO2—(C1-C4 alkyl); C(O)N(H)OH; C(O)N(CH3)OH: C(O)N(CH3)OH; C(O)N(CH3)O—(C1-C4 alkyl); C(O)N(H)—(C1-C4 alkyl); C(O)N(C1-C4 alkyl)2; C(S)N(H)—(C1-C4 alkyl); C(S)N(C1-C4 alkyl)2; C(NH)N(H)—(C1-C4 alkyl); C(H)N(C1-C4 alkyl)2; C(NCH3)N(H)—(C1-C4 alkyl); C(NCH3)N(C1-C4 alkyl)2; C(O)—(C1-C4 alkyl); C(NH)—(C1-C4 alkyl); C(NCH3)—(C1-C4 alkyl); C(NOH)—(C1-C4 alkyl); C(NOCH3)—(C1-C4 alkyl); CN; CHO; CH2OH; CH2O—(C1-C4 alkyl); CH2NH2; CH2N(H)—(C1-C4 alkyl); CH2N(C1-C4 alkyl)2; aryl; 5- to 10-membered heteroaryl; cycloalkyl; and heterocyclyl; or
a pharmaceutically acceptable salt, racemic mixture or stereoisomer thereof.

2. The compound of claim 1, which is:

3. The compound of claim 2, selected from the group consisting of:

4. The compound of claim 3, wherein at least one R1 is selected from the group consisting of:




wherein:
R6 is selected from the group consisting of hydrogen, halo, CN, OH, CH2OH, CF3, CHF2, OCF3, OCHF2, COCH3, SO2CH3, SO2CF3, SO2NH2, SO2NHCH3, SO2N(CH3)2, NH2, NHCOCH3, N(COCH3)2, NHCONH2, NHSO2CH3, alkoxy, alkyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, CO2H,




R9 is independently selected from the group consisting of hydrogen, fluoro, chloro, CH3, CF3, CHF2, OCF3, and OCHF2;
R25 is selected from the group consisting of hydrogen, CH3, COOCH3, COOH, and CONH2.

5. The compound of claim 3, wherein at least one R1 is selected from the group consisting of:

6. The compound of claim 1, wherein at least one R1 is selected from the group consisting of:

7. A compound according to claim 1, selected from the group consisting of:






















or a pharmaceutically acceptable salt thereof.

8. A compound, which is




or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising:
a) an effective amount of a compound according to claim 1;
b) a pharmaceutically acceptable carrier; and
c) a member selected from the group consisting of: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; and (h) a small molecule inhibitor of pro-inflammatory cytokine production.

10. A pharmaceutical composition according to claim 9 comprising at least one compound selected from the group consisting of:




a pharmaceutically acceptable salt, racemic mixture or stereoisomer thereof, and a pharmaceutically acceptable carrier.