# Patent

## Title
Monocyclic and bicyclic compounds and methods of use

## Abstract

Compounds are provided that act as potent antagonists of the CCR1 receptor, and have in vivo anti-inflammatory activity. The compounds are generally monocyclic and bicyclic compounds and are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated diseases, and as controls in assays for the identification of competitive CCR1 antagonists.

## Background
CROSS-REFERENCES TO RELATED APPLICATIONS
This application claims priority to U.S. Provisional Application No. 60/709,266, filed on Aug. 16, 2005, the content of which is incorporated herein in its entirety for all purposes.


STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
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REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK
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BACKGROUND OF THE INVENTION
The present invention provides compounds, pharmaceutical compositions containing one or more of those compounds or their pharmaceutically acceptable salts, which are effective in inhibiting the binding of various chemokines, such as MIP-1α, leukotactin, MPIF-1 and RANTES, to the CCR1 receptor. As antagonists or modulators for the CCR1 receptor, the compounds and compositions have utility in treating inflammatory and immune disorder conditions and diseases.
Human health depends on the body's ability to detect and destroy foreign pathogens that might otherwise take valuable resources from the individual and/or induce illness. The immune system, which comprises leukocytes (white blood cells (WBCs): T and B lymphocytes, monocytes, macrophages granulocytes, NK cell, mast cells, dendritic cell, and immune derived cells (for example, osteoclasts)), lymphoid tissues and lymphoid vessels, is the body's defense system. To combat infection, white blood cells circulate throughout the body to detect pathogens. Once a pathogen is detected, innate immune cells and cytotoxic T cells in particular are recruited to the infection site to destroy the pathogen. Chemokines act as molecular beacons for the recruitment and activation of immune cells, such as lymphocytes, monocytes and granulocytes, identifying sites where pathogens exist.
Despite the immune system's regulation of pathogens, certain inappropriate chemokine signaling can develop and has been attributed to triggering or sustaining inflammatory disorders, such as rheumatoid arthritis, multiple sclerosis and others. For example, in rheumatoid arthritis, unregulated chemokine accumulation in bone joints attracts and activates infiltrating macrophages and T-cells. The activities of these cells induce synovial cell proliferation that leads, at least in part, to inflammation and eventual bone and cartilage loss (see, DeVries, M. E., et al., Semin Immunol 11(2):95-104 (1999)). A hallmark of some demyelinating diseases such as multiple sclerosis is the chemokine-mediated monocyte/macrophage and T cell recruitment to the central nervous system (see, Kennedy, et al., J. Clin. Immunol. 19(5):273-279 (1999)). Chemokine recruitment of destructive WBCs to transplants has been implicated in their subsequent rejection. See, DeVries, M. E., et al., ibid. Because chemokines play pivotal roles in inflammation and lymphocyte development, the ability to specifically manipulate their activity has enormous impact on ameliorating and halting diseases that currently have no satisfactory treatment. In addition, transplant rejection may be minimized without the generalized and complicating effects of costly immunosuppressive pharmaceuticals.
Chemokines, a group of greater than 40 small peptides (7-10 kD), ligate receptors expressed primarily on WBCs or immune derived cells, and signal through G-protein-coupled signaling cascades to mediate their chemoattractant and chemostimulant functions. Receptors may bind more than one ligand; for example, the receptor CCR1 ligates RANTES (regulated on activation normal T cell expressed), MIP-1α (macrophage inflammatory protein), MPIF-1/CKβ8, and Leukotactin chemokines (among others with lesser affinities). To date, 24 chemokine receptors are known. The sheer number of chemokines, multiple ligand binding receptors, and different receptor profiles on immune cells allow for tightly controlled and specific immune responses. See, Rossi, et al., Ann. Rev. Immunol. 18(1):217-242 (2000). Chemokine activity can be controlled through the modulation of their corresponding receptors, treating related inflammatory and immunological diseases and enabling organ and tissue transplants.
The receptor CCR1 and its chemokine ligands, including, for example MIP-1α, MPIF-1/CKβ8, leukotactin and RANTES, represent significant therapeutic targets (see Saeki, et al., Current Pharmaceutical Design 9:1201-1208 (2003)) since they have been implicated in rheumatoid arthritis, transplant rejection (see, DeVries, M. E., et al., ibid.), and multiple sclerosis (see, Fischer, et al., J Neuroimmunol. 110(1-2):195-208 (2000); Izikson, et al., J. Exp. Med. 192(7):1075-1080 (2000); and Rottman, et al., Eur. J. Immunol. 30(8):2372-2377 (2000). In fact, function-blocking antibodies, modified chemokine receptor ligands and small organic compounds have been discovered, some of which have been successfully demonstrated to prevent or treat some chemokine-mediated diseases (reviewed in Rossi, et al., ibid.). Notably, in an experimental model of rheumatoid arthritis, disease development is diminished when a signaling-blocking, modified-RANTES ligand is administered (see Plater-Zyberk, et al., Immunol Lett. 57(1-3):117-120 (1997)). While function-blocking antibody and small peptide therapies are promising, they suffer from the perils of degradation, extremely short half-lives once administered, and prohibitive expense to develop and manufacture, characteristic of most proteins. Small organic compounds are preferable since they often have longer half lives in vivo, require fewer doses to be effective, can often be administered orally, and are consequently less expensive. Some organic antagonists of CCR1 have been previously described (see, Hesselgesser, et al., J. Biol. Chem. 273(25): 15687-15692 (1998); Ng, et al., J. Med. Chem. 42(22):4680-4694 (1999); Liang, et al., J. Biol. Chem. 275(25):19000-19008 (2000); and Liang, et al., Eur. J. Pharmacol. 389(1):41-49 (2000)). In view of the effectiveness demonstrated for treatment of disease in animal models (see, Liang, et al., J. Biol. Chem. 275(25):19000-19008 (2000)), the search has continued to identify additional compounds that can be used in the treatment of diseases mediated by CCR1 signaling.
BRIEF SUMMARY OF THE INVENTION
In one aspect, the present invention provides compounds having the Formula I:




or pharmaceutically acceptable salts and N-oxides thereof, in which each R1 is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, —CO2Ra, —X1CO2Ra, —X1SO2Ra, —X1SO3Ra, —X1ORa, —CORa, —CONRaRb, —X1NRaRb, —X1NRaCORb, —X1CONRaRb, X1NRaS(O)2Rb, X1S(O)2NRaRb and X1S(O)2Ra. In Formula I, X1 is C1-4 alkylene and each Ra and Rb is independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl and C3-6 cycloalkyl. Ra and Rb when attached to the same nitrogen atom are optionally combined to form a 5- to 7-membered ring having from 0-2 heteroatoms selected from the group consisting of N, O and S. Optionally any two R1 substituents attached to the same atom are optionally replaced with the substitutent ═O, ═NH, ═NOH, ═NRa, ═S or ═CRaRb. Optionally, any two R1 substituents attached to the same or adjacent carbon atoms are cyclized to form a 3- to 7-membered ring. The aliphatic portions of each R1 substituent is optionally substituted with from one to three members selected from the group consisting of —OH, —ORm, —OC(O)NHRm, —OC(O)N(Rm)2, —SH, —SRm, —S(O)Rm, —S(O)2Rm, —SO2NH2, —S(O)2NHRm, —S(O)2N(Rm)2, —NHS(O)2Rm, —NRmS(O)2Rm, —C(O)NH2, —C(O)NHRm, —C(O)N(Rm)2, —C(O)Rm, —NHC(O)Rm, —NRmC(O)Rm, —NHC(O)NH2, —NRmC(O)NH2, —NRmC(O)NHRm, —NHC(O)NHRm, —NRmC(O)N(Rm)2, —NHC(O)N(Rm)2, —CO2H, —CO2Rm, —NHCO2Rm, —NRmCO2Rm, —CN, —NO2, —NH2, —NHRm, —N(Rm)2, —NRmS(O)NH2 and —NRmS(O)2NHRm, in which each Rm is independently an unsubstituted C1-6 alkyl, and the subscript m is an integer from 0-4.

The symbols R2a, R2b, R2c, R2d and R2e at each occurrence are each independently selected from the group consisting of hydrogen, halogen, cyano, heteroaryl, —NO2, —CO2Rc, —C(O)NRcRd, —C(O)Rc, —S(O)Re, —S(O)2Re, —NRcS(O)2Re, —Re, —C(NORc)Rd, C(NRcV)═NV, —N(V)C(Rc)═NV, —NRdC(O)2Re, NRcC(O)NRcRd, —NH—C(NH2)═NH, NReC(NH2)═NH, —NH—C(NH2)═NRe, —NH—C(NHRe)═NH, —X2C(NRcV)═NV, —X2N(V)C(Rc)═NV —X2C(NORc)Rd, —X2C(NRcV)═NV, —X2N(V)C(Rc)═NV, —NRcRd, —X2SRc, —X2CN, —X2NO2, —X2CO2Rc, —X2CONRcRd, —X2C(O)Rc, —X2OC(O)NRcRd, —X2NRdC(O)Rc, —X2NRdC(O)2Re, —X2NRcC(O)NRcRd, —X2NH—C(NH2)═NH, —X2NReC(NH2)═NH, —X2NH—C(NH2)═NRe, —X2NH—C(NHRe)═NH, —X2S(O)Re, —X2NRcS(O)2Re, —X2S(O)2NRcRd, —X2N3, —ORc, —SRc, —NRdC(O)Rc, —NRdC(O)2Re, —S(O)2NRcRd, —X2ORc, —O—X2ORc, —X2NRcRd, —O—X2NRcRd and —NRd—X2CO2Rc. The symbol X2 is C1-4 alkylene and each Rc and Rd is independently selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, or optionally, Rc and Rd when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members. Each Re is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl and heteroaryl. Each of Rc, Rd and Re is optionally further substituted with from one to three members selected from the group consisting of —OH, —ORn, —OC(O)NHRn, —OC(O)N(Rn)2, —SH, —SRn, —S(O)Rn, —S(O)2Rn, —SO2NH2, —S(O)2NHRn, —S(O)2N(Rn)2, —NHS(O)2Rn, —NRnS(O)2Rn, —C(O)NH2, —C(O)NHRn, —C(O)N(Rn)2, —C(O)Rn, —NHC(O)Rn, —NRnC(O)Rn, —NHC(O)NH2, —NRnC(O)NH2, —NRnC(O)NHRn, —NHC(O)NHRn, —NRnC(O)N(Rn)2, —NHC(O)N(Rn)2, —CO2H, —CO2Rn, —NHCO2Rn, —NRnCO2Rn, —CN, —NO2, —NH2, —NHRn, —N(Rn)2, —NRnS(O)NH2 and —NRnS(O)2NHRn, wherein each Rn is independently an unsubstituted C1-6 alkyl, and wherein V is independently selected from the group consisting of —Rc, —CN, —CO2Re and —NO2.
The symbol B represents a monocyclic (-B1) or bicyclic (-B1-B2) ring system in which B1 is attached to the remainder of the compound of Formula I. B1 is a 5- to 7-membered non-aromatic nitrogen containing heterocyclic ring optionally having 1-2 additional heteroatom ring members selected from the group consisting of N, O, S, S(O) and S(O)2, and optionally having up to two double bonds; and B2 is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl. When B is a bicyclic ring system, then B1 and B2 are fused or connected with a single bond. The B1 and B2 rings are both each independently further substituted with 0 to 5 R3 substitutents. At each occurrence, R3 is independently selected from the group consisting of hydrogen, halogen, —ORf, —OC(O)Rf, —NRfRg, —SRf, —Rh, —CN, —NO2, —CO2Rf, —CONRfRf, —C(O)Rf, —OC(O)NRfRg, —NRgC(O)Rf, —NRgC(O)2Rh, —NRf—C(O)NRfRg, —NH—C(NH2)═NH, —NRhC(NH2)═NH, —NH—C(NH2)═NRh, —C(NRfRg)═NORf, —S(O)3Rh, X3S(O)3Rf, —NH—C(NHRh)═NH, —S(O)Rh, —S(O)2Rh, —NRfS(O)2Rh, —S(O)2NRfRg, —NRfS(O)2Rh, —NRfS(O)2NRfRg, —N3, —X3ORf, —X3OC(O)Rf, —X3NRfRg, —X3SRf, —X3CN, —X3NO2, —X3CO2Rf, —X3CONRfRg, —X3C(O)Rf, —X3OC(O)NRfRg, —X3NRgC(O)Rf, —X3NRgC(O)2Rh, —X3NRf—C(O)NRfRg, —X3NH—C(NH2)═NH, —X3NRhC(NH2)═NH, —X3NH—C(NH2)═NRh, —X3NH—C(NHRh)═NH, —X3S(O)Rh, —X3S(O)2Rh, —X3NRfS(O)2Rh, —X3S(O)2NRfRg, —Y, —X3Y and —X3N3, wherein Y is a five to ten-membered aryl, heteroaryl or heterocycloalkyl ring, optionally substituted with from one to three substitutents selected from the group consisting of halogen, —ORf, —NRfRg, —Rh, —SRf, —CN, —NO2, —CO2Rf, —CONRfRg, —C(O)Rf, —NRgC(O)Rf, —S(O)Rh, —S(O)2Rh, —NRfS(O)2Rh, —S(O)2NRfRg, —X3ORf, —X3NRfRg, —X3NRfS(O)2Rh, —X3CO2Rf, —X3CONRfRg, —X3C(O)Rf, —X3NRgC(O)Rf, —X3S(O)Rh, —X3S(O)2Rh, and —X3S(O)2NRfRg. Any two R3 substituents attached to the same atom on B1 are optionally replaced with the substitutent ═O, ═NH, ═NOH, ═NRf, ═S or ═CRfRg. Furthermore, when B is a monocyclic ring system (-B1), R3 is not —Y. Optionally any two R3 substituent located on adjacent atoms of B1 or B2 may be combined to form a 5- or 6-membered ring. Each X3 is independently selected from the group consisting of C1-4 alkylene, C2-4 alkenylene and C2-4 alkynylene; and each Rf and Rg substituent is independently selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl and aryloxy-C1-4 alkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members. Each Rh is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl and aryloxy-C1-4 alkyl, wherein the aliphatic portions of X3, Rf, Rg and Rh are optionally further substituted with from one to three members selected from the group consisting of —OH, —ORo, —OC(O)NHRo, —OC(O)N(Ro)2, —SH, —SRo, —S(O)Ro, —S(O)2Ro, —SO2NH2, —S(O)2NHRo, —S(O)2N(Ro)2, —NHS(O)2Ro, —NRoS(O)2Ro, —C(O)NH2, —C(O)NHRo, —C(O)N(Ro)2, —C(O)Ro, —NHC(O)Ro, —NRoC(O)Ro, —NHC(O)NH2, —NRoC(O)NH2, —NRoC(O)NHRo, —NHC(O)NHRo, —NRoC(O)N(Ro)2, —NHC(O)N(Ro)2, —CO2H, —CO2Ro, —NHCO2Ro, —NRoCO2Ro, —CN, —NO2, —NH2, —NHRo, —N(Ro)2, —NRoS(O)NH2 and —NRoS(O)2NHRo, wherein Ro is unsubstituted C1-6 alkyl.
The symbol L1 is a linking group selected from the group consisting of C1-3 alkylene, C1-3 heteroalkylene, optionally substituted with phenyl, —Rk, —X4ORi, —X4OC(O)Ri, —X4NRiRj, —X4SRi, —X4CN or —X4NO2. X4 is selected from the group consisting of C1-4 alkylene, C2-4 alkenylene and C2-4 alkynylene. Each Ri and Rj is independently selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl, and aryloxy-C1-4 alkyl. Each Rk is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl, and aryloxy-C1-4 alkyl.
The symbol U is selected from the group consisting of N, C—Rp and N+—O−, wherein Rp is hydrogen, C1-3 alkylene-ORq, C1-3 alkylene-N(Rq)2, C1-3 alkylene-NH(Rq), —OH, —ORq, —Rq, —CN, —OC(O)NHRq, —OC(O)N(Rq)2, —SH, —SRq, —S(O)Rq, S(O)2Rq, —SO2NH2, S(O)2NHRq, —S(O)2N(Rq)2, —NHS(O)2Rq, —NRqS(O)2Rq, —C(O)NH2, —C(O)NHRq, —C(O)N(Rq)2, —C(O)Rq, —NHC(O)Rq, —NRqC(O)Rq, —NHC(O)NH2, —NRqC(O)NH2, —NRqC(O)NHRq, —NHC(O)NHRq, —NRqC(O)N(Rq)2, —NHC(O)N(Rq)2, —CO2H, —CO2Rq, —NHCO2Rq, —NRqCO2Rq, —NH2, —NHRq, —N(Rq)2, —NRqS(O)NH2, —NHC(═NH)NH2, —NHC(═NH)Rq and —NRqS(O)2NHRq. Rq is each independently C1-8 alkyl, C1-8 haloalkyl, C3-8 cycloalkyl; and the aliphatic portions of Rq is optionally further substituted with from one to three members selected from the group consisting of —OH, —ORr, —OC(O)NHRr, —OC(O)N(Rr)2, —SH, —SRr, —S(O)Rr, —S(O)2Rr, —SO2NH2, —S(O)2NHRr, —S(O)2N(Rr)2, —NHS(O)2Rr, —NRrS(O)2Rr, —C(O)NH2, —C(O)NHRr, —C(O)N(Rr)2, —C(O)Rr, —NHC(O)Rr, —NRqC(O)Rr, —NHC(O)NH2, —NRrC(O)NH2, —NRrC(O)NHRr, —NHC(O)NHRr, —NRrC(O)N(Rr)2, —NHC(O)N(Rr)2, —CO2H, —CO2Rr, —NHCO2Rr, —NRrCO2Rr, —CN, —NO2, —NH2, —NHRr, —N(Rr)2, —NRrS(O)NH2 and —NRrS(O)2NHRr, wherein each Rr is independently an unsubstituted C1-6 alkyl.
The symbol L2 is a linking group selected from the group consisting of a direct bond, C1-3 alkylene, C1-8 heteroalkyl, —O—, —NRs, —C(O)—, —C(Rs)2, —S(O)—, —S(O)2—, —NRsC(O)— and —NRsS(O)2—. The substituent Rs is, at each occurrence, independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, C6-10 aryl and C5-10 heteroaryl; wherein the aliphatic portion of Rs are optionally further substituted with from one to three members selected from the group consisting of —OH, —ORt, —OC(O)NHRt, —OC(O)N(Rt)2, —SH, —SRt, —S(O)Rt, —S(O)2Rt, —SO2NH2, —S(O)2NHRt, —S(O)2N(Rt)2, —NHS(O)2Rt, —NRtS(O)2Rt, —C(O)NH2, —C(O)NHRt, —C(O)N(Rt)2, —C(O)Rt, —NHC(O)Rt, —NRoC(O)Rt, —NHC(O)NH2, —NRoC(O)NH2, —NRoC(O)NHRt, —NHC(O)NHRt, —NRtC(O)N(Rt)2, —NHC(O)N(Rt)2, —CO2H, —CO2Rt, —NHCO2Rt, —NRtCO2Rt, —CN, —NO2, —NH2, —NHRt, —N(Rt)2, —NRtS(O)NH2 and —NRtS(O)2NHRt, wherein each Rt is independently an unsubstituted C1-6 alkyl or C1-6 haloalkyl The subscript n is an integer from 0-2.



BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1A-1F show the structures of certain preferred substituted phenyl moieties comprising the R2a-2e substituents of the invention.



DETAILED DESCRIPTION OF THE INVENTION
I. Abbreviation and Definitions
The term “alkyl”, by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e. C1-8 means one to eight carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term “alkenyl” refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term “alkynyl” refers to an unsaturated alkyl group having one or more triple bonds. Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The term “cycloalkyl” refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C3-6cycloalkyl) and being fully saturated or having no more than one double bond between ring vertices. “Cycloalkyl” is also meant to refer to bicyclic and polycyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The term “heterocycloalkyl” refers to a cycloalkyl group that contain from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. The heterocycloalkyl may be a monocyclic, a bicyclic or a polycylic ring system. Non limiting examples of heterocycloalkyl groups include pyrrolidine, piperidiny, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrhydrothiophene, quinuclidine, and the like. A heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom.
The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by —CH2CH2CH2CH2—. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having four or fewer carbon atoms. Similarly, “alkenylene” and “alkynylene” refer to the unsaturated forms of “alkylene” having double or triple bonds, respectively.
The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Additionally, for dialkylamino groups, the alkyl portions can be the same or different and can also be combined to form a 3-7 membered ring with the nitrogen atom to which each is attached. Accordingly, a group represented as —NRaRb is meant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like.
The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “C1-4 haloalkyl” is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
The term “aryl” means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon group which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. The term “heteroaryl” refers to aryl groups (or rings) that contain from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalaziniyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
For brevity, the term “aryl” when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term “arylalkyl” is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like).
The above terms (e.g., “alkyl,” “aryl” and “heteroaryl”), in some embodiments, will include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below. For brevity, the terms aryl and heteroaryl will refer to substituted or unsubstituted versions as provided below, while the term “alkyl” and related aliphatic radicals is meant to refer to unsubstituted version, unless indicated to be substituted.
Substituents for the alkyl radicals (including those groups often referred to as alkylene, alkenyl, alkynyl and cycloalkyl) can be a variety of groups selected from: -halogen, —OR′, —NR′R′′, —SR′, —SiR′R′′R′′′, —OC(O)R′, —C(O)R′, —CO2R′, —CONR′R′′, —OC(O)NR′R′′, —NR′′C(O)R′, —NR′—C(O)NR′′R′′′, —NR′′C(O)2R′, —NH—C(NH2)═NH, —NRoC(NH2)═NH, —NH—C(NH2)═NR′, —S(O)R′, —S(O)2R′, —S(O)2NR′R′′, —NR′S(O)2R′′, —CN and —NO2 in a number ranging from zero to (2 m′+1), where m′ is the total number of carbon atoms in such radical. R′, R′′ and R′′′ each independently refer to hydrogen, unsubstituted C1-8 alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C1-8 alkyl, C1-8 alkoxy or C1-8 thioalkoxy groups, or unsubstituted aryl-C1-4 alkyl groups. When R′ and R′′ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, —NR′R′′ is meant to include 1-pyrrolidinyl and 4-morpholinyl.
Similarly, substituents for the aryl and heteroaryl groups are varied and are generally selected from: -halogen, —OR′, —OC(O)R′, —NR′R′′, —SR′, —R′, —CN, —NO2, —CO2R′, —CONR′R′′, —C(O)R′, —OC(O)NR′R′′, —NR′′C(O)R′, —NR′′C(O)2R′, —NR′—C(O)NR′′R′′′, —NH—C(NH2)═NH, —NR′C(NH2)═NH, —NH—C(NH2)═NR′, —S(O)R′, —S(O)2R′, —S(O)2NR′R′′, —NR′S(O)2R′′, —N3, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R′, R′′ and R′′′ are independently selected from hydrogen, C1-8 alkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C1-4 alkyl, and unsubstituted aryloxy-C1-4 alkyl. Other suitable substituents include each of the above aryl substituents attached to a ring atom by an alkylene tether of from 1-4 carbon atoms.
Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)—(CH2)q-U-, wherein T and U are independently —NH—, —O—, —CH2— or a single bond, and q is an integer of from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently —CH2—, —O—, —NH—, —S—, —S(O)—, —S(O)2—, —S(O)2NR′— or a single bond, and r is an integer of from 1 to 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula —(CH2)s—X—(CH2)t—, where s and t are independently integers of from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)2—, or —S(O)2NR′—. The substituent R′ in —NR′— and —S(O)2NR′— is selected from hydrogen or unsubstituted C1-6 alkyl.
As used herein, the term “heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
In addition to salt forms, the present invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention. The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
II. General
The present invention derives from the discovery that compounds of Formula I act as potent antagonists of the CCR1 receptor. The compounds have in vivo anti-inflammatory activity. Accordingly, the compounds provided herein are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated diseases, and as controls in assays for the identification of competitive CCR1 antagonists.
III. Compounds
A. Embodiments of Formula I
In one aspect, the present invention provides compounds having the Formula I:




or pharmaceutically acceptable salts and N-oxides thereof, in which each R1 is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, —CO2Ra, —X1CO2Ra, —X1SO2Ra, —X1SO3Ra, —X1ORa, —CORa, CONRaRb, —X1NRaNRb, —X1NRaCORb, —X1CONRaRb, X1NRaS(O)2Rb, X1S(O)2NRaRb and X1S(O)2Ra. In Formula I, X1 is C1-4 alkylene and each Ra and Rb is independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl and C3-6 cycloalkyl. Ra and Rb when attached to the same nitrogen atom are optionally combined to form a 5- to 7-membered ring having from 0-2 heteroatoms selected from the group consisting of N, O and S. Optionally any two R1 substituents attached to the same atom are optionally replaced with the substitutent ═O, ═NH, ═NOH, ═NRa, ═S or ═CRaRb. Optionally, any two R1 substituents attached to the same or adjacent carbon atoms are cyclized to form a 3- to 7-membered ring. The aliphatic portions of each R1 substituent is optionally substituted with from one to three members selected from the group consisting of —OH, —ORm, —OC(O)NHRm, —OC(O)N(Rm)2, —SH, —SRm, —S(O)Rm, —S(O)2Rm, —SO2NH2, —S(O)2NHRm, —S(O)2N(Rm)2, —NHS(O)2Rm, —NRmS(O)2Rm, —C(O)NH2, —C(O)NHRm, —C(O)N(Rm)2, —C(O)Rm, —NHC(O)Rm, —NRmC(O)Rm, —NHC(O)NH2, —NRmC(O)NH2, —NRmC(O)NHRm, —NHC(O)NHRm, —NRmC(O)N(Rm)2, —NHC(O)N(Rm)2, —CO2H, —CO2Rm, —NHCO2Rm, —NRmCO2Rm, —CN, —NO2, —NH2, —NHRm, —N(Rm)2, —NRmS(O)NH2 and —NRmS(O)2NHRm, in which each Rm is independently an unsubstituted C1-6 alkyl.

In one embodiment of the invention, each R1 in Formula I is a substituent selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, —CO2Ra, —X1CO2Ra, —X1SO2Ra, —X1SO3Ra and —X1ORa. In one embodiment of the invention, each R1 in Formula I is a substituent selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, —CO2Ra, —X1CO2Ra, and —X1ORa. In another embodiment, R1 in Formula I is a substituent independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl and C3-6 cycloalkyl. Within each of the above embodiments, the aliphatic portions of each of said R1 substituents is optionally substituted with from one to three members selected from the group consisting of —OH, —ORm, —OC(O)NHRm, —OC(O)N(Rm)2, —SH, —SRm, —S(O)Rm, —S(O)2Rm, —SO2NH2, —S(O)2NHRm, —S(O)2N(Rm)2, —NHS(O)2Rm, —NRmS(O)2Rm, —C(O)NH2, —C(O)NHRm, —C(O)N(Rm)2, —C(O)Rm, —NHC(O)Rm, —NRmC(O)Rm, —NHC(O)NH2, —NRmC(O)NH2, —NRmC(O)NHRm, —NHC(O)NHRm, —NRmC(O)N(Rm)2, —NHC(O)N(Rm)2, —CO2H, —CO2Rm, —NHCO2Rm, —NRmCO2Rm, —CN, —NO2, —NH2, —NHRm, —N(Rm)2, —NRmS(O)NH2 and —NRmS(O)2NHRm, wherein each Rm is independently an unsubstituted C1-6 alkyl.
In another embodiment, R1, when present, is selected from the group consisting of —CO2Ra or C1-4 alkyl, optionally substituted with OH, —ORm, —S(O)2Rm, —CO2H or —CO2Rm. In yet another embodiment, R1, when present, is selected from the group consisting of —CO2H or C1-4 alkyl, optionally substituted with OH, —ORm, —S(O)2Rm, —CO2H or —CO2Rm. In another embodiment, R1 is selected from the group consisting of —CO2H, —CO2CH3 and —CH3.
The subscript m in Formula I is an integer from 0-4. In one embodiment, the subscript m, in Formula I, is an integer from 0-2. In another embodiment the subscript m is an integer from 0-1. In another embodiment, R1 is methyl; and m is from 0-2. In another embodiment, R1 is selected from the group consisting of —CO2H, —CO2CH3 and —CH3; and m is an integer from 0-1.
In Formula I, the symbols R2a, R2b, R2c, R2d and R2e at each occurrence are each independently selected from the group consisting of hydrogen, halogen, cyano, heteroaryl, —NO2, —CO2Rc, —C(O)NRcRd, —C(O)Rc, —S(O)Re, —S(O)2Re, —NRcS(O)2Re, —Re, —C(NORc)Rd, —C(NRcV)═NV, —N(V)C(Rc)═NV, —NRdC(O)2Re, —NRcC(O)NRcRd, —NH—C(NH2)═NH, —NReC(NH2)═NH, —NH—C(NH2)═NRe, —NH—C(NHRe)═NH, —X2C(NRcV)═NV, —X2N(V)C(Rc)═NV —X2C(NORc)Rd, —X2C(NRcV)═NV, —X2N(V)C(Rc)═NV, —NRcRd, —X2SRc, —X2CN, —X2NO2, —X2CO2Rc, —X2CONRcRd, —X2C(O)Rc, —X2OC(O)NRcRd, —X2NRdC(O)Rc, —X2NRdC(O)2Re, —X2NRcC(O)NRcRd, —X2NH—C(NH2)═NH, —X2NReC(NH2)═NH, —X2NH—C(NH2)═NRe, —X2NH—C(NHRe)═NH, —X2S(O)Re, —X2S(O)2Re, —X2NRcS(O)2Re, —X2S(O)2NRcRd, —X2N3, ORc, SRc, NRdC(O)Rc, —NRdC(O)2Re, —S(O)2NRcRd, —X2ORc, —O—X2ORc, —X2NRcRd, —OX2NRcRd and —NRd—X2CO2Rc. The symbol X2 is C1-4 alkylene and each Rc and Rd is independently selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, or optionally, Rc and Rd when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members. Each Re is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl and heteroaryl. Each of Rc, Rd and Re is optionally further substituted with from one to three members selected from the group consisting of —OH, —ORn, —OC(O)NHRn, —OC(O)N(Rn)2, —SH, —SRn, —S(O)Rn, —S(O)2Rn, —SO2NH2, —S(O)2NHRn, —S(O)2N(Rn)2, —NHS(O)2Rn, —NRnS(O)2Rn, —C(O)NH2, —C(O)NHRn, —C(O)N(Rn)2, —C(O)Rn, —NHC(O)Rn, —NRnC(O)Rn, —NHC(O)NH2, —NRnC(O)NH2, —NRnC(O)NHRn, —NHC(O)NHRn, —NRnC(O)N(Rn)2, —NHC(O)N(Rn)2, —CO2H, —CO2Rn, —NHCO2Rn, —NRnCO2Rn, —CN, —NO2, —NH2, NHRn, —N(Rn)2, —NRnS(O)NH2 and —NRnS(O)2NHRn, wherein each Rn is independently an unsubstituted C1-6 alkyl, and wherein V is independently selected from the group consisting of —Rc, —CN, —CO2Re and —NO2.
In one embodiment, the symbols R2a, R2b, R2c, R2d and R2e in Formula I are each is independently selected from the group consisting of hydrogen, halogen, cyano, heteroaryl, —NO2, CO2Rc, CONRcRd, —C(O)Rc, —S(O)Re, —S(O)2Re, Re, C(NORc)Rd, C(NRcV)═NV, —N(V)C(Rc)═NV, —X2C(NORc)Rd, —X2C(NRcV)═NV, —X2N(V)C(Rc)═NV, —X2NRcRd, —X2SRc, —X2CN, —X2NO2, —X2CO2Rc, —X2CONRcRd, —X2C(O)Rc, —X2OC(O)NRcRd, —X2NRdC(O)Rc, —X2NRdC(O)2Re, —X2NRcC(O)NRcRd, —X2NH—C(NH2)═NH, X2NReC(NH2)═NH, —X2NH—C(NH2)═NRe, —X2NH—C(NHRe)═NH, —X2S(O)Re, —X2S(O)2Re, —X2NRcS(O)2Re, —X2S(O)2NRcRd and —X2N3.
In one embodiment, the R2a substitutent in Formula I is selected from the group consisting of hydrogen, F, Cl, Br, I, —CO2Rc, —CONRcRd, —CN, a 5- to 6-membered heteroaryl, —X2NRcRd, —C(NORc)Rd. In yet another embodiment, R2a is hydrogen. In other embodiments, the R2a substitutent in Formula I is selected from the group consisting of F, Cl, Br, I, —CO2Me, —CONH2, CN, oxazolyl, —CH2NH2, —CH2NHMe, —CH2NMe2 and —CH═N—OH. In yet another embodiment, in compounds having Formulae I, the R2a substituent is selected from the group consisting of hydrogen, F, Cl, Br and I. In another embodiment, R2b and R2e are each hydrogen.
In another embodiment, R2b is hydrogen. In another embodiment, R2b is halogen or ORc. In another embodiment, R2b is fluoro, chloro, bromo, iodo, methoxy, or ethoxy.
In another embodiment, the symbols R2c and R2d in Formula I are each substituents independently selected from the group consisting of hydrogen, halogen, —ORc, —SRc, —OC(O)Rc, —NRcRd, —Re, —CN, —NO2, —CO2Rc, —C(O)Rc, NRdC(O)Rc, —NRdC(O)2Re, —S(O)2Re, S(O)2NRcRd, —X2ORc, —O—X2ORc, —X2NRcRd, —O—X2NRcRd and —NRd—X2 CO2Rc. In certain aspects of this embodiment, R2c and R2d are each independently selected from the group consisting of hydrogen, halogen, F, Cl, Br, I and ORc. In another aspect of this embodiment, R2d is hydrogen and R2c is selected from the group consisting of halogen, F, Cl, Br, I and ORc.
In one embodiment, the symbols R2a, R2c and R2d in Formula I are each independently selected from the group consisting of hydrogen, halogen, cyano, heteroaryl, —NO2, —CO2Rc, CONRcRd, —C(O)Rc, —S(O)Re, —S(O)2Re, Re, —C(NORc)Rd, —C(NRcV)═NV, —N(V)C(Rc)═NV, —X2C(NORc)Rd, —X2C(NRcV)═NV, —X2N(V)C(Rc)═NV, —X2NRcRd, —X2SRc, —X2CN, —X2NO2, —X2 CO2Rc, —X2CONRcRd, —X2C(O)Rc, —X2OC(O)NRcRd, —X2NRdC(O)Rc, —X2NRdC(O)2Re, —X2NRcC(O)NRcRd, —X2NH—C(NH2)═NH, —X2NReC(NH2)═NH, —X2NH—C(NH2)═NRe, —X2NH—C(NHRe)═NH, —X2S(O)Re, —X2S(O)2Re, —X2NRcS(O)2Re, —X2S(O)2NRcRd and —X2N3; and R2b and R2e are each hydrogen. In certain aspects of this embodiment, R2a is selected from the group consisting of hydrogen, halogen, —CO2Rc, —C(O)NRcRd, —CN, oxazolyl, —X2NcRd and —C(NORc)Rd; R2b and R2e are each hydrogen; R2c is selected from the group consisting of halogen, —CN, —NO2, —CO2Rc, —C(O)NRcRd, —C(O)Rc and —S(O)2Re; and R2d is selected from the group consisting of hydrogen, —SRc, —O—X2—ORc, —X2—ORc, —Re, —ORc, —NRcRd, —NRcS(O)2Re and —NRdC(O)Rc. In another aspect of this embodiment, R2a is hydrogen.
In another embodiment, R2a and R2b in Formula I are each independently selected from the group consisting of hydrogen, halogen, cyano, heteroaryl, —NO2, —CO2Rc, —CONRcRd, —C(O)Rc, —S(O)Re, —S(O)2Re, —Re, —C(NORc)Rd, —C(NRcV)═NV, —N(V)C(Rc)═NV, —X2C(NORc)Rd, —X2C(NRcV)═NV, —X2N(V)C(Rc)═NV, X2 NRcRd, —X2SRc, —X2CN, —X2NO2, —X2CO2Rc, —X2CONRcRd, —X2C(O)Rc, —X2OC(O)NRcRd, —X2NRdC(O)Rc, —X2NRdC(O)2Re, —X2NRcC(O)NRcRd, —X2NH—C(NH2)═NH, —X2NReC(NH2)═NH, —X2NH—C(NH2)═NRe, —X2NH—C(NHRe)═NH, —X2S(O)Re, —X2S(O)2Re, —X2NRcS(O)2Re, —X2S(O)2NRcRd and —X2N3; and R2c, R2d and R2e are each hydrogen. In another embodiment, R2b is halogen or ORc. In another embodiment, R2b is fluoro, chloro, bromo, iodo, methoxy, or ethoxy.
In another embodiment, the phenyl ring bearing the R2a-2e substituents is independently selected from each of the substituted phenyl moieties shown in FIGS. 1A-1F.
Within each of the above embodiments, the aliphatic portions of R2a-2e are optionally substituted with from one to three members selected from the group consisting of —OH, —ORn, —OC(O)NHRn, —OC(O)N(Rn)2, —SH, —SRn, —S(O)Rn, —S(O)2Rn, —SO2NH2, —S(O)2NHRn, —S(O)2N(Rn)2, —NHS(O)2Rn, —NRnS(O)2Rn, —C(O)NH2, —C(O)NHRn, —C(O)N(Rn)2, —C(O)Rn, —NHC(O)Rn, —NRnC(O)Rn, —NHC(O)NH2, —NRnC(O)NH2, —NRnC(O)NHRn, —NHC(O)NMRn, —NRnC(O)N(Rn)2, —NHC(O)N(Rn)2, —CO2H, —CO2Rn, —NHCO2Rn, —NRnCO2Rn, —CN, —NO2, —NH2, —NHRn, —N(Rn)2, —NRnS(O)NH2 and —NRnS(O)2NHRn, wherein each Rn is independently an unsubstituted C1-6 alkyl, and wherein V is independently selected from the group consisting of —Rc, —CN, —CO2Re and —NO2.
The symbol B in Formula I represents a monocyclic (-B1) or bicyclic (-B1-B2) ring system, wherein the monocyclic or bicyclic ring system is attached to the remainder of Formula I through the B1 ring. The B1 ring is a 5- to 7-membered non-aromatic nitrogen containing heterocyclic ring optionally having 1-2 additional heteroatom ring members selected from the group consisting of N, O, S, S(O) and S(O)2, and optionally having up to two double bonds; and B2 is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl. When B is a bicyclic ring system, then B1 and B2 are fused or connected with a single bond. The B1 and B2 rings are both each independently further substituted with 0 to 5 R3 substitutents. In certain embodiment, the B1 and B2 rings of the symbol B are each independently further substituted with 0 to 4 R3 substitutents, preferably 0-3, or preferably 0-2 R3 substituents. At each occurrence, R3 is independently selected from the group consisting of hydrogen, halogen, —ORf, —OC(O)Rf, —NRfRg, —SRf, —Rh, —CN, —NO2, —CO2Rf, —CONRfRg, —C(O)Rf, —OC(O)NRfRg, —NRgC(O)Rf, —NRgC(O)2Rh, —NRf—C(O)NRfRg, —NH—C(NH2)═NH, —NRhC(NH2)═NH, —NH—C(NH2)═NRh, —C(NRfRg)═NORf, —S(O)3Rh, X3S(O)3Rf, —NH—C(NHRh)═NH, —S(O)Rh, —S(O)2Rh, —NRfS(O)2Rh, —S(O)2NRfRg, —NRfS(O)2Rh, —NRfS(O)2NRfRg, —N3, —X3ORf, —X3OC(O)Rf, —X3NRfRg, —X3SRf, —X3CN, —X3NO2, —X3CO2Rf, —X3CONRfRg, —X3C(O)Rf, —X3OC(O)NRfRg, —X3NRgC(O)Rf, —X3NRgC(O)2Rh, —X3NRf—C(O)NRfRg, —X3NH—C(NH2)═NH, —X3NRhC(NH2)═NH, —X3NH—C(NH2)═NRh, —X3NH—C(NHRh)═NH, —X3S(O)Rh, —X3S(O)2Rh, —X3NRfS(O)2Rh, —X3S(O)2NRfRg, —Y, —X3Y and —X3N3, wherein Y is a five to ten-membered aryl, heteroaryl or heterocycloalkyl ring, optionally substituted with from one to three substitutents selected from the group consisting of halogen, —ORf, —NRfRg, —Rh, —SRf, —CN, —NO2, —CO2Rf, —CONRfRg, —C(O)Rf, —NRgC(O)Rf, —S(O)Rh, —S(O)2Rh, —NRfS(O)2Rh, —S(O)2NRfRg, —X3ORf, —X3NRfRg, —X3NRfS(O)2Rh, —X3CO2Rf, —X3CONRfRg, —X3C(O)Rf, —X3NRgC(O)Rf, —X3S(O)Rh, —X3S(O)2Rh, and —X3S(O)2NRfRg. Any two R3 substituents attached to the same atom on B1 are optionally replaced with the substitutent ═O, ═NH, ═NOH, ═NRf, ═S or ═CRfRg. Furthermore, when B is a monocyclic ring system (-B1), R3 is not —Y. Optionally any two R3 substituent located on adjacent atoms of B1 or B2 may be combined to form a 5- or 6-membered ring. Each X3 is independently selected from the group consisting of C1-4 alkylene, C2-4 alkenylene and C2-4 alkynylene; and each Rf and Rg substituent is independently selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl and aryloxy-C1-4 alkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members. Each Rh is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl and aryloxy-C1-4 alkyl, wherein the aliphatic portions of X3, Rf, Rg and Rh are optionally further substituted with from one to three members selected from the group consisting of —OH, —ORo, —OC(O)NHRo, —OC(O)N(Ro)2, —SH, —SRo, —S(O)Ro, —S(O)2Ro, —SO2NH2, —S(O)2NHRo, —S(O)2N(Ro)2, —NHS(O)2Ro, —NRoS(O)2Ro, —C(O)NH2, —C(O)NHRo, —C(O)N(Ro)2, —C(O)Ro, —NHC(O)Ro, —NRoC(O)Ro, —NHC(O)NH2, —NRoC(O)NH2, —NRoC(O)NHRo, —NHC(O)NHRo, —NRoC(O)N(Ro)2, —NHC(O)N(Ro)2, —CO2H, —CO2Ro, —NHCO2Ro, —NRoCO2Ro, —CN, —NO2, —NH2, —NHRo, —N(Ro)2, —NRoS(O)NH2 and —NRoS(O)2NHRo, wherein Ro is unsubstituted C1-6 alkyl.
In one embodiment, the substituent R3 on the B group of Formula I, at each occurrence, is independently selected from the group consisting of hydrogen, halogen, —ORf, —OC(O)Rf, —NRfRg, —SRf, —Rh, —CN, —NO2, —CO2Rf, —CONRfRg, —C(O)Rf, —OC(O)NRfRg, —NRgC(O)Rf, —NRgC(O)2Rh, —NRf—C(O)NRfRg, —S(O)Rh, —S(O)2Rh, —S(O)3Rh, —NRfS(O)2Rh, —S(O)2NRfRg, —NRfS(O)2NRfRg, —X3 ORf, —X3NRfRg, X3SRf, —X3S(O)2Rh, —X3S(O)3Rh, —X3S(O)2NRfRg, —X3CN, —C(C═NORf)NRfRg, —X3CO2Rf, —X3CONRfRg, —X3C(O)Rf, —X3NRgC(O)Rf, —X3NRgC(O)2Rh, —Y, —X3Y and —X3N3. The symbol Y is a five or six-membered aryl, a five or six membered heteroaryl, or a three to eight membered heterocycloalkyl ring, optionally substituted with from one to three substitutents selected from the group consisting of halogen, —ORf, —NRfRg, —Rh, —SRf, —CN, —NO2, —CO2Rf, —CONRfRg, —C(O)Rf, —NRgC(O)Rf, —S(O)Rh, —S(O)2Rh, —NRfS(O)2Rh and —S(O)2NRfRg. X3 is independently C1-4 alkylene. The symbols Rf and Rg are independently selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl and C3-6 cycloalkyl, and each Rh is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl and C3-6 cycloalkyl.
In another embodiment of the invention, the R3 substituent in the B group of Formula I, at each occurrence, is a member independently selected from the group consisting of hydrogen, halogen, —ORf, —NRfRg, —Rh, —CN, and —Y, wherein Y is a five to six-membered aryl ring, a five to six-membered heteroaryl ring, or a three to eight-membered heterocycloalkyl ring selected from the group consisting of homopiperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, azetidinyl, pyranyl, tetrahydrofuranyl, piperazinyl, phenyl, pyridyl, pyrimidinyl, oxadiazolyl, oxazolyl and thiazolyl, optionally substituted with from one to three substitutents selected from the group consisting of halogen, —ORf, —NRfRg, —Rh, —CN, wherein each Rf and Rg is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl and C3-6 cycloalkyl, and each Rh is independently selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and C3-6 cycloalkyl
In another embodiment of the invention, the R3 substituent in the B group of Formula I, at each occurrence, is selected from the group consisting of —Y and —X3—Y, wherein Y is selected from the group consisting of homopiperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, azetidinyl, pyranyl, tetrahydrofuranyl, piperazinyl, phenyl, thienyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyridizinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl and oxadiazolyl, which is optionally substituted with from one to three substituents independently selected from the group consisting of halogen, —ORf, —NRfRg, —CORf, —CO2Rf, —CONRfRg, —NO2, —Rh and —CN, wherein Rf and Rg are each independently selected from the group consisting of H, C1-8 alkyl, C3-6 cycloalkyl and C1-8 haloalkyl, and each Rh is independently selected from the group consisting of C1-8 alkyl, C3-6 cycloalkyl and C1-8 haloalkyl. In certain aspects of this embodiment, the symbol Y is selected from the group consisting of phenyl, pyridyl, oxazolyl, pyrimidinyl, oxadiazolyl, and thiazolyl, each of which is optionally substituted with from one to three substituents independently selected from the group consisting of halogen, —ORf, —NRfRg, —CORf, —CO2Rf, —CONRfRg, —NO2, —Rh and —CN, wherein Rf and Rg are each independently selected from the group consisting of H, C1-8 alkyl, C3-6 cycloalkyl and C1-8 haloalkyl, and each Rh is independently selected from the group consisting of C1-8 alkyl, C3-6 cycloalkyl and C1-8 haloalkyl.
In yet another embodiment of the invention, the R3 substituent in the B group of Formula I, at each occurrence, is selected from the group consisting of hydrogen, halogen, C1-4 alkyl and C1-4 haloalkyl. In yet another embodiment, B group is selected from the optionally substituted group consisting of hydrogen, fluoro, chloro bromo, iodo, —OCH3, —CN, —OCH2CH2OH, —OCH2CH2NH2, —CH2CO2H, —OCH2CO2H, —CO2H, —OCH2CH2CO2H. In a certain aspect of these embodiments, m is 0 or 1; R2a is preferably hydrogen; and additionally in another aspect, R2c is preferably selected from the group consisting of F, Cl, Br, CN, NO2, —CO2CH3, —C(O)CH3 and —S(O)2CH3.
In yet another embodiment, the R3 substituent of the B group in Formula I is a member independently selected from the group consisting of hydrogen, halogen, —ORf, —NRfRg, —C(O)Rf, —C(O)ORf, —S(O)Rf, —S(O)2Rf, —S(O)3Rf, —S(O)3Rh, —X3C(O)2Rf, X3S(O)3Rf, —S(O)2NRfRg, —X3S(O)2NRfRg, —Rh, —CN, X3NRfRg, NRgC(O)Rf, —X3ORf, —X3CONRfRg, X3N3 and Y, wherein Y is a five to six-membered aryl, a five or six-membered heteroaryl ring or a three to eight-membered heterocycloalkyl ring selected from the group consisting of homopiperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, azetidinyl, pyranyl, tetrahydrofuranyl, piperazinzyl, phenyl, pyridyl, oxazolyl, pyrimidinyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, pyrrolyl and thiazolyl, optionally substituted with from one to three substitutents selected from the group consisting of halogen, —ORf, —NRfRg, —Rh, —CN, wherein each Rf and Rg is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl and C3-6 cycloalkyl, and each Rh is independently selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and C3-6 cycloalkyl.
Within each of the above embodiments, the aliphatic portions of the R3 substitutents is optionally further substituted with from one to three members selected from the group consisting of —OH, —ORo, —OC(O)NHRo, —OC(O)N(Ro)2, —SH, —SRo, —S(O)Ro, —S(O)2Ro, —SO2NH2, —S(O)2NHRo, —S(O)2N(Ro)2, —NHS(O)2Ro, —NRoS(O)2Ro, —C(O)NH2, —C(O)NHRo, —C(O)N(Ro)2, —C(O)Ro, —NHC(O)Ro, —NRoC(O)Ro, —NHC(O)NH2, —NRoC(O)NH2, —NRoC(O)NHRo, —NHC(O)NHRo, —NRoC(O)N(Ro)2, —NHC(O)N(Ro)2, —CO2H, —CO2Ro, —NHCO2Ro, —NRoCO2Ro, —CN, —NO2, —NH2, —NHRo, —N(Ro)2, —NRoS(O)NH2 and —NRoS(O)2NHRo, wherein each Ro is independently an unsubstituted C1-6 alkyl.
In some embodiments, in Formula I, B is a bicyclic ring system (-B1-B2), whereas in other embodiments, -B1-B2 is a fused bicyclic ring system. In yet other embodiments, -B1 and B2 are connected by a single bond. In other embodiments, in Formula I, B is a monocyclic ring system (-B1). In some embodiments, B1 is attached to the remainder of the molecule through a carbon atom. In other embodiments, B1 is attached to the remainder of the molecule through a nitrogen atom.
In a first embodiment of the B group in Formula I, B is a bicyclic ring (-B1-B2) having a formula selected from the group consisting of:




in which X, Y1 and Z are each independently selected from the group consisting of —CH2—, —CHR3—, —C(R3)2—, —NR3—, —NH—, —S—, —O—, —C(O)—, —S(O)— and —S(O)2—. Optionally, any two substituents on the adjacent atoms of X and Y1, or Y1 and Z may be absent and replaced with a bond to form a double bond between X and Y1, or Y1 and Z. In one embodiment, the R3 substituent on the B1 ring in Formula i and ii is selected from the group consisting of halogen, —ORf, —NRfRg, —C(O)Rf, —C(O)ORf, —S(O)Rf, —S(O)2Rf, —S(O)3Rf, —S(O)3Rh, —X3C(O)2Rf, X3S(O)3Rf, —S(O)2NRfRg, —X3S(O)2NRfRg, —Rh, —CN, X3NRfRg, NRgC(O)Rf, —X3ORf, —X3CONRfRg, X3N3, wherein each Rf and Rg is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl and C3-6 cycloalkyl, and each Rh is independently selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and C3-6 cycloalkyl. The aliphatic portions of X3, Rf, Rg and Rh is optionally further substituted with from one to three members selected from the group consisting of —OH, —ORo, —OC(O)NHRo, —OC(O)N(Ro)2, —SH, —SRo, —S(O)Ro, —S(O)2Ro, —SO2NH2, —S(O)2NHRo, —S(O)2N(Ro)2, —NHS(O)2Ro, —NRoS(O)2Ro, —C(O)NH2, —C(O)NHRo, —C(O)N(Ro)2, —C(O)Ro, —NHC(O)Ro, —NRoC(O)Ro, —NHC(O)NH2, —NRoC(O)NH2, —NRoC(O)NHRo, —NHC(O)NHRo, —NRoC(O)N(Ro)2, —NHC(O)N(Ro)2, —CO2H, —CO2Ro, —NHCO2Ro, —NRoCO2Ro, —CN, —NO2, —NH2, —NHRo, —N(Ro)2, —NRoS(O)NH2 and —NRoS(O)2NHRo, wherein each Ro is independently an unsubstituted C1-6 alkyl.

Each of ring vertices a, b, c and d of the B2 ring in Formula i and ii is independently selected from the group consisting of N, N+—O−, C(H) and C(R3); and from 0-2 ring vertices is N or N+—O−. In certain embodiments, 1 or 2 of said ring vertices a, b, c and d in Formula i and ii are N or N—O. In one embodiment, the ring vertex a is N or N+—O− and ring vertices b, c and d are each independently C(H) or C(R3). In another embodiment, the ring vertex d is N or N+—O− and ring vertices a, b and c are each independently C(H) or C(R3). In yet another embodiment, the ring vertex b is N or N+—O− and ring vertices a, c and d are each independently C(H) or C(R3). In yet another embodiment, the ring vertex c is N or N+—O− and ring vertices a, b and d are each independently C(H) or C(R3). In yet another embodiment, the ring vertices a, b, c and d are each independently C(H) or C(R3). Within the above embodiments of Formula i and ii, when any of the ring vertices a, b, c or d of the B2 ring is C(R3), the R3 substituent, in certain embodiments, is independently selected from the group consisting of hydrogen, halogen, —ORf, NRfRg, SRf, —Rh, —Y, —CN, X3N3, —SO2Rh, X3NRfRg, X3Y, —S(O)3Rf, —C(C═NOR)NRfRg, —NO2, —CO2Rf and —NRgC(O)Rf, wherein Y is an optionally substituted group selected from the group consisting of phenyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, pyrrolyl and morpholinyl, and Rh is an optionally substituted group selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl and C3-8 cycloalkyl, and Rf and Rg are each independently an optionally substituted group selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl and C3-8 cycloalkyl wherein the aliphatic portions the R3 substituent are each independently optionally substituted with from one to three members selected from the group consisting of —OH, —ORo, —OC(O)NHRo, —OC(O)N(Ro)2, —SH, —SRo, —S(O)Ro, —S(O)2Ro, —SO2NH2, —S(O)2NHRo, —S(O)2N(Ro)2, —NHS(O)2Ro, —NRoS(O)2Ro, —C(O)NH2, —C(O)NHRo, —C(O)N(Ro)2, —C(O)Ro, —NHC(O)Ro, —NRoC(O)Ro, —NHC(O)NH2, —NRoC(O)NH2, —NRoC(O)NHRo, —NHC(O)NHRo, —NRoC(O)N(Ro)2, —NHC(O)N(Ro)2, —CO2H, —CO2Ro, —NHCO2Ro, —NRoCO2Ro, —CN, —NO2, —NH2, —NHRo, —N(Ro)2, —NRoS(O)NH2 and —NRoS(O)2NHRo, wherein each Ro is independently an unsubstituted C1-6 alkyl.
In one preferred embodiment, R3 substituent on the B2 ring of the B group, at each occurrence, is independently selected from the optionally substituted group consisting of halogen, —ORf, —NRfRg, —SRf, —Rh, —CN, —NO2, —C(NRfRg)═NORf, —CO2Rf and —Y, wherein Y is an optionally substituted group selected from the group consisting of phenyl, pyridyl, oxazolyl, pyrimidinyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, pyrrolyl, and thiazoyl. In a certain aspect of this embodiment, the R3 substituent is independently selected from the group consisting of fluoro, chloro, bromo, iodo, amino, —CH3, oxazolyl, 2-oxazolyl, thiazolyl, pyridyl, pyrimidinyl, morpholinyl, oxdiazolyl, 2-oxadiazolyl, —OH, —OCH3, —OCH2CO2H, —OCH2CO2Et, —OCH2CH2OH, —OCH2CH2NH2, —NHC(O)CH3, —CN, —CH2N3, —CH2SO3H, —NO2, —(C═NOH)NH2, —S(O)2CH3 and —CH2NH2.
In yet another embodiment, in Formula i and ii the ring vertices a, b, c and d of the B ring are C(H) or C(R3), wherein R3 is halogen. In yet another embodiment, the ring vertices a, b, d of the B ring are each C(H) and c is C(R3), wherein R3 is fluoro, chloro, bromo or iodo. In yet another embodiment, the ring vertices a, c, d are each C(H) and b is C(R3), wherein R3 is fluoro, chloro, bromo or iodo.
In one embodiment, -B1-B2 is a bicyclic ring having Formula i and is selected from the group consisting of




and wherein the subscript o is from 0-3, and wherein certain preferred substituents Rf, Rg, R3, Z and the ring vertices a, b, c and d are as described above for Formula i.

In one preferred embodiment, the bicyclic ring -B1-B2 of Formula I has the Formula ia1




in which Z is CH2, CHR3, C(R3)2, NH, NR3 or O, wherein certain preferred embodiments of the R3 substituent (on the B1 ring) and the ring vertices a, b, c and d of the B2 ring are set forth as described for Formula i. Furthermore, in another embodiment, the R3 substitutent, at each occurrence, on the B1 ring is selected from the group consisting of —Rh, —X3ORf, —X3NRfRg, —X3CO2Rf and —X3CONRfRg. In another embodiment, the R3 substitutent, at each occurrence on the B1 ring is selected from the group consisting of methyl, ethyl, propyl, CH2CH2OH, CH2CH2NH2, CH2CH2NMeH, CH2CO2H and CH2CONH2.

Each of ring vertices a, b, c and d in the B2 ring of Formula ia1 is independently selected from the group consisting of N, N+—O−, C(H) and C(R3); and from 0-2 ring vertices is N or N+—O−. When any of the ring vertices a, b, c or d of the B2 ring is C(R3), in one embodiment, the R3 substituent is independently selected from the group consisting of hydrogen, halogen, —ORf, NRfRg, SRf, —Rh, —Y, —CN, X3N3, —SO2Rh, X3NRfRg, X3Y, —S(O)3Rf, —C(C═NOR)NRfRg, —NO2, —CO2Rf and —NRgC(O)Rf, wherein Y is an optionally substituted group selected from the group consisting of phenyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, pyrrolyl and morpholinyl, and Rh is an optionally substituted group selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl and C3-8 cycloalkyl, wherein the aliphatic portions of R3 is each independently optionally substituted with from one to three members selected from the group consisting of —OH, —ORo, —OC(O)NHRo, —OC(O)N(Ro)2, —SH, —SRo, —S(O)Ro, —S(O)2Ro, —SO2NH2, —S(O)2NHRo, —S(O)2N(Ro)2, —NHS(O)2Ro, —NRoS(O)2Ro, —C(O)NH2, —C(O)NHRo, —C(O)N(Ro)2, —C(O)Ro, —NHC(O)Ro, —NRoC(O)Ro, —NHC(O)NH2, —NRoC(O)NH2, —NRoC(O)NHRo, —NHC(O)NHRo, —NRoC(O)N(Ro)2, —NHC(O)N(Ro)2, —CO2H, —CO2Ro, —NHCO2Ro, —NRoCO2Ro, —CN, —NO2, —NH2, —NHRo, —N(Ro)2, —NRoS(O)NH2 and —NRoS(O)2NHRo, wherein each Ro is independently an unsubstituted C1-6 alkyl.
In one embodiment, the ring vertices a, b, c and d in the B2 ring of Formulae ia1 are each independently C(H) or C(R3). In another embodiment, in Formula ia1, the ring vertices a, b, d of the B2 ring are each C(H) and c is C(R3). In another embodiment, the ring vertices a, c, d of the B2 ring are each C(H) and b is C(R3). In another embodiment, the ring vertex a of the B2 ring is N or N+—O− and the ring vertices b, c, d are each C(H) or C(R3). Within each of the above embodiments, R3 is selected from the group consisting of halogen, —ORf, —CN, —NO2, C(NH2)═NORf and —Y, wherein Y is an optionally substituted oxadiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl or thiazolyl group. In a specific aspect of this embodiment, R3 on the B2 ring is selected from the group consisting of fluoro, chloro, bromo, iodo, OMe, CN, —C(NH2)═NOH, oxadiazolyl or ORf, wherein Rf is selected from the group consisting of hydrogen, C1-4 alkyl optionally substituted with —CO2H, —CO2Ro, —NH2, —NRoH and —N(Ro)2. In yet another embodiment, the R3 substituent of the B2 ring is selected from the group consisting of halogen, —ORf, —CN, —NO2, C(NH2)═NORf and —Y, wherein Y is an optionally substituted oxadiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl or thiazolyl group. In certain aspects of this embodiment, R3 on the B2 ring is selected from the group consisting of OMe, CN, —C(NH2)═NOH, oxadiazolyl or ORf, wherein Rf is selected from the group consisting of hydrogen, C1-4 alkyl optionally substituted with —CO2H, —CO2Ro, —NH2, —NRo H and —N(Ro)2.
In another aspect of this embodiment, in Formula ia1, -B1-B2 is selected from the group consisting of:










In another embodiment, in Formula I, -B1-B2 is a bicyclic ring having Formula ii, and is selected from the group consisting of




wherein Y1 and Z are —NH—, N(R3), —CH2—, —CHR3—, —C(R3)2, —O or S; and the subscript o is 0-2. In yet another embodiment, -B1-B2 is a bicyclic ring having Formula ii, in which X is —C(O)—; Y1 is —CH2—, —CHR3— or —C(R3)2; and Z is —NH—, —NR3—, O or S. In each of these embodiments, the substituents, R3 and the ring vertices a, b, c and d are as set forth for Formula ii.

In a preferred embodiment, -B1-B2 is a bicyclic ring having the Formula ii and is selected from the group consisting of:




wherein the symbols Y1 and Z are independently selected from the group consisting of O, NH and NR3, wherein the substituent R3, if present, is halogen or Rh. The subscript o in Formula iia1 and iia2 is an integer from 0-1.

Each of ring vertices a, b, c and d of the B2 ring in Formula iia1 or iia2 is independently selected from the group consisting of N, N+—O−, C(H) and C(R3); and from 0-2 ring vertices is N or N+—O−. When any of the ring vertices a, b, c or d of the B2 ring in Formula iia1 or iia2 is C(R3), the R3 substituent is independently selected from the group consisting of hydrogen, halogen, —ORf, NRfRg, SRf, —Rh, —Y, —CN, X3N3, —SO2Rh, X3NRfRg, X3Y, —S(O)3Rf, —C(C═NORf)NRfRg, —NO2, —CO2Rf and —NRgC(O)Rf, wherein Y is an optionally substituted group selected from the group consisting of phenyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, pyrrolyl and morpholinyl, and Rh is an optionally substituted group selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl and C3-8 cycloalkyl, wherein the aliphatic portions of R3 is each independently optionally substituted with from one to three members selected from the group consisting of —OH, —ORo, —OC(O)NHRo, —OC(O)N(Ro)2, —SH, —SRo, —S(O)Ro, —S(O)2Ro, —SO2NH2, —S(O)2NHRo, —S(O)2N(Ro)2, —NHS(O)2Ro, —NRoS(O)2Ro, —C(O)NH2, —C(O)NHRo, —C(O)N(Ro)2, —C(O)Ro, —NHC(O)Ro, —NRoC(O)Ro, —NHC(O)NH2, —NRoC(O)NH2, —NRoC(O)NHRo, —NHC(O)NHRo, —NRoC(O)N(Ro)2, —NHC(O)N(Ro)2, —CO2H, —CO2Ro, —NHCO2Ro, —NRoCO2Ro, —CN, —NO2, —NH2, —NHRo, —N(Ro)2, —NRoS(O)NH2 and —NRoS(O)2NHRo, wherein each Ro is independently an unsubstituted C1-6 alkyl.
In one embodiment, the ring vertices a, b, c and d in Formulae iia1 and iia2 are independently C(H) or C(R3). In another embodiment, the ring vertices a, b, d in Formulae iia1 and iia2 are each C(H) and c is C(R3). In another embodiment, the ring vertices a, c, d are each C(H) and b is C(R3). In another embodiment, the ring vertex a is N or N+—O−, and the ring vertices b, c and d are each independently C(H) or C(R3). In another embodiment, the ring vertex c is N or N+—O−, and the ring vertices a, b and d are each independently C(H) or C(R3). In preferred aspects of the above embodiments, R3 is selected from the group consisting of halogen, —ORf, —CN, —NO2, C(NH2)═NORf and —Y, wherein Y is an optionally substituted oxadiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl or thiazolyl group. In one embodiment, the R3 on the B2 ring is selected from the group consisting of fluoro, chloro, bromo, iodo, OMe, CN, —C(NH2)═NOH, oxadiazolyl or ORf, wherein Rf is selected from the group consisting of hydrogen, C1-4 alkyl optionally substituted with —CO2H, —CO2Ro, —NH2, —NRoH and —N(Ro)2. In another embodiment, R3 of the B2 ring is halogen or ORf, preferably methoxy, fluoro, chloro, bromo or iodo.
In one embodiment, in Formula iia1 and iia2, -B1-B2 is selected from the group consisting of




In another embodiment, in Formula iia1 and iia2, -B1-B2 is selected from the group consisting of




In a second embodiment of the invention, -B1-B2 is a bicyclic ring having a Formula selected from the group consisting of:




in which X, Y1 and Z are each independently selected from the group consisting of —CH2—, —CHR3—, —C(R3)2—, —C(O)—, —NH— and —N(R3), —O—, —S—, —S(O)— and —S(O)2—. Optionally, any two substituents on adjacent atoms of one of Y1 and Z may be absent and replaced with a bond to form a double bond between Y1 and Z; and each of ring vertices a, b, c and d is independently selected from the group consisting of N, N+—O−, C(H) and C(R3), and from 0-2 ring vertices is N or N+—O−. Certain preferred embodiments for the R3 substituent in the B1 and B2 ring of the B group and the ring vertices a, b, c and d in Formula iii and iv are as set forth for Formula I.

In one embodiment, -B1-B2 is a bicyclic ring having Formula iii, in which -B1-B2 is selected from the group consisting of




wherein X is CH2, CHR3, C(R3)2, —NH—, N(R3), O or S; and the subscript o is 0-2.

In another embodiment, -B1-B2 is a bicyclic ring having Formula iv, in which -B1-B2 is selected from the group consisting of




in which the subscript o is 0-2.

In a third embodiment of the invention, B1-B2 is a bicyclic ring having a formula selected from the group consisting of:




in which X, Y1 and Z are each independently selected from the group consisting of —CH2—, —CHR3—, —C(R3)2, —C(O)—, —S(O)—, —S(O)2—, —NH—, —N(R3), —S— and —O—, wherein at least one of X, Y1 and Z is —NH— or —N(R3)—. Optionally, any two substituents on adjacent atoms of X and C, C and Y1, X and Y1, X and Z, or Y1 and Z may be absent and replaced with a bond to form a double bond between X and C, C and Y, X and Y1, X and Z, or Y1 and Z. Each of ring vertices a, b, c and d is independently selected from the group consisting of N, N+—O−, —CH— and C(R3), and from 0-2 ring vertices is N or N+—O−. In Formulae v, vi, vii and viii, the preferred embodiments of R3 substituent in the B1 and B2 ring of the B group and the ring vertices a, b, c and d are as set forth for Formula I.

In a fourth embodiment, -B1-B2 is a bicyclic ring having the formula:




wherein X is selected from the group consisting of C, N, O and S; the subscript n is an integer from 1-2; the bond  represents a single or double bond. In Formula ix and x, the R3 substituent of the -B1 ring is each independently selected from the group halogen, —ORf, —OC(O)Rf, —NRfRg, —SRf, —Rh, —CN, —NO2, —CO2Rf, —CONRfRg, —C(O)Rf, —OC(O)NRfRg, —NRgC(O)Rf, —NRgC(O)2Rh, —NRf—C(O)NRfRg, —NH—C(NH2)═NH, —NRhC(NH2)═NH, —NH—C(NH2)═NRh, NH—C(NHRh)═NH, —S(O)Rh, —S(O)2Rh, —NRfS(O)2Rh, —S(O)2NRfRg, —NRfS(O)2Rh, —NRfS(O)2NRfRg, —N3, —X3ORf, —X3OC(O)Rf, —X3NRfRg, —X3SRf, —X3 CN, —X3NO2, —X3CO2Rf, —X3CONRfRg, —X3C(O)Rf, —X3OC(O)NRfRg, —X3NRgC(O)Rf, —X3NRgC(O)2Rh, —X3NRf—C(O)NRfRg, —X3NH—C(NH2)═NH, —X3NRhC(NH2)═NH, —X3NH—C(NH2)═NRh, —X3NH—C(NHRh)═NH, —X3S(O)Rh, —X3S(O)2Rh, —X3NRfS(O)2Rh, —X3S(O)2NRfRg, and —X3N3, and wherein any two R3 substituents on attached to the same atom may be replaced with the substitutents ═O, ═NH, ═NOH, ═NRf, ═S or ═CRfRg; and optionally any two R3 substituents on -B1 located on adjacent atoms are absent and replaced with a bond to form a double bond. The subscript o is 0-2; and each of ring vertices a, b, c d and e is independently selected from the group consisting of N, —C(H)— and C(R3), and from 0-2 ring vertices is N or N+—O−, wherein the R3 substituent on the B2 ring as set forth for Formula I.

In another embodiment, in Formula I, B is the monocyclic ring system (-B1). In yet another embodiment, -B1 is a optionally substituted monocyclic ring system wherein the heterocyclic ring is selected from the group consisting of oxazolidinonyl, imidazolidinonyl, thiazolidinonyl, oxazinanonyl, thiazinanonyl, azetidinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, piperazinzyl, butyrolactamyl, valerolactamyl, caprolactamyl, hydantoinyl, dihydropyridinyl and pyridonyl. In yet another embodiment, in Formula I, B is the monocyclic ring system B1 and is attached to the remainder of the molecule through a nitrogen atom. In yet another embodiment, in Formula I, B is the monocyclic ring system B1 and is attached to the remainder of the molecule through a carbon atom. In another embodiment, in Formula I, B is the monocyclic ring system is selected from the group consisting of oxazolidinonyl, imidazolidinonyl, thiazolidinonyl, oxazinanonyl, thiazinanonyl, morpholinyl, thiomorpholinyl, valerolactamyl, caprolactamyl, piperidinyl, piperazinyl and pyrrolidinyl and is optionally substituted with 1 to 2 R3 substituents selected from Rh, —ORf, OC(O)Rf, —OC(O)NRfRg, NRgC(O)Rf, —CN and —CO2Rf. In another embodiment, in Formula I, B is the monocyclic ring system selected from the group consisting of oxazolidinonyl, imidazolidinonyl, oxazinanonyl, morpholinyl, piperidinyl, piperazinyl and is optionally substituted with 1 to 2 R3 substituents selected from Rh, —ORf, OC(O)Rf, —OC(O)NRfRg, —C(O)NRfRg, NRgC(O)Rf, —CN and —CO2Rf. In certain aspects of these embodiments, R3 is selected from —OMe, —NH2, —CN, —CH3, —CH2CH3, —CO2H, —CO2Me and —C(O)NMe2.
In Formula I, the symbol L1 is a linking group selected from the group consisting of C1-3 alkylene, C1-3 heteroalkylene, optionally substituted with phenyl, —Rk, —X4ORi, —X4OC(O)Ri, —X4NRiRj, —X4SRi, —X4CN or —X4NO2. X4 is selected from the group consisting of C1-4 alkylene, C2-4 alkenylene and C2-4 alkynylene. Each Ri and Rj is independently selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl, and aryloxy-C1-4 alkyl. Each Rk is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, heteroaryl, aryl-C1-4 alkyl, and aryloxy-C1-4 alkyl. In one embodiment, L1 is selected from the group consisting of —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2O—, —CH2NH—, —CH2OCH2—, and —CH2NHCH2—. In a preferred embodiment, L1 is —CH2—.
In Formula I, the symbol U is selected from the group consisting of N, C—Rp and N+—O−, wherein Rp is selected from the group consisting of hydrogen, C1-3 alkylene-ORq, C1-3 alkylene-N(Rq)2, C1-3 alkylene-NH(Rq), —OH, —ORq, —Rq, —CN, —OC(O)NHRq, OC(O)N(Rq)2, —SH, —SRq, —S(O)Rq, —S(O)2Rq, —SO2NH2, —S(O)2NHRq, —S(O)2N(Rq)2, —NHS(O)2Rq, —NRqS(O)2Rq, —C(O)NH2, —C(O)NHRq, —C(O)N(Rq)2, —C(O)Rq, —NHC(O)Rq, —NRqC(O)Rq, —NHC(O)NH2, NRqC(O)NH2, NRqC(O)NHRq, —NHC(O)NHRq, —NRqC(O)N(Rq)2, —NHC(O)N(Rq)2, —CO2H, —CO2Rq, —NHCO2Rq, —NRqCO2Rq, —NH2, —NHRq, —N(Rq)2, —NRqS(O)NH2, —NHC(═NH)NH2, —NHC(═NH)Rq and —NRqS(O)2NHRq. Rq is each independently C1-8 alkyl, C1-8 haloalkyl, C3-8 cycloalkyl; and the aliphatic portions of Rq is optionally further substituted with from one to three members selected from the group consisting of —OH, —ORr, —OC(O)NHRr, —OC(O)N(Rr)2, —SH, —SRr, —S(O)Rr, —S(O)2Rr, —SO2NH2, —S(O)2NHRr, —S(O)2N(Rr)2, —NHS(O)2Rr, —NRrS(O)2Rr, —C(O)NH2, —C(O)NHRr, —C(O)N(Rr)2, —C(O)Rr, —NHC(O)Rr, —NRqC(O)Rr, —NHC(O)NH2, —NRrC(O)NH2, —NRrC(O)NHRr, —NHC(O)NHRr, —NRrC(O)N(Rr)2, —NHC(O)N(Rr)2, —CO2H, —CO2Rf, —NHCO2Rr, —NRrCO2Rr, —CN, —NO2, —NH2, —NHRr, —N(Rr)2, —NRrS(O)NH2 and —NRrS(O)2NHRr, wherein each Rr is independently an unsubstituted C1-6 alkyl. In one embodiment, U is selected from the group consisting of N, C—Rp and N—O, wherein Rp is —OH, —NH2, —CH2OH, —CH2NH2, —CN, —ORq, —Rq, —C(O)2Rq and —C(O)Rq. In a preferred embodiment, U is selected from the group consisting of N, C—Rp and N—O, wherein Rp is —OH, —CN, —ORq, Rq, or —C(O)Rq. In another embodiment the symbol U is selected from the group consisting of N, C—Rp and N+—O−, wherein Rp is hydrogen, —OH, —CH2OH, —CH2ORq, —NH2, —CH2NH2, —CH2NHRq, —ORq, —Rq, —CN, —NO2, CO2H, and —CO2Rq. In another embodiment, U is selected from the group consisting of N, C—Rp and N—O, in which Rp is hydrogen, —OH, C1-3 alkylene-ORq, —NH2, —NHC(O)Rq, NHRq, —NHCONH2, —NHC(═NH)NH2, —NHC(═NH)Rq, C1-3 alkylene-NH(Rq), —ORq, —Rq, —CN, —NO2, —CO2H, or —CO2Rq. In another embodiment, U is selected from the group consisting of N, C—Rp and N—O, in which Rp is hydrogen, —OH, —CH2OH, —CH2ORq—NH2, —NHC(O)CH3, NHC(O)CH2NH2, —NHC(O)CH2OH, —NHCH2CH2NH, —NHCH2CH2OH, —NHCONH2, —NHC(═NH)NH2, —NHC(═NH)CH3, —ORq, —Rq, —CN, —NO2, —CO2H, or —CO2CH3. In a preferred embodiment, U is nitrogen. In another preferred embodiment, U is C—Rp.
In Formula I, the symbol L2 is a linking group selected from the group consisting of a direct bond, C1-3 alkylene, C1-8 heteroalkyl, —O—, —NRs, —C(O)—, —C(Rs)2, —S(O)—, —S(O)2—, —NRsC(O)— and —NRsS(O)2—. The substituent Rs is, at each occurrence, independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, C6-10 aryl and C5-10 heteroaryl; wherein the aliphatic portion of Rs are optionally further substituted with from one to three members selected from the group consisting of —OH, —ORt, —OC(O)NHRt, —OC(O)N(Rt)2, —SH, —SRt, —S(O)Rt, —S(O)2Rt, —SO2NH2, —S(O)2NHRt, —S(O)2N(Rt)2, —NHS(O)2Rt, —NRtS(O)2Rt, —C(O)NH2, —C(O)NHRt, —C(O)N(Rt)2, —C(O)Rt, —NHC(O)Rt, —NRoC(O)Rt, —NHC(O)NH2, —NRoC(O)NH2, —NRtC(O)NHRt, —NHC(O)NHRt, —NRtC(O)N(Rt)2, —NHC(O)N(Rt)2, —CO2H, —CO2Rt, —NHCO2Rt, —NRtCO2Rt, —CN, —NO2, —NH2, —NHRt, —N(Rt)2, —NRtS(O)NH2 and —NRtS(O)2NHRt, wherein each Rt is independently an unsubstituted C1-6 alkyl or C1-6 haloalkyl The subscript n is an integer from 0-2. In one embodiment, L2 is selected from the group consisting of direct bond, —CH2—, —O—, —C(Rr)2, —S(O)—, —S(O)2—, —C(O)— and —NRr— wherein Rr is a C1-6 alkyl or C1-6 haloalkyl. In another embodiment, L2 is selected from the group consisting of direct bond, —CH2— and —O—. In another embodiment, L2 is a direct bond or —CH2—.
B. Other Embodiments
In yet another embodiment of the invention, the compound having Formula I has the subformulae Ia, Ib or Ic:




in which R2c is halogen, —CN, or —NO2; R2d is —SRc, —O—X2—ORc, —X2—ORc, —Re, —ORc, —NRcRd, —NRcS(O)2Re or —NRdC(O)Rc; and R2a is halogen, —CO2Rc, —C(O)NRcRd, —CN, oxazolyl, —X2NRcRd or —C(NORc)Rd. The subscript m is 0-1; and wherein R1, when present, is —CO2H or C1-4 alkyl, optionally substituted with —OH, —ORm, —S(O)2Rm, —CO2H and —CO2Rm. In a preferred embodiment, in the compounds having Formulae Ia, Ib and Ic, R2c is —F, —Cl, —Br, —I, cyano, or nitro; R2d is —SCH3, —CH3, —CH2CH3, —CH2OCH3, —OCH3, —OCH2CH3 or —N(CH3)2; and R2a is F, Cl, Br, I, —CO2Me, —CONH2, —CN, oxazolyl, —CH2NH2, —CH2NHMe, —CH2NMe2 or —CH(═N—OH). The subscript m is 0-1 and wherein R1 when present is —CO2H or C1-4 alkyl.

In yet another embodiment of the invention, the compound having Formula I has the subformulae selected from the group consisting of:




wherein R2c is halogen, —CN, or —NO2; R2d is —SRc, —O—X2—ORc, —X2—ORc, —Re, —ORc, —NRcRd, —NRcS(O)2Re or —NRdC(O)Rc; and R2a is halogen, —CO2Rc, —C(O)NRcRd, —CN, oxazolyl, —X2NRcRd or —C(NORc)Rd; the subscript m is 0-1; wherein R1, when present, is —CO2H or C1-4 alkyl, optionally substituted with —OH, —ORm, —S(O)2Rm, —CO2H and —CO2Rm; and wherein; Rp is —OH, C1-3 alkylene-ORq, —NH2, —NHC(O)Rq, NHRq, —NHCONH2, —NHC(═NH)NH2, —NHC(═NH)Rq, C1-3 alkylene-NH(Rq), —ORq, —Rq, —CN, —NO2, —CO2H, or —CO2Rq.

In another embodiment, the compound of Formula I has the Formula Id:




In Formula Id, the subscript m is an integer from 0-2, preferably from 0-1; and the subscript n is an integer from 0-2, preferably from 0-1. The substituent R1 is selected from the group consisting of —CO2Ra or C1-4 alkyl, optionally substituted with OH, —ORm, —S(O)2Rm, —CO2H or —CO2Rm, or optionally any two R1 substituents located on the same atom is replaced with the substituent ═O, or ═S. In another embodiment, R1, when present, is selected from the group consisting of —CO2H or C1-4 alkyl, optionally substituted with OH, —ORm, —S(O)2Rm, —CO2H or —CO2Rm, wherein Rm is a C1-4 alkyl. In one embodiment, R1 is selected from —CO2H, —CO2Me, and methyl; and the subscript m is 0-1.
In Formula Id, the substituent R2a is selected from the group consisting of hydrogen, halogen, —CO2Rc, —C(O)NRcRd, —CN, Re, oxazolyl, —X2NRcRd and —C(NORc)Rd; R2c is selected from the group consisting of halogen, —CN, —NO2, —CO2Rc, —C(O)NRcRd, —C(O)Rc and —S(O)2Re; and R2d is selected from the group consisting of hydrogen, —SRc, —O—X2—ORc, —X2—ORc, —Re, —ORc, —NRcRd, —NRcS(O)2Re and —NRdC(O)Rc. In a specific embodiment, R2a is F, Cl, Br, I, —CO2Me, —CONH2, —CN, —CH3, oxazolyl, —CH2NH2, —CH2NHMe, —CH2NMe2 or —CH(═N—OH); R2c is —F, —Cl, —Br, —I, cyano, or nitro; and R2d is —SCH3, —CH3, —CH2CH3, —CH2OCH3, —OCH3, —OCH2CH3 or —N(CH3)2. In another specific embodiment, R2a is hydrogen; and R2c is —F, —Cl, —Br, —I, cyano, or nitro; and R2d is —SCH3, —CH3, —CH2CH3, —CH2OCH3, —OCH3, —OCH2CH3 or —N(CH3)2. In another specific embodiment, R2a and R2d are each hydrogen and R2c R2c is —F, —Cl, —Br, —I, cyano, or nitro.
The symbol L1, in Formula Id, is a C1-3 alkylene or C1-3 heteroalkylene. In one embodiment, the symbol L1 is selected from the group consisting of —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2O—, —CH2NH—, —CH2OCH2—, and —CH2NHCH2—. In other embodiments, the symbol L1 is —CH2—. The symbol L2 is selected from the group consisting of direct bond, —CH2— and —O—; in certain embodiments, the symbol L2 is a direct bond or —CH2—.
In Formula Id, the symbol U is selected from the group consisting of N and C—Rp, wherein Rp is —OH, C1-3 alkylene-ORq, —NH2, —NHC(O)Rq, NHRq, —NHCONH2, —NHC(═NH)NH2, —NHC(═NH)Rq, C1-3 alkylene-NH(Rq), —ORq, —Rq, —CN, —NO2, —CO2H, or —CO2Rq. In one embodiment, U is selected from the group consisting of N and C—Rp, wherein Rp is hydrogen, —OH, —CH2OH, —CH2ORq, —NH2, —CH2NH2, —CH2NHRq, —ORq, —Rq, —CN, —NO2, CO2H, or —CO2Rq. In one embodiment, the symbol U is N. In another embodiment, the symbol U is C—Rp, wherein Rp is selected from the group consisting of hydrogen, —OH, —Rq, —CN, —CO2H and —CO2Rq. In another embodiment, the symbol U is nitrogen or C—Rp, wherein Rp is selected from hydrogen and OH.
The symbol Z, in Formula Id, is CH2, CHR3, C(R3)2, NH, NR3 or O, wherein R3 (in the B1 ring) is selected from the group consisting of —Rh, —X3ORf, —X3NRfRg, —X3CO2Rf and —X3CONRfRg. In one embodiment, the R3 substituent of the -B1 ring is selected from the group consisting of methyl, ethyl, propyl, CH2CH2OH, CH2CH2NH2, CH2CH2NMeH, CH2CO2H and CH2CONH2.
Each of ring vertices a, b, c and d in Formula Id is independently selected from the group consisting of N, N+—O−, C(H) and C(R3); and from 0-2 ring vertices is N or N+—O−. If any of the ring vertices a, b, c or d in the B2 ring is C(R3), in one embodiment, the R3 substituent is independently selected from the group consisting of hydrogen, halogen, —ORf, NRfRg, SRf, —Rh, —Y, —CN, X3N3, —SO2Rh, X3NRfRg, X3Y, —S(O)3Rf, —C(C═NORf)NRfRg, —NO2, and —NRgC(O)Rf, wherein Y is an optionally substituted group selected from the group consisting of phenyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, pyrrolyl and morpholinyl, and Rh is an optionally substituted group selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl and C3-8 cycloalkyl, and Rf and Rg are each independently an optionally substituted group selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl and C3-8 cycloalkyl.
In another embodiment, R3 is preferably selected from the group consisting of halogen, —ORf, —CN, —NO2, C(NH2)═NORf and —Y, wherein Y is an optionally substituted oxadiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl and thiazolyl group. In a specific embodiment, R3 on the B2 ring is selected from the group consisting of OMe, CN, —C(NH2)═NOH, oxadiazolyl or ORf, wherein Rf is selected from the group consisting of hydrogen, C1-4 alkyl optionally substituted with —CO2H, —CO2Ro, —NH2, —NRoH and —N(Ro)2.
Within each of the above embodiments, the aliphatic portions of the R3 group of the B2 ring are each independently optionally substituted with from one to three members selected from the group consisting of —OH, —ORo, —OC(O)NHRo, —OC(O)N(Ro)2, —SH, —SRo, —S(O)Ro, —S(O)2Ro, —SO2NH2, —S(O)2NHRo, —S(O)2N(Ro)2, —NHS(O)2Ro, —NRoS(O)2Ro, —C(O)NH2, —C(O)NHRo, —C(O)N(Ro)2, —C(O)Ro, —NHC(O)Ro, —NRoC(O)Ro, —NHC(O)NH2, —NRoC(O)NH2, —NRoC(O)NHRo, —NHC(O)NHRo, —NRoC(O)N(Ro)2, —NHC(O)N(Ro)2, —CO2H, —CO2Ro, —NHCO2Ro, —NRoCO2Ro, —CN, —NO2, —NH2, —NHRo, —N(Ro)2, —NRoS(O)NH2 and —NRoS(O)2NHRo, wherein each Ro is independently an unsubstituted C1-6 alkyl.
In one embodiment, in Formula Id, the ring vertices a, b, c and d of the B2 ring are C(H) or C(R3). In one embodiment, in Formula Id the ring vertices a, b, d are each C(H) and c is C(R3). In another embodiment, in Formula Id, the ring vertices a, c, d in Formula Id are each C(H) and b is C(R3). In yet another aspect, in compounds having Formula Id, the ring vertex a is N or N+—O− and the ring vertices b, c and d are each C(H) or C(R3). In yet another aspect, in compounds having Formula Id, the ring vertex c is N or N+—O− and the ring vertices a, b and d are each C(H) or C(R3).
In yet another embodiment, the compounds of Formula I has the formula selected from the group consisting of




In Formula Ie or If, the subscript m is an integer from 0-2, preferably from 0-1; and the subscript n is an integer from 0-2, preferably from 0-1. The substituent R1 is selected from the group consisting of —CO2Ra or C1-4 alkyl, optionally substituted with OH, —ORm, —S(O)2Rm, —CO2H or —CO2Rm, or optionally any two R1 substituents located on the same atom is replaced with the substituent ═O, or ═S. In another embodiment, R1, when present, is selected from the group consisting of —CO2H or C1-4 alkyl, optionally substituted with OH, —ORm, —S(O)2Rm, —CO2H or —CO2Rm, wherein Rm is a C1-4 alkyl. In one embodiment, R1 is selected from —CO2H, —CO2Me, and methyl; and the subscript m is 0-1.
In Formula Ie or If, the substituent R2a is selected from the group consisting of hydrogen, halogen, —CO2Rc, —C(O)NRcRd, —CN, Re, oxazolyl, —X2NRcRd and —C(NORc)Rd; R2c is selected from the group consisting of halogen, —CN, —NO2, —CO2Rc, —C(O)NRcRd, —C(O)Rc and —S(O)2Re; and R2d is selected from the group consisting of hydrogen, —SRc, —O—X2—ORc, —X2—ORc, —Re, —ORc, —NRcRd, —NRcS(O)2Re and —NRdC(O)Rc. In a specific embodiment, R2a is F, Cl, Br, I, —CO2Me, —CONH2, —CN, —CH3, oxazolyl, —CH2NH2, —CH2NHMe, —CH2NMe2 or —CH(═N—OH); R2c is —F, —Cl, —Br, —I, cyano, or nitro; and R2d is —SCH3, —CH3, —CH2CH3, —CH2OCH3, —OCH3, —OCH2CH3 or —N(CH3)2. In another specific embodiment, R2a is hydrogen; and R2c is —F, —Cl, —Br, —I, cyano, or nitro; and R2d is —SCH3, —CH3, —CH2CH3, —CH2OCH3, —OCH3, —OCH2CH3 or —N(CH3)2. In another specific embodiment, R2a and R2d are each hydrogen and R2c is —F, —Cl, —Br, —I, cyano, or nitro.
The symbol L1, in Formula Ie or If, is a C1-3 alkylene or C1-3 heteroalkylene. In one embodiment, the symbol L1 is selected from the group consisting of —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2O—, —CH2NH—, —CH2OCH2—, and —CH2NHCH2—. In other embodiments, the symbol L1 is —CH2—. The symbol L2 is selected from the group consisting of direct bond, —CH2— and —O—; in certain embodiments, the symbol L2 is a direct bond or —CH2—.
In Formula Ie or If, the symbol U is selected from the group consisting of N and C—Rp, wherein Rp is —OH, C1-3 alkylene-ORq, —NH2, —NHC(O)Rq, NHRq, —NHCONH2, —NHC(═NH)NH2, —NHC(═NH)Rq, C1-3 alkylene-NH(Rq), —ORq, —Rq, —CN, —NO2, —CO2H, or —CO2Rq. In one embodiment, U is selected from the group consisting of N and C—Rp, wherein Rp is hydrogen, —OH, —CH2OH, —CH2ORq, —NH2, —CH2NH2, —CH2NHRq, —ORq, —Rq, —CN, —NO2, CO2H, or —CO2Rq. In one embodiment, the symbol U is N. In another embodiment, the symbol U is C—Rp, wherein Rp is selected from the group consisting of hydrogen, —OH, —Rq, —CN, —CO2H and —CO2Rq. In one embodiment, the symbol U is N or C—Rp, wherein Rp is hydrogen or OH.
The symbols Z and Y1, in Formula Ie or If, are each independently selected from CH2, CHR3, C(R3)2, NH, NR3 or O, wherein R3 (in the B1 ring) is selected from the group consisting of —Rh, —X3ORf, —X3NRfRg, —X3CO2Rf and CONRfRg. In one embodiment, the R3 substituent of the -B1 ring is selected from the group consisting of methyl, ethyl, propyl, CH2CH2OH, CH2CH2NH2, CH2CH2NMeH, CH2CO2H and CH2CONH2.
Each of ring vertices a, b, c and d in Formula Ie or If is independently selected from the group consisting of N, N+—O−, C(H) and C(R3); and from 0-2 ring vertices is N or N+—O−. If any of the ring vertices a, b, c or d in the B2 ring is C(R3), in one embodiment, the R3 substituent is independently selected from the group consisting of hydrogen, halogen, —ORf, NRfRg, SRf, —Rh, —Y, —CN, X3N3, —SO2Rh, X3NRfRg, X3Y, —S(O)3Rf, —C(C═NORf)NRfRg, —NO2, and —NRgC(O)Rf, wherein Y is an optionally substituted group selected from the group consisting of phenyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, pyrrolyl and morpholinyl, and Rh is an optionally substituted group selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl and C3-8 cycloalkyl, and Rf and Rg are each independently an optionally substituted group selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl and C3-8 cycloalkyl.
In another embodiment, R3 is preferably selected from the group consisting of halogen, —ORf, —CN, —NO2, C(NH2)═NORf and —Y, wherein Y is an optionally substituted oxadiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl and thiazolyl group. In a specific embodiment, R3 on the B2 ring is selected from the group consisting of OMe, CN, —C(NH2)═NOH, oxadiazolyl or ORf, wherein Rf is selected from the group consisting of hydrogen, C1-4 alkyl optionally substituted with —CO2H, —CO2Ro, —NH2, —NRoH and —N(Ro)2. In certain embodiments, R3 in the B2 ring is halogen or ORf, wherein Rf is selected from the group consisting of hydrogen, C1-4 alkyl optionally substituted with —CO2H, —CO2Ro, —NH2, —NRoH and —N(Ro)2.
Within each of the above embodiments, the aliphatic portions of the R3 group of the B2 ring are each independently optionally substituted with from one to three members selected from the group consisting of —OH, —ORo, —OC(O)NHRo, —OC(O)N(Ro)2, —SH, —SRo, —S(O)Ro, —S(O)2Ro, —SO2NH2, —S(O)2NHRo, —S(O)2N(Ro)2, —NHS(O)2Ro, —NRoS(O)2Ro, —C(O)NH2, —C(O)NHRo, —C(O)N(Ro)2, —C(O)Ro, —NHC(O)Ro, —NRoC(O)Ro, —NHC(O)NH2, —NRoC(O)NH2, —NRoC(O)NHRo, —NHC(O)NHRo, —NRoC(O)N(Ro)2, —NHC(O)N(Ro)2, —CO2H, —CO2Ro, —NHCO2Ro, —NRoCO2Ro, —CN, —NO2, —NH2, —NHRo, —N(Ro)2, —NRoS(O)NH2 and —NRoS(O)2NHRo, wherein each Ro is independently an unsubstituted C1-6 alkyl.
In one embodiment, in Formula Ie or If, the ring vertices a, b, c and d of the B2 ring are C(H) or C(R3). In one embodiment, in Formula Ie or If the ring vertices a, b, d are each C(H) and c is C(R3). In another embodiment, in Formula Id, the ring vertices a, c, d in Formula Ie or If are each C(H) and b is C(R3). In yet another aspect, in compounds having Formula Ie or If, the ring vertex a is N or N+—O− and the ring vertices b, c and d are each C(H) or C(R3). In yet another aspect, in compounds having Formula Ie or If, the ring vertex d is N or N+—O− and the ring vertices a, b and d are each C(H) or C(R3).
In another specific embodiment, in Formula I, the substituent R1 is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, —CO2Ra, —X1CO2Ra, —X1SO2Ra, —X1SO3Ra, —X1ORa, —CORa, CONRaRb, —X1NRaRb, —X1NRaCORb, —X1CONRaRb, X1NRaS(O)2Rb, —X1S(O)2NRaRb and X1S(O)2Ra, wherein X1 is C1-4 alkylene and each Ra and Rb is independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl and C3-6 cycloalkyl, optionally any two R1 substituents attached to the same atom are optionally replaced with the substitutent ═O, ═NH, ═NOH, ═NRa, ═S or ═CRaRb, and wherein the aliphatic portions of each of said R1 substituents is optionally substituted with from one to three members selected from the group consisting of —OH, —ORm, —OC(O)NHRm, —OC(O)N(Rm)2, —SH, —SRm, —S(O)Rm, —S(O)2Rm, —SO2NH2, —S(O)2NHRm, —S(O)2N(Rm)2, —NHS(O)2Rm, —NRmS(O)2Rm, —C(O)NH2, —C(O)NHRm, —C(O)N(Rm)2, —C(O)Rm, —NHC(O)Rm, —NRmC(O)Rm, —NHC(O)NH2, —NRmC(O)NH2, —NRmC(O)NHRm, —NHC(O)NHRm, —NRmC(O)N(Rm)2, —NHC(O)N(Rm)2, —CO2H, —CO2Rm, —NHCO2Rm, —NRmCO2Rm, —CN, —NO2, —NH2, —NHRm, —N(Rm)2, —NRmS(O)NH2 and —NRmS(O)2NHRm, wherein each Rm is independently an unsubstituted C1-6 alkyl. The subscript m is an integer from 0-2; and the subscript n is an integer from 0-1. The substituents R2a, R2c and R2d are each independently selected from the group consisting of hydrogen, halogen, cyano, heteroaryl, —NO2, —CO2Rc, —CONRcRd, —C(O)Rc, —S(O)Re, —S(O)2Re, —Re, —C(NORc)Rd, —C(NRcV)═NV, —N(V)C(Rc)═NV, —X2C(NORc)Rd, —X2C(NRcV)═NV, —X2N(V)C(Rc)═NV, —X2NRcRd, —X2SRc, —X2NO2, —X2CO2Rc, —X2CONRcRd, —X2C(O)Rc, —X2OC(O)NRcRd, —X2NRdC(O)Rc, —X2NRdC(O)2Re, —X2NRcC(O)NRcRd, —X2NH—C(NH2)═NH, —X2NReC(NH2)═NH, —X2NH—C(NH2)═NRe, —X2NH—C(NHRe)═NH, —X2S(O)Re, —X2S(O)2Re, —X2NRcS(O)2Re, —X2S(O)2NRcRd, —X2N3, ORc, —SRc, —Re, —NRdC(O)Rc, NRdC(O)2Re, —S(O)2Re, —S(O)2NRcRd, —X2ORc, —O—X2ORc, —X2NRcRd, —O—X2NRcRd and NRd—X2CO2Rc; wherein within each of R2a, R2c and R2d, X2 is C1-4 alkylene and each Rc and Rd is independently selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, or optionally, Rc and Rd when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members; and each Re is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl and heteroaryl, and each of Rc, Rd and Re is optionally further substituted with from one to three members selected from the group consisting of —OH, —ORn, —OC(O)NHRn, —OC(O)N(Rn)2, —SH, —SRn, —S(O)Rn, —S(O)2Rn, —SO2NH2, —S(O)2NHRn, —S(O)2N(Rn)2, —NHS(O)2Rn, —NRnS(O)2Rn, —C(O)NH2, —C(O)NHRn, —C(O)N(Rn)2, —C(O)Rn, —NHC(O)Rn, —NRnC(O)Rn, —NHC(O)NH2, —NRnC(O)NH2, —NRnC(O)NHRn, —NHC(O)NHRn, —NRnC(O)N(Rn)2, —NHC(O)N(Rn)2, —CO2H, —CO2Rn, —NHCO2Rn, —NRnCO2Rn, —CN, —NO2, —NH2, —NHRn, —N(Rn)2, —NRnS(O)NH2 and —NRnS(O)2NHRn, wherein each Rn is independently an unsubstituted C1-6 alkyl; and wherein V is independently selected from the group consisting of —Rc, —CN, —CO2Re and —NO2. The symbol B represents a monocyclic (-B1) ring system, or a bicyclic (-B1-B2) ring system selected from the group consisting of formulae i, ii, iii, iv, v, vi, vii, viii, ix and x:







wherein in:

    
    
        a) Formulae i and ii, the symbols X, Y and Z are each independently selected from the group consisting of —CH2—, —CHR3—, —C(R3)2—, —NR3—, —NH—, —S—, —O—, —C(O)—, —S(O)— and —S(O)2—; or optionally any two substituents on the adjacent atoms of X and Y1, or Y1 and Z may be absent and replaced with a bond to form a double bond between X and Y1, or Y1 and Z; and each of ring vertices a, b, c and d is independently selected from the group consisting of N, N+—O−, C(H) and C(R3), and from 0-2 ring vertices is N or N+—O−;
        b) Formulae iii and iv, X, Y and Z are each independently selected from the group consisting of —CH2—, —CHR3—, —C(R3)2—, —C(O)—, —NH— and —N(R3), —O—, —S—, —S(O)— and —S(O)2—; or optionally any two substituents on adjacent atoms of one of Y and Z may be absent and replaced with a bond to form a double bond between Y and Z; and each of ring vertices a, b, c and d is independently selected from the group consisting of N, N+—O−, C(H) and C(R3), and from 0-2 ring vertices is N or N—O−;
        c) Formulae v, vi, vii and viii, X, Y and Z are each independently selected from the group consisting of —CH2—, —CHR3—, —C(R3)2, —C(O)—, —S(O)—, —S(O)2—, —NH—, —N(R3), —S— and —O—, wherein at least one of X, Y and Z is —NH— or —N(R3)—; optionally any two substituents on adjacent atoms of X and C, C and Y, X and Y, X and Z, or Y and Z may be absent and replaced with a bond to form a double bond between X and C, C and Y, X and Y, X and Z, or Y and Z; each of ring vertices a, b, c and d is independently selected from the group consisting of N, N+—O−, —CH— and C(R3), and from 0-2 ring vertices is N or N+—O−;
        d) Formulae ix and x, X is selected from the group consisting of C, N, O and S; optionally any two R3 substituents on -B1 located on adjacent atoms are absent and replaced with a bond to form a double bond; the subscript o is 0-2 and the subscript n is from 1-2; and each of ring vertices a, b, c d and e is independently selected from the group consisting of N, N+—O−, —C(H)— and C(R3), and from 0-2 ring vertices is N or N+—O−; and the bond, , represents a single or double bond;

The symbol L1 is a linking group selected from the group consisting of C1-3 alkylene, C1-3 heteroalkylene. The symbol U is selected from the group consisting of N, C—Rp and N+—O−, wherein Rp is —OH, C1-3 alkylene-ORq, —NH2, —NHC(O)Rq, NHRq, —NHCONH2, —NHC(═NH)NH2, —NHC(═NH)Rq, C1-3 alkylene-NH(Rq), —ORq, —Rq, —CN, —NO2, —CO2H, or —CO2Rq, wherein Rq is each independently C1-8 alkyl, C1-8 haloalkyl, C3-8 cycloalkyl wherein the aliphatic portions of Rq is optionally further substituted with from one to three members selected from the group consisting of —OH, —ORr, —OC(O)NHRr, —OC(O)N(Rr)2, —SH, —SRr, —S(O)Rr, —S(O)2Rr, —SO2NH2, —S(O)2NHRr, —S(O)2N(Re)2, —NHS(O)2Rr, —NRrS(O)2Rr, —C(O)NH2, —C(O)NHRr, —C(O)N(Rr)2, —C(O)Rr, —NHC(O)Rr, —NRqC(O)Rr, —NHC(O)NH2, —NRrC(O)NH2, —NRrC(O)NHRr, —NHC(O)NHRr, —NRrC(O)N(Rr)2, —NHC(O)N(Rr)2, —CO2H, —CO2Rr, —NHCO2Rr, —NRrCO2Rr, —CN, —NO2, —NH2, —NHRr, —N(Rr)2, NRrS(O)NH2 and —NRrS(O)2NHRr, wherein each Rr is independently an unsubstituted C1-6 alkyl. The symbol L2 is a linking group selected from the group consisting of a direct bond, C1-3 alkylene, —O—, —NRs—, —C(O)—, —C(Rs)2, —S(O)—, —S(O)2—, —NRsC(O)— and —NRsS(O)2—, wherein Rs is at each occurrence is independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, C6-10 aryl and C5-10 heteroaryl wherein the aliphatic portion of Rs are optionally further substituted with from one to three members selected from the group consisting of —OH, —ORt, —OC(O)NHRt, —OC(O)N(Rt)2, —SH, —SRt, —S(O)Rt, —S(O)2Rt, —SO2NH2, —S(O)2NHRt, —S(O)2N(Rt)2, —NHS(O)2Rt, —NRtS(O)2Rt, —C(O)NH2, —C(O)NHRt, —C(O)N(Rt)2, —C(O)Rt, —NHC(O)Rt, —NRtC(O)Rt, —NHC(O)NH2, —NRtC(O)NH2, —NRtC(O)NHRt, —NHC(O)NHRt, —NRtC(O)N(Rt)2, —NHC(O)N(Rt)2, —CO2H, —CO2Rt, —NHCO2Rt, —NRtCO2Rt, —CN, —NO2, —NH2, —NHRt, —N(Rt)2, —NRtS(O)NH2 and —NRtS(O)2NHRt, wherein each Rt is independently an unsubstituted C1-6 alkyl or C1-6 haloalkyl.

    
    


A family of specific compound of particular interest having Formulae Ia and Ib consists of compounds, pharmaceutically acceptable salts, hydrates or N-oxides thereof, as set forth in Table 1.








TABLE 1







1.
5-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxoethyl}-1,3-



dihydro-indol-2-one


2.
6-chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-



benzooxazol-2-one


3.
6-Chloro-3-{2-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-oxo-



ethyl}-3H-benzooxazol-2-one


4.
6-Chloro-3-{2-[(S)-4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-



yl]-2-oxo-ethyl}-3H-benzooxazol-2-one


5.
6-Chloro-3-{2-[(S)-4-(4-chloro-3-methoxy-phenyl)-2-methylpiperazin-1-yl]-2-oxo-



ethyl}-3H-benzooxazol-2-one


6.
Synthesis of 5-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-



ethyl}-1,3-dihydro-benzoimidazol-2-one


7.
6-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1,3-



dihydro-benzoimidazol-2-one.


8.
(6-Chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-



2,3-dihydro-benzoimidazol-1-yl)-acetic acid ethyl ester


9.
(5-Chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-



2,3-dihydro-benzoimidazol-1-yl)-acetic acid ethyl ester


10.
(6-Chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-



2,3-dihydro-benzoimidazol-1-yl)-acetic acid


11.
(5-Chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-



2,3-dihydrobenzoimidazol-1-yl)-acetic acid


12.
6-chloro-3-{2-[4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-



one


13.
3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-



2-one


14.
5-chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-



benzooxazol-2-one


15.
6-methoxy-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-



benzooxazol-2-one


16.
6-fluoro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-



benzooxazol-2-one


17.
1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-1,3-



dihydro-benzoimidazol-2-one


18.
1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-oxazolidin-2-one.


19.
1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-imidazolidin-2-



one


20.
1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-((2S,6R)-2,6-dimethyl-piperidin-



1-yl)-ethanone


21.
1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-morpholin-4-yl-ethanone


22.
1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-methyl-piperazin-1-yl)-



ethanone


23.
1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-piperazin-1-yl-ethanone


24.
7-Chloro-4-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-



benzo[1,4]oxazin-3-one


25.
6-Chloro-4-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-



benzo[1,4]oxazin-3-one


26.
4-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-



benzo[1,4]oxazin-3-one


27.
4-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-oxazolo[4,5-



b]pyridin-2-one


28.
4-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-



oxazolo[4,5-b]pyridin-2-one


29.
3-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-



oxazolo[4,5-b]pyridin-2-one


30.
6-Chloro-3-{2-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-oxo-



ethyl}-3H-oxazolo[4,5-b]pyridin-2-one


31.
7-Chloro-4-{2-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-oxo-



ethyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one


32.
3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenyl-



oxazolidin-2-one


33.
3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-phenyl-



oxazolidin-2-one


34.
(3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-



dihydro-benzooxazol-6-yloxy)-acetic acid


35.
3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-



[1,2,4]oxadiazol-3-yl-3H-benzooxazol-2-one


36.
3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-(2-hydroxy-



ethoxy)-3H-benzooxazol-2-one


37.
6-(2-Amino-ethoxy)-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-



ethyl}-3H-benzooxazol-2-one


38.
5-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-



methyl-1,3-dihydro-benzoimidazol-2-one


39.
{1-(4-chloro-3-methoxy-phenyl)-4-[2-(6-chloro-2-oxo-2,3-dihydro-benzofuran-3-yl)-



acetyl]-piperazin-2-yl}-acetic acid methyl ester


40.
5-chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1-



methyl-1,3-dihydro-benzoimidazol-2-one


41.
3-(2-(4-(4-Fluorobenzyl)-4-hydroxypiperidin-1-yl)-2-oxoethyl)-6-



chlorobenzo[d]oxazol-2(3H)-one


42.
6-Chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-4-hydroxy-piperidin-1-yl]-2-oxo-



ethyl}-3H-benzooxazol-2-one


43.
6-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1,4-



dihydro-benzo[d][1,3]oxazin-2-one


44.
6-chloro-3-{2-[3-(3-chloro-2-methyl-phenyl)-4-oxo-imidazolidin-1-yl]-2-oxo-ethyl}-



3H-benzooxazol-2-one


45.
5-Chloro-1-{2-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-2-oxo-ethyl}-1,3-



dihydro-benzoimidazol-2-one


46.
6-Chloro-1-{2-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-2-oxo-ethyl}-1,3-



dihydro-benzoimidazol-2-one









Preparation of Compounds

As provided in the examples below, the compounds and intermediates of the present invention can be prepared by one of skill in the art in a component assembly manner. Schemes 1A-1L illustrate a variety of methods for the preparation of a variety of monocyclic and bicyclic groups and derivatives. In each of these schemes, X is halogen; U is —NH—. —O—, —CR′′′R′′′—, or —NR′′′—; the symbol {circle around (N)} within an aryl ring indicate the replacement of one to two carbon(s) of said aryl ring vertex (vertices) with nitrogen atom(s); L is a ligand; and non-interferring substituents are provided as —R, —R′, —R′′, and —R′′′.
Scheme 1A
Scheme 1A shows the synthesis of a bicyclic group of the invention.




Scheme 1B
Scheme 1B shows the synthesis of a bicyclic group of the invention.




Scheme 1C
Scheme 1C shows the synthesis of a bicyclic group of the invention.




Scheme 1D
Scheme 1D shows a halogenation reaction of a bicyclic group of the invention




Scheme 1E
Scheme 1E shows a halogenation reaction of a bicyclic group of the invention




Scheme 1F
Scheme 1F shows the cyanation of a bicyclic group of the invention.




Scheme 1G
Scheme 1G shows the synthesis of a bicyclic compound of the invention.




Scheme 1H
Scheme 1H shows the synthesis of a bicyclic compound of the invention.




Scheme 1I
Scheme 1I shows the functionalization of a bicyclic compound of the invention.




Scheme 1J
Scheme 1J shows the functionalization of a bicyclic compound of the invention.




Scheme 1K
Scheme 1K shows the alkylation of a bicyclic compound of the invention.




Scheme 1L
Scheme 1L shows the alkylation reaction of a bicyclic compound of the invention.




IV. Pharmaceutical Compositions

In addition to the compounds provided above, compositions for modulating CCR1 activity in humans and animals will typically contain a pharmaceutical carrier or diluent.
The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy and drug delivery. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self emulsifications as described in U.S. Patent Application 2002-0012680, hard or soft capsules, syrups, elixirs, solutions, buccal patch, oral gel, chewing gum, chewable tablets, effervescent powder and effervescent tablets. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, antioxidants and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example PVP, cellulose, PEG, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated, enterically or otherwise, by known techniques to delay disintegration and absorption 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 may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Additionally, emulsions can be prepared with a non-water miscible ingredient such as oils and stabilized with surfactants such as mono-diglycerides, PEG esters and the like.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG and surfactants.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. Additionally, the compounds can be administered via ocular delivery by means of solutions or ointments. Still further, transdermal delivery of the subject compounds can be accomplished by means of iontophoretic patches and the like. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. As used herein, topical application is also meant to include the use of mouth washes and gargles.
The compounds of this invention may also be coupled a carrier that is a suitable polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the invention may be coupled to a carrier that is a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels. Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like. In one embodiment of the invention, the compound of the invention is coupled to a polymer or semipermeable polymer matrix that is formed as a stent or stent-graft device.
V. Methods of Treating Diseases Modulated by CCR1
In yet another aspect, the present invention provides methods of treating CCR1-mediated conditions or diseases by administering to a subject having such a disease or condition, a therapeutically effective amount of a compound of Formula I above. The “subject” is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like.
CCR1 provides a target for interfering with or promoting specific aspects of immune cell functions, or more generally, with functions associated with CCR1 expression on a wide range of cell types in a mammal, such as a human. Compounds that inhibit CCR1, are particularly useful for modulating monocyte, macrophage, lymphocyte, granulocyte, NK cell, mast cells, dendritic cell, neutrophils, and certain immune derived cell (for example, osteoclasts) function for therapeutic purposes. Accordingly, the present invention is directed to compounds which are useful in the prevention and/or treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases (see Saeki, et al., Current Pharmaceutical Design 9:1201-1208 (2003)).
For example, an instant compound that inhibits one or more functions of CCR1 may be administered to inhibit (i.e., reduce or prevent) inflammation or cellular infiltration associated with an immune disorder. As a result, one or more inflammatory processes, such as leukocyte emigration or infiltration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, can be inhibited. For example, monocyte infiltration to an inflammatory site (e.g., an affected joint in arthritis, or into the CNS in MS) can be inhibited according to the present method.
Similarly, an instant compound that promotes one or more functions of CCR1 is administered to stimulate (induce or enhance) an inflammatory response, such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, resulting in the beneficial stimulation of inflammatory processes. For example, monocytes can be recruited to combat bacterial infections.
Diseases and conditions associated with inflammation, immune disorders and infection can be treated using the method of the present invention. In a preferred embodiment, the disease or condition is one in which the actions of immune cells such monocyte, macrophage, lymphocyte, granulocyte, NK cell, mast cell, dendritic cell, or certain immune derived cell (for example, osteoclasts) are to be inhibited or promoted, in order to modulate the inflammatory or autoimmune response.
In one group of embodiments, diseases or conditions, including chronic diseases, of humans or other species can treated with modulators of CCR1 function. These diseases or conditions include: (1) allergic diseases such as systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies and food allergies, (2) inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, ileitis and enteritis, (3) vaginitis, (4) psoriasis and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria and pruritus, (5) vasculitis, (6) spondyloarthropathies, (7) scleroderma, (8) asthma and respiratory allergic diseases such as allergic asthma, allergic rhinitis, hypersensitivity lung diseases and the like, (9) autoimmune diseases, such as fibromyalagia, scleroderma, ankylosing spondylitis, juvenile RA, Still's disease, polyarticular juvenile RA, pauciarticular juvenile RA, polymyalgia rheumatica, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, polyarticular arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, type II diabetes, glomerulonephritis, and the like, (10) graft rejection (including allograft rejection and graft-v-host disease), and (11) other diseases in which undesired inflammatory responses or immune disorders are to be inhibited, such as cardiovascular disease including atherosclerosis and restenosis, myositis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, chronic obstructive pulmonary disease, sinusitis, Behcet's syndrome and gout and (12) immune mediated food allergies such as Celiac disease.
In another group of embodiments, diseases or conditions can be treated with modulators of CCR1 function. Examples of diseases to be treated with modulators of CCR1 function include cancers, cardiovascular diseases, diseases in which angiogenesis or neovascularization play a role (neoplastic diseases, retinopathy and macular degeneration), infectious diseases (viral infections, e.g., HIV infection, and bacterial infections) and immunosuppressive diseases such as organ transplant conditions and skin transplant conditions. The term “organ transplant conditions” is meant to include bone marrow transplant conditions and solid organ (e.g., kidney, liver, lung, heart, pancreas or combination thereof) transplant conditions.
The compounds of the present invention are accordingly useful in the prevention and treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases.
Depending on the disease to be treated and the subject's condition, the compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by implantation (e.g., as when the compound is coupled to a stent device), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
In the treatment or prevention of conditions which require chemokine receptor modulation an appropriate dosage level will generally be about 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, hereditary characteristics, general health, sex and diet of the subject, as well as the mode and time of administration, rate of excretion, drug combination, and the severity of the particular condition for the subject undergoing therapy.
Diseases and conditions associated with inflammation, immune disorder, infection and cancer can be treated or prevented with the present compounds, compositions, and methods.
The compounds and compositions of the present invention can be combined with other compounds and compositions having related utilities to prevent and treat the condition or disease of interest, such as inflammatory or autoimmune disorders, conditions and diseases, including inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, polyarticular arthritis, multiple sclerosis, allergic diseases, psoriasis, atopic dermatitis and asthma, and those pathologies noted above.
For example, in the treatment or prevention of inflammation or autoimmunity or for example arthritis associated bone loss, the present compounds and compositions may be used in conjunction with an anti-inflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non steroidal anti-inflammatory agent, or a cytokine-suppressing anti-inflammatory agent, for example with a compound such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like. Similarly, the instant compounds and compositions may be administered with an analgesic listed above; a potentiator such as caffeine, an H2 antagonist (e.g., ranitidine), simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo desoxy ephedrine; an antitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextromethorphan; a diuretic; and a sedating or non sedating antihistamine.
Likewise, compounds and compositions of the present invention may be used in combination with other drugs that are used in the treatment, prevention, suppression or amelioration of the diseases or conditions for which compounds and compositions of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound or composition of the present invention. When a compound or composition of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound or composition of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound or composition of the present invention. Examples of other therapeutic agents that may be combined with a compound or composition of the present invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) VLA-4 antagonists, (b) corticosteroids, such as beclomethasone, methylprednisolone, betamethasone, prednisone, prenisolone, dexamethasone, fluticasone, hydrocortisone, budesonide, triamcinolone, salmeterol, salmeterol, salbutamol, formeterol; (c) immunosuppressants such as cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolirnus (FK-506, Prograf®), rapamycin (sirolimus, Rapamune®) and other FK-506 type immunosuppressants, and mycophenolate, e.g., mycophenolate mofetil (CellCept®); (d) antihistamines (H1-histamine antagonists) such as bromopheniramine, chlorpheniramine, dexchloipheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and the like; (e) non steroidal anti asthmatics (e.g., terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (e.g., zafmlukast, montelukast, pranlukast, iralukast, pobilukast and SKB-106,203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005); (f) non steroidal anti-inflammatory agents (NSAIDs) such as propionic acid derivatives (e.g., alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), acetic acid derivatives (e.g., indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin and zomepirac), fenamic acid derivatives (e.g., flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal), oxicams (e.g., isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (e.g., acetyl salicylic acid and sulfasalazine) and the pyrazolones (e.g., apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone and phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®); (h) inhibitors of phosphodiesterase type IV (PDE IV); (i) gold compounds such as auranofin and aurothioglucose, (j) etanercept (Enbrel®), (k) antibody therapies such as orthoclone (OKT3), daclizumab (Zenapax®), basiliximab (Simulect®) and infliximab (Remicade®), (l) other antagonists of the chemokine receptors, especially CCR5, CXCR2, CXCR3, CCR2, CCR3, CCR4, CCR7, CX3CR1 and CXCR6; (m) lubricants or emollients such as petrolatum and lanolin, (n) keratolytic agents (e.g., tazarotene), (o) vitamin D3 derivatives, e.g., calcipotriene or calcipotriol (Dovonex®), (p) PUVA, (q) anthralin (Drithrocreme®), (r) etretinate (Tegison®) and isotretinoin and (s) multiple sclerosis therapeutic agents such as interferon β-1β (Betaseron®), interferon (β-1α (Avonex®), azathioprine (Imurek®, Imuran®), glatiramer acetate (Capoxone®), a glucocorticoid (e.g., prednisolone) and cyclophosphamide (t) DMARDS such as methotrexate (u) other compounds such as 5-aminosalicylic acid and prodrugs thereof; hydroxychloroquine; D-penicillamine; antimetabolites such as azathioprine, 6-mercaptopurine and methotrexate; DNA synthesis inhibitors such as hydroxyurea and microtubule disrupters such as colchicine. The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSAID the weight ratio of the compound of the present invention to the NSAID will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
VI. Examples
The following examples are offered to illustrate, but not to limit the claimed invention.
Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA). 1H-NMR spectra were recorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaks are provided relative to TMS and are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) and number of protons. Mass spectrometry results are reported as the ratio of mass over charge, followed by the relative abundance of each ion (in parenthesis). In the examples, a single m/e value is reported for the M+H (or, as noted, M−H) ion containing the most common atomic isotopes. Isotope patterns correspond to the expected formula in all cases. Electrospray ionization (ESI) mass spectrometry analysis was conducted on a Hewlett-Packard MSD electrospray mass spectrometer using the HP1100 HPLC for sample delivery. Normally the analyte was dissolved in methanol at 0.1 mg/mL and 1 microlitre was infused with the delivery solvent into the mass spectrometer, which scanned from 100 to 1500 daltons. All compounds could be analyzed in the positive ESI mode, using acetonitrile/water with 1% formic acid as the delivery solvent. The compounds provided below could also be analyzed in the negative ESI mode, using 2 mM NH4OAc in acetonitrile/water as delivery system.
The following abbreviations are used in the Examples set forth herein:

    NMP: N-methyl-2-pyrrolidinone
    HPLC: High Pressure Liquid Chromatography
    DMF: Dimethyl formamide
    TFA: Trifluoroacetic Acid
    THF: Tetrahydrofuran
    NCS: N-Chlorosuccinimide
    EtOAc: Ethyl acetate
    DCM: Dichloromethane
    HATU: N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate
    DMA: Dimethylacetamide
    DIPEA: Diisopropylethylamine
    BOP: (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
    DBU: 1,8-diazabicyclo(5.4.0)undec-7-ene


Compounds within the scope of this invention can be synthesized as described below, using a variety of reactions known to the skilled artisan. A sample of useful routes to the azaindazole derivatives and certain compounds of the invention are provided below or elsewhere within the present application. In the descriptions of the syntheses that follow, some of the arylpiperazine and heteroaromatic subunit precursors were obtained from commercial sources. These commercial sources include Aldrich Chemical Co., Acros Organics, Ryan Scientific Incorporated, Oakwood Products Incorporated, Lancaster Chemicals, Sigma Chemical Co., Lancaster Chemical Co., TCI-America, Alfa Aesar, Davos Chemicals, and GFS Chemicals. Certain relevant arylpiperazine compounds can be commercially obtained. Others could be prepared as described in U.S. patent application Ser. No. 11/008,774, the contents of which is hereby incorporated in its entirety for all purposes. Also, standard chemistries have been employed to link the arylpiperazine and heteroaromatic subunits (whether commercially obtained or prepared by the methods below) using a suitably optimized linker, such as the acetyl unit described in the body of this invention.
One skilled in the art will also recognize that alternative methods may be employed to synthesize the target compounds of this invention, and that the approaches described within the body of this document are not exhaustive, but do provide broadly applicable and practical routes to compounds of interest.
Certain molecules claimed in this patent can exist in different enantiomeric and diastereomeric forms and all such variants of these compounds are claimed.
Regioisomerism is a common property in organic chemistry, and is especially common with regards to certain structural types provided herein. Those skilled in the art will recognize, with respect to the compounds described herein, that the coupling reactions with the heteroaromatic ring systems can lead to either one of or a mixture of detectable regioisomers.
The detailed description of the experimental procedures used to synthesize key compounds in this text lead to molecules that are described by the physical data identifying them as well as by the structural depictions associated with them.
Those skilled in the art will also recognize that during standard work up procedures in organic chemistry, acids and bases are frequently used. Salts of the parent compounds are sometimes produced, if they possess the necessary intrinsic acidity or basicity, during the experimental procedures described within this patent.
Example 1
Synthesis of 5-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-indol-2-one (2)




In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), 5-chloro-1,3-dihydro-indol-2-one (116 mg, 0.69 mmol, 1.05 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.5 mL N-methylpyrrolidinone (NMP). A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 5-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-indol-2-one (2): HPLC retention time, 2.47 minutes, (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 434.3, found, 434.4.
Example 2
Synthesis of 6-chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (3)




In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), 6-chloro-3H-benzooxazol-2-one (105 mg, 0.69 mmol, 1.05 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.5 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 6-chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (3): HPLC retention time, 2.62 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 436.3, found, 436.4.
Example 3
Synthesis of 6-Chloro-3-{2-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (5)




Compound 5 was prepared according to the procedure described in Example 2 using 2-chloro-1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-ethanone (4), 6-chloro-3H-benzooxazol-2-one and K2CO3 in DMF: HPLC retention time, 2.70 minutes, (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 454.3, found, 454.4.
Example 4
Synthesis of 6-Chloro-3-{2-[(S)-4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (7)




Compound 7 was prepared according to the procedure described in Example 2 using 2-chloro-1-[(S)-4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-ethanone (6), 6-chloro-3H-benzooxazol-2-one and K2CO3 in DMF: HPLC retention time, 2.87 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A, 0.1% formic acid/5% acetonitrile/94.9% water, B, 0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 468.3, found, 468.4.
Example 5
Synthesis of 6-Chloro-3-{2-[(S)-4-(4-chloro-3-methoxy-phenyl)-2methylpiperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (9)




Compound 9 was prepared according to the procedure described in Example 2 using 2-chloro-1-[(S)-4-(4-chloro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-ethanone (8), 6-chloro-3H-benzooxazol-2-one and K2CO3 in DMF: HPLC retention time, 2.75 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 450.4, found, 450.4.
Example 6
Synthesis of 5-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1,3-dihydro-benzoimidazol-2-one (10a) and 6-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1,3-dihydro-benzoimidazol-2-one (10b)




In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), 5-Chloro-1,3-dihydro-benzoimidazol-2-one (117 mg, 0.69 mmol, 1.05 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.5 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 5-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1,3-dihydro-benzoimidazol-2-one (10a) and 6-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1,3-dihydro-benzoimidazol-2-one (10b) as a 1:1 mixture:HPLC retention time, 2.29 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 435.3, found, 435.4.
Example 7
Synthesis of (6-Chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-acetic acid ethyl ester (11a) and (5-Chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-acetic acid ethyl ester (11b)




Compounds 10a and 10b (87 mg) were combined with ClCH2CO2Et (1 equiv) and K2CO3 (2 equiv) in 1 mL DMF and heated at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield compounds 11a and 11b as a 1:1 mixture:HPLC retention time, 2.55 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 521.4, found, 521.4.
Example 8
Synthesis of (6-Chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-acetic acid (12a) and (5-Chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydrobenzoimidazol-1-yl)-acetic acid (12b).




Compounds 11a and 11b (52 mg) were stirred with 1N LiOH (2 equiv) and in 1 mL of THF at room temperature overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield compounds 12a and 12b as a 1:1 mixture:HPLC retention time, 2.27 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 493.4, found, 493.4.
Example 9
Synthesis of 6-chloro-3-{2-[4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (14)




In a 4 mL vial was added 1-(4-fluoro-benzyl)-piperazine dihydrochloride (13) (51 mg, 0.22 mmol, 1.0 equiv), (6-chloro-2-oxo-benzooxazol-3-yl)-acetic acid (50 mg, 0.22 mmol, 1.00 equiv), DIEA (153 μL, 0.88 mmol, 4.0 equiv), HATU (100 mg, 0.26 mmol, 1.20 equiv) and 1.5 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at room temperature overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 6-chloro-3-{2-[4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (14): HPLC retention time, 1.05 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 403.8, found, 404.5.
Example 10
Synthesis of 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (15)




In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), 3H-benzooxazol-2-one (94 mg, 0.69 mmol, 1.05 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.5 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (15): HPLC retention time, 2.29 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 mL/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 401.9, found, 402.5.
Example 11
Synthesis of 5-chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (16)




In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), 5-chloro-3H-benzooxazol-2-one (105 mg, 0.69 mmol, 1.05 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.5 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 5-chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (16): HPLC retention time, 2.50 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 mL/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 436.3, found, 436.4.
Example 12
Synthesis of 6-methoxy-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (17)




In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), 6-methoxy-3H-benzooxazol-2-one (114 mg, 0.69 mmol, 1.05 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.5 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 6-methoxy-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (17): HPLC retention time, 2.33 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 431.9, found, 431.9.
Example 13
Synthesis of 6-fluoro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (18)




In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (59 mg, 0.20 mmol, 1.0 equiv), 6-fluoro-3H-benzooxazol-2-one (30 mg, 0.20 mmol, 1.00 equiv), K2CO3 (110 mg, 0.80 mmol, 4.0 equiv) and 800 μL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 6-fluoro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (18): HPLC retention time, 2.35 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 419.8, found, 419.9.
Example 14
Synthesis of 1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-1,3-dihydro-benzoimidazol-2-one (20)




In a 4 mL vial was added 1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1,3-dihydro-benzoimidazol-2-one (19) (10 mg, 0.025 mmol, 1.0 equiv), 5 μL of iodomethane (0.081 mmol, 3.26 equiv), 25 mg Cs2CO3 (0.075 mmol, 3.00 equiv) and 150 μL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-1,3-dihydro-benzoimidazol-2-one (20): HPLC retention time, 2.14 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 414.9, found, 415.5.
Example 15
Synthesis of 1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-oxazolidin-2-one (21)




In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), oxazolidin-2-one (64 mg, 0.73 mmol, 1.10 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.4 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-oxazolidin-2-one (21): HPLC retention time, 1.50 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 353.8, found, 353.9.
Example 16
Synthesis of 1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-imidazolidin-2-one (22)




In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), imidazolidin-2-one (64 mg, 0.73 mmol, 1.10 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.4 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-imidazolidin-2-one (22): HPLC retention time, 1.33 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 352.8, found, 353.5.
Example 17
Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-ethanone (23)




In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), (2S,6R)-2,6-dimethyl-piperidine (100 μL, 0.72 mmol, 1.10 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.4 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-ethanone (23): HPLC retention time=1.31 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 379.9, found, 380.0.
Example 18
Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-morpholin-4-yl-ethanone (24)




In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), and morpholine (575 μL, 6.60 mmol, 10.00 equiv). A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-morpholin-4-yl-ethanone (24): HPLC retention time, 0.32 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 353.9, found, 354.5.
Example 19
Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone (25)




In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv) and 1-methylpiperazine (725 μL, 6.60 mmol, 10.00 equiv). A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone (25): HPLC retention time, 0.32 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 367.5, found, 367.9.
Example 20
Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-piperazin-1-yl-ethanone (26)




In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), piperazine (413 mg, 6.60 mmol, 10.00 equiv), and 2.4 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-piperazin-1-yl-ethanone (26): HPLC retention time, 0.30 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 352.9, found, 353.5.
Example 21
Synthesis of 7-Chloro-4-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-benzo[1,4]oxazin-3-one (29)




7-Chloro-4H-benzo[1,4]oxazin-3-one (28): A mixture of 2-amino-5-chloro-phenol (27) (2.0 g, 14 mmol, 1 equiv) in 30 ml of THF, chloroacetyl chloride (1.26 ml, 16.8 mmol, 1.2 equiv), and saturated aqueous NaHCO3 50 mL was stirred at RT for 2 hrs and then heated at 80° C. overnight. The reaction mixture was diluted with EtOAc, and washed with water. Purification of the crude product by flash chromatography provided 7-chloro-4H-benzo[1,4]oxazin-3-one (28): LCMS Retention time: 1.48 min.; LCMS observed (M+H)+: 184.
7-Chloro-4-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-benzo[1,4]oxazin-3-one (29): A mixture of 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (331 mg, 1.1 mmol, 1 equiv) in 5 ml of DMF, 4H-Benzo[1,4]oxazin-3-one (28) (200 mg, 1.1 mmol, 1.0 equiv) and cesium carbonate (710 mg, 2.2 mmol, 2 equiv) was stirred at RT overnight. The reaction solution was diluted with EtOAc, and the organic solution was washed with water. Purification of the crude reaction mixture using flash chromatography provided 7-chloro-4-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-benzo[1,4]oxazin-3-one (29): LCMS Retention time, 2.58 min.; LCMS observed (M+H)+: 450.
Example 22
Synthesis of 6-Chloro-4-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-benzo[1,4]oxazin-3-one (32)




6-Chloro-4H-benzo[1,4]oxazin-3-one (31): 6-Chloro-4H-benzo[1,4]oxazin-3-one was synthesized by the same procedure used in the synthesis of 7-Chloro-4H-benzo[1,4]oxazin-3-one (28): LCMS Retention time, 1.38 min; LCMS observed (M+H)+, 184.
6-Chloro-4-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-benzo[1,4]oxazin-3-one (32): 6-Chloro-4-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-benzo[1,4]oxazin-3-one (32) was synthesized by the same procedure used in the synthesis of Compound 29: LCMS Retention time, 2.59 min; LCMS observed (M+H)+, 450.
Example 23
Synthesis of 4-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-benzo[1,4]oxazin-3-one (33)




4-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-benzo[1,4]oxazin-3-one (33) was synthesized by the same procedure used in the synthesis of Compound 29. LCMS Retention time, 2.35 min; LCMS observed (M+H)+, 416.
Example 24
Synthesis of 4-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-oxazolo[4,5-b]pyridin-2-one (34)




4-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-oxazolo[4,5-b]pyridin-2-one (34) was synthesized by the same procedure used in the synthesis of Compound 29: LCMS Retention time, 1.62 min; LCMS observed (M+H)+, 403.
Example 25
Synthesis of 4-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-oxazolo[4,5-b]pyridin-2-one (35a) and 3-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-oxazolo[4,5-b]pyridin-2-one (35b)




Compounds 35a and 35b were synthesized according to the procedure outlined for the synthesis of Compound 29.
4-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-oxazolo[4,5-b]pyridin-2-one (35a): LCMS Retention time, 1.83 min.; LCMS observed for (M+H)+, 421.
3-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-oxazolo[4,5-b]pyridin-2-one (35b): LCMS Retention time, 2.33 min.; LCMS observed (M+H)+: 421.
Example 26
Synthesis 6-Chloro-3-{2-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-oxazolo[4,5-b]pyridin-2-one (38)




6-Chloro-3H-oxazolo[4,5-b]pyridin-2-one (37): A mixture of 3H-oxazolo[4,5-b]pyridin-2-one (36) (300 mg, 2.2 mmol, 1 equiv) and NCS (352 mg, 2.65 mmol, 1.2 equiv) in 5 mL of acetonitrile was heated at 85° C. overnight. The reaction solution was diluted with ethyl acetate (EtOAc), and washed with water. The organic solution was concentrated and purified by flash chromatography, to provide 6-Chloro-3H-oxazolo[4,5-b]pyridin-2-one (37): LCMS Retention time, 0.69 min; LCMS observed (M+H)+: 171.
6-Chloro-3-{2-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-oxazolo[4,5-b]pyridin-2-one (38): 6-Chloro-3-{2-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-oxazolo[4,5-b]pyridin-2-one (38) was synthesized by the same procedure used in the synthesis of Compound 29: LCMS Retention time, 2.74 min; LCMS observed for (M+H)+: 455.
Example 27
Synthesis of 7-Chloro-4-{2-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one (41)




7-Chloro-4H-pyrido[3,2-b][1,4]oxazin-3-one (40): 7-Chloro-4H-pyrido[3,2-b][1,4]oxazin-3-one (40) was synthesized by the same procedure used in the synthesis of Compound 37: LCMS Retention time, 0.60 min.; LCMS observed (M+H)+: 185.
7-Chloro-4-{2-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one (41): Compound 41 was synthesized by the same procedure used in the synthesis of Compound 32: LCMS Retention time, 2.64 min.; LCMS observed (M+H)+: 469.
Example 28
Synthesis of 3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenyl-oxazolidin-2-one (42)




Compound 42 was prepared according to the procedure described in Example 2 using 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (0.1 mmol), 4-phenyl-oxazolidin-2-one and Cs2CO3 in DMF: HPLC retention time, 2.30 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 430.2, found, 430.3.
Example 29
Synthesis of 3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-phenyl-oxazolidin-2-one (43)




Compound 43 was prepared according to the procedure described Example 2 using 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (0.1 mmol), 3-phenyl-oxazolidin-2-one and Cs2CO3 in DMF: HPLC retention time, 2.32 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 430.2, found, 430.2.
Example 30
Synthesis of (3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazol-6-yloxy)-acetic acid (46)




(3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazol-6-yloxy)-acetic acid ethyl ester (45): A mixture of 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-hydroxy-3H-benzooxazol-2-one (44) (300 mg, 0.72 mmol, 1 eq), ethyl chloroacetate (132 mg, 1.08 mmol, 1.5 eq), cesium carbonate (467 mg, 1.43 mmol, 2 eq) in DMF (2 ml) was stirred at rt overnight. The reaction mixture was diluted with ethyl acetate, washed with water, and purified by flash chromatography to provide (3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazol-6-yloxy)-acetic acid ethyl ester (45).
(3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazol-6-yloxy)-acetic acid (46): A mixture of (3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazol-6-yloxy)-acetic acid ethyl ester (45) in THF (3 ml) and NaOH (2N, 3 ml) was stirred at rt for 2 hours. The reaction mixture was neutralized with HCl (1 N), extracted with ethyl acetate, washed with water, and purified by flash chromatography to provide (3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazol-6-yloxy)-acetic acid (46): LCMS observed for (M+H)+: 476.5
Example 31
Synthesis of 3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-[1,2,4]oxadiazol-3-yl-3H-benzooxazol-2-one (51)




2-Oxo-2,3-dihydro-benzooxazole-6-carbonitrile (48): A mixture of 6-bromo-3H-benzooxazol-2-one (47) (400 mg, 1.87 mmol, 1 eq), copper cyanide (3.3 g, 37 mmol, 20 eq), in DMF (10 ml) was stirred at 175° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, filtered to remove the precipitated solid material, and the organic phase was washed with water, purified by flash chromatography to give 2-oxo-2,3-dihydro-benzooxazole-6-carbonitrile (48).
3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazole-6-carbonitrile (49): A mixture of 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (190 mg, 0.625 mmol, 1 eq), 2-oxo-2,3-dihydro-benzooxazole-6-carbonitrile (48) (100 mg, 0.625 mmol, 1 eq), cesium carbonate (400 mg, 1.23 mmol, 2 eq) in DMF (2 ml) was stirred at rt overnight. The reaction mixture was diluted with ethyl acetate, washed with water and purified with flash chromatography to give 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazole-6-carbonitrile (49).
3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-N-hydroxy-2-oxo-2,3-dihydro-benzooxazole-6-carboxamidine (50): A mixture of 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazole-6-carbonitrile (49) (150 mg, 0.35 mmol, 1 eq), NH2OH.HCl (73 mg, 1.05 mmol, 3 eq), TEA (270 ml), in ethanol (2 ml) was stirred at 60° C. overnight. The resultant mixture was cooled and precipitated material was removed by filtration. The reaction solution was washed with ethyl acetate to provide 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-N-hydroxy-2-oxo-2,3-dihydro-benzooxazole-6-carboxamidine (50).
3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-[1,2,4]oxadiazol-3-yl-3H-benzooxazol-2-one (51): A mixture 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-N-hydroxy-2-oxo-2,3-dihydro-benzooxazole-6-carboxamidine (65 mg), trimethyl orthoformate (3 ml) and p-toluenesulfonic acid (PTSA) (23 mg) was stirred at 103° C. overnight. The resultant solution was evaporated to dryness and then purified by flash chromatography to provide 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-[1,2,4]oxadiazol-3-yl-3H-benzooxazol-2-one (51): LCMS observed for (M+H)+: 470.5.
Example 32
Synthesis of 3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-(2-hydroxy-ethoxy)-3H-benzooxazol-2-one (56)




(6-Hydroxy-2-oxo-benzooxazol-3-yl)-acetic acid (53): To a solution of (6-methoxy-2-oxo-benzooxazol-3-yl)-acetic acid ethyl ester (52) (251 mg, 1 mmol, 1 equiv) in 3 mL of DCM was added BBr3 (0.3 mL, 3 equiv) and the reaction solution was stirred for 1 h. The reaction mixture was quenched by slow addition of water, followed by the addition of EtOAc. The organic layer was isolated and dried over sodium sulfate, filtered, evaporated in vacuo to provide (6-hydroxy-2-oxo-benzooxazol-3-yl)-acetic acid (53).
3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-hydroxy-3H-benzooxazol-2-one (54): A mixture of (6-hydroxy-2-oxo-benzooxazol-3-yl)-acetic acid (53) (800 mg, 1 equiv), 1-(4-chloro-3-methoxy-phenyl)-piperazine dihydrochloride (1.16 g, 1 equiv), BOP (1.7 g, 1 equiv), triethylamine (5 mL, 5 equiv) in 10 ml of DMF was stirred at room temperature for overnight. The resultant solution was then diluted with EtOAc (50 mL) and washed with water. The organic layer was dried over sodium sulfate and concentrated in vacuo to provide a crude residue which was purified by flash chromatography to provide 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-hydroxy-3H-benzooxazol-2-one (54).
3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-3H-benzooxazol-2-one (55): To a mixture of PPh3 (70 mg, 0.27 mmol, 1.1 eq), and DEAD (40 mg, 0.23 mmol, 1 eq) in THF (0.5 ml), was added 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-hydroxy-3H-benzooxazol-2-one (54) (100 mg, 0.24 mmol, 1 eq) in THF (1 ml). The reaction mixture immediately turned clear and was heated to 85° C. 2-(Tetrahydro-pyran-2-yloxy)-ethanol (38.5 mg, 0.27 mmol, 1.1 eq), was then added to the reaction solution, and stirred for 3 hours at rt. The isolated crude product was purified with HPLC to provide 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-3H-benzooxazol-2-one (55).
3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-(2-hydroxy-ethoxy)-3H-benzooxazol-2-one (56): To a solution of 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-3H-benzooxazol-2-one (55) (50 mg) in THF was added 1 mL of TFA and the resultant solution was stirred for 1 hour. The reaction mixture was purified by HPLC to provide 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-(2-hydroxy-ethoxy)-3H-benzooxazol-2-one (56): LCMS observed for (M+H)+: 462.5.
Example 33
Synthesis of 6-(2-Amino-ethoxy)-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (58)




[2-(3-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazol-6-yloxy)-ethyl]-carbamic acid tert-butyl ester (57): [2-(3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazol-6-yloxy)-ethyl]-carbamic acid tert-butyl ester (57) was prepared by the analogous procedure as described in Example 32 using (2-hydroxy-ethyl)-carbamic acid tert-butyl ester.
6-(2-Amino-ethoxy)-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (58): [2-(3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazol-6-yloxy)-ethyl]-carbamic acid tert-butyl ester (58) (50 mg) was dissolved in HCl-dioxane (2 ml) and the resultant solution was stirred for 1 hour and concentrated to dryness. The crude residue was purified by HPLC to provide 6-(2-amino-ethoxy)-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one: LCMS observed for (M+H)+: 461.5.
Example 34
Synthesis of 5-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-1,3-dihydro-benzoimidazol-2-one (62)




4-Chloro-N2-methyl-benzene-1,2-diamine (60): A mixture of (5-chloro-2-nitro-phenyl)-methyl-amine (59) (500 mg, 2.7 mmol, 1 eq), SnCl2.2H2O (3.0 g, 13.3 mmol, 5 eq) in ethyl acetate (25 ml) was refluxed overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated potassium carbonate solution. The organic phase was concentrated and the crude residue was purified with flash chromatography to give 4-chloro-N2-methyl-benzene-1,2-diamine (60).
6-Chloro-1-methyl-1,3-dihydro-benzoimidazol-2-one (61): A mixture of 4-chloro-N2-methyl-benzene-1,2-diamine (60) (100 mg, 0.64 mmol, 1 eq), triphosgene (95 mg, 0.32 mmol, 0.5 eq), TEA (0.26 ml) in THF (2 ml) was stirred at rt for 4 hours. The reaction solution was washed with ethyl acetate and concentrated to provide 6-chloro-1-methyl-1,3-dihydro-benzoimidazol-2-one (61).
5-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-1,3-dihydro-benzoimidazol-2-one (62): A mixture of 6-chloro-1-methyl-1,3-dihydro-benzoimidazol-2-one (61) (75 mg, 0.41 mmol, 1 eq), 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (125 mg, 0.41 mmol, 1 eq), cesium carbonate (401 mg, 1.23 mmol, 3 eq) in DMF (2 ml) was stirred at rt overnight. The reaction solution was diluted with ethyl acetate, washed with water. The organic layer was evaporated to dryness and the crude residue was purified by flash chromatography to provide the desired product 5-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-1,3-dihydro-benzoimidazol-2-one (62): LCMS observed for (M+H)+: 449.2.
Example 35
Synthesis of {1-(4-chloro-3-methoxy-phenyl)-4-[2-(6-chloro-2-oxo-2,3-dihydro-benzofuran-3-yl)-acetyl]-piperazin-2-yl}-acetic acid methyl ester (65)




(6-Chloro-2-oxo-benzooxazol-3-yl)-acetic acid: (6-Chloro-2-oxo-benzooxazol-3-yl)-acetic acid was prepared by heating 6-chloro-3H-benzooxazol-2-one and ethyl chloroacetate in the presence of cesium carbonate in DMF at 60° C. The crude residue was dissolved followed in 1N LiOH in THF and stirred at rt. The resultant mixture was acidified with 1N HCl to pH  ̃1. The desired product precipitated out of solution and was isolated by filtration, and used directly in subsequent reactions without further purification.
4-(4-Chloro-3-methoxyphenyl)piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (63): To a vial containing piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (907 mg, 4.04 mmol), was added 4-bromo-1-chloro-2-methoxybenzene (913 mg, 4.12 mmol), palladium acetate (33 mg, 0.14 mmol) and 2-(di-tert-butylphosphino)biphenyl (88 mg, 0.29 mmol). The vial was evacuated and back-filled with nitrogen and to it was added toluene (2 mL). The reaction mixture was heated to 80° C. for 5 min to give a homogeneous solution. Upon cooling to room temperature, sodium tert-butoxide (557 mg, 5.80 mmol) was added to the reaction solution. The resultant mixture was again heated to 80° C. After 4 h, the reaction mixture was cooled to room temperature, then diluted with EtOAc (10 mL) and hexanes (10 mL). The resultant solution was filtered through celite, and the filtrate concentrated in vacuo and purified by silica gel flash chromatography (30 g) (20% EtOAc/Hexanes) to afford 4-(4-chloro-3-methoxyphenyl)piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (63) (239 mg, 15% yield): HPLC retention time=2.72 minutes. MS (ES) [M+H]+ expected 385.2, found 385.1.
{1-(4-Chloro-3-methoxy-phenyl)-4-[2-(6-chloro-2-oxo-2,3-dihydro-benzofuran-3-yl)-acetyl]-piperazin-2-yl}-acetic acid methyl ester (64): To a vial containing 4-(4-Chloro-3-methoxyphenyl)piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (63) (239 mg, 0.62 mmol) in DCM (10 mL) at 0° C. was added trifluoroacetic acid (5 mL) and the reaction mixture was stirred for 5 min and then warmed to room temperature. After 2 h, the reaction solution was diluted with EtOAc (25 mL), and the organic phase was washed with sat. aq. NaHCO3 (3×10 mL). The pH of the combined aqueous phase was adjusted to 10 using a 10% solution of NaOH. The aqueous phase was then extracted with EtOAc (2×25 mL). The combined organic phase was then dried over MgSO4 and concentrated in vacuo to afford 1-(4-chloro-3-methoxyphenyl)piperazine-2-carboxylic acid methyl ester (64) (168 mg, 95% yield). HPLC retention time=0.37 minutes. MS (ES) [M+H]+ expected=285.1, found 285.1.
{1-(4-Chloro-3-methoxy-phenyl)-4-[2-(6-chloro-2-oxo-2,3-dihydro-benzofuran-3-yl)-acetyl]-piperazin-2-yl}-acetic acid methyl ester (65): In a 4 mL vial was added 150 mg of [1-(4-chloro-3-methoxy-phenyl)-piperazin-2-yl]-acetic acid methyl ester hydrochloride (64) (0.47 mmol, 1.0 equiv), 107 mg of (6-chloro-2-oxo-benzooxazol-3-yl)-acetic acid (0.47 mmol, 1.0 equiv), 260 μL TEA (1.87 mmol, 4.0 equiv), 266 mg HATU (0.70 mmol, 1.5 equiv), and 3.2 mL NMP. The resultant mixture was stirred at room temperature overnight, and the crude product purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield {1-(4-chloro-3-methoxy-phenyl)-4-[2-(6-chloro-2-oxo-2,3-dihydro-benzofuran-3-yl)-acetyl]-piperazin-2-yl}-acetic acid methyl ester (65): HPLC retention time=2.71 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected=494.0, found=494.1.
Example 36
Synthesis of 5-chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1-methyl-1,3-dihydro-benzoimidazol-2-one (66)




5-Chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1-methyl-1,3-dihydro-benzoimidazol-2-one (66): 33 mg of 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (0.18 mmol, 1.00 equiv), 58 mg of 5-chloro-1-methyl-1,3-dihydro-benzoimidazol-2-one (0.19 mmol, 1.05 equiv), 100 mg of K2CO3 (0.72 mmol, 4.0 equiv), and 0.8 mL of NMP were combined in a 4 mL vial. The resultant mixture was heated at 60° C. in an oil bath overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 5-chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1-methyl-1,3-dihydro-benzoimidazol-2-one (66): HPLC retention time=2.40 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected=449.0, found=449.1.
Example 37
Synthesis of 3-(2-(4-(4-Fluorobenzyl)-4-hydroxypiperidin-1-yl)-2-oxoethyl)-6-chlorobenzo[d]oxazol-2(3H)-one (68)




4-(4-Fluoro-benzyl)-piperidin-4-ol (67): To a round bottom flask equipped with a magnetic stirring bar was added 2.94 g of 4-oxo-piperidine-1-carboxylic acid benzyl ester (12.6 mmol, 1.0 equiv) and 25 mL of ether. The flask was fitted with a septum and a nitrogen inlet and cooled to −40° C. A 0.25 M solution of (4-fluoro)benzylmagnesium chloride (50 mL, 12.5 mmol, 1.0 equiv.) was added via syringe over 10 minutes to the reaction solution. After 1 h, the mixture was warmed to room temperature and stirred for 20 h. Then the solution was cooled to 0° C. and quenched with 30 mL of saturated aqueous ammonium-chloride. The aqueous layer was extracted with 100 mL of EtOAc. The combined organic layers were washed with saturated aqueous NaCl (3×25) and dried over MgSO4. The resultant yellow oil was purified by flash chromatography to afford 1.058 g of 4-(4-Fluoro-benzyl)-4-hydroxy-piperidine-1-carboxylic acid benzyl ester (3.08 mmol, 25% yield). The crude product was diluted in methanol (12 mL) and added to a round bottom flask containing a magnetic stirring bar and 200 mg of 10% Pd/C. The flask was evacuated, and back-filled with hydrogen (1 atm). After 24 h of vigorous stirring under nitrogen atmosphere, the solution was filtered through celite and concentrated in vacuo to afford 4-(4-fluoro-benzyl)-piperidin-4-ol (67) in quantitative yield (644 mg): HPLC retention time=0.26 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 mL/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected=210.1, found 210.1.
3-(2-(4-(4-Fluorobenzyl)-4-hydroxypiperidin-1-yl)-2-oxoethyl)-6-chlorobenzo[d]oxazol-2(3H)-one (68): To a vial containing 2-(6-chloro-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid (67) (60 mg, 0.3 mmol) was added DMA (0.6 mL), BOP (133 mg, 0.3 mmol), 4-(4-fluorobenzyl)piperidin-4-ol (63 mg, 0.3 mmol) and DIPEA (180 μL, 1.0 mmol). The resultant solution was stirred at room temperature for 18 h. The reaction solution was then diluted with EtOAc (50 mL) and washed with 0.1 N HCl (2×10 mL) and 10% aq. NaHCO3 (2×10 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The crude residue was purified by preparative HPLC (20→95% gradient of MeCN—H2O with 0.1% TFA) and the pure fractions were lyophilized to afford the title compound (68) (54 mg, 50% yield): HPLC retention time=2.33 minutes. MS (ES) [M+H]+ expected 419.1, found 419.1.
Example 38
Synthesis of 6-Chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-4-hydroxy-piperidin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (70)




4-(4-Chloro-3-methoxy-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester: Magnesium turnings (2.60 g) in a flask were stirred vigorously under vacuum at room temperature for 12 h and then the flask was filled with nitrogen gas. THF (20 mL) was added followed by the addition of one crystal of 12. The mixture was cooled to 0° C. and a solution of 5-bromo-2-chloroanisole (6.64 g) in THF (100 mL) was added in a period of 10 min. The mixture was warmed up to room temperature and stirred at room temperature for 15 min before it was heated to 45° C. for 2 h to provide a solution of the Grignard solution. To 24 mL of the Grignard solution obtained from above (at −40° C.) was added N-Boc-piperidone (1.0 g) in one portion. The resultant mixture was warmed up to room temperature, stirred for 1 h and quenched by the addition of sat. aqueous NH4Cl solution (20 mL). The organic layer was separated and the aqueous layer was extracted by EtOAc (3×20 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was purified by flash chromatography to provide 4-(4-Chloro-3-methoxy-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil (502 mg).
4-(4-Chloro-3-methoxy-phenyl)-piperidin-4-ol (69): To a solution of 4-(4-Chloro-3-methoxy-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (502 mg) in MeOH (5 mL) was added a solution of HCl in ether (2 M, 9.5 mL). The resultant mixture was stirred at room temperature for 1 h followed by the addition of ether (50 mL). The reaction mixture was stirred at 0° C. for an additional 30 min, then filtered and concentrated to provide 4-(4-Chloro-3-methoxy-phenyl)-piperidin-4-ol (69) in the form of HCl salt as a white solid.
6-Chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-4-hydroxy-piperidin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (70): A mixture of 2-(6-chloro-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid (22.7 mg, 0.1 mmol, 1 equiv), 4-(4-chloro-3-methoxy-phenyl)-piperidin-4-ol hydrochloride (69) (27.7 mg, 1 equiv), BOP (58 mg, 1.3 equiv), triethylamine (56 μL, 4 equiv) in 1 ml of DMF was stirred at room temperature for overnight. The solution was then diluted with EtOAc (50 mL) and washed with water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography to provide 6-chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-4-hydroxy-piperidin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (70): MS (ES) [M+H]+ expected 451.1, found 451.1.
Example 39
Synthesis of 6-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one (73)




(4-Chloro-2-hydroxymethyl-phenyl)-carbamic acid ethyl ester (71): To a solution of (2-amino-5-chloro-phenyl)-methanol (1.58 g, 10 mmol, 1 equiv) in 15 mL of DCM was slowly added ethyl chloroformate (1.05 mL, 1.1 equiv) and pyridine (1.2 mL, 1.5 equiv). After stirring for 1 h, the resultant mixture was diluted with EtOAc and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to provide the crude product, (4-Chloro-2-hydroxymethyl-phenyl)-carbamic acid ethyl ester (71), which was used in subsequent reactions without further purification.
6-Chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one (72): To a solution of (4-chloro-2-hydroxymethyl-phenyl)-carbamic acid ethyl ester (71) obtained from the previous step in 5 mL of toluene was added 3 mL of DBU (2 equiv) and the resultant solution was heated at 110° C. overnight. After cooling to rt, the mixture was diluted with EtOAc and washed with water. The organic layer was dried over sodium sulfate, filtered and dried in vacuo to give 6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one (72).
6-Chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one (73): A mixture of 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (303 mg, 1 mmol, 1 equiv), 6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one (72) (183 mg, 1 equiv), and Cs2CO3 (56 μL, 4 equiv) in 2 ml of DMF was stirred at 60° C. overnight. The reaction solution was then diluted with EtOAc (50 mL) and washed with water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The resultant crude residue was purified by flash chromatography to give 6-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one (73): MS (ES) [M+H]+ expected 450.1, found 450.1.
Example 40
Synthesis of 6-chloro-3-{2-[3-(3-chloro-2-methyl-phenyl)-4-oxo-imidazolidin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (77)




2-Amino-N-(3-chloro-2-methyl-phenyl)-acetamide (74): To a mixture of 2-methyl-3-chloroaniline (14.16 g, 100 mmol, 1 equiv), Boc-glycine (17.52 g, 1 equiv), BOP reagent (48.6 g, 1.1 equiv) in 50 mL of DMF was added TEA (42 mL, 3 equiv). After overnight, standard aqueous workup followed by flash chromatography gave 20 g of [(3-chloro-2-methyl-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester, which was treated with  ̃300 mL of 4N HCl in dioxane overnight to afford 2-amino-N-(3-chloro-2-methyl-phenyl)-acetamide (74).
3-(3-Chloro-2-methyl-phenyl)-imidazolidin-4-one (75): A mixture of 2-amino-N-(3-chloro-2-methyl-phenyl)-acetamide (74) (1.18 g, 1 equiv), paraformaldehyde (HCHO)n (0.77 g, 1.5 equiv) and 3 mL of acetic acid was heated at 90° C. for 3 h and evaporated to dryness to afford 3-(3-chloro-2-methyl-phenyl)-imidazolidin-4-one (75) as acetic acid salt.
1-(2-Chloro-acetyl)-3-(3-chloro-2-methyl-phenyl)-imidazolidin-4-one (76): To a mixture of 3-(3-chloro-2-methyl-phenyl)-imidazolidin-4-one acetic acid salt (75) (422 mg, 1 equiv) and K2CO3 (552 mg) in 5 mL of DCM/water (1:1 v/v) was added chloroacetyl chloride (240 μL, 1.5 equiv). One hour later, the organic layer was separated and dried over sodium sulfate to give 1-(2-chloro-acetyl)-3-(3-chloro-2-methyl-phenyl)-imidazolidin-4-one (76).
6-Chloro-3-{2-[3-(3-chloro-2-methyl-phenyl)-4-oxo-imidazolidin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (77): A mixture of (2-chloro-acetyl)-3-(3-chloro-2-methyl-phenyl)-imidazolidin-4-one (76) (28.6 mg, 1 equiv), 6-Chloro-3H-benzooxazol-2-one (16.9 mg, 1 equiv) and potassium carbonate (27 mg, 2 equiv) in DMF (2 ml) was stirred at 60° C. overnight, diluted with ethyl acetate, washed with water, purified with HPLC to give 6-chloro-3-{2-[3-(3-chloro-2-methyl-phenyl)-4-oxo-imidazolidin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (77): LCMS observed for (M+H)+: 421.2.
Example 41
Synthesis of 5-Chloro-1-{2-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-2-oxo-ethyl}-1,3-dihydro-benzoimidazol-2-one (79) and 6-Chloro-1-{2-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-2-oxo-ethyl}-1,3-dihydro-benzoimidazol-2-one (80)




2-Chloro-1-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-ethanone (78): 2-Chloro-1-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-ethanone was prepared from 4-(4-fluorobenzyl)piperidin-4-ol according to the procedure described for Compound 76 in Example 40.
5-Chloro-1-{2-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-2-oxo-ethyl}-1,3-dihydro-benzoimidazol-2-one (79) and 6-chloro-1-{2-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-2-oxo-ethyl}-1,3-dihydro-benzoimidazol-2-one (80): A mixture of 2-chloro-1-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-ethanone (78) (57 mg, 1 equiv), 6-Chloro-3H-benzooxazol-2-one (34 mg, 1 equiv) and potassium carbonate (54 mg, 2 equiv) in DMF (2 ml) was stirred at 60° C. overnight, diluted with ethyl acetate, washed with water, purified with HPLC to give 5-chloro-1-{2-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-2-oxo-ethyl}-1,3-dihydro-benzoimidazol-2-one (79) (LCMS observed for (M+H)+: 418.0) and 6-chloro-1-{2-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-2-oxo-ethyl}-1,3-dihydro-benzoimidazol-2-one (80) (LCMS observed for (M+H)+: 418.0).
Example 42
This example illustrates the evaluation of the biological activity associated with compounds of interest (candidate compounds) of the invention.
Materials and Methods
A. Cells
1. CCR1 Expressing Cells
a) THP-1 Cells
THP-1 cells were obtained from ATCC (TIB-202) and cultured as a suspension in RPMI-1640 medium supplemented with 2 mM L-glutamine, 1.5 g/L sodium bicarbonate, 4.5 g/L glucose, 10 mM HEPES, 1 mM sodium pyruvate, 0.05% 2-mercaptoethanol and 10% FBS. Cells were grown under 5% CO2/95% air, 100% humidity at 37° C. and subcultured twice weekly at 1:5 (cells were cultured at a density range of 2×105 to 2×106 cells/mL) and harvested at 1×106 cells/mL. THP-1 cells express CCR1 and can be used in CCR1 binding and functional assays.
b) Isolated Human Monocytes
Monocytes were isolated from human buffy coats using the Miltenyi bead isolation system (Miltenyi, Auburn, Calif.). Briefly, following a Ficoll gradient separation to isolate peripheral blood mononuclear cells, cells were washed with PBS and the red blood cells lysed using standard procedures. Remaining cells were labeled with anti-CD14 antibodies coupled to magnetic beads (Miltenyi Biotech, Auburn, Calif.). Labeled cells were passed through AutoMACS (Miltenyi, Auburn, Calif.) and positive fraction collected. Monocytes express CCR1 and can be used in CCR1 binding and functional assays.
B. Assays
1. Inhibition of CCR1 Lipand Binding
CCR1 expressing cells were centrifuged and resuspended in assay buffer (20 mM HEPES pH 7.1, 140 mM NaCl, 1 mM CaCl2, 5 mM MgCl2, and with 0.2% bovine serum albumin) to a concentration of 5×106 cells/mL for THP-1 cells and 5×105 for monocytes. Binding assays were set up as follows. 0.1 mL of cells (5×105 THP-1 cells/well or 5×104 monocytes) was added to the assay plates containing the compounds, giving a final concentration of  ̃2-10 μM each compound for screening (or part of a dose response for compound IC50 determinations). Then 0.1 mL of 125I labeled MIP-1α (obtained from Perkin Elmer Life Sciences, Boston, Mass.) or 0.1 mL of 125, labeled CCL15/leukotactin (obtained as a custom radiolabeling by Perkin Elmer Life Sciences, Boston, Mass.) diluted in assay buffer to a final concentration of  ̃50 μM, yielding  ̃30,000 cpm per well, was added (using 125I labeled MIP-1α with THP-1 cells and 125I labeled CCL15/leukotactin with monocytes), the plates sealed and incubated for approximately 3 hours at 4° C. on a shaker platform. Reactions were aspirated onto GF/B glass filters pre-soaked in 0.3% polyethyleneimine (PEI) solution, on a vacuum cell harvester (Packard Instruments; Meriden, Conn.). Scintillation fluid (40 μl; Microscint 20, Packard Instruments) was added to each well, the plates were sealed and radioactivity measured in a Topcount scintillation counter (Packard Instruments). Control wells containing either diluent only (for total counts) or excess MIP-1α or MIP-1β (1 μg/mL, for non-specific binding) were used to calculate the percent of total inhibition for compound. The computer program Prism from GraphPad, Inc. (San Diego, Calif.) was used to calculate IC50 values. IC50 values are those concentrations required to reduce the binding of labeled MIP-1α to the receptor by 50%. (For further descriptions of ligand binding and other functional assays, see Dairaghi, et al., J. Biol. Chem. 274:21569-21574 (1999), Penfold, et al., Proc. Natl. Acad. Sci. USA. 96:9839-9844 (1999), and Dairaghi, et al., J. Biol. Chem. 272:28206-28209 (1997)).
2. Calcium Mobilization
To detect the release of intracellular stores of calcium, cells (THP-1 or monocytes) were incubated with 3 μM of INDO-1AM dye (Molecular Probes; Eugene, Oreg.) in cell media for 45 minutes at room temperature and washed with phosphate buffered saline (PBS). After INDO-1AM loading, the cells were resuspended in flux buffer (Hank's balanced salt solution (HBSS) and 1% FBS). Calcium mobilization was measured using a Photon Technology International spectrophotometer (Photon Technology International; New Jersey) with excitation at 350 nm and dual simultaneous recording of fluorescence emission at 400 nm and 490 nm. Relative intracellular calcium levels were expressed as the 400 nm/490 rn emission ratio. Experiments were performed at 37° C. with constant mixing in cuvettes each containing 106 cells in 2 mL of flux buffer. The chemokine ligands may be used over a range from 1 to 100 nM. The emission ratio was plotted over time (typically 2-3 minutes). Candidate ligand blocking compounds (up to 10 μM) were added at 10 seconds, followed by chemokines at 60 seconds (i.e., MIP-1α; R&D Systems; Minneapolis, Minn.) and control chemokine (i.e., SDF-1α; R&D Systems; Minneapolis, Minn.) at 150 seconds.
3. Chemotaxis Assays
Chemotaxis assays were performed using 5 m pore polycarbonate, polyvinylpyrrolidone-coated filters in 96-well chemotaxis chambers (Neuroprobe; Gaithersburg, Md.) using chemotaxis buffer (Hank's balanced salt solution (HBSS) and 1% FBS). CCR1 chemokine ligands (i.e., MIP-1α, CCL15/Leukotactin; R&D Systems; Minneapolis, Minn.) are use to evaluate compound mediated inhibition of CCR1 mediated migration. Other chemokines (i.e., SDF-1α; R&D Systems; Minneapolis, Minn.) are used as specificity controls. The lower chamber was loaded with 29 μl of chemokine (i.e., 0.1 nM CCL15/Leukotactin) and varying amounts of compound; the top chamber contained 100,000 THP-1 or monocyte cells in 20 μl. The chambers were incubated 1-2 hours at 37° C., and the number of cells in the lower chamber quantified either by direct cell counts in five high powered fields per well or by the CyQuant assay (Molecular Probes), a fluorescent dye method that measures nucleic acid content and microscopic observation.
C. Identification of Inhibitors of CCR1
1. Assay
To evaluate small organic molecules that prevent the receptor CCR1 from binding ligand, an assay was employed that detected radioactive ligand (i.e, MIP-1α or CCL15/Leukotactin) binding to cells expressing CCR1 on the cell surface (for example, THP-1 cells or isolated human monocytes). For compounds that inhibited binding, whether competitive or not, fewer radioactive counts are observed when compared to uninhibited controls.
THP-1 cells and monocytes lack other chemokine receptors that bind the same set of chemokine ligands as CCR1 (i.e., MIP-1α, MPIF-1, Leukotactin, etc.). Equal numbers of cells were added to each well in the plate. The cells were then incubated with radiolabeled MIP-1α. Unbound ligand was removed by washing the cells, and bound ligand was determined by quantifying radioactive counts. Cells that were incubated without any organic compound gave total counts; non-specific binding was determined by incubating the cells with unlabeled ligand and labeled ligand. Percent inhibition was determined by the equation:




  
    %
    ⁢
    
      
    
    ⁢
    inhibition
  
  =
  
    
      (
      
        1
        -
        
          
            [
            
              
                (
                
                  sample
                  ⁢
                  
                    
                  
                  ⁢
                  cpm
                
                )
              
              -
              
                (
                
                  nonspecific
                  ⁢
                  
                    
                  
                  ⁢
                  cpm
                
                )
              
            
            ]
          
          ⁢
          
            
              /
            
            ⁢
            
              

            
            [
            
              
                (
                
                  total
                  ⁢
                  
                    
                  
                  ⁢
                  cpm
                
                )
              
              -
              
                (
                
                  nonspecific
                  ⁢
                  
                    
                  
                  ⁢
                  cpm
                
                )
              
            
            ]
          
        
      
      )
    
    ×
    100.
  




2. Dose Response Curves
To ascertain a candidate compound's affinity for CCR1 as well as confirm its ability to inhibit ligand binding, inhibitory activity was titered over a 1×10−10 to 1×10−4 M range of compound concentrations. In the assay, the amount of compound was varied; while cell number and ligand concentration were held constant.
3. CCR1 Functional Assays
CCR1 is a seven transmembrane, G-protein linked receptor. A hallmark of signaling cascades induced by the ligation of some such receptors is the pulse-like release of calcium ions from intracellular stores. Calcium mobilization assays were performed to determine if the candidate CCR1 inhibitory compounds were able to also block aspects of CCR1 signaling. Candidate compounds able to inhibit ligand binding and signaling with an enhanced specificity over other chemokine and non-chemokine receptors were desired.
Calcium ion release in response to CCR1 chemokine ligands (i.e., MIP-1α, MPIF-1, Leukotactin, etc.) was measured using the calcium indicator INDO-1. THP-1 cells or monocytes were loaded with INDO-1/AM and assayed for calcium release in response to CCR1 chemokine ligand (i.e., MIP-1α) addition. To control for specificity, non-CCR1 ligands, specifically bradykinin, was added, which also signals via a seven transmembrane receptor. Without compound, a pulse of fluorescent signal will be seen upon MIP-1α addition. If a compound specifically inhibits CCR1-MIP-1α signaling, then little or no signal pulse will be seen upon MIP-1α addition, but a pulse will be observed upon bradykinin addition. However, if a compound non-specifically inhibits signaling, then no pulse will be seen upon both MIP-1α and bradykinin addition.
One of the primary functions of chemokines is their ability to mediate the migration of chemokine receptor-expressing cells, such as white blood cells. To confirm that a candidate compound inhibited not only CCR1 specific binding and signaling (at least as determined by calcium mobilization assays), but also CCR1 mediated migration, a chemotaxis assay was employed. THP-1 myelomonocytic leukemia cells, which resemble monocytes, as wells as freshly isolated monocytes, were used as targets for chemoattraction by CCR1 chemokine ligands (i.e., MIP-1α, CCL15/leukotactin). Cells were place in the top compartment of a microwell migration chamber, while MIP-1α (or other potent CCR1 chemokine ligand) and increasing concentrations of a candidate compound was loaded in the lower chamber. In the absence of inhibitor, cells will migrate to the lower chamber in response to the chemokine agonist; if a compound inhibited CCR1 function, then the majority of cells will remain in the upper chamber. To ascertain a candidate compound's affinity for CCR1 as well as to confirm its ability to inhibit CCR1 mediated cell migration, inhibitory activity was titered over a 1×10−10 to 1×10−4 M range of compound concentrations in this chemotaxis assay. In this assay, the amount of compound was varied; while cell number and chemokine agonist concentrations were held constant. After the chemotaxis chambers were incubated 1-2 hours at 37° C., the responding cells in the lower chamber were quantified by labeling with the CyQuant assay (Molecular Probes), a fluorescent dye method that measures nucleic acid content, and by measuring with a Spectrafluor Plus (Tecan). The computer program Prism from GraphPad, Inc. (San Diego, Calif.) was used to calculate IC50 values. IC50 values are those compound concentrations required to inhibit the number of cells responding to a CCR1 agonist by 50%.
4. In Vivo Efficacy
a) Rabbit Model of Destructive Joint Inflammation
To study the effects of candidate compounds on inhibiting the inflammatory response of rabbits to an intra-articular injection of the bacterial membrane component lipopolysaccharide (LPS), a rabbit model of destructive joint inflammation is used. This study design mimics the destructive joint inflammation seen in arthritis. Intra-articular injection of LPS causes an acute inflammatory response characterized by the release of cytokines and chemokines, many of which have been identified in rheumatoid arthritic joints. Marked increases in leukocytes occur in synovial fluid and in synovium in response to elevation of these chemotactic mediators. Selective antagonists of chemokine receptors have shown efficacy in this model (see Podolin, et al., J. Immunol. 169(11):6435-6444 (2002)).
A rabbit LPS study is conducted essentially as described in Podolin, et al. ibid., female New Zealand rabbits (approximately 2 kilograms) are treated intra-articularly in one knee with LPS (10 ng) together with either vehicle only (phosphate buffered saline with 1% DMSO) or with addition of CCX-105 (dose 1=50 μM or dose 2=100 μM) in a total volume of 1.0 mL. Sixteen hours after the LPS injection, knees are lavaged and cells counts are performed. Beneficial effects of treatment were determined by histopathologic evaluation of synovial inflammation. Inflammation scores are used for the histopathologic evaluation: 1-minimal, 2-mild, 3-moderate, 4-moderate-marked.
b) Evaluation of a Candidate Compound in a Rat Model of Collagen Induced Arthritis
A 17 day developing type II collagen arthritis study is conducted to evaluate the effects of a candidate compound on arthritis induced clinical ankle swelling. Rat collagen arthritis is an experimental model of polyarthritis that has been widely used for preclinical testing of numerous anti-arthritic agents (see Trentham, et al., J. Exp. Med. 146(3):857-868 (1977), Bendele, et al., Toxicologic Pathol. 27:134-142 (1999), Bendele, et al., Arthritis Rheum. 42:498-506 (1999)). The hallmarks of this model are reliable onset and progression of robust, easily measurable polyarticular inflammation, marked cartilage destruction in association with pannus formation and mild to moderate bone resorption and periosteal bone proliferation.
Female Lewis rats (approximately 0.2 kilograms) are anesthetized with isoflurane and injected with Freund's Incomplete Adjuvant containing 2 mg/mL bovine type II collagen at the base of the tail and two sites on the back on days 0 and 6 of this 17 day study. A candidate compound is dosed daily in a sub-cutaneous manner from day 0 till day 17 at a efficacious dose. Caliper measurements of the ankle joint diameter were taken, and reducing joint swelling is taken as a measure of efficacy.
In the table below, structures and activity are provided for representative compounds described herein. Activity is provided as follows for either the chemotaxis assay or binding assay as described above: +++, 1000 nM<IC50<25000 nM; and ++++, IC50<1000 nM.







TABLE 2





Structure

## Claims

1. A compound having Formula I:



or pharmaceutically acceptable salts and N-oxides thereof; wherein
each R1 is independently selected from the group consisting of —CO2Ra and C1-8 alkyl, wherein Ra is selected from the group consisting of hydrogen, and C1-8 alkyl;
the subscript m is 0 or 1;
R2c is halogen or —ORc;
R2d is halogen or —ORc;
R2a, R2b and R2e at each occurrence are each independently selected from the group consisting of hydrogen, halogen, and —ORc, wherein each Rc is independently selected from hydrogen, and C1-8 alkyl;
B represents a benzoxazoline ring system linked through its nitrogen atom to the remainder of the molecule, and is further substituted with 0 to 4 R3 substitutents, and at each occurrence, R3 is independently selected from the group consisting of hydrogen, halogen, —ORf, —CN, unsubstituted C1-6alkyl and an oxadiazole ring, or any two R3 substituents attached to the same atom on B are taken together to form ═O, wherein each Rf is independently selected from hydrogen, and C1-8 alkyl, wherein the aliphatic portions of Rf, are optionally further substituted with a member selected from the group consisting of —OH, —CO2H, —CO2Ro, and —NH2, wherein Ro is unsubstituted C1-6 alkyl;
L1 is CH2;
the symbol U is N;
L2 is a direct bond; and
the subscript n is 1.

2. The compound of claim 1, wherein R1, when present, is selected from the group consisting of —CH3 and —CO2Me.

3. The compound of claim 1, wherein R2c and R2d are each independently selected from the group consisting of halogen and —OCH3; and R2a, R2b and R2e are independently selected from the group consisting of hydrogen, halogen and —OCH3.

4. The compound of claim 1, having a formula selected from the group consisting of



wherein R2c is halogen; R2d is —OCH3; R2a is halogen; the subscript m is 0-1; and R1, when present, is —CH3 or —CO2CH3.

5. The compound of claim 1, wherein said compound is a compound selected from the group consisting of:

6. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and a compound of claim 1.

7. The compound of claim 1, wherein said compound is a compound selected from the group consisting of: