# Patent

## Title
Aryl substituted carboxamide derivatives as calcium or sodium channel blockers

## Abstract

The present invention relates to aryl substituted carboxamide derivatives of formula (I) or a pharmaceutically acceptable salt thereof, which have blocking activities of T-type calcium channels or voltage gated sodium channels as the tetrodotoxin-sensitive (TTX-S) blockers such as NaV1.3 and NaV1.7, and which are useful in the treatment or prevention of disorders and diseases in which T-type calcium channels or voltage gated sodium channels are involved. The invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which T-type calcium channels or voltage gated sodium channels are involved.

## Background
This application is a U.S. national stage of International Application No. PCT/JP2010/003649 filed May 31, 2010, which claims the benefit of U.S. provisional application Ser. Nos. 61/213,324 filed May 29, 2009; 61/272,581 filed Oct. 7, 2009 and 61/282,534 filed Feb. 26, 2010.


TECHNICAL FIELD
The present invention relates to aryl substituted carboxamide derivatives which have blocking activities of T-type calcium channels or voltage gated sodium channels as the tetrodotoxin-sensitive (TTX-S) blockers such as NaV1.3 and NaV1.7, and which are useful in the treatment or prevention of disorders and diseases in which T-type calcium channels or voltage gated sodium channels are involved. The invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which T-type calcium channels or voltage gated sodium channels are involved.
BACKGROUND ART
Plasma membrane calcium channels are members of a diverse superfamily of voltage gated channel proteins. Calcium channels are membrane-spanning, multi-subunit proteins that allow controlled entry of Ca2+ ions into cells from the extracellular fluid. Excitable cells throughout the animal kingdom, and at least some bacterial, fungal and plant cells, possess one or more types of calcium channel. Nearly all “excitable” cells in animals, such as neurons of the central nervous system (CNS), peripheral nerve cells and muscle cells, including those of skeletal muscles, cardiac muscles, and venous and arterial smooth muscles, have voltage dependent calcium channels.
Multiple types of calcium channels have been identified in mammalian cells from various tissues, including skeletal muscle, cardiac muscle, lung, smooth muscle and brain. A major type of this family is the L-type calcium channels, whose function is inhibited by the familiar classes of calcium channel blockers (dihydropyridines such as nifedipine, phenylalkylamines such as verapamil, and benzothiazepines such as diltiazem). Additional classes of plasma membrane calcium channels are referred to as T-type, N-type, P-type, Q-type and R-type.
The “T-type” (or “low voltage-activated”) calcium channels are so named because their openings are of briefer duration (T=transient) than the longer (L=long-lasting) openings of the L-type calcium channels. The L, N, P and Q-type channels activate at more positive potentials (high voltage activated) and display diverse kinetics and voltage-dependent properties.
T-type calcium channels have been implicated in pathologies related to various diseases and disorders, including epilepsy, essential tremor, pain, neuropathic pain, schizophrenia, Parkinson's disease, depression, anxiety, sleep disorders, sleep disturbances, insomnia, psychosis, cardiacarrhythmia, hypertension, cancer, diabetes, infertility and sexual dysfunction (J Neuroscience, 14, 5485 (1994); Drugs Future 30(6), 573-580 (2005); EMBO J, 24, 315-324 (2005); Drug Discovery Today, 11, 5/6,245-253 (2006); Neuropharmacology 53, 308-317 (2007) and J. Biol. Chem., 283(15), 10162-10173 (2008)).
On the other hand, blockers of voltage gated sodium channels as the TTX-S channels also relates to a number of therapeutic applications.
The rat NaV1.3 channel and the human NaV1.3 channel have been cloned in 1988 and 1998/2000 respectively (FEBS Lett. 228 (1), 187-194, 1988; J. Mol. Neurosci., 10 (1), 67-70, 1998; Eur. J. Neurosci. 12 (12), 4281-4289, 2000). The NaV1.3 channel was formerly known as brain type III sodium channel. NaV1.3 is present at relatively high levels in the nervous system of rat embryos but is barely detectable in adult rats. NaV1.3 is up-regulated following axotomy in the Spinal Nerve Ligation (SNL), Chronic Constriction Injury (CCI), and diabetic neuropathy models (J Neurophysiol 82, 2776-2785, 1999. J. A. Black et al; Ann Neurol 52, 786-792, 2002. M. J. Cranner et al; Pain 83, 591-600, 1999. S. Dib-Hajj et al; J Biol Chem 279, 29341-29350, 2004. S. Hong et al; Mol Brain Res 95, 153-161, 2001. C. H. Kim et al.) The up-regulation of NaV1.3 channel contributes to rapidly repriming sodium current in small dorsal root ganglion (DRG) neurons (J Neurophysiol 82, 2776-2785, 1999. J. A. Black et al.). These observations suggest that NaV1.3 may make a key contribution to neuronal hyperexcitability.
In order to validate the contribution of NaV1.3 sodium channel in the pain states, specific antisense oligonucleotides (ASO) were used in animal pain models. NaV1.3 sodium channel ASO treatment significantly attenuated pain-related behaviors after CCI operation (J. Neurosci. 24, 4832-4839, 2004, Haim, B. C. et al.). These finding suggest that NaV1.3 sodium channel antagonist is useful to treat neuropathic pain conditions.
The NaV1.7 channel appears to be the best ‘validated’ pain target. The most exciting findings with respect to NaV1.7 have come from human genetic studies. Cox et al. (Nature 444, 894-898, 2006) discovered SCN9A mutations that cause a loss of NaV1.7 function in three families from Pakistan. Their observations link loss of NaV1.7 function with a congenital inability to experience pain, adding to the evidence indicating NaV1.7 channel as an essential participant in human nociception.
By contrast, Gain-of-function mutations have also been described that lead to enhanced pain, for example, Primary Erythermalgia in one case and Paroxysmal Extreme Pain Disorder in another. These gain-of-function mutations in patients led to different types of gating changes in NaV1.7 sodium currents and, interestingly, different degrees of effectiveness of specific sodium channel blocking drugs. The implication from these findings is that a selective NaV1.7 blocker may be an effective treatment for pain in man.
A local anaesthetic lidocaine and a volatile anaesthetic halothane are known to act on both TTX-R and TTX-S sodium channels with poor selectivity and low potency (IC50 values range from 50 mM to 10 mM). These anaesthetics at high systemic concentrations could cause devastating side effects, e.g., paralysis and cardiacarrest. However, systemic administration of lidocaine at low concentrations is effective to treat chronic pain (Trends in Pharm. Sci 22, 27-31, 2001, Baker, M. D. et al.). In rats, application of a very low dose of TTX to the DRG of the injured segment of the L5 spinal nerve significantly reduces mechanical allodynic behavior (Brain Res 871, 98-103, 2000, Lyu, Y. S. et al.). This suggests that TTX-S subtypes of sodium channels play an important role in maintaining allodynic behaviors in an animal model of neuropathic pain.
The NaV1.5 channel is also a member of TTX-resistant sodium channels. The NaV1.5 channel is almost exclusively expressed in cardiac tissue and has been shown to underlie a variety of cardiacarrhythmias and conduction disorders.
In particular, the aryl substituted carboxamide derivatives of the present invention are selective for the TTX-S channels over the NaV1.5 channel, leading to improvements in the side-effect profile.
The aryl substituted carboxamide derivatives are therefore useful for the treatment of a wide range of disorders, particularly pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain including post-surgical pain, and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back and orofacial pain.
Other conditions that may be treated with the picolinamide derivatives of the present invention include multiple sclerosis, neurodegenerative disorders, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder and causalgia.
WO2007120729, WO2009054982, WO2009054983, and WO2009054984 disclose a series of heterocycle amide compounds which are blockers of T-type calcium channels.
The compounds of the present invention, however, differ structurally from known compounds in the above cited arts by the presence of unique spacer between carbony group and terminal aryl group. Namely, disclosed compounds of the prior arts are introducing only one carbon atom as a spacer between carbonyl group and heteroaryl, whereas the compounds of the present invention are characterized by introducing different unique spacers between carbony group and terminal aryl group.
WO 2003037274 discloses pyrazole derivatives as sodium channel blockers. Then WO2002091830 disclosed pyridinyl fused bicyclic amides as fungicides.
The novel compounds with trifluoroethoxy or methoxy on the pyridine ring or pyrazine ring; and alkyl side chain; are useful for the treatment of a condition or disorder in which voltage gated sodium channels are involved.
On the contrary, cyclopropane carboxamide besides trifluoroethoxy or methoxy on the pyridine ring or pyrazine ring is important for the treatment of a condition or disorder in which T-type calcium channels are involved. The compounds have advantage over the compounds disclosed in WO2007120729, WO2009054982, WO2009054983, and WO2009054984 in terms of metabolism.
The above cited arts, however, have never disclosed the voltage gated sodium channels. Therefore aryl substituted carboxamide derivatives of this invention provide the first knowledge of blocking not only the T-type calcium channels but also voltage gated sodium channels.
It is an objective of the invention to provide new T-type calcium channel blockers or TTX-S blockers that are good drug candidates. Preferred compounds should bind potently to the TTX-S (NaV1.3 and NaV1.7) channels whilst showing little affinity for other sodium channels, particularly the NaV1.5 channel. They should be well absorbed from the gastrointestinal tract, be metabolically stable and possess favorable pharmacokinetic properties. For example, the compounds of this invention have excellent metabolic properties comparing with the compounds disclosed in WO 2007120729, WO 2009054982, WO 2009054983, and WO 2009054984. They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated.
SUMMARY OF INVENTION
The present invention is directed to aryl substituted carboxamide derivatives which are blockers of T-type calcium channels or voltage gated sodium channels, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which T-type calcium channels or voltage gated sodium channels are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which T-type calcium channels or voltage gated sodium channels are involved. It is needless to say that T-type calcium channels or voltage gated sodium channels does cover T-type calcium channels and voltage gated sodium channels.


DESCRIPTION OF EMBODIMENTS
The present invention provides a use of a compound of the following formula (I) for the manufacture of a medicament for the treatment of a condition or disorder in which T-type calcium channels or voltage gated sodium channels are involved:




wherein:
R is hydrogen or C1-6 alkyl which may be substituted with one or more substituents independently selected from R7;
R1 is independently selected from the group consisting of;
(1) hydrogen, (2) halogen, (3) hydroxyl, (4) —On—C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (5) —On—C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (6) C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R7, (7) —On-phenyl or —On-napthyl, where the phenyl or napthyl is unsubstituted or substituted with one or more substituents independently selected from R7, (8) —On-heterocyclic group, where the heterocyclic group is unsubstituted or substituted with one or more substituents independently selected from R7, (9) —(C═O)—NR9R10, (10) —NR 9R10, (11) —S(O)2—NR9R10, (12) —NR9—S(O)2R10, (13) —S(O)t—R9, where t is 0, 1 or 2, (14) —NR9(C═O)R10, (15) —CN, and (16) —NO2;
wherein n is 0 or 1, when n is 0, a chemical bond is present in the place of On;
p is 1, 2, 3, or 4; when p is two or more than two, R1 may be same or different;
R2 is selected from the group consisting of:
(1) hydrogen, (2) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R7, (3) C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R7, (4) C2-6 alkenyl, which is unsubstituted or substituted with one or more substituents independently selected from R7, (5) C2-6 alkynyl, which is unsubstituted or substituted with one or more substituents independently selected from R7, (6) phenyl, which is unsubstituted or substituted with one or more substituents independently selected from R7, (7) —(C═O)—NR9R10, and (8) —(C═O)—O—C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R7;
or R2 form a 5 to 7 membered ring with R1 which may contain nitrogen atom, oxygen atom, sulfur atom or double bond, wherein the 5 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R7, (5) C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R7, (6) —O—C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R7, and (7) —O—C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R7;
X is a chemical bond, —C═C—, -cycloalkylene-, -cycloalkylene-C1-4-alkylene-O—, oxygen atom, sulfur atom, or nitrogen atom; when X is —C═C—, -cycloalkylene-, -cycloalkylene-C1-4-alkylene-O—, or nitrogen atom, said substituent X may have a substituent independently selected from the definitions of R9 and R10;
W, Y and Z are independently selected from nitrogen atom and carbon atom, which are independently optionally substituted with R1;
at least one of W, Y and Z is nitrogen and W, Y and Z are not carbon at the same time;
R3, R4, R5 and R6 are independently selected from the group consisting of:
(1) hydrogen, (2) hydroxyl, (3) halogen, (4) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R7, (5) C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R7, (6) —O—C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R7, (7) —O—C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R7, and (8) —NR7R8;
or R3 and R4 and the carbon atom to which they are attached form an oxo group;
or R3 and R4 and the carbon atom to which they are attached form a C3-6 cycloalkyl ring, which is unsubstituted or substituted with R7;
or R5 and R6 and the carbon atom to which they are attached form an oxo group;
or R5 and R6 and the carbon atom to which they are attached form a C3-6 cycloalkyl ring, which is unsubstituted or substituted with R7;
q is 0, 1, 2, 3, or 4; when q is one or more than one, R3 and R4 may be same or different;
r is 0, 1, 2, 3, or 4; when r is one or more than one, R5 and R6 may be same or different;
when (i) q is 1 and r is 0 or (ii) q is 0 and r is 1, X is not a chemical bond;
R7 is selected from the group consisting of:
(1) hydrogen, (2) halogen, (3) hydroxyl, (4) —(C═O)m—O1—C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R8, (5) —O1—(C1-3)perfluoroalkyl, (6) —(C═O)m—O1—C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R8, (7) —(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R8, (8) —(C═O)m—O1-phenyl or —(C═O)m—O1-napthyl, where the phenyl or napthyl is unsubstituted or substituted with one or more substituents independently selected from R8, (9) —(C═O)m—O1-heterocyclic group, where the heterocyclic group is unsubstituted or substituted with one or more substituents independently selected from R8, (10) —(C═O)—NR9R10, (11) —NR9R10, (12) —S(O)2—NR9R10, (13) —S(O)t—R9, where t is 0, 1 or 2, (14) —CO2H, (15) —CN, and (16) —NO2;
wherein 1 is 0 or 1 and m is 0 or 1; when 1 is 0 or m is 0, a chemical bond is present in the place of (C═O)m or O1, and when 1 is 0 and m is 0, a chemical bond is present in the place of (C═O)m—O1;
R8 is independently selected from the group consisting of:
(1) hydrogen, (2) hydroxyl, (3) halogen, (4) C1-6 alkyl, (5) —C3-6 cycloalkyl, (6) —O—C1-6 alkyl, (7) —O(C═O)—C1-6 alkyl, (8) —NH—C1-6 alkyl, (9) phenyl, (10) heterocyclic group, and (11) —CN;
R9 and R10 are independently hydrogen or C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and —O—C1-6 alkyl; or R9 form a 4 to 7 membered ring with R10 which may contain nitrogen atom, oxygen atom, sulfur atom or double bond, wherein the 4 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R8, (5) C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R8, (6) —O—C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R8, and (7) —O—C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R8;
Ar is aryl which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:
(1) halogen, (2) hydroxyl, (3) —On-phenyl or —On-napthyl, where the phenyl or napthyl is unsubstituted or substituted with one or more substituents independently selected from R7, (4) —On-heterocyclic group, where the heterocyclic group is unsubstituted or substituted with one or more substituents independently selected from R7, (5) —On—C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (6) —On—C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R7, (7) —C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R7, (8) —(C═O)—NR9R10, (9) —NR9R10, (10) —S(O)2—NR9R10, (11) —NR9—S(O)2R10, (12) —S(O)t—R9, where t is 0, 1 or 2, (13) —NR9(C═O)R10, (14) —CN, and (15) —NO2;
wherein n is 0 or 1, when n is 0, a chemical bond is present in the place of On;
or a pharmaceutically acceptable salt thereof.
The present invention provides the compounds of the formula (II)




wherein
R is halogen, or C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and —O—C1-6 alkyl;
v is 0, 1, 2, or 3; when v is two or more than two, R may be same or different;
R1 is —OCH2CF3 or —OCH3;
R2 is C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and —O—C1-6 alkyl;
R3 is independently selected from the group consisting of:
(1) halogen, (2) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R6, (3) C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R6, (4) —O—C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R6, (5) —O—C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R6, and (6) —NR7R8−;
Preferable R3 is independently selected from the group consisting of:
(1) halogen, (2) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from halogen;
w is 0, 1, 2, 3 or 4; when w is two or more than two, R3 may be same or different;
R4 and R5 are independently hydrogen, halogen, or C1-6 alkyl which is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and —O—C1-6 alkyl;
Preferable R4 and R5 are independently hydrogen, halogen, or C1-6 alkyl which is unsubstituted or substituted with one or more substituents independently selected from halogen;
R6 is independently selected from the group consisting of:
(1) hydrogen, (2) hydroxyl, (3) halogen, (4) —O1R7, (5) —CN, (6) —(C═O)—NR7R8, (7) —NR7R8, (8) —S(O)2—NR7R8, (9) —S(O)t—R7, where t is 0, 1 or 2, (10) —CN, and (11) —NO2;
wherein 1 is 0 or 1; when 1 is 0, a chemical bond is present in the place of O1;
R7 and R8 are independently hydrogen, C1-6 alkyl, or C3-8 cycloalkyl, which are un-substituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and —O—C1-6 alkyl; or R7 form a 4 to 7 membered ring with R8 which may contain nitrogen atom, or oxygen atom, wherein the 4 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C1-6 alkyl, and (5) —O—C1-6 alkyl;
p, q, and r are independently 0 or 1; when p is 0, both q and r are 1 or both q and r are 0.
Y and Z are independently selected from nitrogen atom and carbon atom; Y and Z are not carbon atom at the same time;
when p is 0, Ar is selected from the group consisting of phenyl, indolyl and quinolinyl; wherein Ar is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:
(1) halogen, (2) hydroxyl, (3) —O-phenyl or —O-napthyl, where the phenyl or napthyl is unsubstituted or substituted with one or more substituents independently selected from R6, (4) —On-heterocyclic group, where the heterocyclic group is unsubstituted or substituted with one or more substituents independently selected from R6, (5) —On—C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R6, (6) —On—C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R6, (7) —NR7R8, (8) —S(O)2—NR7R8, (9) —S(O)t—R7, where t is 0, 1 or 2, (10) —NR7SO2R8, (11) —(C═O)—NR7R8, (12) —NR7(C═O)R8, (13) —CN, and (14) —NO2;
wherein preferable Ar is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:
(1) halogen, (2) hydroxyl, (3) —O-phenyl, where the phenyl is unsubstituted or substituted with one or more substituents independently selected from halogen, methyl, trifluoromethyl, and trifluoromethoxy, (4) —On-heterocyclic group, where the heterocyclic group is unsubstituted or substituted with one or more substituents independently selected from halogen, methyl, trifluoromethyl, and trifluoromethoxy, (5) —O n-C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, (6) —On—C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, and (7) —CN;
wherein n is 0 or 1, when n is 0, a chemical bond is present in the place of On;
when p is 1, Ar is aryl which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:
(1) halogen, (2) hydroxyl, (3) —On-heterocyclic group, where the heterocyclic group is unsubstituted or substituted with one or more substituents independently selected from R6, (4) —On—C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R6, (5) —On—C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R6, (6) —NR7R8, (7) —S(O)2—NR7R8, (8) —S(O)t—R7, where t is 0, 1 or 2, (9) —NR7SO2R8, (10) —(C═O)—NR7R8, (11) —NR7(C═O)R8, (12) —CN, and (13) —NO2;
when p is 1, preferable Ar is aryl which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:
(1) halogen, (2) hydroxyl, (3) —On—C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, (4) —On—C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, and (5) —CN;
wherein n is 0 or 1, when n is 0, a chemical bond is present in the place of On;
or a pharmaceutically acceptable salt thereof.
Suitable compounds of the invention are:

    (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)acetamide;
    (R)-3,5-dichloro-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)quinoline-2-carboxamide;
    (1R,2R)-2-methyl-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenyl)cyclopropanecarboxamide;
    (R)-4-tert-butyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (R)-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)acetamide;
    (R)-2-(p-tolyloxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide;
    (R)-4-(2,2,2-trifluoroethoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-2-carboxamide;
    (R)-1-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-2-carboxamide;
    (R)-2-(2,4-dichlorophenoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide;
    (R)-2-(4-bromophenoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide;
    (R)-3-(3-fluorophenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)propanamide;
    (R)-3-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzofuran-2-carboxamide;
    (R)-5-tert-butyl-2-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)furan-3-carboxamide;
    (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-3-(trifluoromethyl)benzamide;
    (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-4-(trifluoromethyl)benzamide;
    (R)-5-phenyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2-(trifluoromethyl)furan-3-carboxamide;
    (R)-3-fluoro-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-5-(trifluoromethyl)benzamide;
    (R)-3-fluoro-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-4-(trifluoromethyl)benzamide;
    (R)-4-fluoro-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-3-(trifluoromethyl)benzamide;
    (R)-2-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-6-(trifluoromethyl)-2H-indazole-3-carboxamide;
    (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-5-(trifluoromethyl)picolinamide;


(R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-3-carboxamide;

    (R)-1-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-3-carboxamide;
    (R)-3-(1H-indol-1-yl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)propanamide;
    (R)-1-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-5-(trifluoromethyl)-1H-indole-2-carboxamide;
    (R)-N-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethyl)-5-fluoro-1H-indole-2-carboxamide;
    (R,E)-N-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethyl)-3-(4-(trifluoromethyl)phenyl)acrylamide
    (R,E)-N-(1-(5-(benzyloxy)pyridin-2-yl)ethyl)-3-(4-(trifluoromethyl)phenyl)acrylamide
    (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenyl)thiazole-4-carboxamide;
    (R)-3-(6-fluoro-1H-indol-1-yl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)propanamide;
    (R)-N-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethyl)-3-(6-fluoro-1H-indol-1-yl)propanamide;
    (R)-N-(1-(5-(2-fluorobenzyloxy)pyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)acetamide;
    (R)-5-(2,2,2-trifluoroethoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)picolinamide;
    (R)-N-(1-(5-(pyridin-2-ylmethoxy)pyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)acetamide;
    N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide;
    (R,E)-3-(1H-indol-3-yl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acrylamide (1R,2R)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-(4-(trifluoromethyl)phenyl)cyclopropanecarboxamide;
    (R)-N-(1-(5-((1-methylcyclopropyl)methoxy)pyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)acetamide;
    trans-2-(7-fluoro-1H-indol-3-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (R)-3-chloro-4-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (R)-4-tert-butyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)benzamide;
    (R)-3-chloro-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)quinoxaline-2-carboxamide;
    (R)-4-methoxy-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)quinoline-2-carboxamide;
    (R)-5-isobutyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)isoxazole-3-carboxamide;
    (R)-3-(2-methylthiazol-4-yl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzo[b]thiophene-2-carboxamide;
    (R)-3-(benzyloxy)-4-methoxy-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (R)-3-phenoxy-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (1S*,2S*)-2-(1H-indol-3-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-(1H-indol-3-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (R)-5-chloro-1-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-3-carboxamide;
    (R)-5-methoxy-1-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-3-carboxamide;
    (R)-1,6-dimethyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-3-carboxamide;
    (R)-6-fluoro-1-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-3-carboxamide;
    (R)-5-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-3-carboxamide;
    (R)-5-fluoro-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-3-carboxamide;
    (R)-5-chloro-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-3-carboxamide;
    (R)-6-chloro-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-3-carboxamide;
    trans-2-(1H-indol-6-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
    (R)-1,5-dimethyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-2-carboxamide;
    (R)-5-fluoro-1-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-2-carboxamide;
    (R)-5-chloro-1-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-2-carboxamide;
    (R)-6-fluoro-1-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-2-carboxamide;
    (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-4-(trifluoromethoxy)benzamide;
    (R)-5-phenyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)isoxazole-3-carboxamide;
    (R)-5-bromo-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-2-carboxamide;
    (R)-6-chloro-1-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-2-carboxamide;
    (R)-1-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-5-(trifluoromethoxy)-1H-indole-2-carboxamide;
    (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-3-(trifluoromethoxy)benzamide;
    trans-2-(quinolin-7-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    trans-2-(quinolin-7-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
    trans-2-(isoquinolin-3-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    trans-2-(quinolin-3-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
    trans-2-((4-chlorophenoxy)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
    trans-2-(2-fluoro-5-methoxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    trans-2-((1H-indol-1-yl)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (R)-6-fluoro-1-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1H-indole-2-carboxamide;
    trans-2-(2,5-difluorophenyl)-N-((R)-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    trans-N-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethyl)-2-(2,5-difluorophenyl)cyclopropanecarboxamide;
    trans-2-(2,5-difluorophenyl)-N-((R)-(1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
    trans-N-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethyl)-2-(1H-indol-4-yl)cyclopropanecarboxamide;
    trans-2-(4-methoxy-3-methylphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-(1H-indol-6-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    trans-2-(quinolin-6-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
    trans-2-(5-fluoro-1H-indol-2-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
    trans-2-(quinolin-3-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
    trans-2-(1H-indol-4-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-(8-chloroquinolin-2-yl)-N-((R)-(1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
    (R)-5-methoxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1H-indole-2-carboxamide;
    (R)-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-4-(trifluoromethoxy)benzamide;
    (R)-3-phenoxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)benzamide;
    (R)-6-methoxy-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)quinoline-2-carboxamide;
    (1S*,2S*)-2-(1H-indol-2-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-(1H-indol-2-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-(1H-indol-2-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
    trans-2-(1-methyl-1H-indazol-6-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-(4-(benzyloxy)phenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (R,E)-3-(quinolin-2-yl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acrylamide;
    (1S*,2S*)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2-(2,4,6-trifluorophenyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-(3,5-difluorophenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-(3-methoxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-(4-methoxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-(2-chloro-4-fluorophenyl)-N-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-N-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethyl)-2-(2-fluoro-4-methoxyphenyl)cyclopropanecarboxamide;
    (1S*,2S*)-N-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethyl)-2-(2,4,6-trifluorophenyl)cyclopropanecarboxamide;
    (1S*,2S*)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-2-(2,4,6-trifluorophenyl)cyclopropanecarboxamide;
    (1R*,2R*)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-2-(2,4,6-trifluorophenyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-(1H-indol-4-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-phenyl-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-phenyl-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-phenyl-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-phenyl-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-phenyl-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-(1H-benzo[d]imidazol-2-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-(1H-benzo[d]imidazol-2-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-(1H-benzo[d]imidazol-2-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-(phenoxymethyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-((3-fluorophenoxy)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-((3-cyanophenoxy)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-((4-fluorophenoxy)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-((4-cyanophenoxy)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-(phenoxymethyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-((3-fluorophenoxy)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-((3-cyanophenoxy)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-((4-fluorophenoxy)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-((4-cyanophenoxy)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-(4-((3-methyloxetan-3-yl)methoxy)phenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1S*,2S*)-N-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethyl)-2-(1H-indol-7-yl)cyclopropanecarboxamide;
    (1S*,2S*)-2-(phenoxymethyl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-(quinolin-2-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    4-(benzyloxy)-3-methoxy-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)benzamide;
    2-(4-(trifluoromethyl)phenoxy)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)acetamide;
    (R)-N-(1-(6-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)acetamide;
    (R)-5-fluoro-N-(1-(6-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-2-carboxamide;
    (S)-4-isopropyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (S)-2-(4-chlorophenoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide;
    (S)-4-(2,2,2-trifluoroethoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (1S*,2S*)-2-(4-(benzyloxy)phenyl)-N-((S)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-(4-(benzyloxy)phenyl)-N-((S)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-(2-fluoro-4-methoxyphenyl)-N-((S)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-(2-fluoro-4-methoxyphenyl)-N-((S)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-(2-chloro-4-fluorophenyl)-N-((S)-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-(2-chloro-4-fluorophenyl)-N-((S)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1S*,2S*)-2-phenyl-N-((S)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    (1R*,2R*)-2-phenyl-N-((S)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
    tert-butyl
    ((R)-1-oxo-1-(((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)amino)-3-(2-(trifluoromethoxy)phenyl)propan-2-yl)carbamate;
    tert-butyl
    ((R)-1-oxo-1-(((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)amino)-3-(2-(trifluoromethyl)phenyl)propan-2-yl)carbamate;
    (R)-N-(1-(5-methoxypyridin-2-yl)ethyl)-3-phenoxybenzamide;
    (R)-2-hydroxy-4-phenyl-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)butanamide;
    tert-butyl
    ((S)-1-(4-chlorophenyl)-3-oxo-3-(((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)amino)propyl)carbamate;
    tert-butyl
    ((R)-1-(4-chlorophenyl)-3-oxo-3-4(R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)amino)propyl)carbamate;
    tert-butyl
    ((R)-3-(4-chlorophenyl)-1-oxo-1-(((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)amino)propan-2-yl)carbamate;
    tert-butyl
    ((S)-3-(2-chlorophenyl)-1-oxo-1-(((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)amino)propan-2-yl)carbamate;
    tert-butyl
    ((S)-3-(2-fluorophenyl)-1-oxo-1-(((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)amino)propan-2-yl)carbamate;
    (R)-2-(2-chlorophenoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide;
    (R)-2-(3-chlorophenoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide;
    (R)-2-(2-chlorophenoxy)-2-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)propanamide;
    (R)-2-(2,3-dichlorophenoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide;
    (R)-2-(o-tolyloxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide;
    (R)-2-(m-tolyloxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide;
    (R)-2-(2,4-dimethylphenoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide;
    (R)-2-(2-chloro-6-methylphenoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide;
    (R)-2-(4-(tert-butyl)phenoxy)-N-(1-(5-methoxypyridin-2-yl)ethyl)acetamide;
    (R)-2-amino-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-3-(2-(trifluoromethyl)phenyl)propanamide;
    isobutyl
    ((R)-1-oxo-1-(((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)amino)-3-(2-(trifluoromethyl)phenyl)propan-2-yl)carbamate;
    ethyl
    ((R)-1-oxo-1-(((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)amino)-3-(2-(trifluoromethyl)phenyl)propan-2-yl)carbamate;
    N-((5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-3-(trifluoromethoxy)benzamide;
    4-(2,2,2-trifluoroethoxy)-N-((5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)benzamide;
    6-fluoro-1-methyl-N-((5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1H-indole-2-carboxamide;
    3-(2,2,2-trifluoroethoxy)-N-((5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)benzamide;
    (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)phenoxy)acetamide;
    (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2-(2-(trifluoromethoxy)phenoxy)acetamide;
    (R)-N-(1-(5-methoxypyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)phenoxy)acetamide;
    (R)-3-(2,2,2-trifluoroethoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (R)-N-(1-(5-methoxypyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenyl)thiazole-4-carboxamide;
    (R)-N-(1-(5-methoxypyridin-2-yl)ethyl)-1-methyl-5-(trifluoromethoxy)-1H-indole-2-carboxamide;
    (R)-2-(4-chlorophenoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)acetamide;
    (R)-5-(2,2,2-trifluoroethoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)picolinamide;
    (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-3-(trifluoromethoxy)benzamide;
    (R)-4-fluoro-3-phenoxy-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    4-(tert-butyl)-N-((6-methoxypyridin-3-yl)methyl)benzamide;
    N-((6-methoxypyridin-3-yl)methyl)-2-(4-(trifluoromethyl)phenoxy)acetamide;
    4-(tert-butyl)-N-((5-methoxypyridin-2-yl)methyl)benzamide;
    (S)-4-(tert-butyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (S)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-3-(trifluoromethoxy)benzamide;
    (S)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-4-(trifluoromethoxy)benzamide;
    (S)-3-(2,2,2-trifluoroethoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-4-(trifluoromethoxy)benzamide;
    (R)-4-(2,2,2-trifluoroethoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)benzamide;
    (R)-3-(2,2,2-trifluoroethoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)benzamide;
    4-(tert-butyl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)benzamide;
    3-(trifluoromethoxy)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)benzamide;
    4-(trifluoromethoxy)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)benzamide;
    4-(2,2,2-trifluoroethoxy)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)benzamide;
    3-(2,2,2-trifluoroethoxy)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)benzamide;
    4-(tert-butyl)-N-((6-(piperidin-1-yl)pyridin-3-yl)methyl)benzamide;
    N-((6-(piperidin-1-yl)pyridin-3-yl)methyl)-3-(trifluoromethoxy)benzamide;
    N-((6-(piperidin-1-yl)pyridin-3-yl)methyl)-4-(2,2,2-trifluoroethoxy)benzamide;
    4-(tert-butyl)-N-((6-(pyrrolidin-1-yl)pyridin-3-yl)methyl)benzamide;
    N-((6-(pyrrolidin-1-yl)pyridin-3-yl)methyl)-3-(trifluoromethoxy)benzamide;
    N-((6-(pyrrolidin-1-yl)pyridin-3-yl)methyl)-4-(2,2,2-trifluoroethoxy)benzamide;
    4-(tert-butyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)benzamide;
    3-(trifluoromethoxy)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)benzamide;
    4-(tert-butyl)-N-((6-(pyrrolidin-1-yl)pyridin-2-yl)methyl)benzamide;
    N-((6-(pyrrolidin-1-yl)pyridin-2-yl)methyl)-3-(trifluoromethoxy)benzamide;
    N-((6-(pyrrolidin-1-yl)pyridin-2-yl)methyl)-4-(2,2,2-trifluoroethoxy)benzamide;
    (R)-4-chloro-2-methoxy-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (R)-4-(2-cyanopropan-2-yl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (R)-3-chloro-4-methoxy-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (R)-6-methoxy-1-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-2-carboxamide;
    (R)-N-(1-(6-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-3-(trifluoromethoxy)benzamide;
    (R)-N-(1-(6-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-4-(2,2,2-trifluoroethox y)benzamide;
    (S)-2-(3-chlorophenoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide;
    2-(3-chlorophenoxy)-N-((5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)acetamide;
    (R)-2-(3-chlorophenoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)acetamide;
    (R)-4-ethyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (R)-3-fluoro-4-methyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (R)-5-chloro-2-methoxy-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide;
    (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)quinoxaline-2-carboxamide;
    (R)-N-(1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-5-(trifluoromethyl)picolinamide;

and salts thereof.



Also, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, for the manufacture of a medicament for the treatment of a condition or disorder mediated by T-type calcium channels or voltage gated sodium channels; in particular, T-type calcium channels blocking activity or voltage gated sodium channels blocking activity. In order to use the compounds of formula (I) and pharmaceutically acceptable salts thereof in therapy, they will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
Preferably, the present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, for the manufacture of a medicament for the treatment of diseases selected from T-type calcium channels related diseases or voltage gated sodium channels related diseases.
Also, the present invention provides the use of a compound of the formula (I) or the pharmaceutically acceptable salt thereof, each as described herein, for the manufacture of a medicament for the treatment of a condition or disorder in which voltage gated sodium channels are involved, as described in formula (I) herein wherein when Y is nitrogen atom, and at the same time (i) q is 1 and r is 0 or (ii) q is 0 and r is 1, then X may be a chemical bond;
or as described in formula (I) herein wherein when Y is carbon atom, Z is nitrogen atom, W is nitrogen atom, and at the same time (i) q is 1 and r is 0 or (ii) q is 0 and r is 1, then X may be a chemical bond;
the definition of the other descriptors is the same as described herein.
Also, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, together with a pharmaceutically acceptable carrier for said compound.
Also, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, each as described herein, together with a pharmaceutically acceptable carrier for said compound and another pharmacologically active agent.
Also, the present invention provides a process for preparing a pharmaceutical composition, the process comprising mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
Also, the present invention provides an intermediate in a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Further, the present invention provides a method of treatment of a condition or disorder mediated by T-type calcium channels activity or voltage gated sodium channels activity, in a mammalian subject, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, each as described herein.
In a further aspect, the present invention provides a process for preparing a pharmaceutical composition, the process comprising mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
Examples of conditions or disorders mediated by T-type calcium channels activity or voltage gated sodium channels activity include, but are not limited to, T-type calcium channels related diseases or voltage gated sodium channels related diseases. The compounds of the present invention show the T-type calcium channels blocking activity or voltage gated sodium channels blocking activity. The compounds of the present invention may show less toxicity, good absorption, distribution, good solubility, less protein binding affinity other than T-type calcium channels or voltage gated sodium channels, less drug-drug interaction, good metabolic stability, reduced inhibitory activity at HERG channel, and reduced QT prolongation.
As appreciated by those of skill in the art, “halogen” or “halo” as used herein are intended to include fluoro, chloro, bromo and iodo. Similarly, C1-6, as in C1-6 alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that C1-8 alkyl specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. Similarly, C2-6 alkenyl is defined to identify the group as having 2, 3, 4, 5 or 6 carbons which incorporates at least one double bond, which may be in a E- or a Z-arrangement. A group which is designated as being independently substituted with substituents may be independently substituted with multiple numbers of such substituents.
The term “alkenyl”, as used herein, means a hydrocarbon radical having at least one double bond including, but not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyl and the like.
The term “cycloalkyl”, as used herein, means a mono- or bicyclic ring, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norboranyl, and adamantyl groups and the like.
The term “aryl”, as used herein, means mono- or bi-carbocyclic or mono- or bi-heterocyclic ring which may contain 0-4 heteroatoms selected from O, N and S, but not limited to, phenyl, furyl, thienyl, oxazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl, pyrazinyl, pyridazinyl, isooxazolyl, isothiazolyl, triazolyl, furazanyl, naphthyl, tetrahydronaphthyl, indanyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzoimidazolyl, benzotriazolyl, imidazopyridinyl, pyrazolopyrimidinyl, quinolyl, isoquinolyl, cinnolinyl, naphthyridinyl, phthalazinyl, quinazolinyl, quinoxalinyl, triazolopyrimidinyl, and the said rings which are fully or partially saturated, such as pyridin-2-onyl, piperidinyl, pyrrolidinyl, tetrehydronaphthalenyl, and the like.
The term “heterocyclic group” as used herein includes both unsaturated and saturated heterocyclic moieties, wherein the unsaturated heterocyclic moieties (i.e. “heteroaryl”) include benzoimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and N-oxides thereof, and wherein the saturated heterocyclic moieties include azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof and S-oxides thereof.
The term “C0”, as used herein, means direct bond.
The term “protecting group”, as used herein, means a hydroxy or amino protecting group which is selected from typical hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1991);
The term “treating” and “treatment”, as used herein, refers to curative, palliative and prophylactic treatment, including reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
As used herein, the article “a” or “an” refers to both the singular and plural form of the object to which it refers unless indicated otherwise.
Included within the scope of the “compounds of the invention” are all salts, solvates, hydrates, complexes, polymorphs, prodrugs, radiolabeled derivatives, stereoisomers and optical isomers of the compounds of formula (I).
The compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci, 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, formic, acetic, trifluoroacetic, propionic, fumaric, citric, tartaric, benzoic, ptoluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms. In addition, certain compounds containing an acidic function such as a carboxy can be isolated in the form of their inorganic salt in which the counter ion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.
The compounds of formula (I) and salts thereof may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated. This invention includes within its scope stoichiometric hydrates or solvates as well as compounds containing variable amounts of water and/or solvent.
Salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts.
The compounds of formula (I) may have polymorphs in crystalline form, which are within the scope of the present invention.
Additionally, the compounds of formula (I) may be administered as prodrugs. As used herein, a “prodrug” of a compound of formula (I) is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of formula (I) in vivo. Administration of a compound of formula (I) as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of action of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
In certain of the compounds of formula (I), there may be some chiral carbon atoms. In such cases, compounds of formula (I) exist as stereoisomers. The invention extends to all optical isomers such as stereoisomeric forms of the compounds of formula (I) including enantiomers, diastereoisomers and mixtures thereof, such as racemates. The different stereoisomeric forms may be separated or resolved one from the other by conventional methods or any given isomer may be obtained by conventional stereoselective or asymmetric syntheses.
Certain of the compounds herein can exist in various tautomeric forms and it is to be understood that the invention encompasses all such tautomeric forms.
The invention also includes isotopically-labeled compounds, which are identical to those described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 3H, 11C, 14C, 18F, 123I and 125I. Compounds of the invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. 11C and 18F isotopes are particularly useful in PET (positron emission tomography), and 125I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, Isotopically labeled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, then substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
The potencies and efficacies of the compounds of this invention for T-type calcium channels or voltage gated sodium channels can be determined by methodology well known in the art, including the “Ca2+ influx Assay”, “Electrophysiology assay for T-type Ca2+”, “FRET Assay for Nays” and “Electrophysiology assay for Nays” as described herein. Compounds of formula (I) have demonstrated blocking activity at the T-type calcium channels, using the assays described herein.
The intrinsic T-type calcium channels blocking activity or voltage gated sodium channels blocking activity of a compound which may be used in the present invention may be determined by these assays. In particular, the compounds of the following examples had activity in blocking the T-type calcium channel or voltage gated sodium channels in the aforementioned assays, generally with an IC50 of less than about 10 microM, preferably less than about 1 microM, more preferably less than about 0.3 microM. Some of the compounds within the present invention had activity in blocking the T-type calcium channels or voltage gated sodium channels in the aforementioned assays with an IC50 of less than about 1 microM. Such a result is indicative of the intrinsic activity of the compounds in use as blockers of T-type calcium channels activity or voltage gated sodium channels activity.
With respect to other compounds disclosed in the art, the present compounds exhibit unexpected properties, such as with respect to duration of action and/or metabolism, such as increased metabolic stability, enhanced oral bioavailability or absorption, and/or decreased drug-drug interactions.
T-type calcium channels have been implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species. The compounds of the present invention have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with calcium channels, including one or more of the following conditions or diseases: movement disorders, including akinesias and akinetic-rigid syndromes (including Parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification), chronic fatigue syndrome, fatigue, including Parkinson's fatigue, multiple sclerosis fatigue, fatigue caused by a sleep disorder or a circadian rhythm disorder, medication-induced parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication induced postural tremor), Gilles de la Tourette's syndrome, seizure disorders, epilepsy, and dyskinesias [including tremor (such as rest tremor, essential tremor, postural tremor and intention tremor), chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballism), myoclonus (including generalised myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics), restless leg syndrome and dystonia (including generalised dystonia such as iodiopathic dystonia, drug-induced dystonia, symptomatic dystonia and paroxymal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp and hemiplegic dystonia); heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, sexual and reproductive dysfunction, such as impaired fertility, infertility, diseases or disorders where abnormal oscillatory activity occurs in the brain, including depression, migraine, neuropathic pain, Parkinson's disease, psychosis and schizophrenia, as well as diseases or disorders where there is abnormal coupling of activity, particularly through the thalamus; enhancing cognitive function; enhancing memory; increasing memory retention; increasing trained performance; increasing immune response; increasing immune function; hot flashes; night sweats; extending life span; schizophrenia; muscle-related disorders that are controlled by the excitation/relaxation rhythms imposed by the neural system such as cardiac rhythm and other disorders of the cardiovascular system; conditions related to proliferation of cells such as vasodilation or vasorestriction and blood pressure; cancer; cardiacarrhythmia; hypertension; congestive heart failure; conditions of the genital/urinary system; disorders of sexual function and fertility; adequacy of renal function; responsivity to anesthetics; sleep disorders, sleep disturbances, including enhancing sleep quality, improving sleep quality, increasing sleep efficiency, augmenting sleep maintenance; increasing the value which is calculated from the time that a subject sleeps divided by the time that a subject is attempting to sleep; improving sleep initiation; decreasing sleep latency or onset (the time it takes to fall asleep); decreasing difficulties in falling asleep; increasing sleep continuity; decreasing the number of awakenings during sleep; decreasing intermittent wakings during sleep; decreasing nocturnal arousals; decreasing the time spent awake following the initial onset of sleep; increasing the total amount of sleep; reducing the fragmentation of sleep; altering the timing, frequency or duration of REM sleep bouts; altering the timing, frequency or duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasing the amount and percentage of stage 2 sleep; promoting slow wave sleep; enhancing EEG-delta activity during sleep; increasing the amount of Delta sleep early in the sleep cycle, increasing REM sleep late in the sleep cycle; decreasing nocturnal arousals, especially early morning awakenings; increasing daytime alertness; reducing daytime drowsiness; treating or reducing excessive daytime sleepiness; increasing satisfaction with the intensity of sleep; increasing sleep maintenance; idiopathic insomnia; sleep problems; insomnia, hypersomnia, idiopathic hypersomnia, repeatability hypersomnia, intrinsic hypersomnia, narcolepsy, interrupted sleep, sleep apnea, obstructive sleep apnea, wakefulness, nocturnal myoclonus, REM sleep interruptions, jet-lag, shift workers' sleep disturbances, dyssomnias, night terror, insomnias associated with depression, emotional/mood disorders, Alzheimer's disease or cognitive impairment, as well as sleep walking and enuresis, and sleep disorders which accompany aging; Alzheimer's sundowning; conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules, conditions due to drugs which cause reductions in REM sleep as a side effect; fibromyalgia; syndromes which are manifested by non-restorative sleep and muscle pain or sleep apnea which is associated with respiratory disturbances during sleep; conditions which result from a diminished quality of sleep; mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder, mood disorders due to a general medical condition, and substance-induced mood disorders; anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition; acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiacarrest, hypoglycemic neuronal damage; Huntington's Chorea; amyotrophic lateral sclerosis; multiple sclerosis; ocular damage; retinopathy; cognitive disorders; idiopathic and drug-induced Parkinson's disease; muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions; cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or age related cognitive decline; schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced psychotic disorder; substance-related disorders and addictive behaviors (including substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder; tolerance, dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics); attention deficit/hyperactivity disorder (ADHD); conduct disorder; migraine (including migraine headache); urinary incontinence; overactive bladder (DAB); urge urinary incontinence (UUI); lower urinary tract symptoms (LUTS); substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.); psychosis; schizophrenia; anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder); mood disorders (including depression, mania, bipolar disorders); trigeminal neuralgia; hearing loss; tinnitus; neuronal damage including ocular damage; retinopathy; macular degeneration of the eye; emesis; brain edema; pain, including acute pain, chronic pain, severe pain, intractable pain, inflammatory pain, chronic inflammatory pain, diabetic neuropathy, chronic neuropathic pain, post-traumatic pain, bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain, neuropathic pain, post-traumatic pain, trigeminal neuralgia, migraine and migraine headache.
Thus, in an embodiment the present invention provides methods for: treating, controlling, ameliorating or reducing the risk of epilepsy, including absence epilepsy; treating or controlling Parkinson's disease; treating essential tremor; treating or controlling pain, including neuropathic pain; enhancing the quality of sleep; augmenting sleep maintenance; increasing REM sleep; increasing slow wave sleep; decreasing fragmentation of sleep patterns; treating insomnia; enhancing cognition; increasing memory retention; treating or controlling depression; treating or controlling psychosis; or treating, controlling, ameliorating or reducing the risk of schizophrenia, in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound of the present invention. The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.
In a similar fashion to T-type calcium channels, tetrodotoxin-sensitive (TTX-S) voltage gated sodium channels such as NaV1.3 and NaV1.7 have been also implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species. The compounds of the present invention have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with TTX-S sodium channels, including one or more of the following conditions or diseases: pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, multiple sclerosis, neurodegenerative disorder, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder and causalgia.
The dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The active ingredient may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. The dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize.
Generally, dosage levels of between 0.0001 to 20 mg/kg of body weight daily are administered to the patient, e.g., humans and elderly humans, to obtain effective blockage of T-type calcium channel. The dosage range will generally be about 0.5 mg to 1.0 g per patient per day which may be administered in single or multiple doses.
In one embodiment, the dosage range will be about 0.5 mg to 500 mg per patient per day; in another embodiment about 0.5 mg to 200 mg per patient per day; in another embodiment about 1 mg to 100 mg per patient per day; and in another embodiment about 5 mg to 50 mg per patient per day; in yet another embodiment about 1 mg to 30 mg per patient per day. Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient. The pharmaceutical composition may be provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 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, such as once or twice per day.
The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is envisioned. However, the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention. The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound 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 of the present invention is envisioned. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
The weight ratio of the compound 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 another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, including 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. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
A T-type calcium channels blocker or voltage gated sodium channels blocker may be usefully combined with same or another pharmacologically active compound, or with two or more same or other pharmacologically active compounds, particularly in the treatment of inflammatory, pain and urological diseases or disorders. For example, a T-type calcium channels blocker or a voltage gated sodium channels blocker, particularly a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from:

    
    
        an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;
        a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;
        a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thiopental;
        a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;
        an H1 antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;
        a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;
        a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;
        an NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex(registered trademark), a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g. ifenprodil, traxoprodil or (−)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;
        an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;
        a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;
        an anticonvulsant, e.g. carbamazepine, lamotrigine, topiratmate or valproate;
        a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7-naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S);
        a muscarinic antagonist, e.g. oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;
        a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;
        a coal-tar analgesic, in particular paracetamol;
        a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion(registered trademark) or sarizotan;
        a vanilloid receptor agonist (e.g. resinferatoxin) or antagonist (e.g. capsazepine);
        a beta-adrenergic such as propranolol;
        a local anaesthetic such as mexiletine;
        a corticosteroid such as dexamethasone;
        a 5-HT receptor agonist or antagonist, particularly a 5-HT1B/1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;
        a 5-HT2A receptor antagonist such as  R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);
        a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;
        Tramadol(registered trademark);
        a PDEV inhibitor, such as 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′: 6,1]-pyrido[3,4-b]indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;
        an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin, (1alpha,3 alpha,5 alpha)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3 aminomethyl-5 methyl-heptanoic acid, (3S,5R)-3 amino-5 methyl-heptanoic acid, (3S,5R)-3 amino-5 methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3 aminomethyl-5 methyl-octanoic acid, (3S,5R)-3 amino-5 methyl-nonanoic acid, (3S,5R)-3 amino-5 methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;
        a cannabinoid;
        metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;
        a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;
        a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (VivalanR), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;
        a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine;
        an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarbonitrile; 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl) butyl]thio]-6-(trifluoromethyl)-3 pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, or guanidinoethyldisulfide;
        an acetylcholinesterase inhibitor such as donepezil;
        a prostaglandin E2 subtype 4 (EP4) antagonist such as N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;
        a leukotriene B4 antagonist; such as 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870,
        a 5-lipoxygenase inhibitor, such as zileuton,
    
    
    6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl),1,4-benzoquinone (CV-6504);
    
        a sodium channel blocker, such as lidocaine;
        a calcium channel blocker, such as ziconotide, zonisamide, mibefradil;
        a 5-HT3 antagonist, such as ondansetron;
    
    


and the pharmaceutically acceptable salts and solvates thereof.
Such combinations offer significant advantages, including synergistic activity, in therapy.
A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrate compositions are generally preferred. Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); tabletting lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); and acceptable wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (which may include edible oils e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid), and, if desired, conventional flavourings or colorants, buffer salts and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound or pharmaceutically acceptable salt thereof.
For parenteral administration, fluid unit dosage forms are prepared utilising a compound of formula (I) or pharmaceutically acceptable salt thereof and a sterile vehicle. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose, utilising a compound of formula (I) or pharmaceutically acceptable salt thereof and a sterile vehicle, optionally with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, stabilising agents, solubilising agents or suspending agents. They may also contain a preservative.
The compounds of formula (I) or pharmaceutically acceptable salts thereof may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
The compounds of formula (I) or pharmaceutically acceptable salts may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of formula (I) or pharmaceutically acceptable salts may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
For intranasal administration, the compounds formula (I) or pharmaceutically acceptable salts thereof may be formulated as solutions for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device. Thus compounds of formula (I) or pharmaceutically acceptable salts thereof may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose). The compounds of formula (I) and pharmaceutically acceptable salts thereof may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Ointments for administration to the eye may be manufactured in a sterile manner using sterilized components.
General Synthesis
Throughout the instant application, the following abbreviations are used with the following meanings:

    DIBAL-H Diisobutylaluminium hydride
    DMF N,N-dimethylformamide
    DMSO Dimethyl sulfoxide
    EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride
    HOBT 1-Hydroxybenztriazole
    HBTU 0-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium Hexafluorophosphate
    HPLC High pressure liquid chromatography
    TEMPO 2,2,6,6-Tetramethyl-1-piperidinyloxy
    tR Retention time
    MHz Megahertz
    NMR Nuclear Magnetic Resonance
    TFA Trifluoroacetic acid
    THF Tetrahydrofuran
    TLC Thin layer chromatography


The term of “base” is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include: alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium hydroxide; alkali metal hydrides, such as lithium hydride, sodium hydride, and potassium hydride; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, and potassium t-butoxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal hydrogencarbonates, such as lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), lutidine, and colidine; alkali metal amides, such as lithium amide, sodium amide, potassium amide, lithium diisopropyl amide, potassium diisopropyl amide, sodium diisopropyl amide, lithium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide. Of these, triethylamine, diisopropylethylamine, DBU, DBN, DABCO, pyridine, lutidine, colidine, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium carbonate, potassium hydrogencarbonate, potassium hydroxide, barium hydroxide, and cesium carbonate are preferred.
The reactions are normally and preferably effected in the presence of inert solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include, but not limited to: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethane; ethers, such as diethyl ether, diisopropyl ether, THF, and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as, DMF, N,N-dimethylacetamide, and hexamethylphosphoric triamide; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, N,N-dimethylaniline, and N,N-diethylaniline; alcohols, such as methanol, ethanol, propanol, isopropanol, and butanol; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO) and sulfolane; ketones, such as acetone and diethylketone. Of these solvents, including but not limited to DMF, DMSO, THF, diethylether, diisopropylether, dimethoxyethane, acetonitrile, dichloromethane, dichloroethane and chloroform are preferred.
EXAMPLES
The invention is illustrated in the following non-limiting examples in which, unless stated otherwise: all reagents are commercially available, all operations were carried out at room or ambient temperature, that is, in the range of about 18-25° C.; evaporation of solvent was carried out using a rotary evaporator under reduced pressure with a bath temperature of up to about 60° C.; reactions were monitored by thin layer chromatography (tlc) and reaction times are given for illustration only; the structure and purity of all isolated compounds were assured by at least one of the following techniques: tlc (Merck silica gel 60 F254 precoated TLC plates or Merck NH2F254 precoated HPTLC plates), mass spectrometry or nuclear magnetic resonance (NMR). Yields are given for illustrative purposes only. Flash column chromatography was carried out using Merck silica gel 60 (230-400 mesh ASTM) or Fuji Silysia Chromatorex(registered trademark) DU3050 (Amino Type, 30-50 micrometer) or Biotage silica (32-63 micrometer, KP-Sil) or Biotage amino bounded silica (35-75 mlcrometer, KP-NH) or Hi-Flash ColumnTM (40 micrometer, Silica gel). Low-resolution mass spectral data (ESI) were obtained by the following apparatus and conditions: Apparatus; Waters Alliance HPLC system on ZQ or ZMD mass spectrometer and UV detector. NMR data was determined at 270 MHz (JEOL JNM-LA 270 spectrometer) or 300 MHz (JEOL JNM-LA300) using deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) as solvent unless indicated otherwise, relative to tetramethylsilane (TMS) as internal standard in parts per million (ppm); conventional abbreviations used are: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad, etc. Chemical symbols have their usual meanings;
μm (micrometer(s)), μL (microliter(s)), μg (microgram(s)), M (mol(s) per liter), L(liter(s)), mL (milliliter(s)), g (gram(s)), mg(milligram(s)), mol (moles), mmol (millimoles).
Purification Methods:
Achiral Reversed-phase HPLC:

    
    
        Apparatus: Waters MS-trigger AutopurificationTM System (2525 Binary pump module, 2767 Sample manager, 2996 PDA detector and Z02000 mass spectrometer)
        Column: XBridgeTM Prep C18 5 μm, 19×50 mm
        Column temperature: ambient (room temperature)
        Flow rate: 20 mL/min
        Mobile phase A: Methanol or Acetonitrile/0.05% (v/v) formic acid aqueous solution
        Mobile phase B: Methanol or Acetonitrile/0.05% (v/v) ammonia aqueous solution
        Elution: Optimized gradient program with selected mobile phases
        Run time: 7 min
    
    


MPLC:

    
    
        Apparatus: Biotage SP System
        Column: Hi-FlashTM Column Silica gel 40 μm, 60 Å
        Column Temperature: room temperature
        Solvents:
        
            Less polar solvent: hexane
            High polar solvent: ethyl acetate
        
        
    
    


Chiral Normal Phase HPLC:

    
    
        Apparatus: Shimadzu Preparative-HPLC system
        Column: DAICEL Chiralpak AD-H, 20×250 mm
        
            DAICEL Chiralpak AS-H, 20×250 mm
            DAICEL Chiralcel OJ-H, 20×250 mm
            DAICEL Chiralcel OD-H, 20×250 mm
        
        
        Column temperature: 40° C.
        Solvents:
        
            A1: n-Hexane
            B1: Ethanol or 2-propanol
        
        
        Elution: Optimized isocratic condition with the selected column and mobile phases
    
    


Purity Evaluation Method:
Method A:

    
    
        Apparatus: Waters Acquity Ultra Performance LC on TUV Detector and ZQ mass spectrometer
        Column: XTerra MS C18 3.5 μm, 2.1×30 mm
        Column Temperature: 45° C.
        Solvents:
        
            A1: acetonitrile
            B1: 5 mM ammonium acetate aqueous solution
        
        
    
    











TABLE 1





Time(min)
A1(%)
B1(%)

















0
4
96


2
96
4


4
96
4





run time 4.0 min


flow 0.5 mL/min






Method B:
Achiral Reversed-phase-UPLC:

    
    
        Apparatus: Waters ACQUITY Ultra Performance LC (HPLCTM) with TUV Detector and ZQ2000 mass spectrometer
        Column: Waters ACQUITY HPLCTM BEH C18, 2.1×100 mm, 1.7 μm
        Column temperature: 60° C.
        Flow rate: 0.7 mL/min
        Solvents:
        
            A1: 10 mM ammonium acetate aqueous solution
            B1: Acetonitrile
        
        
    
    









TABLE 2







Eluting program:









Time(min)
A1(%)
B1(%)












0
95
5


0.1
95
5


1.8
5
95


2.3
95
5





Run time: 3 min






All of the aryl substituted carboxamide derivatives of the formula (I) can be prepared by the procedures described in the general methods presented below or by the specific methods described in the Examples section and the Preparations section, or by routine modifications thereof. The present invention also encompasses any one or more of these processes for preparing the aryl substituted carboxamide derivatives of formula (I), in addition to any novel intermediates used therein.
In the following general methods, Ar, W, X, Y, Z, R1, R2, R3, R4, R5, R6, p, p q and r are as previously defined for aryl substituted carboxamide derivatives of the formula (I) unless otherwise stated.




In Step A, a compound of formula (I) can be prepared from a compound of formula (III) by amidation with a compound of formula (II) with using a suitable condensation agent such as EDC, preferably under the presence of a base such as a combination of trimethylamine and HOBT, in a suitable solvent such as dichloromethane at a temperature of from 5 to 40° C. for 5-20 hours.
In order to obtain some other compounds of formula (I), the appropriate conversion reaction of the substituents will be used.
For example, alkyl subsituted derivatives can be prepared from a compound of the corresponding halide by coupling reaction with a suitable boronic acid using a suitable catalyst such as tetra kis triphenylphosphine palladium under the presence of a base such as potassium phosphate and a suitable solvent such as dioxane at a temperature of from 5 to 90 ° C. for 12-24 hours; cyclopropane derivatives can be prepared from a compound of the corresponding alphq,beta-unsaturated amide by cyclization reaction with a suitable alkyl diiodide using a suitable reagent such as diethylzinc in a suitable solvent such as dichloromethane at a temperature of from 5 to 90 ° C. for 12-24 hours or by cyclization reaction with a suitable trialkyl sulfoxonium halide such as trimethylsulfoxonium iodide and suitable base such as sodium hydride in a suitable solvent such as DMSO at a temperature of from 5 to 90 ° C. for 1-24 hours; hydroxyl derivatives can be prepared from a compound of the corresponding benzyloxy derivative by hydrogenation with a suitable palladium catalyst such as hydroxyl palladium in a suitable solvent such as ethanol under hydrogen; ether derivatives can be prepared from a compound of the corresponding hydroxyl derivative by alkylation with alkyl alcohol under the presence of a condensation reagent such as di-ter-butyl azodicarboxylate and triphenyl phosphine and base such as N-N-diisopropylethylamine and a suitable solvent such as tetrahydrofuran or with alkyl halide under the presence of a base such as potassium carbonate and a suitable solvent such as dimethylformamide; N-alkylated derivatives can be prepared from a compound of the corresponding NH-amide derivative by alkylation with a suitable alkyl halide using a base such as sodium hydride in a suitable solvent such as dimethylformamide:
All starting materials in the following general syntheses may be commercially available or obtained by conventional methods known to those skilled in the art, otherwise noted in the intermediate synthesis part.
Intermediate Synthesis Part
Amine Intermediate-1
(R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethanamine 2HCl salt
Step-1: 5-(cyclopropylmethoxy)-2-methylpyridine
To a solution of 6-methylpyridin-3-ol (5.0 g, 46 mmol) in DMF (45 mL) were added cesium carbonate (16.5 g, 53 mmol) and (bromomethyl)cyclopropane (7.1 g, 53 mmol) at room temperature. After being stirred at room temperature for 18 hours, the mixture was poured into H2O, and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3:1 (v/v)) to give 3.9 g (52% yield) of the title compound as a yellow oil:
1H-NMR (300 MHz, CDCl3) δ 8.20 (1H, d, J=2.9 Hz), 7.04-7.14 (2H, m), 3.82 (2H, d, J=6.6 Hz), 2.49 (3H, s), 1.21-1.34 (1H, m), 0.67 (2H, q, J=7.3 Hz), 0.37 (2H, q, J=5.9 Hz), LCMS (Method A) m/z: M+1 obs 164.3, tR=2.07 min.
Step-2: (5-(cyclopropylmethoxy)pyridin-2-yl)methanol
To a solution of 5-(cyclopropylmethoxy)-2-methylpyridine (3.9 g, 24 mmol) in dichloromethane (50 mL) was added 3-chlorobenzoperoxoic acid (7.6 g, 32 mmol) at room temperature. After being stirred at room temperature for 1 hour, the mixture was poured into saturated aqueous sodium bicarbonate solution. The organic phase was extracted with dichloromethane (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in acetic anhydride (50 mL) and the mixture was stirred at 100° C. for 2 hours. Half of the solvent was removed under the reduced pressure. The residue was dissolved into methanol (50 mL). Potassium carbonate (20 g, 143 mmol) was added to the mixture carefully. The mixture was stirred at room temperature for 1 hour. The mixture was poured into H2O, and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1:1 (v/v)) to give 4.5 g (quantitative yield) of the title compound as a brown oil:
1H-NMR (300 MHz, CDCl3) δ 8.25 (1H, d, J=2.9 Hz), 7.21 (1H, dd, J=8.8, 2.9 Hz), 7.17 (1H, d, J=8.8 Hz), 4.70 (2H, s), 3.85 (2H, d, J=7.4 Hz), 1.28 (1H, m), 0.75-0.63 (2H, m), 0.40-0.28 (2H, m), LCMS (Method A) m/z: M+1 obs 180.3, tR=2.09 min.
Step-3: (R,E)-N-((5-(cyclopropylmethoxy)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide
To a solution of (5-(cyclopropylmethoxy)pyridin-2-yl)methanol (4.5 g, 25 mmol) in dichloromethane (50 ml), was added a 15% potassium bromide aqueous solution (20 mL) followed by a saturated bicarbonate solution (20 ml). The biphasic mixture was cooled in an ice bath and TEMPO (200 mg, 1.3 mmol) was added. After stirring for 10 min, 5% sodium hypochlorite (30 ml) was dropwised. The reaction mixture was stirred for 10 min. The solution was poured into a separatory funnel and the organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL). Copper(II) sulfate (10.1 g, 63 mmol) followed by (R)-(+)-2-methyl-2-propanesulfinamide (3.1 g, 25 mmol) were added to the mixture respectively and the mixture was stirred for 18 hours at room temperature. The reaction mixture was filtrated off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1:1 (v/v)) to give 6.2 g (87% yield) of the title compound as a flaky solid:
1H-NMR (300 MHz, CDCl3) δ 8.63 (1H, s), 8.42 (1H, d, J=2.2 Hz), 7.96 (1H, d, J=8.8 Hz), 7.24-7.28 (1H, m), 3.92 (2H, d, J=6.6 Hz), 1.27 (10H, m), 0.67-0.73 (2H, m), 0.39-0.42 (2H, m), LCMS (Method A) m/z: M+1 obs 281.2, tR=2.98 min.
Step-4: (R)-N-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide
A solution of (R,E)-N-((5-(cyclopropylmethoxy)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (6.2 g, 22 mmol) was dissolved into dichloromethane (110 ml). Methyl magnesium bromide (44 ml, 44 mmol, 1.0M in THF) was added to the mixture at −78° C. dropwise. The mixture was stirred for 1 h at −78° C. The mixture was poured into saturated ammonium chloride aqueous solution, and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1:1 (v/v)) to give 3.2 g (49% yield) of the title compound as a white solid:
1H-NMR (300 MHz, CDCl3) δ 8.24 (1H, d, J=2.2 Hz), 7.15-7.23 (2H, m), 4.51-4.57 (2H, m), 3.83 (2H, d, J=6.6 Hz), 1.49 (3H, d, J=6.6 Hz), 1.25 (10H, m), 0.59-0.75 (2H, m) 0.34-0.44 (2H, m), LCMS (Method A) m/z: M+1 obs 297.3, tR=2.81 min.
Step-5: (R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethanamine 2HCl salt
(R)-N-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (3.2 g, 10.9 mmol) was dissolved in 10N HCl/MeOH (50 mL). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated by N2-flow to give the white precipitate. The solid was collected by filtration and washed with diisopropyl ether to give 3.2 g (49% yield) of the title compound as a white solid:
1H-NMR (300 MHz, DMSO-d6) δ 8.67 (3H, brs), 8.41 (1H, d, J=2.2 Hz), 7.70-7.55 (2H, m), 4.56 (1H, m), 4.01 (2H, d, J=7.3 Hz), 1.57 (3H, d, J=6.6 Hz), 1.33 (1H, m), 0.70-0.60 (2H, m), 0.45-0.35 (2H, m), LCMS (Method A) m/z: M+1 obs 193.3, tR=1.90 min.
Amine Intermediate-2
(R)-1-(5-(benzyloxy)pyridin-2-yl)ethanamine 2HCl salt
Step-1: (R,E)-N-((5-(benzyloxy)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide
Prepared as in Step 3 of Amine intermediate-1 from (5-(benzyloxy)pyridin-2-yl)methanol.
1H-NMR (300 MHz, CDCl3) δ 8.64 (1H, s), 8.49 (1H, d, J=2.94 Hz), 7.97 (1H, d, J=8.1Hz), 7.31-7.45 (6H, m), 5.19 (2H, s), 1.27 (9H, s), LCMS (Method A) m/z: M+1 obs 317.2, tR=3.15 min.
Step-2: (R)-N-((R)-1-(5-(benzyloxy)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide
Prepared as in Step-4 of Amine intermediate-1 from (R,E)-N-((5-(benzyloxy)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide.
1H-NMR (300 MHz, CDCl3) δ8.31 (1H, d, J=2.2 Hz), 7.50-7.30 (5H, m), 7.23 (2H, d, J=2.2 Hz), 5.09 (2H, s), 4.57 (2H, m), 1.49 (3H, d, J=6.6 Hz), 1.25 (9H, s), LCMS (Method A) m/z: M+1 obs 333.2, tR=2.97 min.
Step-3: (R)-1-(5-(benzyloxy)pyridin-2-yl)ethanamine 2HCl salt
Prepared as in Step-5 of Amine intermediate-1 from (R)-N-((R)-1-(5-(benzyloxy)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide.
1H-NMR (300 MHz, DMSO-d6) δ 7.50 (2H, brs), 8.38 (1H, d, J=2.9 Hz), 7.65-6.25 (7H, m), 6.01 (2H, brs), 5.22 (2H, s), 4.45 (1H, m), 1.46 (3H, d, J=6.6 Hz), LCMS (Method A) m/z: M+1 obs 229.3, tR=2.24 min.
Amine Intermediate-3
(R)-1-(5-(2-fluorobenzyloxy)pyridin-2-yl)ethanamine 2HCl salt
Step-1: 5-(2-fluorobenzyloxy)picolinonitrile
To a mixture of 2-bromo-5-(2-fluorobenzyloxy)pyridine (1.5 g, 5.3 mmol) and zinc cyanide (0.81 g, 6.9 mmol) in DMF (20 mL) was added Tetrakis(triphenylphosphine)palladium(0) (0.61 g, 0.53 mmol) at room temperature. After being stirred at 60° C. for 4 hours, sat. sodium bicarbonate aqueous solution was added to the mixture. The mixture was filtered off through a pad of Celite. The filtrate was extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2:1 (v/v)) to give 0.69 g (57% yield) of the title compound as a light yellow solid:
1H-NMR (300 MHz, CDCl3) δ 8.45 (1H, d, J=2.9 Hz), 7.65 (1H, d, J=8.7 Hz), 7.50-7.28 (3H, m), 7.24-7.05 (2H, m), 5.24 (2H, s), LCMS (Method A) m/z: M+1 obs 229.3, tR=2.94 min.
Step-2: (R,E)-N-((5-(2-fluorobenzyloxy)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide
To a solution of Reactant 5-(2-fluorobenzyloxy)picolinonitrile (690 mg, 3.0 mmol) in dichloromethane (20 mL) was added DIBAL-H (3.7 mL, 3.6 mmol, 0.99 M) at −78° C. After being stirred at −78° C. for 4 hours, methanol (2 mL) was added to the mixture. 1N hydrochloric acid (0.5 mL) was added to the mixture at room temperature. The mixture was stirred at room temperature for 1 hour. Sat. sodium bicarbonate aqueous solution was added to the mixture until the pH was neutrized. The organic layer was extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane (20 mL). Copper(II) sulfate (1.2 g, 7.6 mmol) followed by (R)-(+)-2-methyl-2-propanesulfinamide (370 mg, 3.0 mmol) were added to the mixture respectively and the mixture was stirred for overnight at room temperature. The reaction mixture was filtrated off through a pad of Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2:1 (v/v)) to give 360 mg (36% yield) of the title compound as a colorless oil:
1H-NMR (300 MHz, CDCl3) δ 8.64 (1H, s), 8.49 (1H, d, J=2.9 Hz), 7.98 (1H, d, J=8.8 Hz), 7.49 (1H, td, J=7.3, 1.5 Hz), 7.40-7.30 (2H, m), 7.23-7.05 (2H, m), 5.26 (2H, s), 1.27 (9H, s), LCMS (Method A) m/z: M+1 obs 335.3, tR=3.14 min.
Step-3: (R)-N-((R)-1-(5-(2-fluorobenzyloxy)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide
Prepared as in Step-4 of Amine intermediate-1 from (R,E)-N-((5-(2-fluorobenzyloxy)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide.
1H-NMR (300 MHz, CDCl3) δ 8.32 (1H, d, J=1.4 Hz), 7.48 (1H, t, J=7.3 Hz), 7.40-7.05 (5H, m), 5.16 (2H, s), 4.60-4.50 (2H, m), 1.49 (3H, d, J=5.9 Hz), 1.25 (9H, s), LCMS (Method A) m/z: M+1 obs 351.3, tR=2.97 min.
Step-4: (R)-1-(5-(2-fluorobenzyloxy)pyridin-2-yl)ethanamine 2HCl salt
Prepared as in Step-5 of Amine intermediate-1 from (R)-N-((R)-1-(5-(2-fluorobenzyloxy)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide
1H-NMR (300 MHz, DMSO-d6) δ 8.97 (2H, brs), 8.40 (1H, m), 7.87 (1H, d, J=8.8 Hz), 7.64 (1H, d, J=8.8 Hz), 7.55-7.35 (2H, m), 7.30-7.08 (2H, m), 5.24 (2H, s), 4.78 (1H, m), 1.76 (3H, d, J=6.6 Hz), LCMS (Method A) m/z: M+1 obs 247.3, tR=2.34 min.
Amine Intermediate-4
(R)-1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine
Step-1: 2,6-dimethyl-3-(2,2,2-trifluoroethoxy)pyridine
Prepared as in Step-1 of Amine intermediate-1 from 2,6-dimethylpyridin-3-ol and 2,2,2-trifluoroethyl trifluoromethanesulfonate.
To a suspension of 2,6-dimethylpyridin-3-ol (5.0 g, 41 mmol) and cesium carbonate (15 g, 47 mmol) in DMF (50 mL) was added 2,2,2-trifluoroethyl trifluoromethane-sulfonate (11 mL, 47 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour. After being stirred at room temperature for 18 hours, the mixture was poured into H2O, and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give 8.3 g (quantitative yield) of the title compound as a brown oil:
1H-NMR (300 MHz, CDCl3) δ 7.01 (1H, d, J=8.0 Hz), 6.95 (1H, d, J=8.0 Hz), 4.33 (2H, q, J=8.0 Hz), 2.48 (6H, s), LCMS (Method A) m/z: M+1 obs 206.2, tR=2.58 min.
Step-2: (6-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol
Prepared as in Step-2 of Amine intermediate-1 from 2,6-dimethyl-3-(2,2,2-trifluoroethoxy)pyridine as a minor product.
1H-NMR (300 MHz, CDCl3) δ 7.12 (1H, d, J=8.0 Hz), 7.08 (1H, d, J=8.0 Hz), 4.68 (2H, s), 4.37 (2H, q, J=8.0 Hz), 2.52 (3H, s), 2.05 (1H, brs) (minor product).
Step-3: (R,E)-2-methyl-N-((6-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylene)propane 2-sulfinamide
Prepared as in Step-3 of Amine intermediate-1 from (6-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol.
1H-NMR (300 MHz, CDCl3) δ 8.63 (1H, s), 7.89 (1H, d, J=8.1Hz), 7.16 (1H, d, J=8.1Hz), 4.44 (2H, q, J=8.1Hz), 2.58 (3H, s), 1.27 (9H, s), LCMS (Method A) m/z: M+1 obs 323.2, tR=3.00 min.
Step-4: (R)-2-methyl-N-((R)-1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide
Prepared as in Step-4 of Amine intermediate-1 from (R,E)-2-methyl-N-((6-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylene)propane-2-sulfinamide.
1H-NMR (300 MHz, CDCl3) δ 7.11 (1H, d, J=8.0 Hz), 7.05 (1H, d, J=8.0 Hz), 4.79 (1H, d, J=5.1Hz), 4.55 (1H, m), 4.33 (2H, q, J=8.1Hz), 2.42 (3H, s), 1.48 (3H, d, J=6.6 Hz), 1.25 (9H, s).
Step-5: (R)-1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine 2HCl salt
Prepared as in Step-5 of Amine intermediate-1 from (R)-2-methyl-N-((R)-1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide. LCMS (Method A) m/z: M+1 obs 235.3, tR=2.24 min.
Amine Intermediate-5
(R)-1-(6-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine
Step-1: (6-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol
Prepared as in Step-2 of Amine intermediate-1 from 2,6-dimethyl-3-(2,2,2-trifluoroethoxy)pyridine as a major product.
1H-NMR (300 MHz, CDCl3) δ 7.03-7.09 (2H, m), 4.74 (2H, d, J=4.4 Hz), 4.36 (2H, q, J=8.1Hz), 2.52 (3H, s), 1.64 (1H, brs), LCMS (Method A) m/z: M+1 obs 222.3, tR=2.17 min.
Step-2: (R,E)-2-methyl-N-((6-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylene)propane-2-sulfinamide
Prepared as in Step-3 of Amine intermediate-1 from (6-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol.
1H-NMR (300 MHz, CDCl3) δ 8.95 (1H, s), 7.28 (2H, m), 4.44 (2H, m), 2.60 (3H, s), 1.27 (9H, s), LCMS (Method A) m/z: M+1 obs 323.2, tR=2.84 min.
Step-3: (R)-2-methyl-N-((R)-1-(6-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide
Prepared as in Step-4 of Amine intermediate-1 from (R,E)-2-methyl-N-((6-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylene)propane-2-sulfinamide.
1H-NMR (300 MHz, CDCl3) δ 7.04 (1H, d, J=8.1Hz), 6.99 (1H, d, J=8.1Hz), 5.21 (1H, d, J=7.3 Hz), 4.86 (1H, m), 4.38 (2H, q, J=8.0 Hz), 2.48 (3H, s), 1.41 (3H, d, J=6.6 Hz), 1.26 (9H, s)
Step-4: (R)-1-(6-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine 2HCl salt
Prepared as in Step-5 of Amine intermediate-1 from (R)-2-methyl-N-((R)-1-(6-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide.
1H-NMR (300 MHz, CDCl3-DMSO-d6) δ 8.43 (3H, brs), 7.60 (1H, d, J=8.8 Hz), 7.32 (1H, d, J=8.1Hz), 4.91 (2H, q, J=8.8 Hz), 4.54 (1H, m), 2.48 (3H, s), 1.41 (3H, d, J=6.6 Hz).
Amine Intermediate-6
(R)-1-(6-(2-fluorobenzyloxy)pyridin-3-yl)ethanamine
Step-1: (R,E)-N-((6-(2-fluorobenzyloxy)pyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide
To a suspension of sodium hydride (640 mg, 16 mmol, 60%) in DMF (20 mL) was added (2-fluorophenyl)methanol (1.9 g, 15 mmol) at 0° C. After being stirred at room temperature for 30 min, 6-chloronicotinonitrile (2.6 g, 19 mmol) was added to the mixture. The mixture was stirred at room temperature for 14 hours. The mixture was poured into saturated ammonium chloride aqueous solution, and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (19:1 (v/v)) to give the intermediate. The intermediate was dissolved into dichloromethane (30 mL). DIBAL-H (6.3 mL, 6.4 mmol, 0.99 M) was added to the mixture at −78° C. After being stirred at −78° C. for 4 hours, methanol (2 mL) was added to the mixture. 1N hydrochloric acid (0.5 mL) was added to the mixture at room temperature. The mixture was stirred at room temperature for 1 hour. Sat. sodium bicarbonate aqueous solution was added to the mixture until the pH was neutrized. The organic layer was extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane (20 mL). Copper(II) sulfate (2.3 g, 14 mmol) followed by (R)-(+)-2-methyl-2-propanesulfinamide (700 mg, 5.8 mmol) were added to the mixture respectively and the mixture was stirred for 18 hours at room temperature. The reaction mixture was filtrated off through a pad of Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (4:1 (v/v)) to give 155 mg (3% yield) of the title compound as a white solid:
1H-NMR (300 MHz, CDCl3) δ 8.55-8.62 (2H, m), 8.14 (1H, dd, J=8.0 Hz), 7.30-7.53 (2H, m), 7.07-7.18 (1H, m), 6.89 (1H, d, J=8.8 Hz), 5.53 (2H, s), 1.26 (9H, s).
Step-2: (R)-N-((R)-1-(6-(2-fluorobenzyloxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide
Prepared as in Step-4 of Amine intermediate-1 from (R,E)-N-((6-(2-fluorobenzyloxy)pyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide.
1H-NMR (300 MHz, CDCl3) δ 8.14 (1H, s), 7.51-7.58 (2H, m), 7.29-7.33 (1H, m), 7.06-7.18 (2H, m), 6.80 (1H, d, J=8.0 Hz), 5.44 (2H, s), 4.55-4.59 (2H, m), 1.54 (3H, d, J=6.6 Hz), 1.20 (9H, s).
Step-3: (R)-1-(6-(2-fluorobenzyloxy)pyridin-3-yl)ethanamine 2HCl salt
Prepared as in Step-5 of Amine intermediate-1 from (R)-N-((R)-1-(6-(2-fluorobenzyloxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide.
1H-NMR (300 MHz, CDCl3-DMSO-d6) δ 8.60 (2H, brs), 8.31 (1H, d, J=3.0 Hz), 7.96 (1H, dd, J=2.2 Hz), 7.51-7.61 (1H, m), 7.38-7.45 (1H, m), 7.20-7.27 (2H, m), 6.76 (1H, d, J=8.0 Hz), 6.49 (2H, m), 5.41 (2H, s), 4.40-4.44 (1H, m), 1.53 (3H, d, J=7.3 Hz), LCMS (Method A) m/z: M+1 obs 247.3, tR=2.44 min.
Amine Intermediate-7
(R)-1-(5-((1-methylcyclopropyl)methoxy)pyridin-2-yl)ethanamine 2HCl salt
Step-1: 2-methyl-5-((1-methylcyclopropyl)methoxy)pyridine
To a solution of 6-methylpyridin-3-ol (0.5 g, 4.6 mmol) in toluene (6 mL) was added (1-methylcyclopropyl)methanol (0.59 g, 6.9 mmol) and stirred under nitrogen atmosphere. The solution was added cyanomethylenetri-n-butylphosphorane (CMBP, 2.5 ml, 9.53 mmol) and stirred at 100° C. for 3 hours. The reaction mixture was evaporated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2:1 (v/v)) to give 820 mg (quantitative yield) of the title compound as a brown oil:
1H-NMR (300 MHz, CDCl3) δ 8.18 (1H, d, J=2.9 Hz), 7.03-7.13 (2H, m), 3.74 (2H, s), 2.48 (3H, s) 1.24 (3H, s), 0.31-0.56 (4H, m), LCMS (Method A) m/z: M+1 obs 178.3, tR=2.54 min.
Step-2: (5-((1-methylcyclopropyl)methoxy)pyridin-2-yl)methanol
Prepared as in Step-2 of Amine intermediate-1 from 2-methyl-5-((1-methylcyclopropyl)methoxy)pyridine.
1H-NMR (300 MHz, CDCl3) δ 8.24 (1H, d, J=1.4 Hz), 7.16-7.27 (2H, m), 4.70 (2H, s), 3.78 (2H, s), 2.83 (1H, brs), 1.25 (3H, s), 0.45-0.58 (4H, m), LCMS (Method A) m/z: M+1 obs 194.32, tR=2.37 min.
Step-3: (R,E)-2-methyl-N-((5-((1-methylcyclopropyl)methoxy)pyridin-2-yl)methylene)propane-2-sulfinamide
Prepared as in Step-3 of Amine intermediate-1 from (5-((1-methylcyclopropyl)methoxy)pyridin-2-yl)methanol.
1H-NMR (300 MHz, CDCl3) δ 8.64 (1H, s), 8.42 (1H, d, J=2.9 Hz), 7.96 (1H, d, J=8.8 Hz), 7.24 (1H, d, J=2.9 Hz), 3.85 (2H, s), 1.28 (9H, s), 1.24 (3H, s), 0.51-0.59 (4H, m), LCMS (Method A) m/z: M+1 obs 295.3, tR=3.14 min.
Step-4: (R)-2-methyl-N-((R)-1-(5-((1-methylcyclopropyl)methoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide
Prepared as in Step-4 of Amine intermediate-1 from (R,E)-2-methyl-N-((5-((1-methylcyclopropyl)methoxy)pyridin-2-yl)methylene)propane-2-sulfinamide.
1H-NMR (300 MHz, CDCl3) δ 8.23 (1H, d, J=2.2 Hz), 7.13-7.22 (2H, m), 4.52-4.56 (2H, m), 3.75 (2H, s), 1.49 (3H, d, J=6.6 Hz), 1.25 (9H, s), 1.23 (3H, s) 0.44-0.56 (4H, m), LCMS (Method A) m/z: M+1 obs 311.3, tR=2.95 min.
Step-5: (R)-1-(5-((1-methylcyclopropyl)methoxy)pyridin-2-yl)ethanamine 2HCl salt
Prepared as in Step-5 of Amine intermediate-1 from (R)-2-methyl-N-((R)-1-(5-((1-methylcyclopropyl)methoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide.
1H-NMR (300 MHz, CDCl3-DMSO-d6) δ 8.52 (2H, brs), 8.34 (1H, s), 7.52 (2H, s), 5.80 (2H, brs), 4.48 (1H, m), 3.88 (2H, s), 1.49 (3H, d, J=6.6 Hz), 1.19 (3H, s), 0.41-0.56 (4H, m), LCMS (Method A) m/z: M+1 obs 207.3, tR=2.07 min.
Amine Intermediate-8
3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroquinolin-8-amine
Step-1: 3-(2,2,2-trifluoroethoxy)quinoline
Prepared as in Step-1 of Amine intermediate-4 from quinolin-3-ol.
1H-NMR (300 MHz, CDCl3): δ 8.77 (1H, d, J=2.9 Hz), 8.08 (1H, d, J=8.0 Hz), 7.75 (1H, d, J=8.1Hz), 7.67-7.50 (2H, m), 7.45 (1H, d, J=2.9 Hz), 4.50 (2H, q, J=8.0 Hz), LCMS (Method A) m/z: M+1 obs 228.3, tR=2.90 min.
Step-2: 3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroquinoline
A mixture of 3-(2,2,2-trifluoroethoxy)quinoline (1.13 g, 5.0 mmol) and platinum (IV) oxide (50 mg) in TFA (8 mL) was stirred at room temperature for 12 hours under hydrogen atmosphere (1 atm). Then the mixture was filtered off through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (10:1-7:1) to give 495 mg (43% yield) of the title compound as a colorless oil:
1H-NMR (300 MHz, CDCl3): δ 8.12 (1H, d, J=2.9 Hz), 6.96 (1H, d, J=2.9 Hz), 4.36 (2H, q, J=8.1Hz), 2.87 (2H, t, J=6.6 Hz), 2.77 (2H, t, J=6.6 Hz), 1.93-1.75 (4H, m), LCMS (Method A) m/z: M+1 obs 232.3, tR=2.84 min.
Step-3: 3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroquinoline 1-oxide
A mixture of 3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroquinoline (495 mg, 2.1 mmol) and 3-chloroperbenzoic acid (ca 75%, 739 mg, 3.2 mmol) in dichloromethane (10 mL) was stirred at room temperature for 1.5 hour. Then, the mixture was poured into saturated sodium bicarbonate aqueous solution (50 mL), and the aqueous phase was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give 740 mg of the crude title compound. This was used for the next step without further purification:
LCMS (Method A) m/z: M+1 obs 248.3, tR=2.52 min.
Step-4: 3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroquinolin-8-ol
A mixture of 3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroquinoline 1-oxide (530 mg, 2.1 mmol) and acetic anhydride (3 mL) was stirred at 100° C. for 2 hours. After cooling to room temperature, acetic anhydride was removed in vacuo. To the residue, methanol (5 mL) and potassium carbonate (1.77 g, 13 mmol) were added, and the mixture was stirred at room temperature for 20 hours. Then, methanol was evaporated in vacuo. To the residue was added ethyl acetate, and the mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1:1-1:2) to give 193 mg (36% yield) of the title compound as a white solid:
1H-NMR (300 MHz, CDCl3): δ 8.17 (1H, d, J=2.9 Hz), 7.00 (1H, d, J=2.9 Hz), 4.69 (1H, brt, J=5.9 Hz), 4.38 (2H, q, J=8.1Hz), 3.64 (1H, s), 2.85-2.75 (2H, m), 2.31-2.20 (1H, m), 2.05-1.94 (1H, m), 1.88-1.75 (2H, m), LCMS (Method A) m/z: M+1 obs 248.2, tR=2.52 min.
Step-5: 3-(2,2,2-trifluoroethoxy)-6,7-dihydroquinolin-8(5H)-one
A mixture of 3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroquinolin-8-ol (193 mg, 0.78 mmol) and manganese (IV) oxide (543 mg, 6.3 mmol) in dichloromethane (10 mL) was stirred at room temperature for 3 hours. Then, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residual solid was washed with diethyl ether to give 155 mg (81% yield) of the title compound as a pale yellow solid:
1H-NMR (300 MHz, CDCl3): δ 8.44 (1H, d, J=2.9 Hz), 7.11 (1H, d, J=2.9 Hz), 4.48 (2H, q, J=8.1Hz), 3.03 (2H, t, J=5.9 Hz), 2.79 (2H, t, J=5.9 Hz), 2.20 (2H, quintet, J=5.9 Hz), LCMS (Method A) m/z: M+1 obs 246.3, tR=2.48 min.
Step-6: 3-(2,2,2-trifluoroethoxy)-6,7-dihydroquinolin-8(5H)-one oxime
A mixture of 3-(2,2,2-trifluoroethoxy)-6,7-dihydroquinolin-8(5H)-one (155 mg, 0.63 mmol), hydroxylamine hydrochloride (88 mg, 1.3 mmol), and sodium acetate (104 mg, 1.3 mmol) in ethanol-water (3:1, 4 mL) was refluxed with stirring for 2 hours. After cooling to room temperature, the mixture was poured into water, and the aqueous layer was extracted with dichloromethane (twice). The combined organic layers were dried over Magnesium sulfate and concentrated in vacuo to give 167 mg of the crude title compound as a brown solid. This was used for the next step without purification:
1H-NMR (300 MHz, DMSO-d6): δ 8.25 (1H, d, J=2.9 Hz), 7.37 (1H, d, J=2.9 Hz), 4.88 (2H, q, J=8.8 Hz), 2.79-2.68 (2H, m), 1.95-1.75 (4H, m) (a signal due to OH was not observed), LCMS (Method A) m/z: M+1 obs 261.3, tR=2.62 min.
Step-7: 3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroquinolin-8-amine
A mixture of 3-(2,2,2-trifluoroethoxy)-6,7-dihydroquinolin-8(5H)-one oxime (167 mg) and 10% palladium on carbon (100 mg) in methanol (7 mL) was stirred at room temperature for 24 h under hydrogen atmosphere (4 atm). Then, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on NH-gel eluting with hexane/ethyl acetate (1:1-0:1) to give 68 mg (43% yield) of the title compound as a pale brown oil:
1H-NMR (300 MHz, CDCl3): δ 8.18 (1H, s), 7.96 (1H, s), 4.37 (2H, q, J=8.1Hz), 4.03-3.95 (1H, m), 2.90-2.68 (2H, m), 2.24-2.13 (1H, m), 2.03-1.90 (1H, m), 1.85-1.66 (2H, m) (a signals due to NH2 were not observed), LCMS (Method A) m/z: M+1 obs 247.3, tR=2.14 min.
Amine Intermediate-9
(R)-1-(3-fluoro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine 2HCl salt
Step-1: 3-fluoro-5-(2,2,2-trifluoroethoxy)picolinonitrile
60% sodium hydride (0.219 g, 5.71 mmol) was added to a solution of 2,2,2-trifluoroethanol (0.257 ml, 3.57 mmol) in N,N,N′,N′,N′′,N′′-hexamethylphosphoric triamide (6 ml) at 0 oC and stirred for 1 hour. Then 3,5-difluoropicolinonitrile (1.0 g, 7.1 mmol) in N,N,N′,N′,N′′,N′′-hexamethylphosphoric triamide (4 mL) was added to the reaction mixture and stirred at room temperature for 20 hours. Then 2,2,2-trifluoroethanol (0.257 ml, 3.57 mmol) and 60% sodium hydride (0.22 g, 5.7 mmol) were added to the reaction mixture and stirred at room temperature for 3 hours. After reaction, the mixture was poured into water, and the aqueous phase was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (6:1-4:1) to give 398 mg (25% yield) of the title compound as a oily solution:
1H-NMR (300 MHz, CDCl3) δ 8.31 (1H, d, J=2.6 Hz), 7.15 (1H, dd, J=9.5, 2.6 Hz), 4.50 (2H, q, J=7.7 Hz).
Step-2: (R,E)-N-((3-fluoro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide
Prepared as in Step-2 of Amine intermediate-3 from 3-fluoro-5-(2,2,2-trifluoroethoxy)picolinonitrile.
1H-NMR (300 MHz, CDCl3) δ 8.83 (1H, s) 8.39 (1H, d, J=2.2 Hz), 7.11 (1H, dd, J=2.2 Hz), 4.89 (2H, q, J=7.4 Hz), 1.30 (9H, s), LCMS (Method A) m/z: M+1 obs 327.2, tR=2.94 min.
Step-3: (R)-N-((R)-1-(3-fluoro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide
Prepared as in Step-4 of Amine intermediate-1 from (R,E)-N-((3-fluoro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide.
1H-NMR (300 MHz, CDCl3) δ 8.14 (1H, s), 7.02 (1H, dd, J=1.5, 2.2 Hz), 4.70-4.88 (2H, m), 4.38 (2H, q, J=6.6 Hz), 1.45 (3H, d, J=6.6 Hz), 1.25 (9H, s), LCMS (Method A) m/z: M+1 obs 343.2, tR=2.92 min.
Step-4: (R)-1-(3-fluoro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine 2HCl salt
Prepared as in Step-5 of Amine intermediate-1 from (R)-N-((R)-1-(3-fluoro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide.
LCMS (Method A) m/z: M+1 obs 222.3, tR=2.00 min.
Amine Intermediate-10
(R)-1-(3-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine dihydrochloride
Step-1: 3-methyl-5-(2,2,2-trifluoroethoxy)picolinonitrile
Prepared as in Step-1 of Amine intermediate-4 from commercially available 5-hydroxy-3-methylpicolinonitrile:
1H-NMR (300 MHz, CDCl3) δ 8.28 (1H, d, J=2.9 Hz), 7.18 (1H, d, J=2.9 Hz), 4.46 (2H, q, J=7.4 Hz), 2.58 (3H, s), LCMS (Method A) m/z: M+1 obs 217.3, tR=2.79 min.
Step-2: (R,E)-2-methyl-N-((3-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylene)propane-2-sulfinamide
Prepared as in Step-2 of Amine intermediate-3 from 3-methyl-5-(2,2,2-trifluoroethoxy)picolinonitrile.
LCMS (Method A) m/z: M+1 obs 323.3, tR=3.02 min.
Step-3: (R)-2-methyl-N-((R)-1-(3-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide
Prepared as in Step-4 of Amine intermediate-1 from (R,E)-2-methyl-N-((3-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylene)propane-2-sulfinamide:
1H-NMR (270 MHz, CDCl3): δ 8.13 (1H, d, J==3.3 Hz), 7.05 (1H, d, J=3.3 Hz), 4.88 (1H, d, J=7.2 Hz), 4.69 (1H, quintet, J=6.5 Hz), 4.38 (2H, q, J=7.9 Hz), 2.38 (3H, s), 1.39 (3H, d, J=6.6 Hz), 1.25 (9H, s), LCMS (Method A) m/z: M+1 obs 339.3, tR=2.95 min.
Step-4: (R)-1-(3-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine dihydrochloride
Prepared as in Step-5 of Amine intermediate-1 from (R)-2-methyl-N-((R)-1-(3-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide:
LCMS (Method A) m/z: M+1 obs 235.3, tR=2.20 min.
Amine Intermediate-11
(S)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine dihydrochloride
The title compound was prepared according to the silimar procedure for (R)-isomer using (S)-(−)-2-methyl-2-propanesulfinamide:
[α]D22−16.7°(c=1.61, MeOH).
Carboxylic Acid Intermediate-1
1-methyl-6-(trifluoromethyl)-1H-indazole-3-carboxylic acid
Step-1: methyl 1-methyl-6-(trifluoromethyl)-1H-indazole-3-carboxylate
To an acetonitrile (5 ml) solution of methyl 6-(trifluoromethyl)-1H-indazole-3-carboxylate (300 mg, 1.2 mmol) were added potassium carbonate (1.0 g, 7.4 mmol) and iodomethane (350 mg, 2.5 mmol) at room temperature respectively. The mixture was stirred at room temperature for 4 hours. The solid was removed by filtration and washed with acetonitrile. The filtrate was concentrated in vacuo. After being filtered off, the filtrate was concentrated under reduced pressure, the residue was applied to a silica gel chromatography column and eluted with a hexane/ethyl acetate=4/1 to furnish 239 mg (75% yield, major product) of the title as a white solid;
1H-NMR (300 MHz, CDCl3) δ 8.36 (1H, d, J=8.0 Hz), 7.79 (1H, s), 7.55 (1H, d, J=8.0 Hz), 4.24 (3H, s), 4.06 (3H, s), LCMS (Method A) m/z: M+1 obs 259.1; tR=3.15 min.
Step-2: 1-methyl-6-(trifluoromethyl)-1H-indazole-3-carboxylic acid
To a tetrahydrofuran (2 mL) of methyl 1-methyl-6-(trifluoromethyl)-1H-indazole-3-carboxylate (50 mg, 0.19 mmol) was added 2N sodium hydroxide (0.2 ml, 4.0 mmol) at room temperature. The mixture was refluxed at 90° C. with stirring for 3 hours. After being cooled to room temperature, 2N hydrochloric acid was added to the mixture until pH became 4.0. The organic layer was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After the filtration to separate solvent and magnesium sulfate, the solvent was removed under reduced pressure to give 47 mg (quantitative yield) of the title as a white solid that was used in the next step without further purification;
LCMS (Method A) m/z: M+1 obs 245.0; tR=2.57 min.
Carboxylic Acid Intermediate-2
2-methyl-6-(trifluoromethyl)-2H-indazole-3-carboxylic acid
Step-1: methyl 2-methyl-6-(trifluoromethyl)-2H-indazole-3-carboxylate
Prepared as in Step 1 of Carboxylic acid intermediate-1 as a minor product.
1H-NMR (300 MHz, CDCl3) δ 8.13 (1H, d, J=8.8 Hz), 8.10 (1H, s), 7.45 (1H, d, J=8.8 Hz), 4.56 (3H, s), 4.06 (3H, s), LCMS (Method A) m/z: M+1 obs 259.1, tR=2.99 min.
Step-2: 2-methyl-6-(trifluoromethyl)-2H-indazole-3-carboxylic acid
Prepared as in Step 2 of Carboxylic acid intermediate-1 from methyl 2-methyl-6-(trifluoromethyl)-2H-indazole-3-carboxylate.
LCMS (Method A) m/z: M+1 obs 245.0, tR=2.52 min.
Carboxylic Acid Intermediate-3
1-methyl-6-(trifluoromethyl)-1H-indole-2-carboxylic acid
Step-1: ethyl 1-methyl-6-(trifluoromethyl)-1H-indole-2-carboxylate
A mixture of ethyl 6-(trifluoromethyl)-1H-indole-2-carboxylate (100 mg, 0.39 mmol), iodomethane (36 microL, 0.58 mmol), and potassium carbonate (134 mg, 0.97 mmol) in DMF was stirred at room temperature for 7 hours. Then, the mixture was poured into water, and the aqueous layer was extracted with dichloromethane (three times). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (20:1-10:1) to give 95.3 mg (90% yield) of the title compound as a white solid:
1H-NMR (300 MHz, CDCl3): δ 7.98 (1H, s), 7.56 (1H, d, J=8.8 Hz), 7.47 (1H, d, J=8.8 Hz), 7.37 (1H, s), 4.40 (2H, q, J=7.4 Hz), 4.11 (3H, s), 1.43 (3H, t, J=7.4 Hz), LCMS (Method A) m/z: M+1 obs 272.1, tR=3.45 min.
Step-2: 1-methyl-6-(trifluoromethyl)-1H-indole-2-carboxylic acid
A mixture of ethyl 1-methyl-6-(trifluoromethyl)-1H-indole-2-carboxylate (90 mg, 0.33 mmol) and 2 mol/L aqueous sodium hydroxide solution (0.42 mL, 0.83 mmol) in methanol (2 mL) was stirred at room temperature for 2 hours. Then, 2 mol/L hydrochloric acid was added, and the formed precipitate was collected by filtration to give 75.6 mg (94% yield) of the title compound as a white solid:
1H-NMR (300 MHz, DMSO-d6): δ 13.23 (1H, br), 8.12 (1H, s), 7.80 (1H, d, J=8.8 Hz), 7.60 (1H, d, J=8.8 Hz), 7.39 (1H, s), 4.08 (3H, s), LCMS (Method A) m/z: M−1 obs 242.1, tR=2.88 min.
Carboxylic Acid Intermediate-4
1-methyl-6-(trifluoromethyl)-1H-indole-3-carboxylic acid
Step-1: 2,2,2-trifluoro-1-[6-(trifluoromethyl)-1H-indol-3-yl]ethanone
To a solution of 6-(trifluoromethyl)-1H-indole (460 mg, 2.5 mmol) in tetrahydrofuran (5 mL) was added trifluoroacetic anhydride (0.52 mL, 3.7 mmol) at 0° C., and the resulting mixture was stirred at the same temperature for 1 hour and at room temperature for 1 hour. Then, the mixture was poured into water, and the formed precipitate was collected by filtration to give 583 mg (83% yield) of the title compound as a pale brown solid:
1H-NMR (300 MHz, DMSO-d6) δ 13.04 (1H, br), 8.72 (1H, s), 8.37 (1H, d, J=8.8 Hz), 7.93 (1H, s), 7.66 (1H, d, J=8.1Hz), LCMS (Method A) m/z: M−1 obs 280.0, tR=3.20 min.
Step-2: 2,2,2-trifluoro-1-(1-methyl-6-(trifluoromethyl)-1H-indol-3-yl)ethanone
To a mixture of 2,2,2-trifluoro-1-[6-(trifluoromethyl)-1H-indol-3-yl]ethanone (200 mg, 0.71 mmol) and potassium carbonate (246 mg, 1.8 mmol) in DMF (2 mL) was added iodomethane (0.067 mL, 1.1 mmol) at room temperature. After stirring at the same temperature for 2 hours, the mixture was poured into water, and the aqueous phase was extracted with EtOAc (ethyl acetate)-hexane (2:1, twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (4:1 (v/v)) to give 195 mg (93% yield) of the title compound as a pale brown solid:
1H-NMR (300 MHz, CDCl3) δ 8.51 (1H, d, J=8.0 Hz), 8.04 (1H, s), 7.70 (1H, s), 7.64 (1H, d, J=8.1Hz), 3.99 (3H, s), LCMS (Method A) m/z: M+1 obs 296.0, tR=3.32 min.
Step-3: 1-methyl-6-(trifluoromethyl)-1H-indole-3-carboxylic acid
A mixture of 2,2,2-trifluoro-1-(1-methyl-6-(trifluoromethyl)-1H-indol-3-yl)ethanone (195 mg, 0.66 mmol) and 20% aqueous sodium hydroxide solution (5 mL) was refluxed with stirring for 10 hours. After cooling to room temperature, the mixture was poured into 1 M hydrochloric acid, and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residual solid was washed with 2-propanol to give 107 mg (67% yield) of the title compound as a pale orange solid:
1H-NMR (300 MHz, DMSO-d6) δ 12.25 (1H, s), 8.26 (1H, s), 8.18 (1H, d, J=8.8 Hz), 7.98 (1H, s), 7.50 (1H, d, J=8.6 Hz), 3.94 (3H, s), LCMS (Method A) m/z: M−1 obs 242.1, tR=2.84 min.
Carboxylic Acid Intermediate-5
5-(2,2,2-trifluoroethoxy)picolinic acid
Step-1: ethyl 5-(2,2,2-trifluoroethoxy)picolinate
Prepared as in Step-1 of Amine intermediate-4 from ethyl 5-hydroxypicolinate (EP1748048):
1H-NMR (300 MHz, CDCl3): δ 8.47 (1H, d, J=2.9 Hz), 8.15 (1H, d, J=8.8 Hz), 7.32 (1H, dd, J=2.9 & 8.8 Hz), 4.52-5.52 (4H, m), 1.44 (3H, t, J=7.2 Hz), LCMS (Method A) m/z: M+1 obs 250.3, tR=2.72 min.
Step-2: 5-(2,2,2-trifluoroethoxy)picolinic acid
A mixture of ethyl 5-(2,2,2-trifluoroethoxy)picolinate (253 mg, 1.0 mmol) and 2 mol/L aqueous sodium hydroxide solution (1.0 mL, 2.0 mmol) in methanol (5 mL) was stirred at room temperature for 4 h. Then, methanol was removed in vacuo. To the residue were added water (2 mL) and 2 mol/L hydrochloric acid (pH ̃4). The formed precipitate was collected by filtration to give 118 mg (52% yield) of the title compound as a gray solid:
1H-NMR (300 MHz, CDCl3): δ 8.49 (1H, d, J=2.9 Hz), 8.06 (1H, d, J=8.8 Hz), 7.66 (1H, dd, J=2.9 & 8.8 Hz), 4.99 (2H, q, J=8.8 Hz) (a signal due to COOH was not observed), LCMS (Method A) m/z: M+1 obs 222.3, tR=1.59 min.
Carboxylic Acid Intermediate-6 trans-2-(1-methyl-1H-indol-3-yl)cyclopropanecarboxylic acid
Step-1: ethyl trans-2-(1-methyl-1H-indol-3-yl)cyclopropanecarboxylate
To a suspension of sodium hydride (ca 60%, 21 mg, 0.52 mmol) in DMSO (1 mL) was added trimethylsulfoxonium iodide (115 mg, 0.52 mmol), and the mixture was stirred at room temperature for 20 minutes. Then, ethyl (E)-3-(1-methyl-1H-indol-3-yl)acrylate (Synlett, (9), 1319-1322 (2006)) (100 mg, 0.44 mmol) was added to the mixture, and the mixture was stirred at room temperature for 1 hour and at 60° C. for 20 hours. After cooling to room temperature, the mixture was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over Magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (7:1) to give 23 mg (21% yield) of the title compound as a pale yellow oil:
1H-NMR (300 MHz, CDCl3): δ 7.65 (1H, d, J=8.0 Hz), 7.30-7,19 (2H, m), 7.16-7.07 (1H, m), 6.79 (1H, s), 4.20 (2H, q, J=8.0 Hz), 3.71 (3H, s), 2.65-2.55 (1H, m), 1.91-1.82 (1H, m), 1.61-1.51 (1H, m), 1.30 (3H, t, J=8.0 Hz), 1.35-1.25 (1H, m), LCMS (Method A) m/z: M+1 obs 244.4, tR=3.22 min.
Step-2: trans-2-(1-methyl-1H-indol-3-yl)cyclopropanecarboxylic acid
A mixture of ethyl trans-2-(1-methyl-1H-indol-3-yl)cyclopropanecarboxylate (20 mg, 0.082 mmol) and 2 mol/L aqueous sodium hydroxide solution (0.20 mL, 0.40 mmol) in methanol (3 mL) was stirred at 60° C. for 3 hours. After cooling to room temperature, 2 mol/L hydrochloric acid (0.20 mL, 0.40 mmol) was added, and the solvent was removed in vacuo. To the residue was added THF (2 mL) and filtered off. The filtrate was concentrated in vacuo to give 25 mg of the title compound as a pale yellow oil. This was used for the next step without purification:
1H-NMR (300 MHz, CDCl3): δ 7.68 (1H, d, J=8.8 Hz), 7.31-7.20 (2H, m), 7.18-7.09 (1H, m), 6.82 (1H, s), 3.73 (3H, s), 2.75-2.64 (1H, m), 1.90-1.80 (1H, m), 1.69-1.60 (1H, m), 1.45-1.35 (1H, m), LCMS (Method A) m/z: M+1 obs 216.4, tR=2.72 min.
Carboxylic Acid Intermediate-7
trans-2-(7-fluoro-1H-indol-3-yl)cyclopropanecarboxylic acid
Step-1: ethyl (E)-3-(7-fluoro-1-tosyl-1H-indol-3-yl)acrylate
To a suspension of sodium hydride (ca 60%, 240 mg, 6.3 mmol) in THF (10 mL) was added dropwise a solution of triethyl phosphonoacetate (1.33 g, 5.9 mmol) in THF (5 mL) at 0° C. After stirring at room temperature for 0.5 hour, a solution of 7-fluoro-1-tos yl-1H-indole-3-carbaldehyde (J. Med. Chem., 48 (19), 6023-6034 (2005)) (1.10 g, 3.48 mmol) in THF (5 mL) was added to the mixture at 0° C. The resulting mixture was stirred at 0° C. for 0.5 hour and at room temperature for 19 hours. The mixture was poured into water, extracted with dichloromethane, dried over sodium sulfate, filtered and concentrated in vacuo. The residual solid was washed with ethyl acetate to give 864 mg (65% yield) of the title compound as a white solid:
1H-NMR (270 MHz, CDCl3): δ 8.03 (1H, s), 7.85-7.75 (3H, m), 7.57 (1H, d, J=7.6 Hz), 7.31-7.15 (3H, m), 6.99 (1H, dd, J=8.2 & 12.2 Hz), 6.50 (1H, d, J=16.1Hz), 4.27 (2H, q, J=7.2 Hz), 2.37 (3H, s), 1.33 (3H, t, J=7.2 Hz).
Step-2: ethyl trans-2-(7-fluoro-1-tos yl-1H-indol-3-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from ethyl (E)-3-(7-fluoro-1-tosyl-1H-indol-3-yl)acrylate:
1H-NMR (270 MHz, CDCl3): δ 7.78 (2H, d, J=7.6 Hz), 7.45 (1H, s), 7.34 (1H, d, J=6.9 Hz), 7.28-7.22 (2H, m), 7.13 (1H, dt, J=4.3 & 7.9 Hz), 6.94 (1H, dd, J=7.9 & 12.2 Hz), 4.19 (2H, q, J=7.3 Hz), 2.51-2.42 (1H, m), 2.36 (3H, s), 1.92-1.84 (1H, m), 1.61-1.52 (1H, m), 1.30 (3H, t, J=7.3 Hz), 1.33-1.20 (1H, m).
Step-3: trans-2-(7-fluoro-1H-indol-3-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl trans-2-(7-fluoro-1-tos yl-1H-indol-3-yl)cyclopropanecarboxylate:
1H-NMR (300 MHz, CDCl3): δ 8.16 (1H, brs), 7.44 (1H, d, J=8.0 Hz), 7.1-6.8 (3H, m), 2.71-2.59 (1H, m), 1.95-1.85 (1H, m), 1.70-1.60 (1H, m), 1.48-1.35 (1H, m) (a signal due to COOH was not observed), LCMS (Method A) m/z: M+1 obs 220.3, tR=2.57 min.
Carboxylic Acid Intermediate-8
trans-2-(5-fluoro-1H-indol-3-yl)cyclopropanecarboxylic acid
Step-1: ethyl(E)-3-(5-fluoro-1-tosyl-1H-indol-3-yl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate-7 from 5-fluoro-1-tosyl-1H-indole-3-carbaldehyde (J. Med. Chem., 41 (25), 4995-5001 (1998)):
1H-NMR (270 MHz, CDCl3): δ 7.95 (1H, dd, J=4.6 & 9.2 Hz), 7.86 (1H, s), 7.79-7.68 (3H, m), 7.44 (1H, dd, J=2.6 & 8.6 Hz), 7.29-7.24 (2H, m), 7.11 (1H, dt, J=2.6 & 8.6 Hz), 6.43 (1H, d, J=16.5 Hz), 4.27 (2H, q, J=7.2 Hz), 2.37 (3H, s), 1.35 (3H, t, J=7.2 Hz), LCMS (Method A) m/z: M+1 obs 388.2, tR=3.52 min.
Step-2: ethyl trans-2-(5-fluoro-1-tosyl-1H-indol-3-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from ethyl (E)-3-(5-fluoro-1-tosyl-1H-indol-3-yl)acrylate:
1H-NMR (300 MHz, CDCl3): δ 7.93-7.86 (1H, m), 7.71 (2H, d, J=9.5 Hz), 7.30-7.17 (4H, m), 7.09-7.00 (1H, m), 4.20 (2H, q, J=7.3 Hz), 2.46-2.35 (1H, m), 2.35 (3H, s), 1.88-1.80 (1H, m), 1.63-1.55 (1H, m), 1.31 (3H, t, J=7.3 Hz), 1.30-1.20 (1H, m)., LCMS (Method A) m/z: M+1 obs 402.3, tR=3.54 min.
Step-3: trans-2-(5-fluoro-1H-indol-3-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl trans-2-(5-fluoro-1-tosyl-1H-indol-3-yl)cyclopropanecarboxylate:
1H-NMR (300 MHz, DMSO-d6): δ 11.00 (1H, brs), 7.36-7.22 (3H, m), 6.98-6.88 (1H, m), 2.43-2.33 (1H, m), 1.75-1.67 (1H, m), 1.42-1.28 (2H, m) (a signal due to COON was not observed), LCMS (Method A) m/z: M+1 obs 220.3, tR=2.59 min.
Carboxylic Acid Intermediate-9
trans-2-(1H-indol-6-yl)cyclopropanecarboxylic acid
Step-1: ethyl(E)-3-(1-tosyl-1H-indol-6-yl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate 7 from 1-tosyl-1H-indole-6-carbaldehyde.
1H-NMR (300 MHz, CDCl3) δ 8.13 (1H, s), 7.90-7.75 (3H, m), 7.62 (1H, d, J=3.7 Hz), 7.52 (1H, d, J=8.8 Hz), 7.43 (1H, d, J=8.8 Hz), 7.24 (2H, d, J=8.1Hz), 6.66 (1H, d, J=3.7 Hz), 6.49 (1H, d, J=16.1Hz), 4.29 (2H, q, J=7.3 Hz), 2.35 (3H, s), 1.37 (3H, t, J=7.3 Hz), LCMS (Method A) m/z: M+1 obs 370.2, tR=3.44 min.
Step-2: ethyl trans-2-(1-tosyl-1H-indol-6-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from ethyl(E)-3-(1-tosyl-1H-indol-6-yl)acrylate.
1H-NMR (300 MHz, CDCl3) δ 7.76 (2H, d, J=8.1Hz), 7.76 (1H, s), 7.53 (1H, d, J=3.7 Hz), 7.43 (1H, d, J=8.1Hz), 7.25 (2H, d, J=8.1Hz), 6.97 (1H, dd, J=8.1, 1.5 Hz), 6.62 (1H, d, J=3.7 Hz), 4.21 (2H, q, J=7.3 Hz), 2.67 (1H, m), 2.37 (3H, s), 1.95 (1H, m), 1.67 (1H, m), 1.39 (1H, m), 1.32 (3H, t, J=7.3 Hz), LCMS (Method A) m/z: M+1 obs 384., tR=3.44 min.
Step-3: trans-2-(1H-indol-6-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl trans-2-(1-tosyl-1H-indol-6-yl)cyclopropanecarboxylate.
1H-NMR (300 MHz, DMSO-d6) δ 11.00 (1H, s), 7.44 (1H, d, J=8.0 Hz), 7.29 (1H, t, J=2.2 Hz), 7.18 (1H, s), 6.79 (1H, d, J=8.1Hz), 6.37 (1H, m), 2.50 (1H, m), 1.78 (1H, m), 1.48-1.30 (2H, m), LCMS (Method A) m/z: M−1 obs 200.3, tR=2.52 min.
Carboxylic Acid Intermediate-10
trans-2-(5-cyano-1H-indol-3-yl)cyclopropanecarboxylic acid
Step-1: ethyl(E)-3-(5-cyano-1-tosyl-1H-indol-3-yl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate 7 from 3-formyl-1-tosyl-1H-indole-5-carbonitrile.
1H-NMR (300 MHz, CDCl3) δ 8.14 (1H, s), 8.11 (1H, d, J=8.8 Hz), 7.94 (1H, s), 7.81 (2H, d, J=8.1Hz), 7.74 (1H, d, J=16.1Hz), 7.63 (1H, dd, J=8.8, 1.5 Hz), 7.30 (2H, d, J=8.0 Hz), 6.49 (1H, d, J=16.1Hz), 4.29 (2H, q, J=6.6 Hz), 2.39 (3H, s), 1.36 (3H, t, J=6.6 Hz), LCMS (Method A) m/z: M+1 obs 395.2, tR=3.40 min.
Step-2: trans-2-(5-cyano-1H-indol-3-yl)cyclopropanecarboxylic acid
Prepared as in Step-1 of Carboxylic acid intermediate 6 and in Step-2 of Carboxylic acid intermediate 6 from ethyl(E)-3-(5-cyano-1-tosyl-1H-indol-3-yl)acrylate. LCMS (Method A) m/z: M+1 obs 227.3, tR=2.39 min.
Carboxylic Acid Intermediate-11
trans-2-(1H-indol-7-yl)cyclopropanecarboxylic acid
Step-1:1-tosyl-1H-indole-7-carbaldehyde
To a suspension of sodium hydride (240 mg, 5.9 mmol) in THF (10 mL) was added 1H-indole-7-carbaldehyde (570 mg, 3.9 mmol) at room temperature. After being stirred at room temperature for 20 min, 4-methylbenzene-1-sulfonyl chloride (1.1 g, 5.9 mmol) was added to the mixture. The mixture was stirred at room temperature for 1 hour. The mixture was poured into saturated ammonium chloride aqueous solution, and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (4:1 (v/v)) to give 1.0 g (89% yield) of the title compound as a white solid:
1H-NMR (300 MHz, CDCl3) δ 10.73 (1H, s), 7.82 (1H, d, J=8.8 Hz), 7.75-7.65 (2H, m), 7.47 (2H, d, J=8.8 Hz), 7.38 (1H, t, J=8.3 Hz), 7.17 (2H, d, J=8.8 Hz), 6.79 (1H, d, J=3.7 Hz), 2.34 (3H, s), LCMS (Method A) m/z: M+1 obs 300.2, tR=3.15 min.
Step-2: ethyl(E)-3-(1-tosyl-1H-indol-7-yl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate 7 from 1-tosyl-1H-indole-7-carbaldehyde.
1H-NMR (300 MHz, CDCl3) δ 8.64 (1H, d, J=15.4 Hz), 7.84 (1H, d, J=3.7 Hz), 7.65-7.55 (3H, m), 7.34 (1H, d, J=7.3 Hz), 7.26-7.10 (3H, m), 6.72 (1H, d, J=4.4 Hz), 6.10 (1H, d, J=15.4 Hz), 4.32 (2H, q, J=7.3 Hz), 2.34 (3H, s), 1.41 (3H, t, J=7.3 Hz), LCMS (Method A) m/z: M+1 obs 370.3, tR=3.40 min.
Step-3: ethyl trans-2-(1-tosyl-1H-indol-7-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from (E)-ethyl 3-(1-tosyl-1H-indol-7-yl)acrylate.
1H-NMR (300 MHz, CDCl3) δ 7.75 (1H, d, J=3.7 Hz), 7.54 (2H, d, J=8.1Hz), 7.38 (1H, d, J=8.9 Hz), 7.21-7.10 (3H, m), 6.91 (1H, d, J=8.0 Hz), 6.67 (1H, d, J=3.7 Hz), 4.29-4.19 (2H, m), 3.17 (1H, m), 2.34 (3H, s), 1.92 (1H, m), 1.48 (1H, m), 1.33 (3H, t, J=6.6 Hz), 1.24 (1H, m), LCMS (Method A) m/z: M+1 obs 384.2, tR=3.42 min.
Step-4: trans-2-(1H-indol-7-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate 6 from ethyl trans-2-(1-tosyl-1H-indol-7-yl)cyclopropanecarboxylate.
1H-NMR (300 MHz, DMSO-d6) δ 11.31 (1H, s), 7.39 (1H, d, J=8.1Hz), 7.33 (1H, t, J=1.5 Hz), 6.91 (1H, t, J=7.3 Hz), 6.68 (1H, d, J=7.3 Hz), 6.44 (1H, t, J=1.5 Hz), 2.79 (1H, m), 1.88 (1H, m), 1.51 (1H, m), 1.34 (1H, m), LCMS (Method A) m/z: M−1 obs 200.3, tR=2.62 min.
Carboxylic Acid Intermediate-12
trans-2-(1H-indol-2-yl)cyclopropanecarboxylic acid
Step-1: ethyl(E)-3-(1-tosyl-1H-indol-2-yl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate-7 from 1-tosyl-1H-indole-2-carbaldehyde (Heterocycles, 76(2), 1155-1170; 2008).
1H-NMR (300 MHz, CDCl3) δ 8.37 (1H, d, J=16.1Hz), 8.22 (1H, d, J=8.4 Hz), 7.62 (2H, d, J=8.4 Hz), 7.48 (1H, d, J=8.1Hz), 7.36 (1H, dt, J=7.3, 1.1Hz), 7.26 (1H, m), 7.16 (2H, d, J=8.1Hz), 6.96 (1H, s), 6.36 (1H, d, J=16.1Hz), 4.30 (2H, q, J=7.3 Hz), 2.32 (3H, s), 1.37 (3H, t, J=7.3 Hz).
Step-2: ethyl trans-2-(1-tosyl-1H-indol-2-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from ethyl(E)-3-(1-tosyl-1H-indol-2-yl)acrylate:
1H-NMR (300 MHz, CDCl3) δ 8.20 (1H, d, J=8.1Hz), 7.73 (2H, d, J=8.1Hz), 7.42-7.19 (5H, m), 6.28 (1H, s), 4.28-4.11 (2H, m), 2.93 (1H, m), 2.34 (3H, s), 1.82 (1H, m), 1.62 (1H, m), 1.35-1.22 (4H, m).
Step-3: trans-2-(1H-indol-2-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl trans-2-(1-tosyl-1H-indol-2-yl)cyclopropanecarboxylate:
1H-NMR (300 MHz, CDCl3) δ 8.04 (1H, s), 7.49 (1H, d, J=7.3 Hz), 7.23 (1H, d, J=8.8 Hz), 7.10 (2H, m), 6.14 (1H, s), 2.60 (1H, m), 1.92 (1H, m), 1.62 (1H, m), 1.41 (1H, m), LCMS (Method A) m/z: M+1 obs 202.3, tR=2.59 min.
Carboxylic Acid Intermediate-13
trans-2-(5-fluoro-1H-indol-2-yl)cyclopropanecarboxylic acid
Step-1: 5-fluoro-N-methoxy-N-methyl-1H-indole-2-carboxamide
N,O-dimethylhydroxylamine hydrochloride (1.089 g, 11.16 mmol) and triethylamine (3.92 ml, 27.9 mmol) were added to a solution of 5-fluoro-1H-indole-2-carboxylic acid (2.0 g, 11.16 mmol) in dichloromethane(30 mL) and stirred at room temperature for 5 min. Then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.140 g, 11.16 mmol) was added and stirred for 20 hours. After reaction, solvent was removed. The residue was suspended in minimum volume of acetone and the insoluble white solid was removed by filtration. After being concentrated in vacuo, the mixture was poured into saturated sodium bicarbonate aqueous solution, and the aqueous phase was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to give 690 mg (28% yield) of the title compound as a white crystal:
1H-NMR (300 MHz, DMSO-d6) δ 11.6 (1H, s), 7.44 (1H, m), 7.38 (1H, d, J=2.6 Hz), 7.12 (1H, d, J=1.5 Hz), 7.06 (1H, dt, J=9.5, 2.6 Hz), 3.78 (3H, s), 3.32 (3H, s).
Step-2: 5-fluoro-1H-indole-2-carbaldehyde
Lithium aluminium hydride (0.094 g, 2.488 mmol) was added to a solution of 5-fluoro-N-methoxy-N-methyl-1H-indole-2-carboxamide (0.691 g, 3.11 mmol) in tetrahydrofuran (10 ml) at 0° C. and stirred for 1 hour. The reaction mixture was cooled to 0° C. and 25% ammonia solution was added dropwise to the reaction mixture until lithium aluminium hydride color turn gray to white. Then dichloromethane and cerite was added to the reaction mixture and stirred for 30 min. The mixture was filtered through a pad of Celite and concentrated in vacuo to give 523 mg of the crude title compound. This was used for the next step without further purification:
1H-NMR (300 MHz, CDCl3) δ 9.85 (1H, s), 9.13 (1H, brs), 7.42-7.36 (2H, m), 7.24 (1H, d, J=1.1Hz), 7.16 (1H, dt, J=9.2, 2.6 Hz).
Step-3: 5-fluoro-1-tosyl-1H-indole-2-carbaldehyde
p-Toluenesulfonyl chloride (2.445 g, 12.82 mmol), N,N-dimethyl-4-aminopyridine (0.196 g, 1.603 mmol) and triethylamine (2.253 ml, 16.03 mmol) were added to a solution of 5-fluoro-1H-indole-2-carbaldehyde (0.523 g, 3.21 mmol) in dichloromethane (10 ml) and stirred at room temperature for 20 hours. After reaction, the mixture was poured into saturated sodium bicarbonate aqueous solution, and the aqueous phase was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (10:1) to give 823 mg (81% yield) of the title compound as a white crystal:
1H-NMR (300 MHz, CDCl3) δ 10.5 (1H, s), 8.20 (1H, dd, J=10.0, 4.2 Hz), 7.62 (2H, d, J=8.4 Hz), 7.40 (1H, s), 7.29-7.19 (4H, m), 2.34 (3H, s).
Step-4: ethyl(E)-3-(5-fluoro-1-tosyl-1H-indol-2-yl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate-7 from 5-fluoro-1-tosyl-1H-indole-2-carbaldehyde.
1H-NMR (300 MHz, CDCl3) δ 8.33 (1H, d, J=16.1Hz), 8.17 (1H, dd, J=9.2, 4.4 Hz), 7.59 (2H, d, J=8.4 Hz), 7.19-7.05 (4H, m), 6.90 (1H, s), 6.35 (1H, d, J=16.1Hz), 4.30 (2H, q, J=7.3 Hz), 2.33 (3H, s), 1.37 (3H, t, J=7.3 Hz).
Step-5: ethyl trans-2-(5-fluoro-1-tosyl-1H-indol-2-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from ethyl (E)-3-(5-fluoro-1-tosyl-1H-indol-2-yl)acrylate.
1H-NMR (300 MHz, CDCl3) δ 8.14 (1H, dd, J=8.8, 4.4 Hz), 7.69 (2H, d, J=8.1Hz), 7.21 (2H, d, J=8.1Hz), 7.07-6.98 (2H, m), 6.23 (1H, s), 4.23 (2H, m), 2.91 (1H, m), 2.35 (3H, s), 1.82 (1H, m), 1.62 (1H, m), 1.32 (3H, t, J=7.3 Hz), 1.28 (1H, m).
Step-6: trans-2-(5-fluoro-1H-indol-2-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl trans-2-(5-fluoro-1-tosyl-1H-indol-2-yl)cyclopropanecarboxylate.
1H-NMR (300 MHz, DMSO-d6) 11.1 (1H, s), 7.21 (1H, dd, J=8.8, 4.8 Hz), 7.10 (1H, dd, J=10.3, 2.6 Hz), 6.81 (1H, dt, J=8.8, 2.6 Hz), 6.18 (1H, d, J=1.8 Hz), 2.48 (1H, m), 1.87 (1H, m), 1.42 (2H, m), LCMS (Method A) m/z: M+1 obs 220.3, tR=2.64 min.
Carboxylic Acid Intermediate-14
trans-2-(4-fluoro-1H-indol-3-yl)cyclopropanecarboxylic acid
Step-1: ethyl(E)-3-(4-fluoro-1-tosyl-1H-indol-3-yl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate-7 from 4-fluoro-1-tosyl-1H-indole-3-carbaldehyde.
1H-NMR (270 MHz, CDCl3): δ 7.88-7.72 (5H, m), 7.32-7.20 (3H, m), 6.95 (1H, dd, J=8.2 & 10.9 Hz), 6.48 (1H, d, J=16.1Hz), 4.24 (2H, q, J=7.2 Hz), 2.35 (3H, s), 1.32 (3H, t, J=7.2 Hz).
Step-2: ethyl trans-2-(4-fluoro-1-tosyl-1H-indol-3-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from ethyl (E)-3-(4-fluoro-1-tosyl-1H-indol-3-yl)acrylate.
1H-NMR (300 MHz, CDCl3): δ 7.77-7.70 (3H, m), 7.6-7.3 (4H, m), 6.95-6.86 (1H, m), 4.18 (2H, q, J=7.3 Hz), 2.72-2.62 (1H, m), 2.36 (3H, s), 1.87-1.79 (1H, m), 1.65-1.55 (1H, m), 1.35-1.25 (1H, m), 1.29 (3H, t, J=7.3 Hz).
Step-3: trans-2-(4-fluoro-1H-indol-3-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl trans-2-(4-fluoro-1-tosyl-1H-indol-3-yl)cyclopropanecarboxylate LCMS (Method A) m/z: M−1 obs 218.3, tR=2.52 min.
Carboxylic Acid Intermediate-15
trans-2-(quinolin-2-yl)cyclopropanecarboxylic acid
Step-1: ethyl trans-2-(quinolin-2-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from (E)-ethyl 3-(quinolin-2-yl)acrylate.
1H-NMR (300 MHz, CDCl3): δ 8.04 (1H, d, J=8.8 Hz), 7.93 (1H, d, J=8.1Hz), 7.75 (1H, d, J=8.1Hz), 7.65 (1H, t, J=8.1Hz), 7.46 (1H, t, J=8.1Hz), 7.33 (1H, d, J=8.8 Hz), 4.18 (2H, d, J=7.3 Hz), 2.80-2.73 (1H, m), 2.47-2.40 (1H, m), 1.82-1.75 (1H, m), 1.71-1.64 (1H, m), 1.29 (3H, t, J=7.3 Hz), LCMS (Method A) m/z: M+1 obs 242.2, tR=3.09 min.
Step-2: trans-2-(quinolin-2-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl trans-2-(quinolin-2-yl)cyclopropanecarboxylate.
1H-NMR (300 MHz, DMSO-d6): δ 8.27 (1H, d, J=8.8 Hz), 7.94 (1H, d, J=8.0 Hz), 7.87 (1H, d, J=8.0 Hz), 7.70 (1H, t, J=8.0 Hz), 7.58 (1H, d, J=8.8 Hz), 7.52 (1H, t, J=8.0 Hz), 2.75 (1H, br), 2.20 (1H, br), 1.68-1.48 (2H, m) (a signal due to COON was not observed), LCMS (Method A) m/z: M−1 obs 212.2, tR=2.27 min.
Carboxylic Acid Intermediate-16 trans-2-(1H-indazol-3-yl)cyclopropanecarboxylic acid
Step-1: methyl(E)-3-(1-tosyl-1H-indazol-3-yl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate-11 from methyl (E)-3-(1H-indazol-3-yl)acrylate.
1H-NMR (300 MHz, CDCl3) δ 8.25 (1H, d, J=8.8 Hz), 7.93-7.84 (4H, m), 7.60 (1H, t, J=7.7 Hz), 7.41 (1H, t, J=7.7 Hz), 7.30-7.24 (2H, m), 6.87 (1H, d, J=16.8 Hz), 3.84 (3H, s), 2.37 (3H, s), LCMS (Method A) m/z: M+1 obs 357.2, tR=3.32 min.
Step-2: methyl trans-2-(1-tosyl-1H-indazol-3-yl)cyclopropanecarboxylate
Prepared as in Stepl of Carboxylic acid intermediate-6 from methyl (E)-3-(1-tosyl-1H-indazol-3-yl)acrylate.
1H-NMR (300 MHz, CDCl3) δ 8.16 (1H, d, J=8.0 Hz), 7.79 (2H, d, J=8.0 Hz), 7.69 (1H, d, J=8.0 Hz), 7.55 (1H, t, J=8.0 Hz), 7.33 (1H, t, J=8.0 Hz), 7.22 (2H, d, J=8.0 Hz), 3.73 (3H, s), 2.80-2.70 (1H, m), 2.35 (3H, s), 2.33-2.27 (1H, m), 1.72-1.62 (2H, m), LCMS (Method A) m/z: M+1 obs 371.2, tR=3.25 min.
Step-3: trans-2-(1H-indazol-3-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from methyl trans-2-(1-tosyl-1H-indazol-3-yl)cyclopropanecarboxylate.
1H-NMR (300 MHz, DMSO-d6) δ 12.75 (1H, br), 7.78 (1H, d, J=8.0 Hz), 7.46 (1H, d, J=8.0 Hz), 7.33 (1H, t, J=8.0 Hz), 7.09 (1H, t, J=8.0 Hz), 2.77-2.65 (1H, m), 2.08-2.00 (1H, m), 1.58-1.47 (2H, m), LCMS (Method A) m/z: M−1 obs 201.3, tR=2.29 min.
Carboxylic Acid Intermediate-17
trans-2-(quinolin-7-yl)cyclopropanecarboxylic acid
Step-1: ethyl(E)-3-(quinolin-7-yl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate-7 from quinoline-7-carbaldehyde.
1H-NMR (300 MHz, CDCl3) δ 8.95 (1H, d, J=4.4 Hz), 8.20 (1H, s), 8.15 (1H, d, J=8.8 Hz), 7.87 (1H, d, J=16.1Hz), 7.83 (1H, d, J=8.8 Hz), 7.73 (1H, d, J=8.8 Hz), 7.42 (1H, dd, J=4.4 & 8.0 Hz), 6.62 (1h, d, J=16.1Hz), 4.31 (2H, q, J=7.3 Hz), 1.37 (3H, t, J=7.3 Hz), LCMS (Method A) m/z: M+1 obs 228.3, tR=2.82 min.
Step-2: ethyl trans-2-(quinolin-7-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from ethyl (E)-3-(quinolin-7-yl)acrylate.
1H-NMR (300 MHz, CDCl3) 8*8.91-8.85 (1H, m), 8.11 (1H, d, J=8.8 Hz), 7.80 (1H, s), 7.74 (1H, d, J=8.8 Hz), 7.40-7.30 (2H, m), 4.19 (2H, q, J=8.0 Hz), 2.76-2.67 (1H, m), 2.10-2.02 (1H, m), 1.76-1.68 (1H, m), 1.54-1.45 (1H, m), 1.30 (3H, t, J=8.0 Hz), LCMS (Method A) m/z: M+1 obs 242.3, tR=2.79 min.
Step-3: trans-2-(quinolin-7-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl trans-2-(quinolin-7-yl)cyclopropanecarboxylate.
1H-NMR (300 MHz, DMSO-d6) δ 8.86 (1H, d, J=4.4 Hz), 8.31 (1H, d, J=8.8 Hz), 7.90 (1H, d, J=9.5 Hz), 7.81 (1H, s), 7.46 (1H, dd, J=4.4 & 8.8 Hz), 7.40 (1H, d, J=9.5 Hz), 2.66-2.58 (1H, m), 2.03-1.95 (1H, m), 1.57-1.50 (2H, m) (a signal due to COOH was not observed), LCMS (Method A) m/z: M−1 obs 212.3, tR=2.13 min.
Carboxylic Acid Intermediate-18
trans-2-(1-methyl-1H-indol-6-yl)cyclopropanecarboxylic acid
Step-1: ethyl(E)-3-(1-methyl-1H-indol-6-yl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate-7 from 1-methyl-1H-indole-6-carbaldehyde.
1H-NMR (300 MHz, CDCl3) δ 7.85 (1H, d, J=15.4 Hz), 7.60 (1H, d, J=8.0 Hz), 7.47 (1H, s), 7.34 (1H, d, J=8.0 Hz), 7.13 (1H, d, J=2.9 Hz), 6.49 (1H, d, J=2.9 Hz), 6.47 (1H, d, J=15.4 Hz), 4.27 (2H, q, J=7.3 Hz), 3.82 (3H, s), 1.35 (3H, t, J=7.3 Hz), LCMS (Method A) m/z: M+1 obs 230.3, tR=3.15 min.
Step-2: ethyl trans-2-(1-methyl-1H-indol-6-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from ethyl (E)-3-(1-methyl-1H-indol-6-yl)acrylate.
1H-NMR (300 MHz, CDCl3) δ 7.52 (1H, d, J=8.1Hz), 7.08 (1H, s), 7.00 (1H, d, J=2.9 Hz), 6.86 (1H, d, J=8.1Hz), 6.43 (1H, d, J=2.9 Hz), 4.18 (2H, q, J=7.4 Hz), 3.76 (3H, s), 2.72-2.63 (1H, m), 1.99-1.90 (1H, m), 1.66-1.59 (1H, m), 1.44-1.35 (1H, m), 1.29 (3H, t, J=7.4 Hz), LCMS (Method A) m/z: M+1 obs 244.3, tR=3.17 min.
Step-3: trans-2-(1-methyl-1H-indol-6-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl trans-2-(1-methyl-1H-indol-6-yl)cyclopropanecarboxylate.
1H-NMR (300 MHz, DMSO-d6) δ12.2 (1H, br), 7.42 (1H, d, J=8.1Hz), 7.26-7.20 (2H, m), 6.82 (1H, d, J=8.0 Hz), 6.35 (1H, d, J=2.9 Hz), 3.75 (3H, s), 2.50-2.44 (1H, m), 1.85-1.77 (1H, m), 1.47-1.38 (2H, m), LCMS (Method A) m/z: M−1 obs 214.2, tR=2.67 min.
Carboxylic Acid Intermediate-19
trans-2-(6-fluoro-1H-indol-3-yl)cyclopropanecarboxylic acid
Step-1: ethyl(E)-3-(6-fluoro-1-tosyl-1H-indol-3-yl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate-7 from 6-fluoro-1-tosyl-1H-indole-3-carbaldehyde.
1H-NMR (300 MHz, CDCl3) δ 7.82-7.70 (6H, m), 7.34-7.25 (2H, m), 7.08 (1H, t, J=8.8 Hz), 6.48 (1H, d, J=16.1Hz), 4.27 (2H, q, J=7.3 Hz), 2.38 (3H, s), 1.34 (3H, t, J=7.3 Hz), LCMS (Method A) m/z: M+1 obs 388.2, tR=3.57 min.
Step-2: ethyl trans-2-(6-fluoro-1-tosyl-1H-indol-3-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from ethyl (E)-3-(6-fluoro-1-tosyl-1H-indol-3-yl)acrylate.
1H-NMR (300 MHz, CDCl3) δ 7.73 (2H, d, J=8.0 Hz), 7.68 (1H, dd, J=2.2 & 9.5 Hz), 7.47 (1H, dd, J=5.1 & 8.8 Hz), 7.28-7.22 (2H, m), 7.00 (1H, dt, J=2.2 & 8.8 Hz), 4.19 (2H, q, J=7.3 Hz), 2.50-2.40 (1H, m), 2.36 (3H, s), 1.87-1.80 (1H, m), 1.61-1.53 (1H, m), 1.31 (3H, t, J=7.3 Hz), 1.28-1.21 (1H, m), LCMS (Method A) m/z: M+1 obs 402.2, tR=3.48 min.
Step-3: trans-2-(6-fluoro-1H-indol-3-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl trans-2-(6-fluoro-1-tosyl-1H-indol-3-yl)cyclopropanecarboxylate.
LCMS (Method A) m/z: M−1 obs 218.3, tR=2.54 min.
Carboxylic Acid Intermediate-20
trans-2-((4-chlorophenoxy)methyl)cyclopropanecarboxylic acid
Step-1: ethyl trans-2-((4-chlorophenoxy)methyl)cyclopropanecarboxylate
To a suspension of sodium hydride (60%, 650 mg, 16.3 mmol) in toluene (25 mL) was added dropwise a solution of triethyl phosphonoacetate (3.64 g, 16.3 mmol) in toluene (5 mL) at 0° C. After stirring at room temprtature for 10 min, 2-((4-chlorophenoxy)methyl)oxirane (1.50 g, 8.1 mmol) was added, and the mixture was refluxed with stirring for 1 day. After cooling to room temperature, the mixture was poured into brine, and the aqueous layer was extracted with EtOAc twice. The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (10:1-5:1) to give 1.25 g (60%) of the title compound as a colorless oil.
1H-NMR (300 MHz, CDCl3) δ 7.22 (2H, d, J=8.8 Hz), 6.80 (2H, d, J=8.8 Hz), 4.15 (2H, q, J=7.3 Hz), 3.92 (1H, dd, J=6.6 & 10.2 Hz), 3.83 (1H, dd, J=6.6 & 10.2 Hz), 1.93-1.82 (1H, m), 1.71-1.65 (1H, m), 1.27 (3H, t, J=7.3 Hz), 1.01-0.93 (1H, m), 0.90-0.76 (1H, m), LCMS (Method A) m/z: M+1 obs 255.2, tR=3.25 min.
Step-2: trans-2-((4-chlorophenoxy)methyl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from trans-2-((4-chlorophenoxy)methyl)cyclopropanecarboxylic acid.
1H-NMR (300 MHz, CDCl3) δ 7.22 (2H, d, J=8.8 Hz), 6.80 (2H, d, J=8.8 Hz), 3.96 (1H, dd, J=5.9 & 10.3 Hz), 8.81 (1H, dd, J=6.6 & 10.3 Hz), 2.00-1.90 (1H, m), 1.75-1.68 (1H, m), 1.41-1.32 (1H, m), 1.12-1.05 (1H, m) (a signal due to COOH was not observed), LCMS (Method A) m/z: M−1 obs 225.2, tR=2.80 min.
Carboxylic Acid Intermediate-21
trans-2-(isoquinolin-3-yl)cyclopropanecarboxylic acid
Step-1: ethyl (E)-3-(isoquinolin-3-yl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate-7 from isoquinoline-3-carbaldehyde.
1H-NMR (300 MHz, CDC13) δ 9.25 (1H, s), 7.99 (1H, d, J=8.0 Hz), 7.85 (1H, d, J=7.3 Hz), 7.83 (1H, d, J=15. 4 Hz), 7.75-7.62 (3H, m), 7.19 (1H, d, J=15.4 Hz), 4.29 (2H, q, J=6.6 Hz), 1.35 (3H, t, J=6.6Hz), LCMS (Method A) m/z: M+1 obs 228.2, tR=2.99 min.
Step-2: ethyl trans-2-(isoquinolin-3-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from ethyl (E)-3-(isoquinolin-3-yl)acrylate.
1H-NMR (300 MHz, CDCl3) δ 9.11 (1H, s), 7.92 (1H, d, J=8.0 Hz), 7.75 (1H, d, J=7.4 Hz), 7.66 (1H, m), 7.58 (1H, s), 7.53 (1H, m), 4.19 (2H, q, J=6.6 Hz), 2.76 (1H, m), 2.33 (1H, m), 1.77-1.63 (2H, m), 1.29 (3H, t, J=6.6 Hz).
Step-3: trans-2-(isoquinolin-3-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl trans-2-(isoquinolin-3-yl)cyclopropanecarboxylate.
LCMS (Method A) m/z: M+1 obs 214.3, tR=2.40 min.
Carboxylic Acid Intermediate-22
trans-2-(quinolin-3-yl)cyclopropanecarboxylic acid
Step-1: ethyl trans-2-(quinolin-3-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from ethyl (E)-3-(quinolin-3-yl)acrylate.
1H-NMR (300 MHz, CDCl3) δ 8.77 (1H, d, J=2.2 Hz), 8.08 (1H, d, J=8.8 Hz), 7.80 (1H, d, J=2.2 Hz), 7.75 (1H, dd, J=8.0, 1.5 Hz), 7.68 (1H, td, J=6.6, 1.5 Hz), 7.54 (1H, m), 4.22 (2H, q, J=7.3 Hz), 2.73 (1H, m), 2.07 (1H, m), 1.75 (1H, m), 1.46 (1H, m), 1.31 (3H, t, J=7.3 Hz), LCMS (Method A) m/z: M+1 obs 242.3, tR=2.85 min.
Step-2: trans-2-(quinolin-3-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl trans-2-(quinolin-3-yl)cyclopropanecarboxylate.
1H-NMR (300 MHz, DMSO-d6) δ 8.83 (1H, d, J=2.2 Hz), 8.10 (1H, d, J=2.2 Hz), 7.99 (1H, d, J=8.0 Hz), 7.89 (1H, d, J=7.3 Hz), 7.71 (1H, m), 7.59 (1H, t, J=8.1Hz), 2.63 (1H, m), 2.05 (1H, m), 1.55 (2H, t, J=6.6 Hz), LCMS (Method A) m/z: M+1 obs 214.3, tR=2.30 min.
Carboxylic Acid Intermediate-23
2-(3-(difluoromethoxy)phenyl)cyclopropanecarboxylic acid
Step-1: ethyl(E)-3-(3-(difluoromethoxy)phenyl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate-7 from 3-(difluoromethoxy)benzaldehyde.
1H-NMR (300 MHz, CDCl3) δ 7.95 (1H, d, J=16.1Hz), 7.62 (1H, dd, J=7.7, 1.8 Hz), 7.38 (1H, dt, J=7.7, 1.5 Hz), 7.26-7.16 (2H, m), 6.56 (1H, t, J=73 Hz), 6.48 (1H, d, J=16.1Hz), 4.27 (2H, q, J=7.0 Hz), 1.34 (3H, t, J=7.0 Hz).
Step-2: ethyl trans-2-(3-(difluoromethoxy)phenyl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from ethyl (E)-3-(3-(difluoromethoxy)phenyl)acrylate.
1H-NMR (300 MHz, CDCl3) δ 7.25-7.09 (3H, m), 6.97 (1H, dd, J=7.7, 1.8 Hz), 6.52 (1H, t, J=74 Hz), 4.19 (2H, m), 2.71 (1H, m), 1.83 (1H, m), 1.61 (1H, m), 1.31 (1H, m), 1.28 (3H, t, J=7.0 Hz).
Step-3: trans-2-(3-(difluoromethoxy)phenyl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl trans-2-(3-(difluoromethoxy)phenyl)cyclopropanecarboxylate.
LCMS (Method A) m/z: M−1 obs 228.2, tR=2.66 min.
Carboxylic Acid Intermediate-24
trans-2-(2-fluoro-5-methoxyphenyl)cyclopropanecarboxylic acid
Step-1: ethyl trans-2-(2-fluoro-5-methoxyphenyl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from ethyl (E)-3-(2-fluoro-5-methoxyphenyl)acrylate.
1H-NMR (270 MHz, CDCl3) δ 6.93 (1H, t, J=9.2 Hz), 6.66 (1H, dt, J=8.9, 3.3 Hz), 6.45 (1H, dd, J=5.9, 3.0 Hz), 4.17 (2H, q, J=7.3 Hz), 3.75 (3H, s), 2.62 (1H, m), 1.93 (1H, m), 1.58 (1H, m), 1.33 (1H, m), 1.28 (3H, t, J=7.3 Hz).
Step-2: trans-2-(2-fluoro-5-methoxyphenyl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl trans-2-(2-fluoro-5-methoxyphenyl)cyclopropanecarboxylate.
LCMS (Method A) m/z: M−1 obs 209.2, tR=2.59 min.
Carboxylic Acid Intermediate-25
trans-2-((1H-indol-1-yl)methyl)cyclopropanecarboxylic acid
Step-1: ethyl trans-2-((1H-indol-1-yl)methyl)cyclopropanecarboxylate
To a suspension of sodium hydride (60%, 55 mg, 1.4 mmol) in DMF (5 mL) was added indole (135 mg, 1.2 mmol). After stirring at room temperature for 10 min, ethyl 2-(((methylsulfonyl)oxy)methyl)cyclopropanecarboxylate (307 mg, 1.4 mmol) was added. After stirring at room temperature for 6 h, the mixture was poured into water, and the aqueous layer was extracted with EtOAc twice. The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (10:1-5:1) to give 153 mg (54%) of the title compound as a pale brown oil;
1H-NMR (300 MHz, CDCl3) δ 7.67-7.60 (1H, m), 7.42-7.09 (4H, m), 6.57-6.50 (1H, m), 4.22-4.02 (4H, m), 1.96-1.86 (1H, m), 1.69-1.62 (1H, m), 1.31-1.25 (1H, m), 1.24 (3H, t, J=7.3 Hz), 0.95-0.87 (1H, m), LCMS (Method A) m/z: M+1 obs 244.3, tR=3.17 min.
Step-2: trans-2-((1H-indol-1-yl)methyl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl trans-2-((1H-indol-1-yl)methyl)cyclopropanecarboxylate.
1H-NMR (300 MHz, CDCl3) δ 7.66-7.61 (1H, m), 7.43-7.08 (4H, m), 6.58-6.50 (1H, m), 4.20-4.06 (2H, m), 2.00-1.91 (1H, m), 1.70-1.62 (1H, m), 1.36-1.27 (1H, m), 1.01-0.94 (1H, m) (a signal due to COOH was not observed), LCMS (Method A) m/z: M−1 obs 214.3, tR=2.72 min.
Carboxylic Acid Intermediate-26
trans-2-(1-((3-methyloxetan-3-yl)methyl)-1H-indol-6-yl)cyclopropanecarboxylic acid
Step-1:1-((3-methyloxetan-3-yl)methyl)-1H-indole-6-carbaldehyde
Prepared as in Step-1 of Carboxylic acid intermediate-11 from 1H-indole-6-carbaldehyde.
1H-NMR (300 MHz, CDCl3) δ10.06 (1H, s), 7.93 (1H, s), 7.73 (1H, d, J=8.0 Hz), 7.64 (1H, d, J=8.0 Hz), 7.30 (1H, d, J=3.7 Hz), 6.63 (1H, d, J=3.7 Hz), 4.67 (2H, d, J=6.6 Hz), 4.45 (2H, s), 4.42 (2H, d, J=6.6 Hz), 1.31 (3H, s), LCMS (Method A) m/z: M+1 obs 230.2, tR=2.62 min.
Step-2: ethyl(E)-3-(1-((3-methyloxetan-3-yl)methyl)-1H-indol-6-yl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate-7 from 1-((3-methyloxetan-3-yl)methyl)-1H-indole-6-carbaldehyde.
1H-NMR (300 MHz, CDCl3) δ 7.83 (1H, d, J=16.1Hz), 7.62 (1H, d, J=8.1Hz), 7.50 (1H, s), 7.36 (1H, d, J=8.1Hz), 7.15 (1H, d, J=3.0 Hz), 6.55 (1H, d, J=3.0 Hz), 6.47 (1H, d, J=16.1Hz), 4.68 (2H, d, J=5.9 Hz), 4.43 (2H, d, J=5.9 Hz), 4.40 (2H, s), 4.29 (2H, q, J=7.4 Hz), 1.36 (3H, t, J=7.4 Hz), 1.32 (3H, s), LCMS (Method A) m/z: M+1 obs 300.2, tR=3.09 min.
Step-3: ethyl trans-2-(1-((3-methyloxetan-3-yl)methyl)-1H-indol-6-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from ethyl (E)-3-(1-((3-methyloxetan-3-yl)methyl)-1H-indol-6-yl)acrylate.
1H-NMR (300 MHz, CDCl3) δ 7.52 (1H, d, J=8.1Hz), 7.13 (1H, s), 7.01 (1H, d, J=2.9 Hz), 6.83 (1H, d, J=8.1Hz), 6.48 (1H, d, J=3.0 Hz), 4.67 (2H, d, J=6.6 Hz), 4.41 (2H, d, J=6.6 Hz), 4.34 (2H, s), 4.18 (2H, q, J=7.3 Hz), 2.67 (1H, m), 1.93 (1H, m), 1.63 (1H, m), 1.40-1.25 (7H, m), LCMS (Method A) m/z: M+1 obs 314.2, tR=3.10 min.
Step-4: trans-2-(1-((3-methyloxetan-3-yl)methyl)-1H-indol-6-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl trans-2-(1-((3-methyloxetan-3-yl)methyl)-1H-indol-6-yl)cyclopropanecarboxylate.
1H-NMR (300 MHz, CDCl3) δ 7.54 (1H, d, J=8.1Hz), 7.17 (1H, s), 7.03 (1H, d, J=3.7 Hz), 6.85 (1H, d, J=8.1Hz), 6.50 (1H, d, J=3.6 Hz), 4.69 (2H, d, J=6.6 Hz), 4.43 (2H, d, J=5.9 Hz), 4.35 (2H, s), 2.76 (1H, m), 1.96 (1H, m), 1.72 (1H, m), 1.49 (1H, m), 1.32 (3H, s).
Carboxylic Acid Intermediate-27
trans-2-(2-(isopropylamino)pyridin-4-yl)cyclopropanecarboxylic acid
Step-1: ethyl trans-2-(2-chloropyridin-4-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from (E)-ethyl 3-(2-chloropyridin-4-yl)acrylate.
1H-NMR (300 MHz, CDCl3) δ 8.25 (1H, d, J=5.1Hz), 7.04 (1H, s), 6.91 (1H, dd, J=5.1, 1.4 Hz), 4.18 (2H, q, J=6.6 Hz), 2.46 (1H, m), 2.00 (1H, m), 1.71 (1H, m), 1.36 (1H, m), 1.29 (3H, t, 6.6 Hz), LCMS (Method A) m/z: M+1 obs 226.2, tR=2.82 min.
Step-2: ethyl trans-2-(2-(isopropylamino)pyridin-4-yl)cyclopropanecarboxylate
To a dioxane (5 mL) solution of ethyl trans-2-(2-chloropyridin-4-yl)cyclopropanecarboxylate (250 mg, 1.1 mmol) and isopropylamine (393 mg, 6.7 mmol) were added cesium carbonate (1.1 g, 3.3 mmol), Xantophos (224 mg, 0.4 mmol) and palladium acetate (50 mg, 0.2 mmol) at room temperature respectively. The mixture was sealed and stirred at 100 ° C. for 14 hours. After being filtered off, the filtrate was concentrated under reduced pressure, the residue was applied to a silica gel chromatography column and eluted with a hexane/ethyl acetate =6/1 to furnish 100 mg (36% yield) of the title as a colorless oil.
1H-NMR (300 MHz, CDCl3) δ 7.93 (1H, d, J=5.9 Hz), 6.18 (1H, d, J=5.9 Hz), 6.11 (1H, s), 4.32 (1H, brd, J=7.3 Hz), 4.16 (2H, q, J=7.3 Hz), 3.87 (1H, m), 2.36 (1H, m), 1.93 (1H, m), 1.60 (1H, m), 1.33-1.18 (10H, m), LCMS (Method A) m/z: M+1 obs 249.3, tR=2.04 min.
Step-3: trans-2-(2-(isopropylamino)pyridin-4-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl trans-2-(2-(isopropylamino)pyridin-4-yl)cyclopropanecarboxylate.
LCMS (Method A) m/z: M+1 obs 221.3, tR=0.82 min.
Carboxylic Acid Intermediate-28
2-(1H-indol-4-yl)cyclopropanecarboxylic acid
Step-1: ethyl 2-(1-tosyl-1H-indol-4-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from (E)-ethyl 3-(1-tosyl-1H-indol-4-yl)acrylate.
1H-NMR (300 MHz, CDCl3) δ 7.86 (1H, d, J=8.8 Hz), 7.76 (2H, d, J=8.1Hz), 7.59 (1H, d, J=4.4 Hz), 7.26-7.19 (3H, m), 6.85-6.80 (2H, m), 4.19 (2H, q, J=6.6 Hz), 2.73 (1H, m), 2.34 (3H, s), 1.94 (1H, m), 1.64 (1H, m), 1.36 (1H, m), 1.29 (3H, t, J=7.3 Hz), LCMS (Method A) m/z: M+1 obs 384.2, tR=3.47 min.
Step-2: 2-(1H-indol-4-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl 2-(1-tosyl-1H-indol-4-yl)cyclopropanecarboxylate.
1H-NMR (300 MHz, CDCl3) δ 8.25 (1H, brs), 7.33-7.24 (2H, m), 7.14 (1H, t, J=7.3 Hz), 6.80 (1H, d, J=7.3 Hz), 6.72 (1H, m), 2.98 (1H, m), 2.05 (1H, m), 1.75 (1H, m), 1.58 (1H, m), LCMS (Method A) m/z: M+1 obs 202.2, tR=2.38 min.
Carboxylic Acid Intermediate-29
2-(8-chloroquinolin-2-yl)cyclopropanecarboxylic acid
Step-1: (E)-ethyl 3-(8-chloroquinolin-2-yl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate-7 from 8-chloroquinoline-2-carbaldehyde.
1H-NMR (300 MHz, CDCl3) δ 8.23 (1H, d, J=8.8 Hz), 7.96 (1H, d, J=15.4 Hz), 7.88 (1H, dd, J=7.3, 1.4 Hz), 7.77 (1H, d, J=7.3 Hz), 7.69 (1H, d, J=8.8 Hz), 7.50 (1H, t, J=8.1Hz), 7.13 (1H, d, J=15.4 Hz), 4.34 (2H, q, J=6.6 Hz), 1.40 (3H, t, J=6.6 Hz), LCMS (Method A) m/z: M+1 obs 262.1, tR=3.24 min.
Step-2: ethyl 2-(8-chloroquinolin-2-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from (E)-ethyl 3-(8-chloroquinolin-2-yl)acrylate.
LCMS (Method A) m/z: M+1 obs 276.1, tR=3.40 min.
Step-3: 2-(8-chloroquinolin-2-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl 2-(8-chloroquinolin-2-yl)cyclopropanecarboxylate.
LCMS (Method A) m/z: M+1 obs 248.2, tR=2.82 min.
Carboxylic Acid Intermediate-30
2-(1-methyl-1H-indazol-6-yl)cyclopropanecarboxylic acid
Step-1: (E)-ethyl 3-(1-methyl-1H-indazol-6-yl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate-7 from 1-methyl-1H-indazole-6-carbaldehyde.
1H-NMR (270 MHz, CDCl3) δ 7.97 (1H, s), 7.82 (1H, d, J=16.1Hz), 7.71 (1H, d, J=8.2 Hz), 7.50 (1H, s), 7.35 (1H, dd, J=8.6, 1.0 Hz), 6.53 (1H, d, J=16.1Hz), 4.28 (2H, q, J=6.9 Hz), 4.09 (3H, s), 1.35 (3H, t, J=6.9 Hz), LCMS (Method A) m/z: M+1 obs 231.2, tR=2.88 min.
Step-2: ethyl 2-(1-methyl-1H-indazol-6-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from (E)-ethyl 3-(1-methyl-1H-indazol-6-yl)acrylate.
1H-NMR (270 MHz, CDCl3) δ 7.91 (1H, s), 7.61 (1H, d, J=8.6 Hz), 7.13 (1H, s), 6.87 (1H, dd, J=8.6, 1.3 Hz), 4.18 (2H, q, J=7.3 Hz), 4.04 (3H, s), 2.67 (1H, m), 1.98 (1H, m), 1.66 (1H, m), 1.41 (1H, m), 1.29 (3H, t, J=7.3 Hz), LCMS (Method A) m/z: M+1 obs 245.3, tR=2.95 min.
Step-3: 2-(1-methyl-1H-indazol-6-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl 2-(1-methyl-1H-indazol-6-yl)cyclopropanecarboxylate.
1H-NMR (300 MHz, DMSO-d6) δ 7.94 (1H, s), 7.62 (1H, d, J=8.1Hz), 7.42 (1H, s), 6.92 (1H, d, J=8.4 Hz), 3.98 (3H, s), 2.49 (1H, m), 1.90 (1H, m), 1.48-1.43 (2H, m), LCMS (Method A) m/z: M+1 obs 217.2, tR=2.37 min.
Carboxylic Acid Intermediate-31
2-(1H-indol-5-yl)cyclopropanecarboxylic acid
Step-1: (E)-ethyl 3-(1-tosyl-1H-indol-5-yl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate-7 from 1-tosyl-1H-indole-5-carbaldehyde.
1H-NMR (270 MHz, CDCl3) δ 7.98 (1H, d, J=8.6 Hz), 7.76 (2H, d, J=8.6 Hz), 7.74 (1H, d, J=15.8 Hz), 7.66 (1H, s), 7.58 (1H, d, J=3.9 Hz), 7.50 (1H, d, J=8.6 Hz), 7.23 (2H, d, J=8.6 Hz), 6.66 (1H, d, J=3.3 Hz), 6.41 (1H, d, J=15.8 Hz), 4.26 (2H, q, J=7.2 Hz), 2.34 (3H, s), 1.33 (3H, t, J=7.2 Hz), LCMS (Method A) m/z: M+1 obs 370.2, tR=3.45 min.
Step-2: ethyl 2-(1-tosyl-1H-indol-5-yl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from (E)-ethyl 3-(1-tosyl-1H-indol-5-yl)acrylate.
1H-NMR (300 MHz, CDCl3) δ 7.88 (1H, d, J=8.8 Hz), 7.74 (2H, d, J=8.1Hz), 7.53 (1H, d, J=3.7 Hz), 7.25 (1H, d, J=2.2 Hz), 7.21 (2H, d, J=8.1Hz), 7.05 (1H, dd, J=8.8, 2.2 Hz), 6.58 (1H, d, J=3.7 Hz), 4.18 (2H, q, J=7.3 Hz), 2.57 (1H, m), 2.34 (3H, s), 1.88 (1H, m), 1.61 (1H, m), 1.32 (1H, m), 1.27 (3H, t, J=7.3 Hz), LCMS (Method A) m/z: M+1 obs 384.3, tR=3.45 min.
Step-3: 2-(1H-indol-5-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl 2-(1-tosyl-1H-indol-5-yl)cyclopropanecarboxylate.
1H-NMR (300 MHz, DMSO-d6) δ 12.2 (1H, brs), 11.1 (1H, s), 7.36-7.30 (3H, m), 6.92 (1H, d, J=8.1Hz), 6.39 (1H, s), 2.49 (1H, m), 1.77 (1H, m), 1.49-1.37 (2H, m).
Carboxylic Acid Intermediate-32
2-(3-(benzyloxy)phenyl)cyclopropanecarboxylic acid
Step-1: ethyl 2-(3-(benzyloxy)phenyl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from (E)-ethyl 3-(3-(benzyloxy)phenyl)acrylate.
1H-NMR (300 MHz, CDCl3) δ 7.44-7.32 (5H, m), 7.19 (1H, m), 6.81 (1H, m), 6.72-6.69 (2H, m), 5.04 (2H, s), 4.16 (2H, q, J=7.3 Hz), 2.48 (1H, m), 1.89 (1H, m), 1.58 (1H, m), 1.30 (1H, m), 1.27 (3H, t, J=7.3 Hz).
Step-2: 2-(3-(benzyloxy)phenyl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl 2-(3-(benzyloxy)phenyl)cyclopropanecarboxylate. LCMS (Method A) m/z: M−1 obs 267.2, tR=3.03 min.
Carboxylic Acid Intermediate-33
2-(2-chloro-4-fluorophenyl)cyclopropanecarboxylic acid
Step-1: (E)-ethyl 3-(2-chloro-4-fluorophenyl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate-7 from 2-chloro-4-fluorobenzaldehyde.
1H-NMR (300 MHz, CDCl3) δ 8.02 (1H, d, J=16.1Hz), 7.62 (1H, dd, J=8.8, 6.6 Hz), 7.18 (1H, dd, J=7.3, 1.5 Hz), 7.02 (1H, m), 6.38 (1H, d, J=16.1Hz), 4.28 (2H, q, J=7.3 Hz), 1.35 (3H, t, J=7.3 Hz), LCMS (Method A) m/z: M−1 obs 229.2, tR=3.22 min
Step-2: ethyl 2-(2-chloro-4-fluorophenyl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from (E)-ethyl 3-(2-chloro-4-fluorophenyl)acrylate.
1H-NMR (300 MHz, CDCl3) δ 7.12 (1H, dd, J=8.8, 2.9 Hz), 6.99 (1H, m), 6.89 (1H, m), 4.20 (2H, q, J=7.3 Hz), 2.66 (1H, m), 1.77 (1H, m), 1.61 (1H, m), 1.29 (3H, t, J=7.3 Hz), 1.29 (1H, m), LCMS (Method A) m/z: M−1 obs 243.2, tR=3.27 min.
Step-3: 2-(2-chloro-4-fluorophenyl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl 2-(2-chloro-4-fluorophenyl)cyclopropanecarboxylate.
1H-NMR (300 MHz, DMSO-d6) δ 7.44 (1H, d, J=8.8 Hz), 7.25-7.10 (2H, m), 2.48 (1H, m), 1.70 (1H, m), 1.45-1.35 (2H, m), LCMS (Method A) m/z: M−1 obs 213.2, tR=2.72 min.
Carboxylic Acid Intermediate-34
2-(2-fluoro-4-methoxyphenyl)cyclopropanecarboxylic acid
Step-1: ethyl 2-(2-fluoro-4-methoxyphenyl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from (E)-ethyl 3-(2-fluoro-4-methoxyphenyl)acrylate.
1H-NMR (300 MHz, CDCl3) δ 6.90 (1H, t, J=6.6 Hz), 6.65-6.55 (2H, m), 4.17 (2H, q, J=7.3 Hz), 3.77 (3H, s), 2.57 (1H, m), 1.86 (1H, m), 1.54 (1H, m), 1.28 (3H, t, J=7.3 Hz), 1.28 (1H, m), LCMS (Method A) m/z: M+1 obs 239.3, tR=3.13 min.
Step-2: 2-(2-fluoro-4-methoxyphenyl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl 2-(2-fluoro-4-methoxyphenyl)cyclopropanecarboxylate.
1H-NMR (300 MHz, DMSO-d6) δ 7.01 (1H, t, J=8.8 Hz), 6.79 1H, m), 6.69 (1H, m), 3.72 (3H, s), 2.34 (1H, m), 1.71 (1H, m), 1.40-1.30 (2H, m), LCMS (Method A) m/z: M−1 obs 209.2 tR=2.60 min.
Carboxylic Acid Intermediate-35
2-(2,4,6-trifluorophenyl)cyclopropanecarboxylic acid
Step-1: (E)-ethyl 3-(2,4,6-trifluorophenyl)acrylate
Prepared as in Step-1 of Carboxylic acid intermediate-7 from 2,4,6-trifluorobenzaldehyde.
1H-NMR (300 MHz, CDCl3) δ 7.69 (1H, d, J=16.8 Hz), 6.77-6.65 (3H, m), 4.28 (2H, q, J=7.3 Hz), 1.35 (3H, t, J=7.3 Hz), LCMS (Method A) m/z: M+1 obs 231.2, tR=3.18 min.
Step-2: ethyl 2-(2,4,6-trifluorophenyl)cyclopropanecarboxylate
Prepared as in Step-1 of Carboxylic acid intermediate-6 from (E)-ethyl 3-(2,4,6-trifluorophenyl)acrylate.
1H-NMR (300 MHz, CDCl3) δ 6.66-6.50 (2H, m), 4.18 (2H, q, J=7.3 Hz), 2.40 (1H, m), 2.07 (1H, m), 1.58-1.44 (2H, m), 1.30 (3H, t, J=7.3 Hz), LCMS (Method A) m/z: M+1 obs 245.2 tR=3.23 min.
Step-3: 2-(2,4,6-trifluorophenyl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl 2-(2,4,6-trifluorophenyl)cyclopropanecarboxylate.
1H-NMR (300 MHz, DMSO-d6) δ 7.18-7.10 (2H, m), 2.17 (1H, m), 1.88 (1H, m), 1.45-1.30 (2H, m), LCMS (Method A) m/z: M−1 obs 215.2 tR=2.65 min.
Carboxylic Acid Intermediate-36
2-(5-cyano-1H-benzo[d]imidazol-2-yl)cyclopropanecarboxylic acid
Step-1: ethyl 2-(5-cyano-1H-benzo[d]imidazol-2-yl)cyclopropanecarboxylate
To a mixture of 3,4-diaminobenzonitrile (326 mg, 2.45 mmol), trans-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (323 mg, 2.04 mmol), and triethylamine (1.44 mL, 10.2 mmol) in DMF (10 mL) was added HBTU (1.01 g, 2.66 mmol). After stirring at room temperature for 3 h, the mixture was poured into water, and the aqueous phase was extracted with EtOAc twice. The combined organic layer was dried over sodium sulfate and concentrated in vacuo. To the residue was added acetic acid (10 mL), and the mixture was stirred at 90° C. for 12 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was poured into saturated sodium bicarbonate aqueous solution, and the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate to give 210 mg (40%) of the title compound as a white amorphous:
1H-NMR (300 MHz, CDCl3): δ 9.65 (1H, m), 7.73-7.68 (1H, m), 7.53-7.43 (2H, m), 4.20 (2H, q, J=7.3 Hz), 2.66-2.57 (1H, m), 2.51-2.41 (1H, m), 1.88-1.80 (1H, m), 1.80-1.70 (1H, m), 1.30 (3H, t, J=7.3 Hz), LCMS (Method A) m/z: M+1 obs 256.2, tR=2.61 min.
Step-2: 2-(5-cyano-1H-benzo[d]imidazol-2-yl)cyclopropanecarboxylic acid
Prepared as in Step-2 of Carboxylic acid intermediate-6 from ethyl 2-(5-cyano-1H-benzo[d]imidazol-2-yl)cyclopropanecarboxylate.
1H-NMR (300 MHz, CDCl3) δ 8.01 (1H, s), 7.63 (1H, d, J=8.1Hz), 7.53 (1H, d, J=8.1Hz), 2.63-2.55 (1H, m), 2.20-2.12 (1H, m), 1.65-1.51 (2H, m) (signals due to NH and COOH were not observed), LCMS (Method A) m/z: M+1 obs 228.2, tR=1.88 min.
Carboxylic Acid Intermediate-37
4-((1H-imidazol-1-yl)methyl)-1H-indole-2-carboxylic acid
Step-1: Methyl 3-(2-methyl-6-nitrophenyl)propenoate
2-Bromo-3-nitrotoluene (0.5 g, 23 mmol), methyl acrylate (0.39 g, 46 mmol,), palladium acetate (29 mg, 1.3 mmol), triphenylphosphine (0.06 g, 0.23 mmol,) and TEA (0.4 mL) were combined in a sealed tube and heated to 95° C. for 24 h. The residue was dissolved in MeOH, the solvent was removed and the crude product was purified by column chromatography (EtOAc:hexane=7.5:92.5) to give 0.024 g (48% yield) of the title compound as a yellow oil:
1H-NMR (300 MHz, CDCl3) δ 7.86 (1H, d, J=16.4 Hz), 7.75 (1H, d, J=8.0 Hz), 7.46 (1H, d, J=7.6 Hz), 7.35 (1H, q, J=8.0 Hz, 7.6 Hz), 3.79 (3H, s), 2.37 (3H, s).
Step-2: Methyl 4-methylindole-2-carboxylate
Methyl 3-(2-methyl-6-nitrophenyl)propenoate (0.24 g, 1.1 mmol) was dissolved in triethylphosphite (1 mL) and heated under reflux for 20 h. The solvent was removed in vacuo and the crude product was purified by silica gel chromatography (EtOAc:hexane=8:92) to give 0.15 g (71% yield) of the title compound as a pale yellow solid:
1H-NMR (300 MHz, CDCl3) δ 8.82 (1H, br s), 7.25-7.18 (3H, m), 6.92 (1H, d, J=6.0 Hz), 3.93 (3H, s), 2.54 (3H, s).
Step-3: Methyl 1-tert-butoxycarbonyl-4-methylindole-2-carboxylate
Di-tert-butyl dicarbonate (0.35 g, 1.6 mmol,) and DMAP (0.015 g, 0.12 mmol) were added to a solution of Methyl 4-methylindole-2-carboxylate (0.15 g, 0.8 mmol) in acetonitrile (7.5 mL). The resulting mixture was stirred at room temperature for 16 h and the solvent evaporated in vacuo. The residue was portioned between ethyl acetate (7.5 mL) and water (7.5 mL). The aqueous layer was further extracted with ethyl acetate (2×7.5 mL) and the organic extracts combined, washed with saturated sodium bicarbonate, dried over sodium sulfate, evaporated in vacuo and purified by silica gel column (EtOAc:hexane=5:95) to give 0.13 g (59% yield) of the title compound as a pale yellow oil:
1H-NMR (300 MHz, CDCl3) δ 7.88 (1H, d, J=8.4 Hz), 7.31-7.03 (3H, m), 3.90 (3H, s), 2.50 (3H, s), 1.60 (9H, s).
Step-4: Methyl 4-bromomethyl-1-tert-butoxycarbonylindole-2-carboxylate
A solution of methyl 1-tert-butoxycarbonyl-4-methylindole-2-carboxylate (0.13 g, 0.48 mmol), NBS (0.087 g, 0.48 mmol), and AIBN (4 mg, 0.024 mmol) in carbon tetrachloride (1.9 mL) was heated to reflux for 3 h. The reaction mixture was cooled to room temperature and filtered and washed with carbon tetrachloride. The filtrate was evaporated to give a yellow oil that was purified by silica gel chromatography (EtOAc:hexane=8:92) to give 0.12 g (72% yield) of the title compound as a pale yellow solid:
1H-NMR (300 MHz, CDCl3) δ 8.06 (1H, d, J=8.4 Hz), 7.38-7.27 (3H, m), 4.73 (2H, s), 3.94 (3H, s).
Step-5: 4-Imidazol-1-ylmethyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methy ester
A solution of Methyl 4-bromomethyl-1-tert-butoxycarbonylindole-2-carboxylate (0.92 g, 2.4 mmol) and imodazole (0.82 g, 12 mmol) was stirred at 90° C. in acetonitrile (14 mL) for 5 h. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was purified by silica gel column chromatography (MeOH:DCM=8:92) to give 0.413 g (46% yield) of the title compound as a white solid:
1H-NMR (300 MHz, CDCl3) δ 8.10 (1H, d, J=8.4 Hz), 7.59 (1H, s), 7.39 (1H, q, J=7.6 Hz, 8.4 Hz), 7.08 (1H, s), 7.04 (1H, d, J=7.6 Hz), 6.94 (1H, s), 6.88 (1H, s), 5.33 (2H, s), 3.91 (3H, s), 1.62 (9H, s).
Step-6: 4-((1H-imidazol-1-yl)methyl)-1H-indole-2-carboxylic acid
The mixture of 4-Imidazol-1-ylmethyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methy ester (350 mg, 0.99 mmol) and 2N aqueous sodium hydroxide solution (1 mL. 2 mmol) in THF (5 mL) was refluxed at 80° C. with stirring for 2 days. 2N hydrochloric acid was added until pH was 7.0. The mixture was concentrated in vacuo. The resulting percipitate was collected by filtration and washed with dichloromethane, methanol, H2O and ethyl acetate to give 63 mg (27% yield) of the title compound as a white solid:
1H-NMR (300 MHz, DMSO-d6) δ 7.82 (1H, s), 6.72 (1H, d, J=8.8 Hz), 6.65 (1H, s), 6.55 (1H, s), 6.50 (1H, t, J=7.3 Hz), 6.36 (1H, s), 6.29 (1H, d, J=6.6 Hz), 4.86 (2H, s).
Example 1
(R)-5-tert-butyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)isoxazole-3-carbox amide
To a suspension of (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine 2HCl salt (18 mg, 0.06 mmol) and 5-tert-butylisoxazole-3-carboxylic acid (10 mg, 0.06 mmol) in dichloromethane (2 mL) were added triethylamine (19 mg, 0.18 mmol), EDC (19 mg, 0.1 mmol) and HOBT (9.4 mg, 0.06 mmol) respectively. The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated by N2-flow. The resulting residue was dissolved into ethyl acetate and water was added to the mixture. The organic layer was then washed with brine, and dried over sodium sulfate. After the filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give the residue. The residue was diluted with methanol and applied onto a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.), and the solid phase matrix was rinsed with methanol (6 mL). The crude mixture was eluted in a collection tube with 1 mol/L ammonia in methanol (6 mL) and concentrated in vacuo. The residue was purified by preparative LC-MS to give 17 mg, (75% yield) of the title compound.
By a method similar to Example 1 except that the reactant is different, the following compounds of Examples 2-27, 30-80, 82-241, 243-254, 258-291, 307-313, 315-423 and 426-464 were similarly prepared (also see Table 1). The reactants were used commercial available materials, otherwise noted in the intermediate parts.
Example 28
(R)-2-(4-bromophenoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamid e
To a suspension of (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine 2HCl salt (173 mg, 0.79 mmol) and 2-(4-bromophenoxy)acetic acid (200 mg, 0.87 mmol) in dichloromethane (5 mL) were added triethylamine (400 mg, 3.9 mmol), EDC (180 mg, 0.94 mmol) and HOBT (60 mg, 0.39 mmol) respectively. The reaction mixture was stirred at room temperature for 18 hours. Sat. ammonia hydrochloride aqueous solution was added to the mixture. The organic layer was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After the filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give the residue, which was applied to a silica gel chromatography column and eluted with a hexane/ethylacetate=2/1 (v/v) to furnish 276 mg (81% yield) of the title as a colorless oil;
1H-NMR (300 MHz, CDCl3) δ 8.30 (1H, m), 7.66 (1H, brd, J=8.1Hz), 7.41 (2H, d, J=8.8 Hz), 7.26-7.24 (2H, m), 6.84 (2H, d, J=8.8 Hz), 5.22 (1H, m), 4.48 (2H, qAB, J=14.6 Hz), 4.40 (2H, qAB, J=8.1Hz), 1.49 (3H, d, J=7.3 Hz), LCMS (Method A) m/z: M+1 434.8; tR=3.15 min.
Example 29
(R)-2-(4-cyclopropylphenoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acet amide
To a solution of (R)-2-(4-bromophenoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide (100 mg, 0.23 mmol) and cyclopropylboronic acid (26 mg, 0.30 mmol) in dioxane (2 mL) were added 1.27 M potassium phosphate (0.36 mL) and tetrakistriphenyl phosphine palladium (13 mg, 0.012 mmol) at room temperature. The mixture was stirred at 120° C. using microwave oven for 2 hours. The mixture was dried over magnesium sulfate. After the filtration to separate solvent and magnesium sulfate, the solvent was removed under reduced pressure to give the residue. The residue was diluted with methanol and applied onto a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.), and the solid phase matrix was rinsed with methanol (6 mL). The crude mixture was eluted in a collection tube with 1 mol/L ammonia in methanol (6 mL) and concentrated in vacuo. The residue was purified by preparative LC-MS to give 6.5 mg, (7% yield) of the title compound.
Example 81
(R)-N-(1-(5-(pyridin-2-ylmethoxy)pyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)acetamide
Step-1: (R)-N-(1-(5-hydroxypyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)acetamide
A mixture of (R)-N-(1-(5-(benzyloxy)pyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)acetamide (Example 63, 550 mg, 1.3 mmol) and palladium hydroxide on carbon (20 wt. %, 50 mg) in methanol (30 mL) was hydrogenated for 6 hours. The mixture was filtered through a pad of celite, washed with methanol, the filtrate was concentrated gave 410 mg (94% yield) of (R)-N-(1-(5-hydroxypyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)acetamide as a white crystalline solid;
1H-NMR (300 MHz, CDCl3) δ 8.19 (1H, d, J=2.9 Hz), 7.77 (1H, d, J=7.3 Hz), 7.58 (2H, d, J=8.1Hz), 7.14 (1H, dd, J=8.8 Hz, 2.9 Hz), 7.08-7.02 (3H, m), 5.20-5.10 (1H, m), 4.58 (1H, d, J=13.9 Hz), 4.51 (1H, d, J=13.9 Hz), 1.48 (3H, d, J=6.6 Hz), LCMS (Method A) m/z: M+1 obs 341.
Step-2: (R)-N-(1-(5-(pyridin-2-ylmethoxy)pyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)a cetamide
A mixture of (R)-N-(1-(5-hydroxypyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)acetamide (30 mg, 0.088 mmol), 2-(bromomethyl)pyridine hydrobromide (22 mg, 0.088 mmol), and cesium carbonate (115 mg, 0.35 mmol) in DMF (3 mL) was heated at 90° C. overnight. After cooling, the mixture was filtered through a pad of celite, washed with dichloromethane, the filtrate was concentrated, and the residue was purified by SCX cartridge to give 34 mg (89% yield) of (R)-N-(1-(5-(pyridin-2-ylmethoxy)pyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)a cetamide as a clear colorless oil; LCMS (Method A) m/z: M+1 obs 432, M−1 obs 430
Alternated route for Mixture of Example 133 and 134 trans-2-(1H-indol-3-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopr opanecarboxamide
Step-1: (R,E)-3-(1H-indol-3-yl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acrylamide
To a suspension of (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine 2HCl salt (1.1 g, 3.8 mmol) and (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yDacrylic acid (1.0 g, 3.5 mmol) in dichloromethane (8 mL) were added triethylamine (1.8 g, 17 mmol), EDC (800 mg, 4.2 mmol) and HOBT (270 mg, 1.7 mmol) respectively. The reaction mixture was stirred at room temperature for 6 hours. Sat. sodium bicarbonate aqueous solution was added to the mixture. The organic layer was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After the filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give the residue, which was applied to a silica gel chromatography column and eluted with a hexane/ethylacetate=2/1 (v/v) to furnish 900 mg (53% yield) of the title as a yellow solid;
1H-NMR (300 MHz, CDCl3) δ 8.31 (1H, d, J=1.5 Hz), 8.18 (1H, d, J=8.0 Hz), 7.90-7.70 (3H, m), 7.40-7.20 (4H, m), 6.93 (1H, d, J=8.0 Hz), 6.59 (1H, d, J=16.1Hz), 5.30 (1H, m), 4.39 (2H, q, J=8.0 Hz), 1.08 (9H, s), 1.53 (3H, d, J=6.6 Hz), LCMS (Method A) m/z: M+1 490.3; tR=3.44 min.
Step-2: trans-2-(1H-indol-3-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanec arboxamide
To a solution of (R,E)-3-(1H-indol-3-yl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acrylamide (600 mg, 1.3 mmol) in dichloromethane (10 mL) was added ethylzinc (4.1 mL, 4.1 mmol, 1.0 M) at room temperature. After being stirred at room temperature for 3 min, diiodomethane (1.8 g, 6.7 mmol) was added to the mixture. The mixture was refluxed at 55° C. with stirring for 18 hours. sat. ammonia hydrochloride aqueous solution was added to the mixture. The organic layer was extracted with ethyl acetate, washed with brine, dried over sodium sulfate. After the filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give the residue, which was applied to a silica gel chromatography column and eluted with a hexane/ethylacetate=1/1 (v/v) and preparative LC-MS to give 14 mg, (3% yield) of the title compound as a white solid (2:1 mixture of the diastereomers).
1H-NMR (600 MHz, CDCl3) δ 8.28 (1H, s), 7.99 (1H, brs), 7.60 (1H, m), 7.34 (1H, m), 7.26-7.22 (2H, m), 7.18 (1H, m), 7.08 (1H, m), 6.95-6.86 (2H, m),5.21 (1H, m), 4.40 (2H, q, J=7.9 Hz), 2.54 (1H, m), 1.68 (1H, m), 1.60 (1H, m), 1.48 (3H, d, J=6.8 Hz), 1.29 (1H, m),LCMS (Method A) m/z: M+1 404.3; tR=2.98 min.
Example 242
(1S*,2S*)-2-(4-hydroxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethy
Dcyclopropanecarboxamide
A mixture of palladium hydroxide on carbon 20 wt % loading (63 mg) and (1S*,2S*)-2-(4-(benzyloxy)phenyl)-N-(R-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethy l)cyclopropanecarboxamide (631 mg, 1.341 mmol) in methanol (30 ml) was stirring for 4 hours at room temperature under H2 atmosphere. The mixture was filtered through a pad of celite, washed with ethyl acetate, the filtrate was concentrated to give 485 mg (95% yield) of title compound as a white amorphous. 8 mg of the residue was purified by preparative LC-MS to give 4.8 mg of the title compound.
Example 255
(1S*,2S*)-2-(3-hydroxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethy 1)cyclopropanecarboxamide
Prepared as in Example 242 from (1S*,2S*)-2-(3-(benzyloxy)phenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)et hyl)cyclopropanecarboxamide. The residue was purified by preparative LC-MS to give 5.4 mg of the title compound.
Example 256
(1S*,2S*)-2-(4-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethoxy)phenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide
Step-1: tert-butyl 2-(4-((1S*,2S*)-2-(((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)carbamoyl)cycl opropyl)phenoxy)acetate
A mixture of tert-butyl 2-bromoacetate (0.063 ml, 0.434 mmol), potassium carbonate (109 mg, 0.789 mmol) and (1S*,2S*)-2-(4-hydroxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide (150 mg, 0.394 mmol) in dichloromethane (4 ml) was refluxed with stirring for 3 hours. After cooling to room temperature, the mixture was poured into water, and the aqueous layer was extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from tetrahydrofuran/hexane. To give 137 mg (70% yield) of title compound as a white crystal:
1H-NMR (300 MHz, DMSO-d6) δ 8.55 (1H, d, J=8.1Hz), 8.31 (1H, d, J=2.6 Hz), 7.49 (1H, dd, J=8.8, 2.9 Hz), 7.28 (1H, d, J=8.4 Hz), 7.03 (2H, d, J=8.4 Hz), 6.78 (2H, d, J=8.4 Hz), 4.95 (1H, t, J=7.3 Hz), 4.84 (2H, q, J=8.8 Hz), 4.59 (2H, s), 2.17 (1H, m), 1.89 (1H, m), 1.41 (9H, s), 1.32 (2H, d, J=6.6 Hz), 1.22 (1H, m), 1.09 (1H, m), LCMS (Method A) m/z: M+1 obs 495.1, tR=3.25 min.
Step-2: 2-(4-((1S*,2S*)-24(R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)carbamoyl)cyclopropyl)phenoxy)acetic acid
A mixture of trifluoroacetic acid (0.213 ml, 2.77 mmol) and tert-butyl 2-(4-((lS*,2S*)-2-(((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)carbamoyl)cyclopropyl)phenoxy)acetate (137 mg, 0.277 mmol) in dichloromethane (5 ml) was refluxed with stirring for 6 hours. Excess trifluoroacetic acid and dichloromethane were removed under reduced pressure to give 200 mg of title compound as white solid. This was used next step without purification:
LCMS (Method A) m/z: M+1 obs 439.0, tR=2.54 min.
Step-3: (1S*,2S*)-2-(4-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethoxy)phenyl)-N-((R)-1-(5-(2,2, 2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide
A mixture of HBTU (28 mg, 0.075 mmol), triethylamine (0.03 mL, 0.25 mmol), 4,4-difluoropiperidine hydrochloride (9.5 mg, 0.060 mmol) and 2-(4-((1S*,2S*)-2-(((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)carbamoyl)cycl opropyl)phenoxy)acetic acid (28 mg, 0.050 mmol) was stirring for 4 hours at room temperature. The mixture was poured into 2 mol/l hydrochloric acid, and the aqueous layer was extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 13.7 mg (50% yield) of the title compound.
Example 257
(1S*,2S*)-2-(3-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethoxy)phenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide
Step-1: tert-butyl 2-(3-((1S*,2S*)-2-(((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)carbamoyl)cycl opropyl)phenoxy)acetate
Prepared as in Step-1 of Example 256 from (1S*,2S*)-2-(3-hydroxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide.
1H-NMR (300 MHz, DMSO-d6) δ 8.56 (1H, d, J=7.7 Hz), 8.31 (1H, d, J=2.9 Hz), 7.49 (1H, dd, J=8.4, 2.9 Hz), 7.29 (1H, d, J=8.8 Hz), 7.16 (1H, t, J=7.7 Hz), 6.72-6.65 (3H, m), 4.95 (1H, t, J=7.3 Hz), 4.84 (2H, q, J=8.8 Hz), 4.61 (2H, s), 2.19 (1H, m), 1.98 (1H, m), 1.41 (9H, s), 1.32 (2H, d, J=7.0 Hz), 1.25 (1H, m), 1.15 (1H, m), LCMS (Method A) m/z: M+1 obs 495.1, tR=3.28 min.
Step-2: 2-(3-((1S*,2S*)-2-(((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)carbamoyl)cycl opropyl)phenoxy)acetic acid
Prepared as in Step-2 of Example 256 from tert-butyl 2-(3-((1S*,2S*)-2-(((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)carbamoyl)cycl opropyl)phenoxy)acetate.
LCMS (Method A) m/z: M+1 obs 439.0, tR=2.61 min.
Step-3: (1S*,2S*)-2-(3-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethoxy)phenyl)-N-((R)-1-(5-(2,2, 2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide
Prepared as in Step-3 of Example 256 from 2-(3-((1S*,2S*)-2-(((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)carbamoyl)cycl opropyl)phenoxy)acetic acid. The residue was purified by preparative LC-MS to give 11.4 mg of the title compound.
Example 292
(R)-4-(tert-butyl)-N-(1-(5-hydroxypyridin-2-yl)ethyl)benzamide
Prepared as in Example 242 from (R)-N-(1-(5-(benzyloxy)pyridin-2-yl)ethyl)-4-(tert-butyl)benzamide (Example 313).
1H-NMR (300 MHz, DMSO-d6) δ 9.74 (1H, s), 8.60 (1H, d, J=8.1Hz), 8.04 (1H, d, J=2.9 Hz), 7.81 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.1Hz), 7.19 (1H, d, J=8.4 Hz), 7.10 (1H, dd, J=8.4, 2.9 Hz), 5.11 (1H, quintet, J=7.0 Hz), 1.43 (3H, d, J=7.0 Hz), 1.28 (9H, s), LCMS (Method A) m/z: M+1 obs 299.2, tR=3.21 min.
Example 293
(1S*,2S*)-2-(phenoxymethyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide
Step-1: (1R*,2R*)-2-(hydroxymethyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)c yclopropanecarboxamide and (1S*,2S*)-2-(hydroxymethyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cy clopropanecarboxamide
To a mixture of (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine dihydrochloride (997 mg, 3.40 mmol), trans-2-(hydroxymethyl)cyclopropanecarboxylic acid (329 mg, 2.83 mmol), and triethylamine (1.99 mL, 14.2 mmol) in acetonitrile was added HBTU. After stirring at room temperature for 5 h, the mixture was poured into water, and the aqueous layer was extracted with dichloromethane three times. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (20:1) to give 263 mg (29%) of upper spot (tentatively assigned as (1R*,2R*)-2-(hydroxymethyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)c yclopropanecarboxamide) as a colorless oil and 292 mg of lower spot (tentatively assigned as (1S*,2S*)-2-(hydroxymethyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cy clopropanecarboxamide) as a crystal. (1R*,2R*)-2-(Hydroxymethyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropa necarboxamide: 1H-NMR (300 MHz, CDCl3): δ 8.26 (1H, s), 7.27-7.21 (2H, m), 6.91 (1H, d, J=7.3 Hz), 5.11 (quintet, J=6.6 Hz), 3.66 (1H, dd, J=5.9 & 11.0 Hz), 3.41 (1H, dd, J=7.3 & 11.0 Hz), 1.70-1.60 (2H, m), 1.45 (3H, d, J=6.6 Hz), 1.27-1.19 (1H, m), 0.81-0.73 (1H, m) (a signal due to OH was not observed), LCMS (Method A) m/z: M+1 obs 319.1, tR=2.40 min. (1S*,2S*)-2-(Hydroxymethyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropa necarboxamide: 1H-NMR (300 MHz, CDCl3): δ 8.29 (1H, s), 7.27-7.20 (2H, m), 6.89 (1H, d, J=6.6 Hz), 5.11 (1H, quintet, J=6.6 Hz), 4.40 (2H, q, J=8.0 Hz), 3.66 (1H, dd, J=5.9 & 11.7 Hz), 3.49 (1H, dd, J=6.6 & 11.7 Hz), 1.77-1.65 (2H, m), 1.20-1.12 (1H, m), 0.77-0.70 (1H, m) (a signal due to OH was not observed), LCMS (Method A) m/z: M+1 obs 319.1, tR=2.37 min.
Step-2: (1S*,2S*)-2-(phenoxymethyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cy clopropanecarboxamide
To a mixture of (1S*,2S*)-2-(hydroxymethyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cy clopropanecarboxamide (30 mg, 0.094 mmol) and phenol (16.0 mg, 0.17 mmol) in tetrahydrofuran (1 mL), triphenylphosphine (45 mg, 0.17 mmol) and di-tert-butyl azodicarboxylate (28.2 mg, 0.12 mmol) were added successively. After stirring at room temperature for 1 day, the mixture was poured into water, and the aqueous layer was extracted with dichloromethane three times. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 12.1 mg (33% yield) of the title compound.
By a method similar to Example 293 except that the reactant is different, the following compounds of Examples 294-302 were similarly prepared (also see Table 3). The reactants were used commercially available materials, otherwise noted in the intermediate parts.
Example 303
(1S*,2S*)-2-(3-((3-methyloxetan-3-yl)methoxy)phenyl)-N-((R)-1-(5-(2,2,2-trifluoroe thoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide
A mixture of (1S*,2S*)-2-(3-hydroxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide (15 mg, 0.039 mmol), 3-(Chloromethyl)-3-methyloxetane (24 mg, 0.197 mmol) and potassium carbonate (27 mg, 0.197 mmol) in DMF (2 mL) was heated at 70° C. with stirring for 15 hours. The mixture was poured into water, and the aqueous layer was extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 8.9 mg (49% yield) of the title compound.
Example 304
(1S*,2S*)-2-(44(3-methyloxetan-3-yl)methoxy)phenyl)-N-((R)-1-(5-(2,2,2-trifluoroe thoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide
Prepared as in Example 303 from (1S*,2S*)-2-(4-hydroxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide. The residue was purified by preparative LC-MS to give 8 mg of the title compound.
Example 305
(1S*,2S*)-2-(4-(pyridin-2-ylmethoxy)phenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyr idin-2-yl)ethyl)cyclopropanecarboxamide
A mixture of (1S*,2S*)-2-(4-hydroxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide (15 mg, 0.039 mmol), 2-(Bromomethyl)pyridine hydrobromide (100 mg, 0.394 mmol) and potassium carbonate (27 mg, 0.197 mmol) in DMF (2 mL) was heated at 70 oC with stirring for 2 days. The mixture was poured into water, and the aqueous layer was extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 5 mg (27% yield) of the title compound.
Example 306
(1S*,2S*)-2-(3-(pyridin-2-ylmethoxy)phenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyr idin-2-yl)ethyl)cyclopropanecarboxamide
Prepared as in Example 305 from (1S*,2S*)-2-(3-hydroxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide. The residue was purified by preparative LC-MS to give 12 mg of the title compound.
Example 314
(R)-4-tert-butyl-N-(1-(5-(pyridin-2-ylmethoxy)pyridin-2-yl)ethyl)benzamide
Prepared as in Example 81 and Example 305 from (R)-N-(1-(5-(benzyloxy)pyridin-2-yl)ethyl)-4-tert-butylbenzamide (Example 313).
Example 424
(R)-6-fluoro-N,1-dimethyl-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-ind ole-2-carboxamide
To a stirred solution of (R)-6-fluoro-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1H-indole-2-carboxami de (Example 48, 18 mg, 0.046 mmol) in DMF (1 mL) was added sodium hydride (60%, 1.6 mg, 0.068 mmol) at room temperature. After 20 min, Iodomethane (0.0034 mL, 0.055 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was poured into water, and extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The residue was diluted with methanol and applied onto a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.), and the solid phase matrix was rinsed with methanol (6 mL). The crude mixture was eluted in a collection tube with 1 mol/L ammonia in methanol (6 mL) and concentrated in vacuo. The residue was purified by preparative LC-MS to give 9.4 mg (50% yield) of the title compound
Example 425
(1S*,2S*)-N-methyl-2-(quinolin-2-yl)-N-((12)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide
Step-1: (1S*,2S*)-2-(quinolin-2-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide
Prepared as in Example 1 from 2-(quinolin-2-yl)cyclopropanecarboxylic acid (purified by chiral HPLC).
1H-NMR (300 MHz, CDCl3) δ 8.25 (1H, s), 8.07 (1H, s), 8.00 (1H, d, J=8.0 Hz), 7.90 (1H, d, J=8.0 Hz), 7.74 (1H, d, J=8.0 Hz), 7.65 (1H, t, J=8.0 Hz), 7.45 (1H, t, J=8.0 Hz), 7.31 (1H, d, J=8.0 Hz), 6.58 (1H, d, J=8.0 Hz), 5.27 (1H, quintet, J=7.3 Hz), 4.80-4.67 (2H, m), 2.73-2.66 (1H, m), 2.35-2.27 (1H, m), 1.73-1.66 (2H, m), 1.50 (3H, d, J=7.3 Hz).
Step-2: (1S*,2S*)-N-methyl-2-(quinolin-2-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide
Prepared as in Example 424 from (1S*,2S*)-2-(quinolin-2-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide. The residue was purified by preparative LC-MS to give 11 mg of the title compound.
Example 426
(1R*,2R*)-N-methyl-2-(quinolin-2-yl)-N-((12)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide
Prepared as in Example 424 from (1R*,2R*)-2-(quinolin-2-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide (Example 222). The residue was purified by preparative LC-MS to give 2.3 mg of the title compound.
Quality control analytical condition (Method B), the amine/carboxylic acid used, the purification method, and spectra data are described below for Examples 1-464 in Table 3 and Table 4.









TABLE 3







Example
Name
STRUCTURE





Example  1
(R)-5-tert-butyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)isoxazole-3-carboxamide






 


Example  2
(R)-6-tert-butyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)nicotinamide






 


Example  3
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-2-(4-(trifluoromethyl) phenoxy)acetamide






 


Example  4
(R)-4-(benzyloxy)-3-methoxy- N-(1-(5- (2,2,2-trifluoroethoxy)pyridin- 2-yl)ethyl)benzamide






 


Example  5
(R)-4-tert-butyl-2-methoxy- N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example  6
(R)-2-(4-chloro-3- (trifluoromethyl)phenoxy)- N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)acetamide






 


Example  7
(R)-3,5-dichloro-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example  8
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)quinoline-2-carboxamide






 


Example  9
(R)-4-(3-(1,1,1-trifluoro-2- methylpropan-2-yl)phenyl)-N-(1- (5-(2,2,2-trifluoroethoxy)pyridin- 2-yl)ethyl)thiazole-2-carboxamide






 


Example  10
(1R,2R)-2-methyl-N-((R)-1- (5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-2-(4-(trifluoromethyl) phenyl)cyclopropanecarboxamide






 


Example  11
(R)-2-(1,1,1-trifluoro- 2-methylpropan-2-yl)-N-(1- (5-(2,2,2-trifluoroethoxy)pyridin- 2-yl)ethyl)quinoline-6-carboxamide






 


Example  12
trans-2-(4-tert-butylphenyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl) ethyl)cyclopropanecarboxamide






 


Example  13
(R)-4-tert-butyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example  14
(R)-4-isopropyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example  15
(R)-4-tert-butyl-2-methoxy-N-(1- (6-(2,2,2-trifluoroethoxy)pyridin- 3-yl)ethyl)benzamide






 


Example  16
(R)-N-(1-(6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-2-(4-(trifluoromethyl) phenoxy)acetamide






 


Example  17
(R)-2-(p-tolyloxy)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)acetamide






 


Example  18
(R)-2-(4-chlorophenoxy)-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)acetamide






 


Example  19
(R)-4-(2,2,2-trifluoroethoxy)- N-(1-(5- (2,2,2-trifluoroethoxy)pyridin- 2-yl)ethyl)benzamide






 


Example  20
(R)-2-(biphenyl-4-yloxy)-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)acetamide






 


Example  21
(R)-2-(4-phenoxyphenoxy)-N-(1- (5-(2,2,2-trifluoroethoxy)pyridin- 2-yl)ethyl)acetamide






 


Example  22
(R)-2-(2-tert-butylphenoxy)-N- (1-(5-(2,2,2-trifluoroethoxy)pyridin- 2-yl)ethyl)acetamide






 


Example  23
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-2-(2- (trifluoromethyl)phenoxy)acetamide






 


Example  24
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1H- indole-2-carboxamide






 


Example  25
(R)-5-fluoro-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1H- indole-2-carboxamide






 


Example  26
(R)-1-methyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1H- indole-2-carboxamide






 


Example  27
(R)-2-(2,4-dichlorophenoxy)-N- (1-(5-(2,2,2-trifluoroethoxy)pyridin- 2-yl)ethyl)acetamide






 


Example  28
(R)-2-(4-bromophenoxy)-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)acetamide






 


Example  29
(R)-2-(4-cyclopropylphenoxy)-N-(1- (5-(2,2,2-trifluoroethoxy)pyridin- 2-yl)ethyl)acetamide






 


Example  30
(R)-3-(3-fluorophenyl)-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin- 2-yl)ethyl)propanamide






 


Example  31
(R)-3-methyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)benzofuran-2-carboxamide






 


Example  32
(R)-5-butyl-butyl-2-methyl-N-(1- (5-(2,2,2-trifluoroethoxy)pyridin- 2-yl)ethyl)furan-3-carboxamide






 


Example  33
(R)-3-(1H-indol-3-yl)-N-(1- (5-(2,2,2-trifluoroethoxy)pyridin- 2-yl)ethyl)propanamide






 


Example  34
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-3- (trifluoromethyl)benzamide






 


Example  35
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-4- (trifluoromethyl)benzamide






 


Example  36
(R)-5-phenyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-2- (trifluoromethyl)furan-3- carboxamide






 


Example  37
(R)-2-methyl-5-phenyl-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin- 2-yl)ethyl)furan-3-carboxamide






 


Example  38
(R)-3-fluoro-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-5- (trifluoromethyl)benzamide






 


Example  39
(R)-3-fluoro-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-4- (trifluoromethyl)benzamide






 


Example  40
(R)-4-fluoro-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-3- (trifluoromethyl)benzamide






 


Example  41
(R)-2-methyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-6- (trifluoromethyl)-2H-indazole- 3-carboxamide






 


Example  42
(R)-1-methyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-6- (trifluoromethyl)-1H-indazole- 3-carboxamide






 


Example  43
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-5- (trifluoromethyl)picolinamide






 


Example  44
(R)-5-chloro-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1H- indole-2-carboxamide






 


Example  45
(R)-5-methoxy-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1H- indole-2-carboxamide






 


Example  46
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1H- indole-3-carboxamide






 


Example  47
(R)-1-methyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1H- indole-3-carboxamide






 


Example  48
(R)-5-fluoro-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1H- indole-2-carboxamide






 


Example  49
(R)-7-fluoro-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1H- indole-2-carboxamide






 


Example  50
(R)-3-(1H-Indol-1-yl)-N-(1-(5- (2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)propanamide






 


Example  51
(R)-5-methyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl-1H- indole-2-carboxamide






 


Example  52
(R)-1-methyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-5- (trifluoromethyl)-1H-indole-2- carboxamide






 


Example  53
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin- 2-yl)ethyl)-5-(trifluoromethyl)- 1H-indole-2-carboxamide






 


Example  54
(R)-1-methyl-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin- 2-yl)ethyl)-6- (trifluoromethyl)-1H-indole- 3-carboxamide






 


Example  55
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin- 2-yl)ethyl)-5-(trifluoromethyl)- 1H-benzo[d]imidazole-2- carboxamide






 


Example  56
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin- 2-yl)ethyl)-6-(trifluoromethyl)- 1H-indazole-3-carboxamide






 


Example  57
(R)-4-(1H-indol-3-yl)-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)butanamide






 


Example  58
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin- 2-yl)ethyl)-6-(trifluoromethyl)- 1H-indole-3-carboxamide






 


Example  59
(R)-N-(1-(5- (cyclopropylmethoxy)pyridin- 2-yl)ethyl)-2-(4- (trifluoro- methyl)phenoxy)acetamide






 


Example  60
(R)-N-(1-(5- (cyclopropylmethoxy)pyridin- 2-yl)ethyl)-3-(1H-indol-3- yl)propanamide






 


Example  61
(R)-N-(1-(5- (cyclopropylmethoxy)pyridin- 2-yl)ethyl)-5-fluoro-1H- indole-2-carboxamide






 


Example  62
trans-2-(4-tert-butylphenyl)-N- ((R)-1- (5-(cyclopropylmethoxy)pyridin- 2-yl)ethyl)cyclopropane- carboxamide






 


Example  63
(R)-N-(1-(5-(benzyloxy)pyridin- 2-yl)ethyl)-2-(4- (trifluoromethyl)phenoxy)acetamide






 


Example  64
(R)-N-(1-(5-(benzyloxy)pyridin- 2-yl)ethyl)-3-(1H-indol-3- yl)propanamide






 


Example  65
(R)-N-(1-(5-(benzyloxy)pyridin- 2-yl)ethyl)-5-fluoro-1H-indole- 2-carboxamide






 


Example  66
trans-N-((R)-1-(5- (benzyloxy)pyridin- 2-yl)ethyl)-2-(4-tert-butylphenyl) cyclopropanecarboxamide






 


Example  67
(R,E)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-3-(4- (trifluoromethyl)phenyl)acrylamide






 


Example  68
(R,E)-N-(1-(5-(cyclopropylmethoxy) pyridin-2-yl)ethyl)-3-(4- (trifluoromethyl)phenyl)acrylamide






 


Example  69
(R,E)-N-(1-(5-(benzyloxy)pyridin- 2-yl)ethyl)-3-(4-(trifluoromethyl) phenyl)acrylamide






 


Example  70
(R)-N-(1-(5-(2,2,2-trifluoroethoxy) pyridin-2-yl)ethyl)-2-(4- (trifluoromethyl) phenyl)thiazole-4-carboxamide






 


Example  71
(R)-3-(5-fluoro-1H-indol-3-yl)- N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)propanamide






 


Example  72
(R)-N-(1-(5-(cyclopropylmethoxy) pyridin-2-yl)ethyl)-3-(5-fluoro- 1H-indol-3-yl)propanamide






 


Example  73
(R)-3-(6-fluoro-1H-indol-1-yl)- N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)propanamide






 


Example  74
(R)-N-(1-(5-(cyclopropylmethoxy) pyridin-2-yl)ethyl)-3-(6-fluoro- 1H-indol-1-yl)propanamide






 


Example  75
(R)-3-(5-fluoro-2-phenyl-1H-indol- 3-yl)-N-(1-(5-(2,2,2-trifluoroethoxy) pyridin-2-yl)ethyl)propanamide






 


Example  76
(R)-N-(1-(5-(cyclopropylmethoxy) pyridin-2-yl)ethyl)-3-(5-fluoro-2- phenyl-1H-indol-3-yl)propanamide






 


Example  77
(R)-N-(1-(5-(2-fluorobenzyloxy) pyridin-2-yl)ethyl)-2-(4-(trifluoro- methyl)phenoxy)acetamide






 


Example  78
(R)-N-(1-(6-methyl-5-(2,2,2- trifluoroethoxy)pyridin- 2-yl)ethyl)-2-(4-(trifluoro- methyl)phenoxy)acetamide






 


Example  79
(R)-5-fluoro-N-(1-(6-methyl-5- (2,2,2-trifluoroethoxy)pyridin- 2-yl)ethyl)-1H- indole-2-carboxamide






 


Example  80
(R)-5-(2,2,2-trifluoroethoxy)-N- (1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)picolinamide






 


Example  81
(R)-N-(1-(5-(pyridin-2- ylmethoxy)pyridin-2-yl)ethyl)-2- (4-(trifluoromethyl)phenoxy) acetamide






 


Example  82
(1S,2S)-N-((R)-1-(5-(2- fluorobenzyloxy)pyridin- 2-yl)ethyl)-2-methyl-2-(4-(trifluoro- methyl)phenyl) cyclopropanecarboxamide






 


Example  83
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin- 2-yl)ethyl)-3-(4-(trifluoro- methyl)phenyl)propanamide






 


Example  84
N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin- 2-yl)ethyl)-1,2,3,4-tetra- hydronaphthalene-2-carboxamide






 


Example  85
(1S,2S)-N-((R)-1-(6-(2-fluorobenzyloxy)pyridin- 3-yl)ethyl)-2-methyl-2-(4-(trifluoro- methyl)phenyl) cyclopropanecarboxamide






 


Example  86
(R)-N-(1-(6-(2- fluorobenzyloxy)pyridin- 3-yl)ethyl)-3- (1H-indol-3-yl)propanamide






 


Example  87
(R)-N-(1-(5-(2- fluorobenzyloxy)pyridin- 2-yl)ethyl)-3- (1H-indol-3-yl)propanamide






 


Example  88
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin- 2-yl)ethyl)-2-(4- (trifluoromethyl)phenyl)oxazole- 4-carboxamide






 


Example  89
(R,E)-3-(1H-indol-3-yl)-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)acrylamide






 


Example  90
(R,E)-3-(1H-indol-3-yl)-N-(1-(6- (2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)acrylamide






 


Example  91
(1R,2R)-N-((R)-1-(5-(2,2,2- trifluoro- ethoxy)pyridin-2-yl)ethyl)-2-(4- (trifluoro- methyl)phenyl) cyclopropanecarboxamide






 


Example  92
(1R,2R)-N-((R)-1-(6-(2,2,2- trifluoro-ethoxy)pyridin-3- yl)ethyl)-2-(4-(trifluoro- methyl)phenyl) cyclopropanecarboxamide






 


Example  93
(R)-3-(1H-Indol-3-yl)-N-(1-(6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)propanamide






 


Example  94
(1S,2S)-2-methyl-N-((R)-1-(6- (2,2,2-trifluoro- ethoxy)pyridin-3-yl)ethyl)-2-(4- (trifluoro- methyl)phenyl) cyclopropanecarboxamide






 


Example  95
(R)-5-fluoro-N-(1-(5-(2- fluorobenzyloxy)pyridin-2- yl)ethyl)- 1H-indole-2-carboxamide






 


Example  96
(R)-N-(1-(5-((1- methylcyclopropyl) methoxy)pyridin- 2-yl)ethyl)-2-(4- (trifluoromethyl)phenoxy)acetamide






 


Example  97
(R)-3-(1H-indol-3-yl)-N-(1-(5-((1- methylcyclopropyl)methoxy) pyridin-2- yl)ethyl)propanamide






 


Example  98
(R)-5-fluoro-N-(1-(5-((1- methylcyclopropyl)methoxy) pyridin-2- yl)ethyl)-1H-indole-2-carboxamide






 


Example  99
(1S,2S)-2-methyl-N-((R)-1-(5-((1- methylcyclopropyl)methoxy) pyridin-2-yl)ethyl)-2-(4- (trifluoromethyl)phenyl) cyclopropanecarboxamide






 


Example 100
N-(3-(2,2,2-trifluoroethoxy)-5,6,7,8- tetrahydroquinolin-8-yl)-2-(4- (trifluoromethyl)phenoxy)acetamide






 


Example 101
3-(1H-indol-3-yl)-N-(3-(2,2,2- trifluoroethoxy)-5,6,7,8- tetrahydroquinolin-8- yl)propanamide






 


Example 102
trans-2-(4-tert-butylphenyl)-N-(3- (2,2,2-trifluoroethoxy)-5,6,7,8- tetrahydroquinolin-8- yl)cyclopropanecarboxamide






 


Example 103
(R)-N-(1-(3-fluoro-5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-3- (1H-indol-3-yl)propanamide






 


Example 104
(R)-3-(1H-indol-3-yl)-N-(1-(3- methyl- 5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)propanamide






 


Example 105
(R)-4-((1H-imidazol-1- yl)methyl)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1H-indole-2-carboxamide






 


Example 106
trans-2-(1-methyl-1H-indol-3-yl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 107
(R)-2-(4-chlorophenexyl)-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)nicotinamide






 


Example 108
trans-2-(7-fluoro-1H-indol-3-yl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 109
trans-2-(1H-indol-5-yl)-N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin- 2-yl)ethyl) cyclopropanecarboxamide






 


Example 110
trans-2-(5-fluoro-1H-indol-3-yl)-N- ((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 111
trans-2-(5-cyano-1H-indol-3-yl)-N- ((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 112
(R)-3-chloro-4-methyl-N-(1-(5- (2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 113
(R)-4-tert-butyl-N-(1-(6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)benzamide






 


Example 114
(R)-3-chloro-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 115
(R)-3-chloro-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl) ethyl)isoquinoline-3-carboxamide






 


Example 116
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)quinoxaline-2-carboxamide






 


Example 117
(R)-4-methoxy-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)quinoline-2-carboxamide






 


Example 118
(R)-6-phenyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)pyrimidine-4-carboxamide






 


Example 119
(R)-6-phenoxy-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)nicotinamide






 


Example 120
(R)-5-isobutyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)isoxazole-3-carboxamide






 


Example 121
(R)-2-benzyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)thiazole-4-carboxamide






 


Example 122
(R)-5-methyl-2-phenyl-N-(1- (5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-2H- 1,2,3-triazole-4-carboxamide






 


Example 123
(R)-3-(2-methylthiazol-4-yl)-N- (1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 124
trans-2-(1H-indol-2-yl)-N-((R)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 125
trans-2-(5-fluoro-1H-indol-2-yl)-N- ((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 126
trans-2-(4-fluoro-1H-indol-3-yl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 127
(R)-6-methoxy-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1H- indole-2-carboxamide






 


Example 128
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin- 2-yl)ethyl)benzo[b]thiophene-2- carboxamide






 


Example 129
(R)-3-(benzyloxy)-4-methoxy- N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 130
(R)-4-phenoxy-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 131
(R)-3-phenoxy-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 132
(R)-5-tert-butyl-2-methoxy-N-(1- (5-(2,2,2-trifluoroethoxy)pyridin- 2-yl)ethyl)benzamide






 


Example 133
(1S*,2S*)-2-(1H-indol-3-yl)-N- ((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 134
(1R*,2R*)-2-(1H-indol-3-yl)-N- ((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 135
(R)-5-chloro-1-methyl-N-(1-(5- (2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indole-3-carboxamide






 


Example 136
(R)-5-methoxy-1-methyl-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)-1H-indole-3-carboxamide






 


Example 137
(R)-1,6-dimethyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1H- indole-3-carboxamide






 


Example 138
(R)-6-fluoro-1-methyl-N-(1-(5- (2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1H- indole-3-carboxamide






 


Example 139
(R)-6-chloro-1-methyl-N-(1-(5- (2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indole-3-carboxamide






 


Example 140
(R)-5-methyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1H- indole-3-carboxamide






 


Example 141
(R)-5-fluoro-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indole-3-carboxamide






 


Example 142
(R)-5-chloro-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indole-3-carboxamide






 


Example 143
(R)-5-methoxy-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indole-3-carboxamide






 


Example 144
(R)-6-chloro-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indole-3-carboxamide






 


Example 145
trans-2-(1H-indazol-3-yl)-N-((R)- 1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 146
(R)-6-fluoro-N-(1-(6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)- 1H-indole-2-carboxamide






 


Example 147
trans-2-(1H-indol-6-yl)-N-((R)-1-(6- (2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 148
(R)-1,5-dimethyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indole-2-carboxamide






 


Example 149
(R)-5-fluoro-1-methyl-N-(1-(5- (2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indole-2-carboxamide






 


Example 150
(R)-5-chloro-1-methyl-N-(1-(5- (2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indole-2-carboxamide






 


Example 151
(R)-6-fluoro-1-methyl-N-(1-(5- (2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indole-2-carboxamide






 


Example 152
(R)-1,2,3-trimethyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indole-5-carboxamide






 


Example 153
(R)-6-methyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indole-2-carboxamide






 


Example 154
(R)-6-chloro-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indole-2-carboxamide






 


Example 155
(R)-4-fluoro-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indole-2-carboxamide






 


Example 156
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 4-(trifluoromethoxy)benzamide






 


Example 157
(R)-5-phenyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)isoxazole-3-carboxamide






 


Example 158
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin- 2-yl)ethyl)-5-(trifluoromethoxy)- 1H-indole-2-carboxamide






 


Example 159
(R)-5-bromo-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indole-2-carboxamide






 


Example 160
(R)-1,6-dimethyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indole-2-carboxamide






 


Example 161
(R)-6-chloro-1-methyl-N-(1-(5- (2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indole-2-carboxamide






 


Example 162
(R)-1-methyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin- 2-yl)ethyl)-5-(trifluoromethoxy)- 1H-indole-2-carboxamide






 


Example 163
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 3-(trifluoromethoxy)benzamide






 


Example 164
(R)-1,5-dimethyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indazole-3-carboxamide






 


Example 165
(R)-5-chloro-1-methyl-N-(1-(5- (2,2,2- trifluomethoxy)pyridin-2-yl)ethyl)- 1H-indazole-3-carboxamide






 


Example 166
trans-2-(quinolin-7-yl)-N-((R)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarbaxamide






 


Example 167
trans-2-(1-methyl-1H-indol-6-yl)-N- ((R)-1-(5-(2,2,2-trifluoroethoxy) pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 168
trans-2-(6-fluoro-1H-indol-3-yl)-N- ((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 169
trans-2-((4-chlorophenoxy)methyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 170
trans-2-(quinolin-7-yl)-N-((R)-1-(5- (2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 171
trans-2-(5-fluoro-1H-indol-2-yl)-N- ((R)-1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 172
trans-2-(isoquinolin-3-yl)-N- ((R)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 173
trans-2-(quinolin-3-yl)-N-(R)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 174
trans-2-(quinolin-3-yl)-N-((R)-1-(5- (2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 175
trans-2-((4-chlorophenoxy)methyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 176
trans-2-(3- (difluoromethoxy)phenyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 177
trans-2-(2-fluoro-5-methoxyphenyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 178
(R)-6-chloro-1-methyl-N-(1-(5- (2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indazole-3-carboxamide






 


Example 179
(R)-4-tert-butyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)benzamide






 


Example 180
(R)-6-fluoro-N-(1-(5-(2,2,2- trifluoroethoxy)pyrazin-2-yl)ethyl)- 1H-indole-2-carboxamide






 


Example 181
trans-N-((R)-1-(5- (cyclopropylmethoxy)pyridin- 2-yl)ethyl)-2-(5-fluoro-1H-indol-2- yl)cyclopropanecarboxamide






 


Example 182
trans-2-((1H-indol-1-yl)methyl)-N- ((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 183
(R)-6-fluoro-1-methyl-N-(1-(5- (2,2,2- trifluoroethoxy)pyrazin-2-yl)ethyl)- 1H-indole-2-carboxamide






 


Example 184
(R)-4-tert-butyl-N-(1-(5- (cyclopropylmethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 185
(R)-N-(1-(5-(cyclopropylmethoxy) pyridin-2-yl)ethyl)-6-fluoro-1H- indole-2-carboxamide






 


Example 186
(R)-N-(1-(5-(cyclopropylmethoxy) pyridin-2-yl)ethyl)-6-fluoro-1- methyl-1H-indole-2-carboxamide






 


Example 187
trans-2-(1H-indol-6-yl)-N-(R)-1-(5- (2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 188
trans-N-((R)-1-(5- (cyclopropylmethoxy)pyridin- 2-yl)ethyl)-2-(1H-indol-6- yl)cyclopropanecarboxamide






 


Example 189
trans-2-(1-((3-methyloxetan-3- yl)methyl)- 1H-indol-6-yl)-N-((R)-1-(5-(2,2,2- trifluoro-ethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 190
trans-2-(1-((3-methyloxetan-3- yl)methyl)-1H- indol-6-yl)-N-((R)-1-(5-(2,2,2- trifluoro-ethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 191
trans-N-((R)-1-(5- (cyclopropylmethoxy) pyridin-2-yl)ethyl)-2-(1-((3- methyloxetan-3- yl)methyl)-1H-indol-6- yl)cyclopropanecarboxamide






 


Example 192
trans-N-((R)-1-(5- (cyclopropylmethoxy) pyridin-2-yl)ethyl)-2-(1-methyl-1H- indol-6- yl)cyclopropanecarboxamide






 


Example 193
trans-N-((R)-1-(5- (cyclopropylmethoxy) pyridin-2-yl)ethyl)-2-(3,5- difluorophenyl) cyclopropanecarboxamide






 


Example 194
trans-2-(3,5-difluorophenyl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 195
trans-2-(2,5-difluorophenyl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 196
trans-N-((R)-1-(5- (cyclopropylmethoxy) pyridin-2-yl)ethyl)-2-(2,5- difluorophenyl) cyclopropanecarboxamide






 


Example 197
trans-2-(2,5-difluorophenyl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 198
(R)-N-(1-(5-(2,2,2-trifluoroethoxy) pyridin-2-yl)ethyl)-6- (trifluoromethoxy)- 1H-indazole-3-carboxamide






 


Example 199
(R)-1-methyl-N-(1-(5-(2,2,2- trifluoroethoxy) pyridin-2-yl)ethyl)-6- (trifluoromethoxy)- 1H-indazole-3-carboxamide






 


Example 200
trans-2-(2-(isopropylamino)pyridin- 4-yl)-N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 201
trans-N-((R)-1-(5- (cyclopropylmethoxy) pyridin-2-yl)ethyl)-2-(1H-indol-4- yl)cyclopropanecarboxamide






 


Example 202
trans-2-(4-methoxy-3- methylphenyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 203
(1S*,2S*)-2-(1H-indol-6-yl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 204
(1R*,2R*)-2-(1H-indol-6-yl)-N- ((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 205
trans-2-(quinolin-2-yl)-N-((R)-1-(6- (2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 206
trans-2-(quinolin-7-yl)-N-((R)-1-(6- (2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 207
trans-2-(quinolin-6-yl)-N-((R)-1-(6- (2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 208
trans-2-(1-methyl-1H-indol-6-yl)- N-((R)-1-(6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 209
trans-2-((4-chlorophenoxy)methyl)- N-((R)-1-(6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 210
trans-2-(5-fluoro-1H-indol-2-yl)-N- ((R)-1-(6-(2,2,2- trifluoroethoxy)pridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 211
trans-2-(quinolin-3-yl)-N-((R)-1-(6- (2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 212
trans-2-(1H-indol-7-yl)-N-((R)-1-(6- (2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 213
trans-2-(1-((3-methyloxetan-3- yl)methyl)- 1H-indol-6-yl)-N-((R)-1-(6-(2,2,2- trifluoro-ethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 214
trans-2-(1H-indol-4-yl)-N-((R)-1-(6- (2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 215
(1S*,2S*)-2-(8-chloroquinolin-2- yl)-N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 216
(R)-6-fluoro-1-methyl-N-(1-(6- (2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)-1H- indole-2-carboxamide






 


Example 217
(R)-5-methoxy-N-(1-(6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)- 1H-indole-2-carboxamide






 


Example 218
(R)-N-(1-(6-(2,2,2-trifluoroethoxy) pyridin-3-yl)ethyl)benzo[b] thiophene-2-carboxamide






 


Example 219
(R)-N-(1-(6-(2,2,2-trifluoroethoxy) pyridin-3-yl)ethyl)-4- (trifluoromethoxy)benzamide






 


Example 220
(R)-3-phenoxy-N-(1-(6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)benzamide






 


Example 221
(R)-6-methoxy-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)quinoline-2-carboxamide






 


Example 222
(1R*,2R*)-2-(quinolin-2-yl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 223
(1S*,2S*)-2-(1H-indol-2-yl)- N-((R)-1- (6-(2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 224
(1R*,2R*)-2-(1H-indol-2-yl)- N-((R)-1- (6-(2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 225
(1S*,2S*)-2-(1H-indol-2-yl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 226
(1R*,2R*)-2-(1H-indol-2-yl)-N- ((R)-1- (5-(2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 227
(1S*,2S*)-2-(1-methyl-1H-indazol- 6-yl)-N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 228
trans-2-(1-methyl-1H-indazol-6-yl)- N-((R)-(6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 229
trans-2-(1-methyl-1H-indazol-6-yl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxemide






 


Example 230
trans-N-((R)-1-(5- (cyclopropylmethoxy)pyridin- 2-yl)ethyl)-2-(1-methyl-1H- indazol-6- yl)cyclopropanecarboxamide






 


Example 231
(R)-3-(pyridin-2-yloxy)-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 232
(R)-4-(tetrahydro-2H-pyran-4- yloxy)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin- 2-yl)ethyl)benzamide






 


Example 233
(R)-N-(1-(5-(2,2,2-trifluoroethoxy) pyridin-2-yl)ethyl)pyrazolo[1,5-a] pyridine-2-carboxamide






 


Example 234
(R)-N-(1-(5-(2,2,2-trifluoroethoxy) pyridin-2-yl)ethyl)pyrazolo[1,5-a] pyridine-7-carboxamide






 


Example 235
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin- 2-yl)ethyl)-1-(2- (trifluoromethyl)phenyl)- 1H-imidazole-2-carboxamide






 


Example 236
(R)-4-methyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 4H- thieno[3,2-b]pyrrole-5-carboxamide






 


Example 237
(1S*,2S*)-2-(4-(benzyloxy)phenyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 238
(1R*,2R*)-2-(4-(benzyloxy)phenyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 239
(R,E)-3-(quinolin-2-yl)-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)acrylamide






 


Example 240
(1S*,2S*)-2-(3-(benzyloxy)phenyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 241
(1R*,2R*)-2-(3-(benzyloxy)phenyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 242
(1S*,2S*)-2-(4-hydroxyphenyl)-N- ((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 243
trans-2-(1-methyl-1H- benzo[d]imidazol- 2-yl)-N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 244
trans-2-(1-methyl-1H- benzo[d]imidazol- 2-yl)-N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 245
trans-2-(1-methyl-1H- benzo[d]imidazol-2- yl)-N-((R)-1-(6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 246
(1S*,2S*)-2-(2-chloro-4- fluorophenyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 247
(1R*,2R*)-2-(2-chloro-4- fluorophenyl)-N- ((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 248
(1S*,2S*)-2-(2-fluoro-4- methoxyphenyl)-N- ((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 249
(1R*,2R*)-2-(2-fluoro-4- methoxyphenyl)-N- ((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 250
(1S*,2S*)-N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin- 2-yl)ethyl)-2-(2,4,6- trifluorophenyl) cyclopropanecarboxamide






 


Example 251
(1S*,2S*)-2-m-tolyl-N-((R)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 252
(1R*,2R*)-2-m-talyl-N-((R)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 253
(1S*,2S*)-2-(3,5-difluorophenyl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 254
(1R*,2R*)-2-(3,5-difluorophenyl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 255
(1S*,2S*)-2-(3-hydroxyphenyl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 256
(1S*,2S*)-2-(4-(2-(4,4- difluoropiperidin-1- yl)-2-oxoethoxy)phenyl)-N-((R)- 1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 257
(1S*,2S*)-2-(3-(2-(4,4- difluoropiperidin-1- yl)-2-oxoethoxy)phenyl)-N-((R)- 1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 258
(1S*,2S*)-2-(3-methoxyphenyl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 259
(1S*,2S*)-2-(4-methoxyphenyl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 260
(1R*,2R*)-2-(1H-benzo[d]imidazol- 2-yl)-N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 261
(1S*,2S*)-2-(2-chloro-4- fluorophenyl)-N-((R)-1-(5- (cyclopropylmethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 262
(1S*,2S*)-2-(2-chloro-4- fluorophenyl)-N-((R)-1-(5- (cyclopropylmethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 263
(1S*,2S*)-N-((R)-1-(5- (cyclopropylmethoxy)pyridin- 2-yl)ethyl)-2-(2-fluoro-4-methoxy- phenyl)cyclopropanecarboxamide






 


Example 264
(1R*,2R*)-N-((R)-1-(5- (cyclopropylmethoxy)pyridin- 2-yl)ethyl)-2-(2-fluoro-4-methoxy- phenyl)cyclopropanecarboxamide






 


Example 265
(1S*,2S*)-N-((R)-1-(5- (cyclopropylmethoxy)pyridin- 2-yl)ethyl)-2-(2,4,6-trifluorophenyl) cyclopropanecarboxamide






 


Example 266
(1R*,2R*)-N-((R)-1-(5- (cyclopropylethoxy) pyridin-2-yl)ethyl)-2-(2,4,6- trifluorophenyl) cyclopropanecarboxamide






 


Example 267
(1S*,2S*)-N-((R)-1-(5- (cyclopropylmethoxy) pyridin-2-yl)ethyl)-2-m- tolylcyclopropanecarboxamide






 


Example 268
(1S*,2S*)-2-(2-chloro-4- fluorophenyl)-N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 269
(1R*,2R*)-2-(2-chloro-4- fluorophenyl)-N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 270
(1S*,2S*)-2-(2-fluoro-4- methoxyphenyl)-N- ((R)-1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 271
(1S*,2S*)-N-((R)-1-(5-(2,2,2- trifluoroethoxy) pyrazin-2-yl)ethyl)-2-(2,4,6- trifluorophenyl) cyclopropanecarboxamide






 


Example 272
(1R*,2R*)-N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyrazin- 2-yl)ethyl)-2-(2,4,6- trifluorophenyl) cyclopropanecarboxamide






 


Example 273
(1S*,2S*)-2-m-tolyl-N-((R)-1-(5- (2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 274
(1R*,2R*)-2-m-tolyl-N-((R)-1-(5- (2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 275
(1S*,2S*)-2-(1H-indol-7-yl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 276
(1R*,2R*)-2-(1H-indol-7-yl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 277
(1R*,2R*)-2-(1H-indol-4-yl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 278
(1S*,2S*)-2-(1H-indol-4-yl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 279
(1R*,2R*)-2-(1H-Indol-4-yl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 280
(1S*,2S*)-2-phenyl-N-((R)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 281
(1R*,2R*)-2-phenyl-N-((R)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 282
(1S*,2S*)-2-phenyl-N-((R)-1-(5- (2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 283
(1R*,2R*)-2-phenyl-N-((R)-1-(5- (2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 284
(1S*,2S*)-2-phenyl-N-((R)-1-(6- (2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 285
(1R*,2R*)-2-phenyl-N-((R)-1-(6- (2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 286
(1S*,2S*)-2-(1H-benzo[d]imidazol- 2-yl)-N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyrazin- 2-yl)ethyl)cyclopropanecarboxamide






 


Example 287
(1S*,2S*)-2-(1H-benzo[d]imidazol- 2-yl)-N-((R)-1-(6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 288
(1R*,2R*)-2-(1H-benzo[d]imidazol- 2-yl)-N-((R)-1-(6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 289
(1R*,2R*)-2-(5-fluoro-1H- benzo[d]imidazol-2-yl)- N-((R)-1-(6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl) cyclopropanecarboxamide






 


Example 290
(1S*,2S*)-2-(5-fluoro-1H- benzo[d]imidazol-2-yl)- N-((R)-1-(6-(2,2,2-trifluoro- ethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 291
(1R*,2R*)-2-(5-cyano-1H- benzo[d]imidazol-2-yl)-N- ((R)-1-(5-(2,2,2-trifluoroethoxy) pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 292
(R)-4-tert-butyl-N-(1-(5-hydroxy- pyridin-2-yl)ethyl)benzamide






 


Example 293
(1S*,2S*)-2-(phenoxymethyl)- N-((R)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 294
(1S*,2S*)-2-((3- fluorophenoxy)methyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 295
(1S*,2S*)-2-((3- cyanophenoxy)methyl)-N- ((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanacarboxamide






 


Example 296
(1S*,2S*)-2-((4- fluorophenoxy)methyl)-N- ((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 297
(1S*,2S*)-2-((4- cyanophenoxy)methyl)-N- ((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 298
(1R*,2R*)-2-(phenoxymethyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Exemple 299
(1R*,2R*)-2-((3- fluorophenoxy)methyl)-N- ((R)-1-(5-(2,2,2- trifluomethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 300
(1R*,2R*)-2-((3- cyanophenoxy)methyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 301
(1R*,2R*)-2-((4- fluorophenoxy)methyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 302
(1R*,2R*)-2-((4- cyanophenoxy)methyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 303
(1S*,2S*)-2-(3-((3-methyloxetan-3- yl)methoxy)phenyl)-N-((R)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 304
(1S*,2S*)-2-(4-((3-methyloxetan-3- yl)methoxy)phenyl)-N-((R)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 305
(1S*,2S*)-2-(4-(pyridin-2- ylmethoxy)phenyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 306
(1S*,2S*)-2-(3-(pyridin-2- ylmethoxy)phenyl)-N-((R)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 307
(1S*,2S*)-N-((R)-1-(5-(cyclopropyl- methoxy)pyridin-2-yl)ethyl)-2-(4- methoxy-3-methylphenyl) cyclopropanecarboxamide






 


Example 308
(1R*,2R*)-N-((R)-1-(5- (cyclopropylmethoxy) pyridin-2-yl)ethyl)-2-(4-methoxy-3- methylphenyl) cyclopropanecarboxamide






 


Example 309
(1S*,2S*)-2-(4-methoxy-3- methylphenyl)- N-((R)-1-(5-(2,2,2- trifluomethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 310
(1R*,2R*)-2-(4-methoxy-3- methylphenyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 311
tert-butyl (R)-1-oxo-3-phenyl-1- ((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethylamino)propan-2-ylcarbamate






 


Example 312
tert-butyl (S)-1-oxo-3-phenyl-1- ((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethylamino)propan-2-ylcarbamate






 


Example 313
(R)-N-(1-(5-(benzyloxy)pyridin-2- yl)ethyl)-4-tert-butylbenzamide






 


Example 314
(R)-4-tert-butyl-N-(1-(5-(pyridin-2- yl-methoxy)pyridin-2- yl)ethyl)benzamide






 


Example 315
(R)-4-tert-butyl-N-(1-(5- methoxypyridin-2- yl)ethyl)benzamide






 


Example 316
(1S*,2S*)-N-((R)-1-(5- (cyclopropylmethoxy) pyridin-2-yl)ethyl)-2-(1H-indol-7- yl)cyclopropanecarboxamide






 


Example 317
(1R*,2R*)-N-((R)-1-(5- (cyclopropylmethoxy) pyridin-2-yl)ethyl)-2-(1H-indol-7- yl)cyclopropanecarboxamide






 


Example 318
(1S*,2S*)-2-(phenoxymethyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 319
(1R*,2R*)-2-(phenoxymethyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 320
(1S*,2S*)-2-(phenoxymethyl)- N-((R)-1-(6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Example 321
(1R*,2R*)-2-(phenoxymethyl)- N-((R)-1-(6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)cyclopropanecarboxamide






 


Exemple 322
(1S*,2S*)-2-(1H-indol-7-yl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 323
(1R*,2R*)-2-(1H-indol-7-yl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 324
(1S*,2S*)-2-(quinolin-2-yl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 325
(1R*,2R*)-2-(quinolin-2-yl)- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 326
(1R*,2R*)-N-((R)-1-(5- (cyclopropyl-methoxy)pyridin-2- yl)ethyl)-2-m- tolylcyclopropanecarboxamide






 


Example 327
(1S*,2S*)-2-(2,5-difluorophenyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 328
(1R*,2R*)-2-(2,5-difluorophenyl)- N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 329
4-(benzyloxy)-3-methoxy-N-((6- (trifluoromethyl)pyridin-3- yl)methyl)benzamide






 


Example 330
2-(4-(trifluoromethyl)phenoxy)-N- ((6-(trifluoromethyl)pyridin-3- yl)methyl)acetamide






 


Example 331
N-(5,6,7,8-tetrahydroquinolin-8- yl)-2-(4-(trifluoromethyl)phenoxy) acetamide






 


Example 332
2-(4-(tert-butyl)phenyl)-N- (5,6,7,8-tetrahydroquinolin-8- yl)cyclopropanecarboxamide






 


Example 333
(R)-N-(1-(6-methyl-3-(2,2,2- trifluoroethoxy)pyridin- 2-yl)ethyl)-2-(4- (trifluoromethyl)phenoxy)acetamide






 


Example 334
(R)-5-fluoro-N-(1-(8-methyl-3- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)-1H-indole-2-carboxamide






 


Example 335
(R)-1-benzyl-2-oxo-N-(1-(5-(2,2,2- trifluoro-ethoxy)pyridin-2-yl)ethyl)- 1,2-dihydropyridine-3-carboxamide






 


Example 336
(R)-1-benzyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)piperidine-4-carboxamide






 


Example 337
(S)-3-phenoxy-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 338
(S)-4-isopropyl-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 339
(S)-N-(1-(5-(2,2,2-trifluoroethoxy) pyridin-2-yl)ethyl)-2-(2- (trifluoromethyl)phenoxy)acetamide






 


Example 340
(S)-2-(4-chlorophenoxy)-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)acetamide






 


Example 341
(S)-2-(4-chloro-3-(trifluoromethyl) phenoxy)-N-(1-(5-(2,2,2- trifluoroethoxy) pyridin-2-yl)ethyl)acetamide






 


Example 342
(S)-6-methoxy-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)quinoline-2-carboxamide






 


Example 343
(S)-4-(2,2,2-trifluoroethoxy)-N-(1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 344
(S)-5-(2,2,2-trifluoroethoxy)-N-(1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)picolinamide






 


Example 345
(1S*,2S*)-2-(3-(benzyloxy)phenyl)- N-((S)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 346
(1R*,2R*)-2-(3-(benzyloxy)phenyl)- N-((S)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 347
(1S*,2S*)-2-(4-(benzyloxy)phenyl)- N-((S)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 348
(1R*,2R*)-2-(4-(benzyloxy)phenyl)- N-((S)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 349
(1S*,2S*)-2-(2-fluoro-4- methoxyphenyl)-N- ((S)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 350
(1R*,2R*)-2-(2-fluoro-4- methoxyphenyl)- N-((S)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 351
(1S*,2S*)-2-(2-chloro-4- fluorophenyl)-N- ((S)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 352
(1R*,2R*)-2-(2-chloro-4- fluorophenyl)-N- ((S)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 353
(1S*,2S*)-2-phenyl-N-((S)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 354
(1R*,2R*)-2-phenyl-N-((S)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 355
tert-butyl((R)-1-oxo-1-(((R)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)amino)-3-(2- (trifluoromethoxy)phenyl)propan- 2-yl)carbamate






 


Example 356
tert-butyl ((R)-1-oxo-1-(((R)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)amino)-3-(2- (trifluoromethyl)phenyl)propan-2- yl)carbamate






 


Example 357
(1R*,2R*)-2-(3-methoxyphenyl)- N-((R)- 1-(5-(2,2,2-trifluoroethoxy)pyridin- 2-yl)ethyl)cyclopropanecarboxamide






 


Example 358
(R)-2-amino-N-((R)-1-(5-(2,2,2- trifluoroethoxy) pyridin-2-yl)ethyl)-3-(2- (trifluoromethoxy) phenyl)propanamide






 


Example 359
(R)-N-(1-(5-(benzyloxy)pyridin-2- yl)ethyl)-3-phenoxybenzamide






 


Example 360
(R)-N-(1-(5-methoxypyridin-2- yl)ethyl)-3-phenoxybenzamide






 


Example 361
(S)-2-(dimethylamino)-3-phenyl- N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)propanamide






 


Example 362
(R)-2-hydroxy-4-phenyl-N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)butanamide






 


Example 363
(S)-6-fluoro-1-methyl-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)-1H-indole-2-carboxamide






 


Example 364
(S)-4-(tert-butyl)-2-methoxy-N- (1-(5-(2,2,2-trifluoroethoxy)pyridin- 2-yl)ethyl)benzamide






 


Example 365
tert-butyl ((S)-3-oxo-3-(((R)-1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)amino)-1-(4-(trifluoro- methyl)phenyl)propyl)carbamate






 


Example 366
tert-butyl ((S)-1-(4-chlorophenyl)- 3-oxo-3-(((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin- 2-yl)ethyl)amino)propyl)carbamate






 


Example 367
tert-butyl ((R)-1-(4-chlorophenyl)- 3-oxo-3-(((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)amino)propyl)carbamate






 


Example 368
tert-butyl ((R)-3-oxo-3-(((R)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)amino)-1-(4- (trifluoromethyl)phenyl) propylcarbamate






 


Example 369
tert-butyl ((3)-3-(4-fluorophenyl)- 1-oxo-1-(((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)amino)propan-2- yl)carbamate






 


Example 370
tert-butyl ((S)-3-(4-chlorophenyl)- 1-oxo-1-(((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)amino)propan-2- yl)carbamate






 


Example 371
tert-butyl ((R)-3-(4-chlorophenyl)- 1-oxo-1-(((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)amino)propan-2- yl)carbamate






 


Example 372
tert-butyl ((S)-1-oxo-1-(((R)-1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)amino)-3-(4- (trifluoromethyl)phenyl) propan-2-yl)carbamate






 


Example 373
tert-butyl ((S)-3-(2-chlorophenyl)- 1-oxo-1-(((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)amino)propan-2- yl)carbamate






 


Example 374
tert-butyl((S)-3-(2-fluorophenyl)- 1-oxo-1-(((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)amino)propan-2- yl)carbamate






 


Example 375
tert-butyl ((S)-3-(3-chlorophenyl)- 1-oxo-1-(((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)amino)propan-2- yl)carbamate






 


Example 376
tert-butyl ((3)-1-oxo-1-(((R)-1- (5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)amino)-3-(2- (trifluoromethyl)phenyl)propan-2- yl)carbamate






 


Example 377
tert-butyl ((S)-1-oxo-1-(((R)-1- (5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)amino)-3-(3- (trifluoromethyl)phenyl)propan- 2-yl)carbamate






 


Example 378
(R)-2-(2-chlorophenoxy)-N-(1- (5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)acetamide






 


Example 379
(R)-2-(3-chlorophenoxy)-N-(1- (5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)acetamide






 


Example 380
(R)-2-(2-chlorophenoxy)-2-methyl- N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)propanamide






 


Example 381
(R)-2-(2,3-dichlorophenoxy)-N-(1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)acetamide






 


Example 382
(R)-2-(o-tolyloxy)-N-(1-(5-(2,2,2- trifluoroethoxy) pyridin-2-yl)ethyl)acetamide






 


Example 383
(R)-2-(m-tolyloxy)-N-(1-(5-(2,2,2- trifluoroethoxy) pyridin-2-yl)ethyl)acetamide






 


Example 384
(R)-2-(2,4-dimethylphenoxy)-N- (1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)acetamide






 


Example 385
(R)-2-(3,5-dimethylphenoxy)-N-(1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)acetamide






 


Example 386
(R)-2-(2-chloro-6- methylphenoxy)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)acetamide






 


Example 387
(R)-2-(4-(tert-butyl)phenoxy)-N- (1-(5-methoxypyridin-2- yl)ethyl)acetamide






 


Example 388
(R)-2-amino-N-((R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-3-(2-(trifluoromethyl) phenyl)propanamide






 


Example 389
isobutyl ((R)-1-oxo-1-(((R)-1-(5- (2,2,2-trifluoro- ethoxy)pyridin-2-yl)ethyl)amino)- 3-(2-(trifluoromethyl) phenyl)propan-2-yl)carbamate






 


Example 390
ethyl ((R)-1-oxo-1-(((R)-1-(5- (2,2,2-trifluoro- ethoxy)pyridin-2-yl)ethyl)amino)- 3-(2-(trifluoromethyl) phenyl)propan-2-yl)carbamate






 


Example 391
N-((5-(2,2,2-trifluoroethoxy)pyridin- 2-yl)methyl)-4- (trifluoromethoxy)benzamide






 


Example 392
N-((5-(2,2,2-trifluoroethoxy)pyridin- 2-yl)methyl)-3- (trifluoromethoxy)benzamide






 


Example 393
4-(2,2,2-trifluoroethoxy)-N-((5- (2,2,2-trifluoroethoxy)pyridin-2- yl)methyl)benzamide






 


Example 394
6-fluoro-1-methyl-N-((5-(2,2,2- trifluoroethoxy) pyridin-2-yl)methyl)-1H-indole-2- carboxamide






 


Example 395
N-((5-(2,2,2-trifluoroethoxy)pyridin- 2-yl)methyl)-2-(4- (trifluoromethyl)phenoxy)ecetamide






 


Example 396
4-(tert-butyl)-2-methoxy-N-((5- (2,2,2-trifluoroethoxy)pyridin-2- yl)methyl)benzamide






 


Example 397
4-(tert-butyl)-N-((5-(2,2,2- trifluoroethoxy) pyridin-2-yl)methyl)benzamide






 


Example 398
3-(2,2,2-trifluoroethoxy)-N-((5- (2,2,2-trifluoroethoxy)pyridin-2- yl)methyl)benzamide






 


Example 399
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-2-(3- (trifluoromethoxy)phenoxy) acetamide






 


Example 400
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-2-(3- (trifluoromethyl)phenoxy)acetamide






 


Example 401
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-2-(2- (trifluoromethoxy)phenoxy) acetamide






 


Example 402
(R)-N-(1-(5-methoxypyridin-2- yl)ethyl)-2-(3- (trifluoromethyl)phenoxy)acetamide






 


Example 403
(R)-N-(1-(5-methoxypyridin-2-yl) ethyl)-2-(2-(trifluoromethoxy) phenoxy)acetamide






 


Example 404
(R)-3-(4-chlorophenoxy)-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)propanamide






 


Example 405
(R)-3-(2,2,2-trifluoroethoxy)-N-(1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 406
(R)-2-(2-(tert-butyl)phenoxy)-N- (1-(5-methoxypyridin-2- yl)ethyl)acetemide






 


Example 407
(R)-N-(1-(5-methoxypyridin-2- yl)ethyl)-2-(2- (trifluoromethyl)phenoxy)acetamide






 


Example 408
(R)-N-(1-(5-methoxypyridin-2- yl)ethyl)-2-(3- trifluoromethoxy)phenoxy) acetamide






 


Example 409
(R)-N-(1-(5-methoxypyridin-2- yl)ethyl)-2- (4-(trifluoromethyl)phenyl)thiazole- 4-carboxamide






 


Example 410
(R)-N-(1-(5-methoxypyridin-2- yl)ethyl)-5- phenylisoxazole-3-carboxamide






 


Example 411
(R)-N-(1-(5-methoxypyridin-2- yl)ethyl)-5- methyl-2-phenyl-2H-1,2,3-triazole- 4-carboxamide






 


Example 412
(R)-N-(1-(5-methoxypyridin-2- yl)ethyl)-5- (trifluoromethoxy)-1H-indole-2- carboxamide






 


Example 413
(R)-N-(1-(5-methoxypyridin-2- yl)ethyl)-1- methyl-5-(trifluoromethoxy)-1H- indole-2-carboxamide






 


Example 414
(R)-6-(tert-butyl)-N-(1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)nicotinamide






 


Example 415
(R)-2-(4-chlorophenoxy)-N-(1-(5- (2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)acetamide






 


Example 416
(R)-5-(2,2,2-trifluoroethoxyl)-N-(1- (5-(2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)picolinamide






 


Example 417
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)-2-(4- (trifluoromethyl)phenoxy)acetamide






 


Example 418
(R)-N-(1-(5-(2,2,2-trifluoroethoxy) pyrazin-2-yl)ethyl)-3- (trifluoromethoxy)benxamide






 


Exemple 419
(R)-4-fluoro-3-phenoxy-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Exemple 420
(R)-3-(4-fluorophenoxy)-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 421
4-(tert-butyl)-N-((6- methoxypyridin-3- yl)methyl)benzamide






 


Example 422
N-((6-methoxypyridin-3- yl)methyl)-2-(4- (trifluoromethyl)phenoxy)acetamide






 


Example 423
4-(tert-butyl)-N-((5- methoxypyridin-2- yl)methyl)benzamide






 


Example 424
(R)-6-fluoro-N,1-dimethyl-N-(1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)-1H-indole-2-carboxamide






 


Example 425
(1S*,2S*)-N-methyl-2-(quinolin-2- yl)-N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 426
(1R*,2R*)-N-methyl-2-(quinolin-2- yl)-N-((R)-1- (5-(2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)cyclopropanecarboxamide






 


Example 427
(S)-4-(tert-butyl)-N-(1-(5-(2,2,2- trifluoroethoxy) pyridin-2-yl)ethyl)benzamide






 


Example 428
(S)-N-(1-(5-(2,2,2-trifluoroethoxy) pyridin-2-yl)ethyl)-3- (trifluoromethoxy)benzamide






 


Example 429
(S)-N-(1-(5-(2,2,2-trifluoroethoxy) pyridin-2-yl)ethyl)-4- (trifluoromethoxy)benzamide






 


Example 430
(5)-3-(2,2,2-trifluoroethoxy)-N-(1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 431
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)-4- (trifluoromethoxy)benzamide






 


Example 432
(R)-4-(2,2,2-trifluoroethoxy)-N-(1- (5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)benzamide






 


Example 433
(R)-3-(2,2,2-N-(1-trifluoroethoxy)- N-(1- (5-(2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)benzamide






 


Example 434
4-(tert-butyl)-N-((5- (trifluoromethyl) pyridin-2-yl)methyl)benzamide






 


Example 435
3-(trifluoromethoxy)-N-((5- (trifluoromethyl) pyridin-2-yl)methyl)benzamide






 


Example 436
4-(trifluoromethoxy)-N-((5- (trifluoromethyl) pyridin-2-yl)methyl)benzamide






 


Example 437
4-(2,2,2-trifluoroethoxy)-N-((5- (trifluoromethyl) pyridin-2-yl)methyl)benzamide






 


Example 438
3-(2,2,2-trifluoroethoxy)-N-((5- (trifluoromethyl) pyridin-2-yl)methyl)benzamide






 


Example 439
4-(tert-butyl)-N-((6-(piperidin-1- yl)pyridin-3-yl)methyl)benzamide






 


Example 440
N-((6-(piperidin-1-yl)pyridin-3- yl)methyl)- 3-(trifluoromethoxy)benzamide






 


Example 441
N-((6-(piperidin-1-yl)pyridin-3- yl)methyl)-4- (2,2,2-trifluoroethoxy)benzamide






 


Example 442
4-(tert-butyl)-N-((6-(pyrrolidin-1- yl)pyridin-3-yl)methyl)benzamide






 


Example 443
N-((6-(pyrrolidin-1-yl)pyridin-3- yl)methyl)-3- (trifluoromethoxy)benzamide






 


Example 444
N-((6-(pyrrolidin-1-yl)pyridin-3- yl)methyl)-4- (2,2,2-trifluoroethoxy)benzamide






 


Example 445
4-(tert-butyl)-N-((6- (trifluoromethyl) pyridin-3-yl)methyl)benzamide






 


Example 446
3-(trifluoromethoxy)-N-((6- (trifluoromethyl) pyridin-3-yl)methyl)benzamide






 


Example 447
4-(tert-butyl)-N-((6-(pyrrolidin-1- yl)pyridin-2-yl)methyl)benzamide






 


Example 448
N-((6-(pyrrolidin-1-yl)pyridin-2-yl) methyl)-3- (trifluoromethoxy)benzamide






 


Example 449
N-((6-(pyrrolidin-1-yl)pyridin-2- yl)methyl)-4- (2,2,2-trifluoroethoxy)benzamide






 


Example 450
(R)-4-chloro-2-methoxy-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 451
(N)-4-(2-cyanopropan-2-yl)-N-(1- (5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 452
(R)-3-chloro-4-methoxy-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 453
(R)-6-methoxy-1-methyl-N-(1-(5- (2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)- 1H-indole-2-carboxamide






 


Example 454
(R)-N-(1-(6-methyl-3-(2,2,2- trifluoroethoxy) pyridin-2-yl)ethyl)-3- (trifluoromethoxy)benzamide






 


Example 455
(R)-N-(1-(6-methyl-3-(2,2,2- trifluoroethoxy) pyridin-2-yl)ethyl)-4-(2,2,2- trifluoroethoxy)benzamide






 


Example 456
(S)-2-(3-chlorophenoxy)-N-(1-(5- (2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)acetamide






 


Example 457
2-(3-chlorophenoxy)-N-((5-(2,2,2- trifluoroethoxy) pyridin-2-yl)methyl)acetamide






 


Example 458
(R)-2-(3-chlorophenoxy)-N-(1-(5- (2,2,2-trifluoroethoxy)pyrazin-2- yl)ethyl)acetamide






 


Example 459
(R)-4-ethyl-N-(1-(5-(2,2,2- trifluoroethoxy) pyridin-2-yl)ethyl)benzamide






 


Example 460
(R)-3-fluoro-4-methyl-N-(1-(5- (2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 461
(R)-5-chloro-2-methoxy-N-(1-(5- (2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)benzamide






 


Example 462
(R)-6-(2,2,2-trifluoroethoxy)-N-(1- (5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)nicotinamide






 


Example 463
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)quinoxaline-2-carboxamide






 


Example 464
(R)-N-(1-(5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)-5- (trifluoromethyl)picolinamide






















Ob-
Re-
Puri-



Structure of
Structure of
served
tention
fication


Example 
amine part
caboxylic acid part
MS
Time
Method





Example  1








372.0
0.85 min
HPLC


 


Example  2








382.0
0.79 min
HPLC


 


Example  3








423.0
0.83 min
HPLC


 


Example  4








461.0
0.82 min
HPLC


 


Example  5








411.0
0.9 min
HPLC


 


Example  6








457.0
0.86 min
HPLC


 


Example  7








393.0
0.86 min
HPLC


 


Example  8








376.0
0.83 min
HPLC


 


Example  9








518.0
2.08 min
HPLC


 


Example  10








447.0
1.91 min
HPLC


 


Example  11








486.0
1.94 min
HPLC


 


Example  12








421.0
1.99 min
HPLC


 


Example  13








381.2
1.89 min
HPLC


 


Example  14








367.2
1.83 min
HPLC


 


Example  15








411.2
2.06 min
HPLC


 


Example  16








423.1
3.24 min
HPLC


 


Example  17








369.1
1.77 min
HPLC


 


Example  18








389.1
1.78 min
HPLC


 


Example  19








423.1
1.73 min
HPLC


 


Example  20








431.1
1.90 min
HPLC


 


Example  21








447.1
1.89 min
HPLC


 


Example  22








411.2
2.04 min
HPLC


 


Example  23








423.1
1.84 min
HPLC


 


Example  24








364.2
1.67 min
HPLC


 


Example  25








382.2
1.69 min
HPLC


 


Example  26








378.2
1.80 min
HPLC


 


Example  27








423.1
1.92 min
HPLC


 


Example  28








433.1
1.80 min
HPLC


 











Example
Alternative route
395.2
1.84 min
HPLC


 29






 












Example  30








371.2
1.65 min
HPLC


 


Example  31








379.2
1.88 min
HPLC


 


Example  32








385.2
1.93 min
HPLC


 


Example  33








392.2
1.59 min
HPLC


 


Example  34








393.2
1.76 min
HPLC


 


Example  35








393.2
1.76 min
HPLC


 


Example  36








459.2
1.96 min
HPLC


 


Example  37








405.2
1.89 min
HPLC


 


Example  38








411.2
1.83 min
HPLC


 


Example  39








411.2
1.81 min
HPLC


 


Example  40








411.2
1.79 min
HPLC


 


Example  41








446.9
1.87 min
HPLC


 


Example  42








446.9
1.89 min
HPLC


 


Example  43








393.9
1.83 min
HPLC


 


Example  44








398.0
1.77 min
HPLC


 


Example  45








394.0
1.64 min
HPLC


 


Example  46








364.0
1.55 min
HPLC


 


Example  47








378.0
1.66 min
HPLC


 


Example  48








382.0
1.70 min
HPLC


 


Example  49








382.0
1.70 min
HPLC


 


Example  50








392.0
1.70 min
HPLC


 


Example  51








378.0
1.76 min
HPLC


 


Example  52








446.0
1.93 min
HPLC


 


Example  53








432.0
1.82 min
HPLC


 


Example  54








446.0
1.81 min
HPLC


 


Example  55








432.9
1.80 min
HPLC


 


Example  56








432.9
1.76 min
HPLC


 


Example  57








406.0
1.65 min
HPLC


 


Example  58








431.9
1.73 min
HPLC


 


Example  59








395.0
1.87 min
HPLC


 


Example  60








364.0
1.62 min
HPLC


 


Example  61








354.0
1.74 min
HPLC


 


Example  62








393.0
2.06 min
HPLC


 


Example  63








430.9
1.94 min
HPLC


 


Example  64








400.0
1.72 min
HPLC


 


Example  65








390.0
1.82 min
HPLC


 


Example  66








429.0
2.11 min
HPLC


 


Example  67








418.9
1.82 min
HPLC


 


Example  68








391.0
1.85 min
HPLC


 


Example  69








427.0
1.92 min
HPLC


 


Example  70








475.9
2.01 min
HPLC


 


Example  71








410.0
1.62 min
HPLC


 


Example  72








382.0
1.64 min
HPLC


 


Example  73








410.0
1.73 min
HPLC


 


Example  74








382.0
1.76 min
HPLC


 


Example  75








486.0
1.81 min
HPLC


 


Example  76








458.1
1.84 min
HPLC


 


Example  77








449.1
3.24 min
HPLC


 


Example  78








436.9
1.92 min
HPLC


 


Example  79








395.9
1.80 min
HPLC


 


Example  80








423.9
1.79 min
HPLC


 











Example
Alternative route
431.9
1.68 min
HPLC


 81






 












Example  82








472.9
2.04 min
HPLC


 


Example  83








420.9
1.77 min
HPLC


 


Example  84








378.9
1.77 min
HPLC


 


Example  85








473.0
2.09 min
HPLC


 


Example  86








418.0
1.79 min
HPLC


 


Example  87








418.0
1.72 min
HPLC


 


Example  88








459.9
1.95 min
HPLC


 


Example  89








389.9
1.60 min
HPLC


 


Example  90








389.9
1.71 min
HPLC


 


Example  91








433.1
3.15 min
HPLC


 


Example  92








433.1
3.32 min
HPLC


 


Example  93








392.2
2.92 min
HPLC


 


Example  94








447.1
3.47 min
HPLC


 


Example  95








408.2
3.04 min
HPLC


 


Example  96








409.2
3.34 min
HPLC


 


Example  97








378.2
2.80 min
HPLC


 


Example  98








368.2
3.09 min
HPLC


 


Example  99








433.2
3.49 min
HPLC


 


Example 100








449.2
3.19 min
HPLC


 


Example 101








418.2
2.77 min
HPLC


 


Example 102








447.2
3.47 min
HPLC


 


Example 103








409.9
1.68 min
HPLC


 


Example 104








406.0
1.70 min
HPLC


 


Example 105








444.1
1.47 min
HPLC


 


Example 105








417.9
1.77 min
HPLC


 


Example 107








451.9
1.92 min
HPLC


 


Example 108








421.9
1.68 min
HPLC


 


Example 109








403.9
1.61 min
HPLC


 


Example 110








421.9
1.65 min
HPLC


 


Example 111








429.0
1.57 min
HPLC


 


Example 112








372.9
1.80 min
HPLC


 


Example 113








381.0
1.98 min
HPLC


 


Example 114








358.9
1.72 min
HPLC


 


Example 115








375.9
1.77 min
HPLC


 


Example 116








376.9
1.70 min
HPLC


 


Example 117








405.9
1.90 min
HPLC


 


Example 118








402.9
1.87 min
HPLC


 


Example 119








417.9
1.72 min
HPLC


 


Example 120








371.9
1.86 min
HPLC


 


Example 121








421.9
1.85 min
HPLC


 


Example 122








405.9
1.92 min
HPLC


 


Example 123








421.9
1.70 min
HPLC


 


Example 124








404.0
1.72 min
HPLC


 


Example 125








422.0
1.72 min
HPLC


 


Example 126








422.0
1.64 min
HPLC


 


Example 127








394.0
1.66 min
HPLC


 


Example 128








380.9
1.78 min
HPLC


 


Example 129








460.9
1.80 min
HPLC


 


Example 130








416.9
1.86 min
HPLC


 


Example 131








416.9
1.88 min
HPLC


 


Example 132








411.0
1.99 min
HPLC


 











Example 133








Confirmed by NMR (see Table 2)
Chiral-HPLC


 


Example 134








Confirmed by NMR (see Table 2)
Chiral-HPLC


 












Example 135








410.1
1.75 min
HPLC


 


Example 136








406.2
1.63 min
HPLC


 


Example 137








390.1
1.74 min
HPLC


 


Example 138








394.1
1.68 min
HPLC


 


Example 139








410.1
1.77 min
HPLC


 


Example 140








376.2
1.62 min
HPLC


 


Example 141








380.2
1.57 min
HPLC


 


Example 142








396.1
1.65 min
HPLC


 


Example 143








392.1
1.53 min
HPLC


 


Example 144








396.1
1.65 min
HPLC


 


Example 145








403.2
1.52 min
HPLC


 


Example 146








380.2
1.78 min
HPLC


 


Example 147








402.2
1.75 min
HPLC


 


Example 148








390.2
1.85 min
HPLC


 


Example 149








394.2
1.80 min
HPLC


 


Example 150








410.1
1.90 min
HPLC


 


Example 151








394.1
1.81 min
HPLC


 


Example 152








404.1
1.77 min
HPLC


 


Example 153








376.0
1.73 min
HPLC


 


Example 154








395.9
1.78 min
HPLC


 


Example 155








380.0
1.71 min
HPLC


 


Example 156








406.9
1.81 min
HPLC


 


Example 157








390.0
1.84 min
HPLC


 


Example 158








445.9
1.83 min
HPLC


 


Example 159








439.8
1.80 min
HPLC


 


Example 160








390.0
1.87 min
HPLC


 


Example 161








410.0
1.90 min
HPLC


 


Example 162








459.9
1.94 min
HPLC


 


Example 163








406.9
1.79 min
HPLC


 


Example 164








393.0
1.81 min
HPLC


 


Example 165








411.1
1.84 min
HPLC


 


Example 166








414.1
1.55 min
HPLC


 


Example 167








418.0
1.74 min
HPLC


 


Example 168








420.1
1.65 min
HPLC


 


Example 169








427.1
1.80 min
HPLC


 


Example 170








415.2
1.62 min
HPLC


 


Example 171








421.1
1.78 min
HPLC


 


Example 172








414.2
1.66 min
HPLC


 


Example 173








414.2
1.58 min
HPLC


 


Example 174








415.1
1.64 min
HPLC


 


Example 175








428.1
1.87 min
HPLC


 


Example 176








429.1
1.72 min
HPLC


 


Example 177








411.1
1.71 min
HPLC


 


Example 178








411.1
1.88 min
HPLC


 


Example 179








380.2
1.96 min
HPLC


 


Example 180








381.1
1.75 min
HPLC


 


Example 181








392.2
1.74 min
HPLC


 


Example 182








416.1
1.75 min
HPLC


 


Example 183








1.88 min
1.88 min
HPLC


 


Example 184








353.0
1.94 min
HPLC


 


Example 185








352.2
1.72 min
HPLC


 


Example 186








366.1
1.85 min
HPLC


 


Example 187








403.1
1.69 min
HPLC


 


Example 188








374.1
1.65 min
HPLC


 


Example 189








487.9
1.70 min
HPLC


 


Example 190








487.1
1.77 min
HPLC


 


Example 191








460.0
1.73 min
HPLC


 


Example 192








390.0
1.77 min
HPLC


 


Example 193








371.1
1.78 min
HPLC


 


Example 194








400.0
1.88 min
HPLC


 


Example 195








399.1
1.78 min
HPLC


 


Example 196








371.1
1.77 min
HPLC


 


Example 197








400.0
1.81 min
HPLC


 


Example 198








447.0
1.79 min
HPLC


 


Example 199








461.0
1.93 min
HPLC


 


Example 200








422.1
1.64 min
HPLC


 


Example 201








374.1
1.62 min
HPLC


 


Example 202








408.8
1.79 min
HPLC


 











Example 203








Confirmed by NMR (see Table 2)
Chiral- HPLC


 


Example 204








Confirmed by NMR (see Table 2)
Chiral- HPLC


 












Example 205








414.1
1.82 min
HPLC


 


Example 206








414.1
1.68 min
HPLC


 


Example 207








414.1
1.66 min
HPLC


 


Example 208








416.1
1.87 min
HPLC


 


Example 209








427.0
1.92 min
HPLC


 


Example 210








420.1
1.83 min
HPLC


 


Example 211








414.1
1.71 min
HPLC


 


Example 212








402.1
1.84 min
HPLC


 


Example 213








486.1
1.84 min
HPLC


 


Example 214








402.1
1.74 min
HPLC


 











Example 215








Confirmed by NMR (see Table 2)
MPLC


 












Example 216








394.0
1.93 min
HPLC


 


Example 217








392.1
1.74 min
HPLC


 


Example 218








379.0
1.88 min
HPLC


 


Example 219








407.0
1.91 min
HPLC


 


Example 220








415.0
1.97 min
HPLC


 


Example 221








405.8
1.85 min
HPLC


 











Example 222








Confirmed by NMR (see Table 2)
Chiral- HPLC


 


Example 223








Confirmed by NMR (see Table 2)
Chiral- HPLC


 


Example 224








Confirmed by NMR (see Table 2)
Chiral- HPLC


 


Example 225








Confirmed by NMR (see Table 2)
MPLC


 


Example 226








Confirmed by NMR (see Table 2)
MPLC


 


Example 227








Confirmed by NMR (see Table 2)
Chiral- HPLC


 












Example 228








417.1
1.69 min
HPLC


 


Example 229








418.1
1.64 min
HPLC


 


Example 230








389.2
1.59 min
HPLC


 


Example 231








416.1
1.66 min
HPLC


 


Example 232








423.1
1.61 min
HPLC


 


Example 233








363.1
1.60 min
HPLC


 


Example 234








363.0
1.76 min
HPLC


 


Example 235








457.1
1.78 min
HPLC


 


Example 236








382.1
1.75 min
HPLC


 











Example 237








Confirmed by NMR (see Table 2)
MPLC


 


Example 238








Confirmed by NMR (see Table 2)
MPLC


 












Example 239








400.1
1.62 min
HPLC


 











Example 240








Confirmed by NMR (see Table 2)
MPLC


 


Example 241








Confirmed by NMR (see Table 2)
MPLC


 











Example
Alternative route
378.9
1.48 min
HPLC


242






 












Example 243








416.9
1.52 min
HPLC


 


Example 244








418.0
1.58 min
HPLC


 


Example 245








416.9
1.64 min
HPLC


 


Example 246








414.9
1.81 min
MPLC


 


Example 247








414.9
1.79 min
MPLC


 


Example 248








411.0
1.73 min
MPLC


 


Example 249








411.0
1.72 min
MPLC


 


Example 250








416.9
1.78 min
MPLC


 


Example 251








377.0
1.80 min
MPLC


 


Example 252








377.0
1.80 min
MPLC


 


Example 253








399.0
1.77 min
MPLC


 


Example 254








399.0
1.77 min
MPLC


 











Example
Alternative route
379.0
1.51 min
HPLC


255






Example
Alternative route
539.9
1.66 min
HPLC


256






Example
Alternative route
539.9
1.68 min
HPLC


257






 












Example 258








393.0
1.71 min
MPLC


 


Example 259








393.0
1.69 min
MPLC


 


Example 260








403.0
1.44 min
MPLC


 


Example 261








387.0
1.85 min
MPLC


 


Example 262








387.0
1.83 min
MPLC


 


Example 263








383.1
1.76 min
MPLC


 


Example 264








383.1
1.75 min
MPLC


 


Example 265








389.0
1.81 min
MPLC


 


Example 266








389.0
1.82 min
MPLC


 


Example 267








349.1
1.83 min
MPLC


 


Example 268








415.9
1.89 min
MPLC


 


Example 269








415.9
1.87 min
MPLC


 


Example 270








412.0
1.80 min
MPLC


 


Example 271








417.9
1.86 min
MPLC


 


Example 272








418.0
1.85 min
MPLC


 


Example 273








378.1
1.88 min
MPLC


 


Example 274








378.1
1.87 min
MPLC


 


Example 275








402.0
1.75 min
Chiral- HPLC


 


Example 276








402.0
1.73 min
Chiral- HPLC


 


Example 277








402.0
1.62 min
Chiral- HPLC


 


Example 278








403.0
1.67 min
Chiral- HPLC


 


Example 279








403.0
1.69 min
Chiral- HPLC


 


Example 280








363.0
1.72 min
MPLC


 


Example 281








363.0
1.72 min
MPLC


 


Example 282








364.0
1.79 min
MPLC


 


Example 283








364.0
1.79 min
MPLC


 


Example 284








363.0
1.84 min
MPLC


 


Example 285








363.0
1.83 min
MPLC


 


Example 286








404.0
1.49 min
MPLC


 


Example 287








403.0
1.55 min
MPLC


 


Example 288








403.0
1.56 min
MPLC


 


Example 289








421.0
1.59 min
MPLC


 


Example 290








421.0
1.59 min
MPLC


 


Example 291








428.0
1.44 min
MPLC


 










Example 
Alternative route
Confirmed by
HPLC


292

NMR





(see Table 2)












Example
Alternative route
393.0
1.72 min
HPLC


293






Example
Alternative route
411.0
1.75 min
HPLC


294






Example
Alternative route
418.0
1.66 min
HPLC


295






Example
Alternative route
411.0
1.73 min
HPLC


296






Example
Alternative route
418.0
1.63 min
HPLC


297






Example
Alternative route
393.0
1.72 min
HPLC


298






Exemple
Alternative route
411.0
1.75 min
HPLC


299






Example
Alternative route
418.0
1.66 min
HPLC


300






Example
Alternative route
411.0
1.72 min
HPLC


301






Example
Alternative route
418.0
1.63 min
HPLC


302






Example
Alternative route
463.0
1.72 min
HPLC


303






Example
Alternative route
463.0
1.70 min
HPLC


304






Example
Alternative route
470.0
1.68 min
HPLC


305






Example
Alternative route
470.0
1.70 min
HPLC


306






 












Example 307








379.1
1.83 min
MPLC


 


Example 308








379.2
1.83 min
MPLC


 


Example 309








408.1
1.87 min
MPLC


 


Example 310








408.0
1.86 min
MPLC


 


Example 311








467.8
1.81 min
HPLC


 


Example 312








467.8
1.82 min
HPLC


 


Example 313








387.1
2.04 min
HPLC


 











Example
Alternative route
388.1
1.77 min
HPLC


314






 












Example 315








311.2
1.78 min
HPLC


 


Example 316








374.1
1.76 min
Chiral- HPLC


 


Example 317








374.1
1.78 min
Chiral- HPLC


 


Example 318








394.0
1.79 min
Chiral- HPLC


 


Example 319








394.0
1.78 min
Chiral- HPLC


 


Example 320








393.0
1.83 min
Chiral- HPLC


 


Example 321








393.0
1.82 min
Chiral- HPLC


 


Exemple 322








403.0
1.80 min
Chiral- HPLC


 


Example 323








403.0
1.80 min
Chiral- HPLC


 


Example 324








414.0
1.70 min
Chiral- HPLC


 


Example 325








414.0
1.70 min
Chiral- HPLC


 


Example 326








349.1
1.83 min
MPLC


 


Example 327








399.0
1.75 min
MPLC


 


Example 328








399.0
1.74 min
MPLC


 


Example 329








417.1
3.00 min
HPLC


 


Example 330








379  
2.95 min
HPLC


 


Example 331








351.1
2,27 min
HPLC


 


Example 332








349.2
2.45 min
HPLC


 


Example 333








436.9
1.95 min
HPLC


 


Example 334








395.9
1.84 min
HPLC


 


Example 335








430  
1.72 min
HPLC


 


Example 336








420.1
1.52 min
HPLC


 


Example 337








415  
1.88 min
HPLC


 


Example 338








365.1
1.85 min
HPLC


 


Example 339








421  
1.87 min
HPLC


 


Example 340








387  
1.79 min
HPLC


 


Example 341








454.9
1.90 min
HPLC


 


Example 342








405.8
1.84 min
HPLC


 


Example 343








421  
1.74 min
HPLC


 


Example 344








422  
1.79 min
HPLC


 


Example 345








469.1
1.94 min
MPLC


 


Example 346








469.1
1.94 min
MPLC


 


Example 347








469.1
1.93 min
MPLC


 


Example 348








469.1
1.93 min
MPLC


 


Example 349








411.1
1.73 min
MPLC


 


Example 350








411.1
1.72 min
MPLC


 


Example 351








415  
1.81 min
MPLC


 


Example 352








415  
1.79 min
MPLC


 


Example 353








363.1
1.71 min
MPLC


 


Example 354








363.1
1.71 min
MPLC


 


Example 355








552.1
3.42 min
HPLC


 


Example 356








536.1
3.37 min
HPLC


 











Example 357








Confirmed by NMR (see Table 2)
MPLC


 












Example 358








450  
1.66 min
HPLC


 


Example 359








423.1
2.00 min
HPLC


 


Example 360








347.1
1.76 min
HPLC


 


Example 361








394.2
1.64 min
HPLC


 


Example 362








381.1
1.64 min
HPLC


 


Example 363








394.1
1.83 min
HPLC


 


Example 364








409.1
2.00 min
HPLC


 


Example 365








534  
1.88 min
HPLC


 


Example 366








500.1
1.84 min
HPLC


 


Example 367








500  
1.82 min
HPLC


 


Example 368








534.1
1.87 min
HPLC


 


Example 369








485.8
1.82 min
HPLC


 


Example 370








501.8
1.90 min
HPLC


 


Example 371








501.8
1.89 min
HPLC


 


Example 372








534.1
1.93 min
HPLC


 


Example 373








501.8
1.89 min
HPLC


 


Example 374








485.8
1.83 min
HPLC


 


Example 375








500.1
1.90 min
HPLC


 


Example 376








535.8
1.93 min
HPLC


 


Example 377








534  
1.93 min
HPLC


 


Example 378








387.1
1.81 min
HPLC


 


Example 379








387.1
1.79 min
HPLC


 


Example 380








415.1
1.95 min
HPLC


 


Example 381








421  
1.91 min
HPLC


 


Example 382








367.1
1.83 min
HPLC


 


Example 383








367.1
1.77 min
HPLC


 


Example 384








381.2
1.92 min
HPLC


 


Example 385








381.2
1.87 min
HPLC


 


Example 386








401.1
1.88 min
HPLC


 


Example 387








341.1
1.88 min
HPLC


 


Example 388








434.1
1.62 min
HPLC


 


Example 389








535.8
1.92 min
HPLC


 


Example 390








506  
8.11 min
HPLC


 


Example 391








393.1
1.72 min
HPLC


 


Example 392








393.1
1.73 min
HPLC


 


Example 393








407  
1.56 min
HPLC


 


Example 394








380.1
1.73 min
HPLC


 


Example 395








407.1
1.73 min
HPLC


 


Example 396








395.2
1.89 min
HPLC


 


Example 397








365.2
1.82 min
HPLC


 


Example 398








407.1
1.69 min
HPLC


 


Example 399








437.1
1.85 min
HPLC


 


Example 400








421.1
1.81 min
HPLC


 


Example 401








437.1
1.87 min
HPLC


 


Example 402








353.2
1.68 min
HPLC


 


Example 403








369.1
1.75 min
HPLC


 


Example 404








401.1
1.74 min
HPLC


 


Example 405








421.1
1.76 min
HPLC


 


Example 406








341.3
1.95 min
HPLC


 


Example 407








353.2
1.72 min
HPLC


 


Example 408








369.1
1.73 min
HPLC


 


Example 409








406.1
1.90 min
HPLC


 


Example 410








324.1
1.71 min
HPLC


 


Example 411








338.1
1.80 min
HPLC


 


Example 412








378.1
1.73 min
HPLC


 


Example 413








392.1
1.85 min
HPLC


 


Example 414








381.1
1.79 min
HPLC


 


Example 415








388.1
1.83 min
HPLC


 


Example 416








423.1
1.84 min
HPLC


 


Example 417








422.1
1.86 min
HPLC


 


Example 418








408  
1.87 min
HPLC


 


Exemple 419








433.1
1.87 min
HPLC


 


Exemple 420








433.1
1.87 min
HPLC


 


Example 421








297.3
1.74 min
HPLC


 


Example 422








339.1
1.64 min
HPLC


 


Example 423








297.3
1.68 min
HPLC


 











Example
Alternative route
409.9
1.89 min
HPLC


424






Example
Alternative route
430.9
1.92 min
HPLC


425






Example
Alternative route
430.9
1.91 min
HPLC


426






 












Example 427








379.3
1.90 min
HPLC


 


Example 428








407.2
1.81 min
HPLC


 


Example 429








407.2
1.80 min
HPLC


 


Example 430








421.2
1.76 min
HPLC


 


Example 431








408.1
1.86 min
HPLC


 


Example 432








422.3
1.79 min
HPLC


 


Example 433








422.1
1.82 min
HPLC


 


Example 434








335.3
1.86 min
HPLC


 


Example 435








363.1
1.76 min
HPLC


 


Example 436








363.2
1.75 min
HPLC


 


Example 437








377.1
1.68 min
HPLC


 


Example 438








377.2
1.71 min
HPLC


 


Example 439








350.4
1.95 min
HPLC


 


Example 440








378.3
1.87 min
HPLC


 


Example 441








392.3
1.77 min
HPLC


 


Example 442








336.4
1.81 min
HPLC


 


Example 443








364.3
1.73 min
HPLC


 


Example 444








378.3
1.64 min
HPLC


 


Example 445








335.3
1.84 min
HPLC


 


Example 446








363.2
1.75 min
HPLC


 


Example 447








335.3
2.05 min
HPLC


 


Example 448








363.2
1.95 min
HPLC


 


Example 449








378.3
1.84 min
HPLC


 


Example 450








387.2
1.82 min
HPLC


 


Example 451








390.3
1.67 min
HPLC


 


Example 452








387.2
1.70 min
HPLC


 


Example 453








406.3
1.77 min
HPLC


 


Example 454








421.2
1.95 min
HPLC


 


Example 455








435.2
1.86 min
HPLC


 


Example 456








387.2
1.79 min
HPLC


 


Example 457








373.2
1.69 min
HPLC


 


Example 458








388.2
1.84 min
HPLC


 


Example 459








351  
1.75 min
HPLC


 


Example 460








357.2
1.71 min
HPLC


 


Example 461








387.2
1.81 min
HPLC


 


Example 462








423.9
1.74 min
HPLC


 


Example 463








376.1
1.78 min
HPLC


 


Example 464








393.1
1.89 min
HPLC
















TABLE 4







spectra data








Example
spectra data





Example133
1H-NMR (300 MHz, DMSO-d6) δ 10.85 (1H, s), 8.57 (1H,



d, J = 8.0 Hz), 8.36 (1H, d, J = 2.9 Hz), 7.55 (1H, dd, J =



8.8, 2.9 Hz), 7.47 (1H, d, J = 7.3 Hz), 7.37 (1H, d, J = 8.8



Hz), 7.34 (7.3 Hz), 7.15-6.95 (3H, m), 5.04 (1H, m), 4.88



(2H, q, J = 8.8 Hz), 2.23 (1H, m), 1.97 (1H, m), 1.39 (3H,



d, J = 6.6 Hz), 1.31 (1H, m), 1.16 (1H, m)


Example134
1H-NMR (300 MHz, DMSO-d6) δ 10.86 (1H, s), 8.57 (1H,



d, J = 8.1 Hz), 8.36 (1H, s), 7.53 (2H, d, J = 7.4 Hz), 7.35



(2H, d, J = 8.1 Hz), 7.15-6.95 (3H, m), 5.04 (1H, m), 4.88



(2H, q, J = 8.8 Hz), 2.31 (1H, m), 1.99 (1H, m), 1.39 (3H,



d, J = 6.6 Hz), 1.25 (1H, m), 1.18 (1H, m)


Example203
1H-NMR (300 MHz, DMSO-d6) δ 8.28 (1H, brs), 8.26 (1H,



s), 7.53 (1H, d, J = 8.1 Hz), 7.23-7.13 (4H, m), 6.99 (1H, d,



J = 7.3 Hz), 6.82 (1H, dd, J = 8.0, 1.5 Hz) 6.50 (1H, t, J =



2.9 Hz), 5.20 (1H, m), 4.36 (2H, q, J = 8.0 Hz), 2.60 (1H,



m), 1.77-1.60 (2H, m), 1.49 (3H, d, J = 6.6 Hz), 1.31 (1H,



m)


Example204
1H-NMR (300 MHz, CDCl3) δ 8.30 (1H, t, J = 1.4 Hz),



8.20 (1H, brs), 7.56 (1H, d, J = 8.0 Hz), 7.25 (2H, d, J = 2.2



Hz), 7.19 (2H, t, J = 2.2 Hz), 6.94 (1H, d, J = 8.1 Hz), 6.87



(1H, dd, J = 8.0, 1.5 Hz), 6.53 (1H, t, J = 2.2 Hz), 5.20 (1H,



m), 4.38 (2H, q, J = 7.3 Hz), 2.64 (1H, m), 1.74 (1H, m),



1.63 (1H, m)., 1.47 (3H, d, J = 7.3 Hz), 1.27 (1H, m).


Example215
1H-NMR (300 MHz, CDCl3) δ 8.27 (1H, s), 8.05 (1H, s),



8.03 (1H, d, J = 8.6 Hz), 7.78 (1H, d, J = 6.6 Hz), 7.69 (1H,



d, J = 7.9 Hz), 7.44-7.34 (2H, m), 6.62 (1H, brd, J = 7.3



Hz), 5.29 (1H, m), 4.75 (2H, q, J = 7.9 Hz), 2.75 (1H, m),



2.39 (1H, m), 1.84-1.70 (2H, m), 1.52 (3H, d, J = 6.6 Hz),


Example222
1H-NMR (300 MHz, CDCl3) δ 8.30 (1H, s), 8.10 (1H, s),



8.04 (1H, d, J = 8.0 Hz), 7.92 (1H, d, J = 8.0 Hz), 7.76 (1H,



d, J = 8.0 Hz), 7.66 (1H, t, J = 8.0 Hz), 7.46 (1H, t, J = 8.0



Hz), 7.38 (1H, d, J = 8.0 Hz), 6.59 (1H, d, J = 7.3 Hz), 5.27



(1H, quintet, J = 7.3 Hz), 4.81-4.72 (2H, m), 2.82-2.74 (1H,



m), 2.37-2.30 (1H, m), 1.68-1.60 (2H, m). 1.47 (3H. d. J =



7.3 Hz).


Example223
1H-NMR (300 MHz, DMSO-d6) δ 11.0 (1H, s), 8.68 (1H, d,



J = 7.7 Hz), 8.11 (1H, d, J = 2.2 Hz), 7.73 (1H, dd, J = 8.4,



2.2 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.23 (1H, d, J =7.7 Hz),



7.00-6.88 (3H, m), 6.12 (1H, s), 5.00-4.91 (3H, m), 2.34



(1H, m), 1.93 (1H, m), 1.37-1.27 (2H, m), 1.35 (3H, d, J =



7.0 Hz).


Example224
1H-NMR (300 MHz, DMSO-d6) δ 11.0 (1H, s), 8.65 (1H, d,



J = 8.1 Hz), 8.11 (1H, d, J = 2.2 Hz), 7.74 (1H, dd, J = 8.4,



2.2 Hz), 7.35 (1H, d, J = 7.7 Hz), 7.21 (1H, d, J = 7.7 Hz),



6.99-6.86 (3H, m), 6.09 (1H, s), 4.99-4.90 (3H, m), 2.28



(1H, m). 1.93 (1H, m), 1.74 (1H, m), 1.36 (3H, d, J =7.3



Hz), 1.31 (1H, m).


Example225
1H-NMR (300 MHz, DMSO-d6) δ 11.0 (1H, s), 8.73 (1H, d,



J = 7.3 Hz), 8.43 (1H, d, J = 1.1 Hz), 8.18 (1H, d, J =



1.1 Hz), 7.36 (1H, d, J = 7.7 Hz), 7.23 (1H, d, J = 7.7 Hz),



7.00-6.88 (2H, m), 6.12 (1H, s), 5.06-4.97 (3H, m),



2.34 (1H, m), 2.01 (1H, m), 1.39 (3H, d, J = 7.0 Hz), 1.30-



1.26 (2H, m).


Example226
1H-NMR (300 MHz, DMSO-d6) δ 11.0 (1H, s), 8.72 (1H, d,



J = 7.7 Hz), 8.42 (1H, d, J = 1.1 Hz), 8.20 (1H, d, J =



1.1 Hz), 7.35 (1H, d, J = 7.7 Hz), 7.21 (1H, d, J = 8.1 Hz),



6.99-6.87 (2H, m), 6.09 (1H, s), 5.06-4.97 (3H, m),



2.29 (1H, m), 2.01 (1H, m), 1.39 (3H, d, J = 7.0 Hz), 1.37-



1.29 (2H, m).


Example227
1H-NMR (300 MHz, DMSO-d6) δ 8.60 (1H, d, J = 7.7 Hz),



8.31 (1H, d, J = 2.9 Hz), 7.94 (1H, s), 7.62 (1H, d, J =



8.4 Hz), 7.49 (1H, dd, J = 8.4, 2.9 Hz), 7.40 (1H, s), 7.30



(1H, d, J = 8.8 Hz), 6.87 (1H, d, J = 8.4 Hz), 4.97 (1H,



quintet, J = 7.3 Hz), 4.83 (2H, q, J = 8.8 Hz), 3.98 (3H, s),



2.39 (1H, m), 2.07 (1H, m), 1.33 (3H, d, J = 7.3 Hz),



1.35-1.28 (2H. m).


Example237
1H-NMR (300 MHz, DMSO-d6) δ 8.55 (1H, d, J = 7.7 Hz),



8.30 (1H, d, J = 2.9 Hz), 7.48 (1H, dd, J = 8.8, 2.9 Hz),



7.42-7.27 (6H, m), 7.02 (2H, d, J = 8.8 Hz), 6.89 (2H, d, 



J = 8.4 Hz), 5.05 (2H, s), 4.95 (1H, quintet, J = 7.3 Hz),



4.83 (2H, q, J = 8.8 Hz), 2.17 (1H, m), 1.88 (1H, m), 1.32



(3H, d, J = 7.3 Hz), 1.21 (1H, m), 1.08 (1H, m).


Example238
1H-NMR (300 MHz, DMSO-d6) δ 8.54 (1H, d, J = 8.1 Hz),



8.28 (1H, d, J = 2.9 Hz), 7.47 (1H, dd, J = 8.8, 2.9 Hz),



7.41-7.26 (6H, m), 6.99 (2H, d, J = 8.8 Hz), 6.88 (2H, d,



J = 8.4 Hz), 5.04 (2H, s), 4.95 (1H, quintet, J = 7.3 Hz),



4.81 (2H, q, J = 8.8 Hz), 2.11 (1H, m), 1.90 (1H, m), 1.33



(3H, d, J = 7.3 Hz), 1.27 (1H, m), 1.09 (1H, m).


Example240
1H-NMR (300 MHz, DMSO-d6) δ 8.57 (1H, d, J = 7.7 Hz),



8.30 (1H, d, J = 2.9 Hz), 7.50-7.27 (7H, m), 7.16 (1H, t,



J = 7.7 Hz), 6.81-6.76 (2H, m), 6.68 (1H, d, J = 7.3 Hz),



5.06 (2H, s), 4.95 (1H, quintet, J = 7.0 Hz), 4.83 (2H, q,



J = 8.8 Hz), 2.19 (1H, m), 1.99 (1H, m), 1.32 (3H, d, J =



7.0 Hz), 1.25 (1H, m), 1.15 (1H, m).


Example241
1H-NMR (300 MHz, DMSO-d6) δ 8.56 (1H, d, J = 8.1 Hz),



8.28 (1H, d, J = 2.9 Hz), 7.49-7.27 (7H, m), 7.15 (1H, t,



J = 7.7 Hz), 6.81-6.64 (3H, m), 5.04 (2H, s), 4.96 (1H,



quintet, J = 7.0 Hz), 4.81 (2H, q, J = 8.8 Hz), 2.14 (1H, m),



2.01 (1H, m), 1.33 (3H, d, J = 7.0 Hz), 1.32 (1H, m), 1.16



(1H, m).


Example246
1H-NMR(300 MHz, CDCl3) δ 8.29 (1H, s), 7.31-7.21 (2H,



m), 7.13 (1H, dd, J = 8.8, 2.9 Hz), 7.08-6.85 (3H, m),



5.19 (1H, m), 4.40 (2H, q, J = 8.1 Hz), 2.65 (1H, m), 1.63-



1.51 (2H, m), 1.48 (3H, d, J = 6.6 Hz), 1.21 (1H, m)


Example247
1H-NMR (300 MHz, CDCl3) δ 8.30 (1H, s), 7.26 (2H, m),



7.08 (1H, dd, J = 7.1, 2.2 Hz), 7.00 (1H, m), 6.96-6.83



(2H, m), 5.19 (1H, m), 4.40 (2H, q, J = 7.3 Hz), 2.58 (1H,



m), 1.65 (1H, m), 1.54 (1H, m), 1.47 (3H, d, J = 6.6



Hz), 1.23 (1H, m)


Example248
1H-NMR (300 Mhz, CDCl3) δ 8.29 (1H, s), 7.24 (2H, d, J =



2.2 Hz), 6.90 (2H, t, J = 8.1 Hz), 6.63-6.57 (2H, m),



5.17 (1H, m), 4.39 (2H, q, J = 8.0 Hz), 3.78 (3H, s), 2.55



(1H, m), 1.67 (1H, m), 1.53 (1H, m), 1.47 (3H, d, J = 6.6



Hz), 1.19 (1H, m)


Example249
1H-NMR (300 MHz, CDCl3) δ 8.28 (1H, s), 7.24 (2H, d,



J = 1.5 Hz), 6.95-6.80 (2H, m) 6.64-6.51 (2H, m), 5.17



(1H, m), 4.39 (2H, d, J = 8.0 Hz), 3.76 (3H, s), 2.50 (1H,



m), 1.67 (1H, m), 1.58 (1H, m), 1.46 (3H, d, J = 6.6 Hz),



1.23 (1, m)


Example250
1H-NMR (300 MHz, CDCl3) δ 8.30 (1H, s), 7.25 (2H, d,



J = 6.6 Hz), 6.94 (1H, brd, J = 7.3 Hz), 6.65-6.55 (2H, m),



5.18 (1H, m), 4.40 (2H, q, J = 8.0 Hz), 2.39 (1H, m), 1.93



(1H, m), 1.55 (1H, m), 1.48 (3H, d, J = 6.6 Hz), 1.32 (1H,



m)


Example251
1H-NMR (300 MHz, CDCl3) δ 8.29 (1H, s), 7.25 (2H, m),



7.18 (1H, t, J = 7.3 Hz), 7.02 (1H, d, J = 7.3 Hz), 6.96-



6.85(3H, m), 5.16 (1H, m), 4.39 (2H, q, J = 8.0 Hz), 2.45



(1H, m), 2.33 (3H, s), 1.68 (1H, m), 1.58 (1H, m), 1.45



(3H d J = 6.6 Hz). 1.21 (1H. m)


Example252
1H-NMR (300 MHz, CDCl3) δ 8.26 (1H, s), 7.26-7.29 (2H,



m), 7.15 (1H, t, J = 7.3 Hz), 6.99 (1H, d, J = 7.4 Hz),



6.94-6.84(3H, m,), 5.16 (1H, m), 4.38 (2H, q, J = 8.1 Hz),



2.41 (1H, m), 2.30 (3H, s), 1.71-1.59 (2H, m), 1.46



(3H, d, J = 6.6 Hz), 1.26 (1H, m)


Example253
1H-NMR (300 MHz, CDCl3) δ 8.28 (1H, d, J = 1.5 Hz),



7.28-7.20 (2H, m), 6.99 (1H, brd, J = 8.4 Hz), 6.70-6.55



(3H, m), 5.15 (1H, m), 4.40 (2H, q, J = 8.1 Hz), 2.49 (1H,



m), 1.70 (1H, m), 1.62 (1H, m), 1.46 (3H, d, J = 6.6



Hz), 1.18 (1H, m)


Example254
1H-NMR (300 MHz, CDCl3) δ 8.27 (1H, d, J = 1.5 Hz),



7.26-7.20 (2H, m), 6.96 (1H, brd, J = 7.3 Hz), 6.67-6.53



(3H, m), 5.15 (1H, m), 4.39 (2H, q, J = 8.1 Hz), 2.44 (1H,



m), 1.74-1.62 (2H, m), 1.46 (3H, d, J = 6.6 Hz), 1.22



(1H. m)


Example260
1H-NMR (300 MHz, CDCl3) δ 8.29 (1H, s), 7.57-7.50 (2H,



m), 7.30-7.20 (4H, m), 5.16 (1H, quintet, J = 6.6 Hz),



4.39 (2H, q, J = 8.1 Hz), 2.75-2.68 (1H, m), 2.45-2.37 (1H,



m), 1.75-1.65 (2H, m), 1.44 (3H, d, J = 6.6 Hz).



(signals due to two NH were not observed)


Example261
1H-NMR (300 MHz, CDCl3) δ 8.33 (1H, s), 7.41 (2H, s),



7.31-7.25 (2H, m), 7.19-7.13 (2H, m), 7.05 (1H, m), 5.29



(1H, m), 3.97 (2H, d, J = 6.6 Hz), 2.79 (1H, m), 1.72 (1H,



m), 1.61 (3H, d, J = 6.6 Hz), 1.42 (1H, m), 1.33 (1H,



m), 0.81 (2H, m), 0.51 (2H, m)


Example262
1H-NMR (300 MHz, CDCl3) δ 8.37 (1H, s), 7.32 (2H, d,



J = 2.2 Hz), 7.22 (1H, dd, J = 8.8, 2.9 Hz), 7.17-7.10 (2H,



m), 7.03 (1H, m), 5.30 (IH, m), 3.98 (2H, d, J = 6.6 Hz),



2.73 (1H, m), 1.77 (1H, m), 1.60 (3H, d, J = 6.6 Hz),



1.50-1.30 (2H, m), 0.82 (2H, m), 0.52 (2H, m)


Example263
1H-NMR (300 MHz, CDCl3) δ 8.37 (1H, s), 7.30 (2H, s),



7.10-7.00 (2H, m), 6.80-6.70 (2H, m), 5.27 (1H, m), 3.97



(2H, d, J = 6.6 Hz), 3.92 (3H, s), 2.69 (1H, m), 1.81 (1H,



m), 1.65 (1H, m), 1.60 (3H, d, J = 6.6 Hz), 1.42 (1H, m),



1.32 (1H, m), 0.81 (2H, m), 0.51 (1H, m)


Example264
1H-NMR (300 MHz, CDCl3) δ 8.37 (1H, s), 7.30 (2H, s),



7.10-6.98 (2H, m), 6.75-6.65 (2H, m), 5.28 (1H, m), 3.97



(2H, d, J = 7.3 Hz), 3.90 (3H, s), 2.65 (1H, m), 1.82 (1H,



m), 1.75 (1H, m), 1.59 (3H, d, J = 6.6 Hz), 1.45-1.30



(2H, m), 0.82 (2H, m), 0.51 (2H, m)


Example265
1H-NMR (300 MHz, CDCl3) δ 8.38 (1H, s), 7.31 (2H, d,



J = 1.5 Hz), 7.16 (1H, brd, J = 7.3 Hz), 6.80-6.65 (2H, m),



5.28 (1H, m), 3.98 (2H, d, J = 7.4 Hz), 2.50 (1H, m), 2.10



(1H, m), 1.77-1.60 (2H, m), 1.60 (3H, d, J = 7.3 Hz),



1.53 (1H, m), 1.42 (1H, m), 0.81 (2H, m), 0.52 (2H, m)


Example266
1H-NMR (300 MHz, CDCl3) δ 8.38 (1H, s), 7.31 (1H, d,



J = 1.5 Hz), 7.15 (1H, brd, J = 7.3 Hz), 6.80-6.70 (2H, m),



5.28 (1H, m), 3.98 (2H, d, J = 7.3 Hz), 2.53 (1H, m), 2.07 



(1H, m), 1.68 (1H, m), 1.61 (3H, d, J = 6.6 Hz), 1.50-



1.40 (2H, m), 0.80 (2H, m), 0.51 (2H, m)


Example267
1H-NMR (300 MHz, CDCl3) δ 8.37 (1H, s), 7.35-7.28 (3H,



m), 7.15 (1H, d, J = 8.0 Hz), 7.10-7.00 (2H, m), 5.26



(1 H, m), 3.97 (2H, d, J = 7.3 Hz), 2.61 (1H, m), 2.47 (3H,



s), 1.83 (1H, m), 1.73 (1H, m), 1.58 (3H, d, J = 6.6 Hz),



1.42 (1H, m), 1.33 (1H, m), 0.82 (2H, m), 0.51 (2H, m)


Example268
1H-NMR (300 MHz, CDCl3) δ 8.33 (1H, s), 8.12 (1H, d,



J = 1.5 Hz), 7.16 (1H, dd, J = 8.1, 2.2 Hz), 7.05 (1H, dd, 



J = 8.8, 5.9 Hz), 6.94 (1H, m), 6.57 (1H, brd, J = 8.1 Hz),



5.31 (1H, m), 4.79 (2H, q, J = 8.1 Hz), 2.65 (1H, m),



1.65-1.49 (2H, m), 1.53 (3H, d, J = 6.6 Hz), 1.23 (1H, m)


Example269
1H-NMR (300 MHz, CDCl3) δ 8.33 (1H, s), 8.14 (1H, s),



7.11 (1H, dd, J = 8.1, 2.2 Hz), 7.03 (1H, dd, J = 8.1, 6.6



Hz), 6.90 (1H, m), 6.57 (1H, brd, J = 8.0 Hz), 5.30 (1H, m),



4.85-4.70 (2H, m), 2.57 (1H, m), 1.68 (1H, m), 1.52



(3H, d, J = 7.3 Hz), 1.52 (1H, m), 1.27 (1H, m)


Example270
1H-NMR (300 MHz, CDCl3) δ 8.33 (1H, s), 8.12 (1H, s),



6.93 (1H, t, J = 8.0 Hz), 6.66-6.60 (2H, m), 6.51 (1H, brd,



J = 8.1 Hz), 5.29 (1H, m), 4.79 (2H, q, J = 8.8 Hz), 3.81



(3H, s), 2.57 (1H, m), 1.67 (1H, m), 1.54 (1H, m), 1.52



(3H, d, J = 6.6 Hz), 1.23 (1H, m)


Example271
1H-NMR(300 MHz, CDl3) δ 8.34 (1H, s), 8.12 (1H, s),



6.70-6.55 (3H, m), 5.29 (1H, m), 4.83-4.73 (2H, m), 2.42



(1H, m), 1.89 (1H, m), 1.58 (1H, m), 1.54 (3H, d, J = 6.6



Hz), 1.35 (1H, m)


Example272
1H-NMR (300 MHz, CDCl3) δ 8.34 (1H, s), 8.12 (1H, s),



6.67-6.55 (3H, m), 5.29 (1H, m), 4.83-4.73 (2H, m), 2.35



(1H, m), 1.90 (1H, m), 1.61 (1H, m), 1.53 (3H, d, J = 7.3



Hz), 1.40 (1H, m)


Example273
1H-NMR (300 MHz, CDCl3) δ 8.33 (1H, s), 8.11 (1H, d,



J = 1.5 Hz), 7.21 (1H, t, J = 7.4 (1H, m), 7.04 (1H, d, J =



7.3 Hz), 6.94 (1H, s), 6.92 (1H, d, J = 8.8 Hz), 6.50 (1H,



brd, J = 8.1 Hz), 5.28 (1H, m), 4.79 (2H, q, J = 7.3 Hz),



2.50 (1H, m), 2.36 (3H, s), 1.70-1.55 (2H, m), 1.50 (3H, d,



J = 7.3 Hz)1.23 (1H, m)


Example274
1H-NMR (300 MHz, CDCl3) δ 8.30 (1H, s), 8.10 (1H, s),



7.17 (1H, t, J = 7.3 Hz), 7.02 (1H, d, J = 8.0 Hz), 6.89



(1H, s), 6.88 (1H, d, J = 7.3 Hz), 6.52 (1H, brd, J = 8.0 Hz),



5.28 (1H, m), 4.83-4.70 (2H, m), 2.43 (1H, m), 2.33



(3H, s), 1.69-1.55 (2H, m), 1.51 (3H, d, J = 6.6 Hz), 1.29



(1H, m)


Example275
1H-NMR (300 MHz, CDCl3) δ 9.58 (1H, brs), 8.29 (1H, s),



7.54 (1H, d, J = 8.0 Hz), 7.29-7.26 (3H, m), 7.04 (1H, t,



J = 8.0 Hz), 6.89 (1H, d, J = 6.6 Hz), 6.71 (1H, d, J = 8.0



Hz), 6.59 (1H, s), 5.19 (1H, m), 4.38 (2H, q, J = 8.0



Hz), 2.53 (1H, m), 1.75-1.65 (2H, m), 1.49 (3H, d, J = 6.6



Hz), 1.42 (1H, m).


Example276
1H-NMR (300 MHz, CDCl3) δ 8.75 (1H, brs), 8.29 (1H, s),



7.53 (1H, d, J = 8.1 Hz), 7.30-7.20 (3H, m), 7.07-6.90



(2H, m), 6.85 (1H, d, J = 7.3 Hz), 6.58 (1H, s), 5.18 (1H,



m), 4.39 (2H, q, J = 8.1 Hz), 2.72 (1H, m), 1.78 (1H, m),



1.58 (1H, m). 1.49 (3H, d, J = 6.6 Hz), 1.35 (1H, m)


Example277
1H-NMR (300 MHz, CDCl3) δ 8.28 (1H, s), 1.25 (1H, brs),



7.29-7.23 (4H, m), 7.13 (1H, t, J = 8.0 Hz), 6.89 (1H, d,



J = 7.3 Hz), 6.77-6.72 (2H, m), 5.21 (1H, m), 4.39 (2H, q,



J = 7.3 Hz), 2.85 (1H, m), 1.83 (1H, m), 1.66 (1H, m),



1.48 (3H, d, J = 6.6 Hz). 1.38 (1H, m)


Example278
1H-NMR (300 MHz, CDCl3) δ 8.28 (1H, d, J = 1.4 Hz),



8.22 (1H, brs), 8.10 (1H, d, J = 1.5 Hz), 7.25 (1H, m), 7.20



(1H, m), 7.10 (1H, t, J = 7.4 Hz), 6.71 (1H, d, J = 7.3 Hz),



6.60 (1H, d, J = 2.9 Hz), 6.51 (1H, brd, J = 8.1 Hz),



5.29 (1H, m), 4.81-4.70 (2H, m), 2.78 (1H, m), 1.79 (1H,



m), 1.73 (1H, m), 1.50 (3H, d, J = 7.3 Hz), 1.44 (1H, m)


Example279
1H-NMR (300 MHz,CDCl3) δ 8.30 (1H, d, J = 1.5 Hz),



8.25 (1H, brs), 8.11 (1H, s), 7.29-7.25 (2H, m), 7.13 (1H, t,



J = 7.3 Hz), 6.75-6.70 (2H, m), 6.50 (1H, brd, J = 7.3 Hz),



5.30 (1H, m), 4.80-4.70 (2H, m), 2.86 (1H, m), 1.77



(1H. m). 1.64 (1H. m). 1.50 (3H. d. J = 6.6 Hz). 1.39 (1H,



m)


Example280
1H-NMR(300 MHz, CDCl3) δ 8.29 (1H, s), 7.32-7.10 (7H,



m), 6.88 (1H, brs), 5.15 (1H, m), 4.40 (2H, q, J = 8.0



Hz), 2.53 (1H, m), 1.70 (1H, m), 1.660 (1H, m), 1.46 (3H,



d, J = 6.6 Hz), 1.21 (1H, m)


Example281
1H-NMR (300 MHz, CDCl3) δ 8.26 (1H, d, J = 1.5 Hz),



7.29-7.14 (5H, m), 7.06 (2H, d, J = 6.6 Hz), 6.89 (1H, brd,



J =8.0 Hz), 5.16 (1H, m), 4.38 (2H, q, J = 8.0 Hz), 2.45



(1H, m), 1.73-1.60 (2H, m), 1.46 (3H, d, J = 6.6 Hz),



1.25 (1H, m)


Example282
1H-NMR (300 MHz, CDCl3) δ 8.30 (1H, d, J = 1.5 Hz),



8.09 (1H, s), 7.35-7.17 (3H, m), 7.10 (2H, d, J = 6.6 Hz),



6.48(1H, brd, J = 7.3 Hz), 5.27 (1H, m), 4.75 (2H, q, J =



7.3 Hz), 2.50 (1H, m), 1.67-1.54 (2H, m), 1.47 (3H, d,



J= 6.6 Hz), 1.21 (1H, m)


Example283
1H-NMR (300 MHz, CDCl3) δ 8.27 (1H, d, J = 1.5 Hz),



8.07 (1H, d, J = 1.5 Hz), 7.28-2.14 (3H, m), 7.05 (2H, d, 



J = 7.5 Hz), 6.50 (1H, brd, J = 7.3 Hz), 5.25 (1H, m), 4.81-



4.68 (2H, m), 2.45 (1H, m), 1.67-1.62 (2H, m), 1.48 (3H,



d, J = 6.6 Hz), 1.26 (1H, m)


Example284
1H-NMR (300 MHz, CDCl3) δ 8.12 (1H, d, J = 2.2 Hz),



7.61 (1H, dd, J = 8.8, 2.9 Hz), 7.31-7.18 (3H, m), 7.08 (2H,



d, J = 6.6 Hz), 6.85 (1H, d, J = 8.1 Hz), 5.81 (1H, brd, J =



7.3 Hz), 5.13 (1H, m), 4.75 (2H, q, J = 8.8 Hz), 2.49



(1H, m), 1.65-1.55 (2H, m), 1.50 (2H, d, J = 6.6 Hz), 1.23



(1H, m)


Example285
1H-NMR (300 MHz, CDCl3) δ 8.11 (1H, d, J = 2.2 Hz),



7.61 (1H, m), 7.29-7.06 (3H, m), 7.05 (2H, d, J = 6.6 Hz),



8.83(1H, d, J = 8.8 Hz), 5.80 (1H, brd, J = 7.3 Hz), 5.13



(1H, m), 4.73 (2H, q, J = 8.8 Hz), 2.46 (1H, m), 1.67-



1.55 (2H, m), 1.51 (3H, d, J = 6.6 Hz), 1.25 (1H, m)


Example286
1H-NMR(300 MHz, CDCl3) δ 11.67 (1H, brs), 8.29 (1H, s),



8.11 (1H, s), 7.68-7.30 (3H, m), 7.23-7.12 (2H, m),



5.20 (1H, m), 4.77 (2H, q, J = 8.8 Hz), 2.60 (1H, m), 2.37



(1H, m), 1.66-1.56 (2H, m), 1.48 (3H, d, J = 6.6 Hz)


Example287
1H-NMR (300 MHz, CDCl3) δ 11.78 (1H, s), 8.13 (1H, s),



7.91 (1H, m), 7.68 (1H, d, J = 8.8 Hz), 7.55 (1H, m),



7.40 (1H, m), 7.23-7.08 (2H, m), 6.83 (1H, m), 5.08 (1H,



m), 4.84-4.67 (2H, m), 2.60 (1H, m), 2.37 (1H, m), 1.61



(2H, m), 1.46 (3H, d, J = 6.6 Hz)


Example288
1H-NMR (300 MHz, CDCl3) δ 11.66 (1H, brs), 8.10 (1H, d,



J = 2.2 Hz), 7.71 (1H, d, J = 7.3 Hz), 7.64 (1H, dd, J =



8.0, 2.2 Hz), 7.47 (1H, m), 7.37 (1H, m), 7.21-7.11 (2H,



m), 6.79 (1H, d, J = 8.1 Hz), 5.07 (1H, m), 4.74 (2H, q, 



J=8.8 Hz), 2.56 (1H, m), 2.32 (1H, m), 1.70-1.60 (2H, m),



1.48 (3H, d, J = 6.6 Hz)


Example289
1H-NMR (300 MHz, CDCl3) δ 8.13 (1H, d, J = 2.9 Hz),



7.61 (1H, dd, J = 2.2 & 8.8 Hz), 7.45-7.35 (1H, m), 7.20-



7.13 (1H, m), 6.97 (1H, dt, J = 2.2 & 8.8 Hz), 6.87 (1H, d,



J = 8.8 Hz), 6.23 (1H, d, J = 7.3 Hz), 5.10 (1H, quintet,



J = 7.3 Hz), 4.76 (2H, q, J = 8.8 Hz), 2.70-2.60 (1H, m),



2.36-2.29 (1H, m), 1.70-1.58 (2H, m), 1.50 (3H, d, J =



7.3 Hz) (a signal due to NH was not observed)


Example290
1H-NMR (300 MHz, CDCl3) δ 7.97 (1H, d, J = 2.2 Hz),



7.46 (1H, dd, J = 2.2 & 8.8 Hz), 7.40-7.34 (1H, m), 7.17-



7.10 (1H, m), 6.94 (1H, dt, J = 2.2 & 8.8 Hz), 6.70 (1H, d,



J = 7.4 Hz), 6.62 (1H, d, J = 8.8 Hz), 5.05 (1H, quintet,



J =7.3 Hz), 4.62 (2H, q, J = 7.3 Hz), 2.62-2.53 (1H, m),



2.30-2.23 (1H, m), 1.77-1.69 (2H, m), 1.51 (3H, d, J =



7.3 Hz) (a signal due to NH was not observed)


Example291
1H-NMR (300 MHz, CDCl3) δ 8.31 (1H, d, J = 2.9 Hz),



7.90-7.80 (1H, m), 7.63-7.50 (1H, m), 7.50-7.44 (2H, m),



7.32-7.24(1H, m), 5.16 (1H, quintet, J = 7.3 Hz), 4.42 (2H,



q, J = 8.1 Hz), 2.82-2.76 (1H, m), 2.52-2.45 (1H, m),



1.75-1.68 (2H, m), 1.45 (3H, d, J = 7.3 Hz) (a signal due to



NH was not observed)


Example292
1H-NMR (300 MHz, DMSO-d6) δ 9.74 (1H, s), 8.60 (1H, d,



J = 8.1 Hz), 8.04 (1H, d, J = 2.9 Hz), 7.81 (2H, d, J =



8.4 Hz), 7.45 (2H, d, J = 8.1 Hz), 7.19 (1H, d, J = 8.4 Hz),



7.10 (1H, dd, J = 8.4, 2.9 Hz), 5.11 (1H, quintet, J =



7.0 Hz), 1.43 (3H, d, J = 7.0 Hz), 1.28 (9H, s), LCMS



(Method A) m/z: M + 1 obs 299.2, tR = 3.21 min.


Example307
1H-NMR (300 MHz, CDCl3) δ 8.23 (1H, s), 7.16 (2H, d,



J = 1.4 Hz), 6.96-7.84 (3H, m), 6,74 (1H, d, J = 7.7 Hz),



5.12 (1H, m), 3.83 (2H, d, J = 7.3 Hz), 3.81 (3H, s), 2.44



(1H, m), 2.20 (3H, s), 1.62 (1H, m), 1.53 (1H, m), 1.44



(3H, d, J = 6.6 Hz), 1.28 (1H, m), 1.14 (1H, m), 0.67 (2H,



m), 0.37 (2H, m)


Example308
1H-NMR (300 MHz, CDCl3) δ 8.21 (1H, s), 7.15 (2H, s),



6.98-6.79 (3H, m), 6.71 (1H, d, J = 8.1 Hz), 5.12 (1H, m),



3.82 (2H, d, J = 7.3 Hz), 3.79 (3H, s), 2.38 (1H, m), 2.17



(3H, s), 1.66-1.53 (2H, m), 1.44 (3H, d, J = 6.6 Hz),



1.27 (1H, m), 1.19 (1H, m), 0.67 (2H, m), 0.36 (2H, m)


Example309
1H-NMR (300 MHz, CDCl3) δ 8.30 (1H, s), 8.09 (1H, s),



6.92 (1H, d, J = 7.9 Hz), 6.87 (1H, s), 6.74 (1H, d, J = 7.9



Hz), 6.44 (1H, brd, J = 7.3 Hz), 5.25 (1H, m), 4.76 (2H, q,



J = 8.8 Hz), 3.81 (3H, s), 2.44 (1H, m), 2.20 (3H, s),



1.58-1.50 (2H, m), 1.47 (3H, d, J = 6.6 Hz), 1.16 (1H, m)


Example310
1H-NMR (300 MHz, CDCl3) δ 8.28 (1H, s), 8.08 (1H, s),



6.87 (1H, d, J = 8.1 Hz), 6.82 (1H, s), 6.71 (1H, d, J = 8.1



Hz), 6.47 (1H, brd, J = 7.3 Hz), 5.26 (1H, m), 4.81-4.69



(2H, m), 3.79 (3H, s), 2.38 (1H, m), 2.17 (3H, s), 1.62-



1.53 (2H, m), 1.48 (3H, d, J = 6.6 Hz), 1.21 (1H, m)


Example316
1H-NMR (300 MHz, CDCl3) δ 8.79 (1H, brs), 8.24 (1H, s),



7.54 (1H, d, J = 8.0 Hz), 7.178 (2H, d, J = 1.4 Hz),



7.08-7.02 (2H, m), 6.85 (1H, d, J = 6.6 Hz), 6.58 (1H, m),



5.14 (1H, m), 3.84 (2H, d, J = 7.4 Hz), 2.72 (1H, m), 



1.79 (1H, m), 1.59 (1H, m), 1.49 (3H, d, J = 6.6 Hz), 1.36



(1H, m), 1.28 (1H, m), 0.68 (2H, m), 0.37 (2H, m)


Example317
1H-NMR (300 MHz, CDCl3) δ 9.77 (1H, brs), 8.24 (1H, s),



7.54 (1H, d, J = 8.0 Hz), 7.26 (1H, m), 7.21 (2H, d, J =



1.4 Hz), 7.04 (1H, t, J = 7.3 Hz), 6.89 (1H, d, J = 6.6 Hz),



6.71 (1H, brd, J = 8.1 Hz), 6.59 (1H, m), 5.17 (1H, m),



3.82 (2H, d, J = 6.6 Hz), 2.52 (1H, m), 1.73-1.62 (2H, m),



1.48 (3H, d, J = 6.6 Hz), 1.45 (1H, m), 1.27 (1H, m),



0.66 (2H, m), 0.35 (2H, m)


Example318
1H-NMR (300 MHz, CDCl3) δ 8.31 (1H, s), 8.08 (1H, s),



7.31-7.26 (2H,, m), 6.96 (1H, t, J = 7.4 Hz), 6.89 (2H, t, 



J = 8.3 Hz), 6.47 (1H, d, J = 7.3 Hz), 5.23 (1H, m), 4.75



(2H, q, J = 8.8 Hz), 4.04 (1H, dd, J = 10.3, 2.9 Hz), 3.84



(1H, dd, J = 10.3, 6.6 Hz), 1.89 (1H, m), 1.52 (1H, m), 1.49



(3H, d, J = 6.6 Hz), 1.24 (1H, m), 0.89 (1H, m)


Example319
1H-NMR (300 MHz, CDCl3) δ 8.31 (1H, s), 8.08 (1H, s),



7.28-7.23 (2H, m), 6.94 (1H, t, J = 6.6 Hz), 6.84 (2H, d, 



J = 8.8 Hz), 6.50 (1H, d, J = 7.4 Hz), 5.23 (1H, m), 4.77



(2H, q, J = 8.0 Hz), 3.99 (1H, dd, J = 10.3, 5.9 Hz), 3.82



(1H, dd, J = 10.3, 6.6 Hz), 1.84 (1H, m), 1.52 (1H, m), 1.48



(3H, d, J = 6.6 Hz), 1.31 (1H, m), 0.93 (1H, m)


Example320
1H-NMR (300 MHz, CDCl3) δ 8.11 (1H, d, J = 2.9 Hz),



7.61 (1H, dd, J = 8.8, 2.9 Hz), 7.31-7.26 (2H, m), 6.96 (1H,



t, J = 7.3 Hz), 6.90-6.82 (3H, m), 5.82 (1H, brd, J = 7.3



Hz), 5.11 (1H, m), 4.75 (2H, q, J = 8.8 Hz), 4.08 (1H, dd,



J = 10.3, 5.1 Hz,), 3.79 (1H, dd, J = 10.3, 4.5 Hz), 1.88



(1H, m), 1.51 (3H, d, J = 6.6 Hz), 1.45 (1H, m), 1.26 (1H,



m), 0.89 (1H, m)


Example321
1H-NMR (300 MHz, CDCl3) δ 8.11 (1H, d, J = 2.2 Hz),



7.59 (1H, dd, J = 8.0, 1.9 Hz), 7.29-7.24 (2H, m), 6.95 (1H,



t, J = 7.3 Hz), 6.87-6.82 (3H, m), 5.80 (1H, brd, J = 8.1



Hz), 5.11 (1H, m), 4.75 (2H, q, J = 8.8 Hz), 4.05 (1H, dd,



J = 10.2, 5.9 Hz), 3.81 (1H, dd, J = 10.2, 7.4 Hz), 1.84 (1H,



m), 1.51 (3H, d, J = 6.6 Hz), 1.45 (1H, m), 1.30 (1H,



m), 0.93 (1H, m)


Example322
1H-NMR (300 MHz, CDDCl3) δ 8.99 (1H, brs), 8.32 (1H,



s), 8.14 (1H, s), 7.53 (1H, d, J = 8.1 Hz), 7.24 (1H, m),



7.04 (1H, t, J = 7.3 Hz), 6.85 (1H, d, J = 7.3 Hz), 6.58 (1H,



t, J = 2.2 Hz), 6.51 (1H, brd, J = 7.4 Hz), 5.29 (1H,



m), 4.84-4.70 (2H, m), 2.55 (1H, m), 1.71-1.61 (2H, m),



1.52 (3H, d, J = 6.6 Hz), 1.44 (1H, m) 


Example323
1H-NMR (300 MHz, CDCl3) δ 8.71 (1H, brs), 8.31 (1H, s),



8.11 (1H, s), 7.54 (1H, d, J = 7.3 Hz), 7.06 (1H, t, 



J = 10.3 Hz), 6.83 (1H, d, J = 7.3 Hz), 6.64-6.55 (3H, m),



5.28 (1H, m), 4.77 (2H, q, J = 8.1 Hz), 2.73 (1H, m), 1.75



(1H, m), 1.58 (1H, m), 1.52 (3H, d, J = 6.6 Hz), 1.37 (1H,



m)


Example324
1H-NMR (300 MHz, CDCl3) δ 8.24 (1H, s), 8.00 (1H, d,



J = 8.0 Hz), 7.92 (1H, d, J = 8.8 Hz), 7.75 (1H, d, J = 8.1



Hz), 7.66 (1H, t, J = 7.3 Hz), 7.45 (1H, t, J = 7.3 Hz), 7.33



(1H, d, J = 8.0 Hz), 7.22 (2H, d, J = 1.4 Hz), 6.96 (1H,



brd, J = 7.3 Hz), 5.18 (1H, m), 4.36 (2H, q, J = 8.0 Hz),



2.73 (1H, m), 2.33 (1H, m), 1.70 (2H, t, J = 7.3 Hz), 1.48



(3H, d, J = 6.5 Hz)


Example325
1H-NMR (300 MHz, CDCl3) δ 8.29 (1H, t, J = 2.2 Hz),



8.04 (1H, d, J = 8.0 Hz), 7.93 (1H, d, J = 8.8 Hz), 7.77 (1H,



d, J = 8.1 Hz), 7.66 (1H, m), 7.39 (1H, d, J = 8.1 Hz), 7.30-



7.22 (2H, m), 6.99 (1H, brd, J = 7.3 Hz), 5.18 (1H, m),



4.40 (2H, q, J = 8.0 Hz), 2.78 (1H, m), 2.36 (1H, m), 1.65



(2H, t, J = 7.3 Hz), 1.45 (3H, d, 6.6 Hz)


Example328
1H-NMR (300 MHz, CDCl3) δ 8.20 (1H, s), 7.19-7.11 (3H,



m), 6.99-6.85 (4H, m), 5.12 (1H, m), 3.82 (2H, d, J =



7.3 Hz), 2.43 (1H, m), 2.30 (3H, s), 1.65 (1H, m), 1.49 (1H,



m), 1.45 (3H, d, J = 6.6 Hz), 1.40-1.20 (2H, m), 0.66



(2H, m), 0.35 (2H, m)


Example327
1H-NMR (300 MHz, CDCl3) δ 8.29 (1H, s), 7.26-7.21 (2H,



m), 7.03-76.92 (2H, m), 6.85 (1H, m), 6.66 (1H, m),



6.17(1H, m), 4.40 (2H, q, J = 8.1 Hz), 2.64 (1H, m), 1.75



(1H, m), 1.60 (1H, m), 1.47 (3H, d, J = 6.6 Hz), 1.22



(1H, m)


Example328
1H-NMR (300 MHz, CDCl3) δ 8.38 (1H, s), 7.26-7.21 (2H,



m), 6.99-6.89 (2H, m), 6.82 (1H, m), 6.64 (1H, m), 5.17



(1H, m), 4.39 (2H, q, J = 8.0 Hz), 2.58 (1H, m), 1.75 (1H,



m), 1.65 (1H, m), 1.47 (3H, 6.6 Hz), 1.26 (1H, m)


Example345
1H-NMR (300 MHz, CDCl3) δ 8.30 (1H, m), 7.48-7.17



(7H, m), 6.90 (1H, d, J = 7.3 Hz), 6.82 (1H, m), 6.74 (1H,



s), 6.73 (1H, d, J = 7.3 Hz), 5.17 (1H, m), 5.07 (2H, s), 4.41



(2H, q, J = 8.0 Hz), 2.50 (1H, m), 1.70 (1H, m), 1.60



(1H, m), 1.46 (3H, d, J = 6.6 Hz), 1.21 (1H, m)


Example346
1H-NMR (300 MHz, CDCl3) δ 8.28 (1H, d, J = 1.5 Hz),



7.45-7.15 (7H, m), 6.90 (1H, d, J = 7.3 Hz), 6.80 (1H, m),



6.71 (1H, s), 6.69 (1H, d, J = 7.3 Hz), 5.17 (1H, m), 5.04



(2H, s), 4.40 (2H, q, J = 8.1 Hz), 2.44 (1H, m), 1.72-



1.60 (2H, m), 1.47 (3H, d, J = 6.6 Hz), 1.26 (1H, m)


Example347
1H-NMR (300 MHz, CDCl3) δ 8.29 (1H, s), 7.45-7.22 (6H,



m), 7.04 (2H, d, J = 8.8 Hz), 6.91 (2H, d, J = 8.8 Hz),



6.87 (1H, m), 5.17 (1H, m), 5.07 (2H, s), 4.40 (2H, q, J =



8.1 Hz), 2.48 (1H, m), 1.66-1.52 (2H, m), 1.46 (3H, d, 



J = 6.6 Hz), 1.17 (1H, m)


Example348
1H-NMR (300 MHz, CDCl3) δ 8.28 (1H, m), 7.47-7.21



(6H, m), 7.01 (2H, d, J = 8.0 Hz), 6.89 (1H, m), 6.88 (2H, 



d, J = 8.0 Hz), 5.17 (1H, m), 5.05 (2H, s), 4.40 (2H, q, J =



8.1 Hz), 2.44 (1H, m), 1.69-1.60 (2H, m), 1.47 (3H, d, J =



6.6 Hz), 1.22 (1H, m)


Example349
1H-NMR (300 MHz, CDCl3) δ 8.31 (1H, s), 7.28-7.25 (2H,



m), 6.95-6.87 (2H, m), 6.65-6.58 (2H, m), 5.18 (1H,



m),4.41 (2H, q, J = 8.1 Hz), 3.80 (3H, s), 2.56 (1H, m),



1.69 (1H, m), 1.54 (1H, m), 1.48 (3H, d, J = 6.6 Hz), 1.20



(1H, m)


Example350
1H-NMR (300 MHz, CDCl3) δ 8.29 (1H, m), 7.31-7.25



(2H, m), 6.93-6.86 (2H, m), 6.63-6.54 (2H, m), 5.19 (1H,



m),4.41 (2H, q, J = 8.0 Hz), 3.77 (3H, s), 2.51 (1H, m),



1.69 (1H, m), 1.59 (1H, m), 1.48 (3H, d, J = 6.6 Hz), 1.24



(1H, m)


Example351
1H-NMR(300 MHz, CDCl3) δ 8.30 (1H, m), 7.29-7.25 (2H,



m), 7.15 (1H, m), 7.03 (1H, m), 7.00-6.88 (2H, m),



5.21 (1H, m), 4.41 (2H, q, J = 8.1 Hz), 2.66 (1H, m), 1.65-



1.53 (2H, m), 1.49 (3H, d, J = 6.6 Hz), 1.20 (1H, m)


Example352
1H-NMR(300 MHz, CDCl3) δ 8.30 (1H, m), 7.36-6.87 (6H,



m), 5.20 (1H, m), 4.41 (2H, q, J = 8.1 Hz), 2.59 (1H,



m), 1.73-1.47 (2H, m), 1.46 (3H, d, J = 6.6 Hz), 1.26 (1H,



m)


Example353
1H-NMR (300 MHz, CDCl3) δ 8.29 (1H, m), 7.33-7.11



(7H, m), 6.90 (1H, d, J = 7.3 Hz), 5.18 (1H, m), 4.41 (2H, 



q, J = 8.0 Hz), 2.53 (1H, m), 1.72 (1H, m), 1.60 (1H, m),



1.46 (3H, d, J = 6.6 Hz), 1.22 (1H, m)


Example354
1H-NMR (300 MHz, CDCl3) δ 8.27 (1H, m), 7.29-7.06



(7H, m), 6.90 (1H, d, J = 7.3 Hz), 5.18 (1H, m), 4.39 (2H, 



q, J = 8.0 Hz), 2.47 (1H, m), 1.73-1.61 (2H, m), 1.47 (3H,



d, J = 6.6 Hz), 1.27 (1H, m)


Example357
1H-NMR (300 MHz, CDCl3) δ 8.27 (1H, d, J = 2.2 Hz),



7.27-7.14 (3H, m), 6.89 (1H, brd, J = 7.3 Hz), 6.74-6.62



(3H, m), 5.16 (1H, m), 4.39 (2H, q, J = 8.1 Hz), 3.78 (3H,



s), 2.44 (1H, m), 1.72-1.59 (2H, m), 1.46 (3H, d, J =



7.3 Hz), 1.26 (1H, m)









Pharmacological Assays
In Vitro Human T-Type Ca2+ Channel Activity
T-type calcium channel activity of compounds was determined by methodology well known in the art, including the “Ca2+ influx Assay” and the “T-type Ca2+ Blocker Voltage-Clamp Assay”.
Ca2+ Influx Assay
Inhibition of T-type calcium channel activity was determined by cell-based flu-orescent Ca2+ influx assay, in which potassium ionophore was added to decrease resting membrane potential and extra-cellular high-K+ stimulation was used to modulate the membrane potential of the cell. The changes in fluorescent signal were monitored by the cell imaging technology by Hamamatsu Photonics's Functional Drug Screening System (FDSS).
Cell Maintenance:
HEK 293 cells expressing the human T-type channel alpha-1H (CaV 3.2) were maintained in DMEM supplemented with 10% heat-inactivated FBS, 100 units/ml Penicillin, 100 microg/ml Streptomycin, 150 microg/ml Zeocin, 300 microg/ml Geneticin. The cells were grown in a 5% CO2 humidified incubator at 37° C.
Assay Protocol:
Day One:


    1. Cells were harvested and seeded in a poly-D-lysine coated black-sided clear bottom 384-well plate at density of 10,000 cells/well at 24 hours prior to assay.
    2. Incubate at 37° C. in 5% CO2.

Day Two:

    1. Wash each well with assay buffer (see below) and leave 20 RI using plate washer, ELx-405 Select CW (BIO-TEK).
    2. Add 20 μL of assay buffer containing 6 μM Fluo-4-AM (Molecular Probes) and 0.005% Pluronic F-127 to each well.
    3. Incubate the plate at 37° C. for 1 hour.
    4. Wash each well assay buffer (see below) and leave 20 μl using plate washer, ELx-405 Select CW (BIO-TEK).
    5. Add 10 μl of compound solution into each well by FDSS6000 and leave the plate for 4.5 min, and then add 10 μl of potassium ionophore solution.
    6. Add 20 μl of high-K+ depolarizing solution (see below) and monitor the change of fluorescent signal.


The IC50 values for compounds of the present invention were determined from 7-point dose-response studies. Curves were generated using the average of duplicate wells for each data point. Finally, the IC50 values are calculated with the best-fit dose curve determined by XLfit.







TABLE 5







Assay buffer (pH 7.4, Adjusted by HCl)











Reagent
Final conc. (mM)
Volume (mL)














NMDG (1.4M)
140
100



KCl (1.17M)
5
4.25



MgCl2 (80 mM)
1
12.5



Glucose (0.5M)
5
10



CaCl2 (1M)
1
1



HEPES buffer (1M)
16
16



MQ water
—
856.25
















TABLE 6







High-K+ depolarizing solution











Reagent
Final conc. (mM)
Volume (mL)














KCl (1.17M)
90
83.3



MgSO4 (1M)
0.5
0.5



KH2PO4 (1M)
1.2
1.2



Glucose (0.5M)
11.7
23.4



CaCl2 (1M)
2
2



HEPES buffer (1M)
18.4
18.4



MQ water
—
871.2









Electrophysiology Assay for T-type Ca2+
In a typical experiment ion channel function from HEK 293 cells expressing the human T-type channel alpha-1H (CaV 3.2) is recorded to determine the activity of compounds in blocking the calcium current mediated by the T-type channel. Cells expressing the T-type channels were grown in growth media which comprised: DMEM, 10% heat-inactivated FBS, 100 units/ml Penicillin, 100 mg/ml Streptomycin, 150 mg/ml Zeocin, 300 mg/ml Geneticin. T-type Ca channel expressing HEK293 cells were dissociated by 0.05% Trypsine-EDTA, and then seeded on cover glass for 24 hr.
Glass pipettes are pulled to a tip diameter of 1-2 micrometer on a pipette puller. The pipettes are filled with the intracellular solution and a chloridized silver wire is inserted along its length, which is then connected to the headstage of the voltage-clamp amplifier. The extracellular recording solution consists of (mM): 150 mM NMDG, 2 mM CaCl2, 10 mM HEPES, 10 mM Glucose, pH 7.4. The internal solution consists of (mM): 110 CsF, 10 EGTA, 10 HEPES, 3 ATP-Mg, 0.6 GTP pH 7.2; Upon insertion of the pipette tip into the bath, the series resistance is noted (acceptable range is between 1-4 megaohm). The junction potential between the pipette and bath solutions is zeroed on the amplifier. The cell is then patched, the patch broken, and, after compensation for series resistance (>=80%), the voltage protocol is applied while recording the whole cell Ca2+ current response. Voltage protocols: (1) −80 mV holding potential every 30 seconds pulse to −20 mV for 100 msec duration; the effectiveness of the drug in inhibiting the current mediated by the channel is measured directly from measuring the reduction in peak current amplitude initiated by the voltage shift from −80 mV to −20 mV; (2). −140 mV holding potential every 30 seconds pulse to −20 mV for 100 msec duration; the effectiveness of the drug in inhibiting the current mediated by the channel is measured directly from measuring the reduction in peak current amplitude initiated by the shift in potential from −140 mV to −20 mV. The difference in block at the two holding potentials was used to determine the effect of drug at differing levels of inactivation induced by the level of resting state potential of the cells. After obtaining control baseline calcium currents, extracellular solutions containing increasing concentrations of a test compound are washed on. Once steady state inhibition at a given compound concentration is reached, a higher concentration of compound is applied. % inhibition of the peak inward control Ca2+ current during the depolarizing step to −20 mV is plotted as a function of compound concentration.
(3) The normalized steady-steady inactivation curve is constructed using 5 sec (for vehicle) or 60 sec (for drugs) conditioning pulse to different potentials followed immediately by the test pulse to −20 mV. Peak currents are plotted as fraction of the maximum current at the conditioning potentials ranging from −140 mV to −20 mV. V1/2 or k values are estimated from Boltzmann fits. The affinity of drugs to resting state of T-type Ca channels (Kresting or Kr) is assessed by 30 msec test pulse from a negative holding potential of −140 mV, where virtually all channels are in the resting state. Kr value is calculated by a conventional 1:1 binding model:

Kresting (Kr)={[drug]Imax,drug/(Imax, control-Imax, drug)}

where Kresting (═Kr) is a dissociation constant for the resting state and [drug] is compound concentration. Imax, control and Imax, drug are peak currents in the absence and presence of compound, respectively.
The affinity of drug to inactivated state of T-type Ca channels (Kinact or Ki) is estimated from the shift of the availability curve by compound. Interaction of the compound with the inactivated state channel is evaluated as suggested by Bean et al (1983 Journal of general pharmacology 81, 613-) by fitting experimental points of the compound-induced steady-state inactivation mid-point potential shifts to the equation:

Kinact(Ki)={[drug]/((1+[drug]/Kr)*exp(−ΔV/k)−1)}  [Math.1]

where Kinact (═Ki) is a dissociation constant for the inactivated state. AV is the compound-induced voltage shift of half maximal voltage of Boltzmann curve and k is the slope factor of compound.

All examples of the invention have an IC50=<1 microM in the Ca2+ Influx Assay or IC50=<3 microM in NaV1.3 FRET Assays or NaV1.7 FRET Assays.
Especially, Example 3, Example 33, Example 57, Example 104, Example 106, Example 108, Example 110, Example 111, Example 124, Example 125, Example 133, Example 134, Example 147, Example 167, Example 168, Example 169, Example 171, Example 172, Example 181, Example 182, Example 190, Example 193, Example 194, Example 202, Example 203, Example 204, Example 205, Example 206, Example 207, Example 208, Example 210, Example 211, Example 212, Example 213, Example 222, Example 223, Example 224, Example 225, Example 226, Example 227, Example 228, Example 229, Example 237, Example 240, Example 243, Example 244, Example 245, Example 246, Example 248, Example 250, Example 251, Example 253, Example 258, Example 259, Example 260, Example 261, Example 263, Example 266, Example 267, Example 268, Example 270, Example 271, Example 273, Example 275, Example 276, Example 277, Example 279, Example 280, Example 282, Example 284, Example 286, Example 287, Example 289, Example 294, Example 296, Example 305, Example 306, Example 307, Example 309, Example 310, Example 316, Example 317, Example 318, Example 320, Example 322, Example 323, Example 325, Example 327, and Example 346 of the invention have an IC50=<0.3 microM in the Ca2+ Influx assay.
In Vitro Human Voltage Gated Sodium Channels Activity
Voltage gated sodium channels activity of compounds was determined by methodology well known in the art.
The ability of the aryl substituted carboxamid derivatives of the formula (I) to inhibit the NaV1.3,NaV1.7 and NaV1.5 channels was measured by FRET assay and electrophysiology assay described below.
FRET Assay for Navs
This screen is used to determine the effects of compounds on human NaV1.3, human NaV1.7, and human NaV1.5 channels, utilising the cell imaging technology by Hamamatsu Photonics's Functional Drug Screening System (FDSS). This experiment is based on FRET (Fluorescence Resonance Energy Transfer) and uses two fluorescent molecules. The first molecule, Oxonol (DiSBAC2(3)), is a highly fluorescent, negatively charged, and hydrophobic ion that “senses” the trans-membrane electrical potential. In response to changes in membrane potential, it can rapidly redistribute between two binding sites on opposite sides of the plasma membrane. The voltage dependent redistribution is transduced into a ratiometric fluorescent readout via a second fluorescent molecule (Coumarin (CC2-DMPE)) that binds specifically to one face of the plasma membrane and functions as a FRET partner to the mobile voltage-sensing ion. To enable the assay to work, the channels have to be pharmacologically held in the open state. This is achieved by treating the cells with veratridine.
Cell Maintenance:
Each HEK293 cells expressing human NaV1.3 channels and HEK293 cells expressing human NaV1.5 channels were grown in T225 flasks, in a 5% CO2 humidified incubator to about 80% confluence. Media composition consisted of Dulbecco's Modified Eagle Medium (high glucose), 10% fetal calf serum (FCS), 100 units/ml Penicillin, 100 microg/ml Streptomycin and 500 microg/ml Geneticine.
CHO cells expressing human NaV1.7 channels were grown in T225 flasks, in a 5% CO2 humidified incubator to about 80% confluence. Media composition consisted of HAM/F12 with Glutamax I, 10% fetal calf serum (FCS), 100 units/ml Penicillin and 100 microg/ml Hygromycin.
Protocol:


    
    
        Seed each cell lines (1.5×104 cells/well) into poly-D-lysine coated 384-well plates prior to experimentation.
        Incubate at 37° C. in 5% CO2 for 24 hours.
        Wash each well with buffer #1 (140 mM NaCl, 4.5 mM KCl, 10 mM D-Glucose, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, pH 7.4 adjusted with NaOH) twice using plate washer.
        Add 1st loading solution containing 5 μM CC2-DMPE and 0.02% Pluronic F-127 in buffer #1.
        Incubate the plate at room temperature in dark for 0.5 hours.
        Wash each well with buffer #2 (160 mM Choline, 10 mM D-Glucose, 0.1 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, pH 7.4 adjusted with KOH) twice using plate washer.
        Add 2nd loading solution containing 15 μM DiSBAC2(3), 0.5 mM VABSC-1, 10 μM veratridine and 0.004% Pluronic F-127 in buffer #2.
        Add compound solutions into the assay plate and leave the plate for 30 minutes under the dark at room temperature.
        Measure by FDSS.
    
    


The data was analyzed and reported as normalized ratios of intensities measured in the 465 nm and 575 nm channels. The process of calculating these ratios was performed as follows:

“FI465B”=the mean of fluorescence intensity as baseline (before Na+ligand addition) at 465nm

“FI575B”=the mean of fluorescence intensity as baseline (before Na+ligand addition) at 575nm

“FI465Max”=maximum fluorescence intensity at 465nm after Na+stimulation

“FI575Min”=minimum fluorescence intensity at 575nm after Na+stimulation

“FR”=fluorescence ratio=(FI465Max/FI575Min)−(FI465B/FI575B)





  
    
      
        
          Inhibition
          ⁡
          
            (
            %
            )
          
        
        =
        
          100
          -
          
            
              
                
                  
                    
                      
                        (
                        
                          FR
                          ⁢
                          
                            
                          
                          ⁢
                          of
                          ⁢
                          
                            
                          
                          ⁢
                          each
                          ⁢
                          
                            
                          
                          ⁢
                          well
                        
                        )
                      
                      -
                    
                  
                
                
                  
                    
                      (
                      
                        median
                        ⁢
                        
                          
                        
                        ⁢
                        FR
                        ⁢
                        
                          
                        
                        ⁢
                        in
                        ⁢
                        
                          
                        
                        ⁢
                        positive
                        ⁢
                        
                          
                        
                        ⁢
                        controls
                      
                      )
                    
                  
                
              
              
                
                  
                    
                      
                        (
                        
                          median
                          ⁢
                          
                            
                          
                          ⁢
                          FR
                          ⁢
                          
                            
                          
                          ⁢
                          in
                          ⁢
                          
                            
                          
                          ⁢
                          negative
                          ⁢
                          
                            
                          
                          ⁢
                          controls
                        
                        )
                      
                      -
                    
                  
                
                
                  
                    
                      (
                      
                        median
                        ⁢
                        
                          
                        
                        ⁢
                        FR
                        ⁢
                        
                          
                        
                        ⁢
                        i
                        ⁢
                        
                          
                        
                        ⁢
                        n
                        ⁢
                        
                          
                        
                        ⁢
                        positive
                        ⁢
                        
                          
                        
                        ⁢
                        controls
                      
                      )
                    
                  
                
              
            
            ×
            100
          
        
      
    
    
      
        [
        
          Math
          .
          
            
          
          ⁢
          2
        
        ]
      
    
  




This analysis is performed using a computerized specific program designed for FDSS generated data. Fluorescence ratio values are plotted using XLfit to determine an IC50 value for each compound.
Electrophysiology Assay for Navs
Whole cell patch clamp recording was used to assess the efficacy or selectivity of Na channel blocker on human NOV1.3 (hSCN3A) expressing HEK293 cells or human NOV1.7 (hSCN9A) expressing CHO cells. Human NOV1.3 expressing HEK293 cells were grown in growth media which comprised: DMEM, 10% heat-inactivated FBS (Hyclone Laboratories Inc), 100 microgram/ml Penicillin/100 U/ml Streptomycin, 150 microgram/ml Zeocin, 3 microgram/ml Geneticin. Human NOV7, expressing CHO cells were grown in growth media which comprised: HAM/F-12, 9% heat-inactivated FBS (Hyclone Laboratories Inc), 100 microgram/ml Penicillin/100 U/ml Streptomycin, 100 microgram/ml Hygromycin.
Na channel expressing cells were dissociated by 0.05% Trypsine-EDTA, and then seeded on cover glass for 24-48 hr.
Glass pipettes were pulled to a tip diameter of 1-2 micrometer on a pipette puller. The pipettes were filled with the intracellular solution and a chloridized silver wire was inserted along its length, which was then connected to the headstage of the voltage-clamp amplifier (Axon Instruments or HEKA electronik). The extracellular recording solution consists of (mM): 140 NaCl, 5 KCl, 2 CaCl2, 1 MgCl2, 10 HEPES, 10 Glucose, pH 7.4 adjusted with NaOH. The internal solution consists of (mM): 120 CsF, 15 NaCl, 10 EGTA, 10 HEPES, pH 7.2 adjusted with CsOH; Upon insertion of the pipette tip into the bath, the pipette resistance was noted (acceptable range is between 1-3 megaohm). The junction potential between the pipette and bath solutions was zeroed on the amplifier. After establishing the whole-cell configuration, approximately 10 minutes were allowed for the pipette solution to equilibrate within the cell before beginning recording. Currents were lowpass filtered between 2-5 kHz and digitally sampled at 10 kHz. Series resistance was compensated (>80%) and was monitored continuously.
The normalized steady-steady inactivation curve was constructed using 5 sec (for vehicle) or 60 sec (for drugs) conditioning pulse to different potentials followed immediately by the test pulse to 0mV. Peak currents were plotted as fraction of the maximum current at the conditioning potentials ranging from −120 mV to −40 mV. V1/2 or k values were estimated from Boltzmann fits. The affinity of drugs to resting state of Na channels (Kresting or Kr) was assessed by 30 msec test pulse from a negative holding potential of −120 mV, where virtually all channels are in the resting state. Kr value was calculated by a conventional 1:1 binding model:

Kresting (Kr)={[drug]Imax,drug/(Imax,control−Imax,drug)}

where Kresting (═Kr) is a dissociation constant for the resting state and [drug] is compound concentration. Imax, control and Imax, drug are peak currents in the absence and presence of compound, respectively.

The affinity of drug to inactivated state of Na channels (Kinact or Ki) was estimated from the shift of the availability curve by compound. Interaction of the compound with the channel on inactivated state was evaluated by the following equation:

Kinact(Ki)={[drug]/((1+[drug]/Kr)*exp(−ΔV/k)−1)}  [Math.3]

where Kinact (═K1) is a dissociation constant for the inactivated state. ΔV is the compound-induced voltage shift of half maximal voltage of Boltzmann curve and k is the slope factor on presence of compound.

The compounds of the examples were tested in the above-described assay. The results are as follows:
All examples of the invention have an IC50=<1 microM in the Ca2+ Influx Assay or IC50=<3 microM in NaV1.3 FRET or NaV1.7 FRET Assays.
Especially, Example 1, Example 4, Example 5, Example 6, Example 9, Example 10, Example 11, Example 12, Example 13, Example 14, Example 15, Example 16, Example 18, Example 20, Example 21, Example 22, Example 23, Example 28, Example 29, Example 32, Example 36, Example 37, Example 41, Example 42, Example 44, Example 45, Example 48, Example 51, Example 52, Example 53, Example 54, Example 56, Example 59, Example 62, Example 63, Example 64, Example 65, Example 66, Example 67, Example 68, Example 69, Example 70, Example 74, Example 75, Example 76, Example 77, Example 78, Example 80, Example 82, Example 85, Example 86, Example 87, Example 88, Example 89, Example 90, Example 91, Example 92, Example 93, Example 94, Example 95, Example 99, Example 102, Example 103, Example 113, Example 130, Example 131, Example 138, Example 143, Example 146, Example 150, Example 151, Example 152, Example 154, Example 156, Example 157, Example 158, Example 161, Example 162, Example 175, Example 184, Example 192, Example 195, Example 196, Example 197, Example 201, Example 209, Example 214, Example 220, Example 238, Example 241, Example 269, Example 274, Example 285, Example 308, Example 313, Example 314, Example 315, Example 321, Example 324, Example 326, Example 328, Example 332, Example 333, Example 337, Example 338, Example 339, Example 341, Example 345, Example 359, Example 377, Example 424, Example 3, Example 57, Example 104, Example 124, Example 125, Example 147, Example 169, Example 182, Example 194, Example 202, Example 204, Example 205, Example 206, Example 208, Example 210, Example 211, Example 212, Example 213, Example 226, Example 240, Example 246, Example 248, Example 251, Example 253, Example 261, Example 267, Example 268, Example 273, Example 279, Example 294, Example 306, Example 307, Example 310, Example 316, Example 317, Example 318, Example 320, Example 322, Example 323, Example 325, Example 327, Example 346, Example 329, Example 347, Example 355, Example 386, Example 396, Example 397, Example 399, Example 400, Example 413, Example 415, Example 417, Example 419, Example 420, Example 427, Example 431, Example 432, Example 434, Example 439, Example 440, Example 441, Example 442, Example 443, Example 444, Example 447, Example 448, Example 449, Example 454, Example 455, Example 456, and Example 458 of the invention have an IC50=<1.0 microM in NaV1.3 FRET or NaV1.7 FRET Assays.
In Vivo Assay
Chronic constriction injury (CCI)-induced static allodynia
Male Sprague-Dawley rats weighing 210-240 g were purchased from Charles River Japan (Kanagawa, Japan). Animals were housed in groups of two under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. The CCI was made according to the method of Bennett GJ and Xie YK (Pain 1988, 33: 87-107). Animals were anesthetized with intraperitoneal injection of sodium pentobarbital. The left common sciatic nerve was exposed at the level of the middle of the thigh and four ligatures were loosely tided around it by using 4-0 silk thread (Ethicon Inc, Brussels, Belgium) with approximately 1 mm apart. The incision was sutured, and the rats were allowed to recover. Sham operation was performed in the same manner except of sciatic nerve ligation. After 2 to 3 weeks, static allodynia was assessed using von Frey hairs (VFHs; North Coast Medical Inc., San Jose, Calif.) as described by Field M J et al. (Pain 1999, 83: 303-311). The animals were placed in grid bottom cages and allowed to acclimate for at least 30 min prior to the start of experiment. VFHs in ascending order of force (0.16, 0.4, 0.6, 1, 1.4, 2, 4, 6, 8, 10, 15 and 26 g) were applied to the plantar surface of the hind paw. Each VFH was applied to the ipsilateral paw for 6 seconds or until a withdrawal response occurred. Once a withdrawal response was happened, the paw was re-tested, starting with the next descending VFH until no response was occurred. The lowest amount of force required to elicit a response was defined as paw withdrawal threshold (PWT) in g. Animals with <2 g of PWTs were selected for evaluation and randomized to be nearly equal across all groups. The compounds of the invention or their vehicles were administered systemically. All tested compounds of the invention showed potent activities in this model.
Complete Freund's Adjuvant (CFA)-induced thermal hyperalgesia
Male Sprague-Dawley rats weighing 200-250 g were purchased from Charles River Japan (Kanagawa, Japan). Animals were housed under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. CFA-induced thermal hyperalgesia was assessed using the plantar test apparatus (Ugo Basile, Verse, Italy) as describe by Hargreaves K et al. (Pain 1988, 32: 77-88). Animals were placed in an apparatus consisting of individual testing box on an elevated glass table and allowed to acclimate for at least 10 min. Following habituation, a mobile radiant heat source was located under the table and heat stimulation was applied to the plantar surface of the right hind paw. The latency to remove its hind paw was defined as paw withdrawal latency (PWL) in sec. CFA was prepared at a concentration of 200 microg/100 microl of Mycobacterium tuberculosis H37 RA (Difco Laboratories Inc.) in liquid paraffin and injected into the plantar surface of the right hind paw. PWL was measured before and 2 days after CFA injection. Animals showing decrease of the PWL on day 2 were selected for evaluation and randomized to be nearly equal across all groups. The compounds of the invention or their vehicles were administered systemically. PWLs were measured at the appropriated time after compound administration.
Metabolic Stability Assay:
Half-life in human liver microsomes (HLM)
Test compounds (1 microM) were incubated with 3.3 mM MgCl2 and 0.78 mg/mL HLM (HL101) in 100 mM potassium phosphate buffer (pH 7.4) at 37° C. on the 96-deep well plate. The reaction mixture was split into two groups, a non-P450 and a P450 group. NADPH was only added to the reaction mixture of the P450 group. (NADPH generation system was also used instead of NADPH.) An aliquot of samples of P450 group was collected at 0, 10, 30, and 60 min time point, where 0 min time point indicated the time when NADPH was added into the reaction mixture of P450 group. An aliquot of samples of non-P450 group was collected at −10 and 65 min time point. Collected aliquots were extracted with acetonitrile solution containing an internal standard. The precipitated protein was spun down in centrifuge (2000 rpm, 15 min). The compound concentration in supernatant was measured by LC/MS/MS system.
The half-life value was obtained by plotting the natural logarithm of the peak area ratio of compounds/internal standard versus time. The slope of the line of best fit through the points yields the rate of metabolism (k). This was converted to a half-life value using following equations: Half-life=1n 2/k
Drug-drug Interaction Assay
This method essentially involves determining the percent inhibition of metabolites formation from probes (Tacrine (Sigma A3773-1G) 2 microM, Dextromethorphan (Sigma D-9684) 5 microM, Diclofenac (Sigma D-6899-10G) 5 microM, and Midazolam(ULTRAFINE UC-429) 2 microM) at 3 microM of the each compound.
More specifically, the assay is carried out as follows. The compounds (60 microM, 10 microL) were pre-incubated in 170 microL of mixture including human liver microsomes, 100 mM potassium phosphate buffer and probes as substrate for 5 min. Reaction was started by adding a NADPH (10 mM, 20 microL) (NADPH generating system, which consist of 0.5 mM NADP, 10 mM MgCl2, 6.2 mM DL-lsocitric acid and 0.5 U/ml Isocitric Dehydrogenase, was also used). The assay plate was incubated at 37° C. Acetonitril was added to the incubate solution at appropriate time (e.g. 8 min).
The metabolites' concentration in the supernatant was measured by LC/MS/MS system.
The degree of drug interaction was interpreted based on generation % of metabolites in the presence or absence of test compound.
Human Dofetilide Binding Assay
Human HERG transfected HEK293S cells were prepared and grown in-house. The collected cells were suspended in 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCl2, Complete (Roche) (pH 7.4 at 4° C.) and homogenized using a hand held Polytron PT 1300 D disruptor set at 15,000 rpm for 20 sec on ice. The homogenates were centrifuged at 48,000×g at 4° C. for 20 min. The pellets were then resuspended, homogenized, and centrifuged once more in the same manner. The final pellets were re-suspended in an appropriate volume of 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCl2, Complete (pH 7.4 at 4° C.), homogenized, aliquoted and stored at −80° C. until use. An aliquot of membrane fractions was used for protein concentration determination using BCA protein assay kit (PIERCE) and ARVOsx plate reader (Wallac). Binding assays were conducted in a total volume of 30 microL in 384-well plates. The activity was measured by PHERAstar (BMG LABTECH) using fluorescence polarization technology. Ten microL of test compounds were incubated with 10 microL of fluorescence ligand (6 nM Cy3B tagged dofetilide derivative) and 10 microL of membrane homogenate (6 microg protein) for 120 minutes at room temperature. Nonspecific binding was determined by 10 microM E4031 at the final concentration. The IC50 values were calculated using Dose Response One Site Models, 4 Parameter Logistic Model (XLfit).
All publications, including but not limited to, issued patents, patent applications, and journal articles, cited in this application are each herein incorporated by reference in their entirety. Although the invention has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

## Claims

1. A compound of the formula (II)




wherein
R is halogen, or C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and —O—C1-6 alkyl;
v is 0, 1, 2, or 3; when v is two or more than two, R may be same or different;
R1 is —OCH2CF3 or —OCH3;
R2 is C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and —O—C1-6 alkyl;
R3 is independently selected from the group consisting of:
(1) halogen, (2) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R6, (3) C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R6, (4) —O—C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R6, (5) —O—C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R6, and (6) —NR7R8;
w is 0, 1, 2, 3 or 4; when w is two or more than two, R3 may be same or different;
R4 and R5 are independently hydrogen, halogen, or C1-6 alkyl which is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and —O—C1-6 alkyl;
R6 is independently selected from the group consisting of:
(1) hydrogen, (2) hydroxyl, (3) halogen, (4) —O1R7, (5) —CN, (6) —(C═O)—NR7R8, (7) —NR7R8, (8) —S(O)2—NR7R8, (9) —S(O)t—R7, where t is 0, 1 or 2, (10) —CN, and (11) —NO2;
wherein 1 is 0 or 1; when 1 is 0, a chemical bond is present in the place of O1;
R7 and R8 are independently hydrogen, C1-6 alkyl, or C3-8 cycloalkyl, which are unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and —O—C1-6 alkyl; or R7 form a 4 to 7 membered ring with R8 which may contain nitrogen atom, or oxygen atom, wherein the 4 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C1-6 alkyl, and (5) —O—C1-6 alkyl;
p is 1; q, and r are independently 0 or 1;
Y and Z are independently selected from nitrogen atom and carbon atom; Y and Z are not carbon atom at the same time;
wherein n is 0 or 1, when n is 0, a chemical bond is present in the place of On;
Ar is aryl which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:
(1) halogen, (2) hydroxyl, (3) —On-heterocyclic group, where the heterocyclic group is unsubstituted or substituted with one or more substituents independently selected from R6, (4) —On—C1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R6, (5) —On—C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R6, (6) —NR7R8, (7) —S(O)2—N R7R8, (8) —S(O)t—R7, where t is 0, 1 or 2, (9) —NR7SO2 R8, (10) —(C═O)—NR7R8 , (11) —NR7(C═O)R8, (12) —CN, and (13) —NO2;
wherein n is 0 or 1; when n is 0, a chemical bond is present in the place of On;
or a pharmaceutically acceptable salt thereof.

2. The compound as claimed in claim 1, wherein R3 is independently selected from the group consisting of:
(1) halogen, and (2) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from halogen;
R4 and R5 are independently hydrogen, halogen, or C1-6 alkyl which is unsubstituted or substituted with one or more substituents independently selected from halogen;
wherein n is 0 or 1; when n is 0, a chemical bond is present in the place of On;
Ar is aryl which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:
(1) halogen, (2) hydroxyl, (3) —On—C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, (4) —On—C3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, and (5) —CN;
wherein n is 0 or 1; when n is 0, a chemical bond is present in the place of On;
or a pharmaceutically acceptable salt thereof.

3. The compound selected from:
(1R,2R)-2-methyl-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenyl)cyclopropanecarboxamide;
(R)-N-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethyl)-3-(6-fluoro-1H-indol-1-yl)propanamide;
(1R,2R)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-(4-(trifluoromethyl)phenyl)cyclopropanecarboxamide;
trans-2-(7-fluoro-1H-indol-3-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2-(1H-indol-3-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2-(1H-indol-3-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
trans-2-(1H-indol-6-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
trans-2-(quinolin-7-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
trans-2-(quinolin-7-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
trans-2-(isoquinolin-3-yl)-N-((R)-1-(5(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
trans-2-(quinolin-3-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
trans-2((4-chlorophenoxy)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
trans-2-(2-fluoro-5-methoxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
trans-2((1H-indol-1-yl)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
trans-2-(2,5-difluorophenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
trans-N-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethyl)-2-(2,5-difluorophenyl)cyclopropanecarboxamide;
trans-2-(2,5-difluorophenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
trans-N-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethyl)-2-(1H-indol-4-yl)cyclopropanecarboxamide;
trans-2(4-methoxy-3-methylphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2-(1H-indol-6-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
trans-2-(quinolin-6-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
trans-2-(5-fluoro-1H-indol-2-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
trans-2-(quinolin-3-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
trans-2(1H-indol-4-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2-(8chloroquinolin-2-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2(1H-indol-2-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2-(1H-indol-2-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2-(1H-indol-2-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
trans-2-(1-methyl-1H-indazol-6-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2-(4-(benzyloxy)phenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(R,E)-3-(quinolin-2-yl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acrylamide;
(1S*,2S*)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2-(2,4,6-trifluorophenyl)cyclopropanecarboxamide;
(1S*,2S*)-2-(3,5-difluorophenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2-(3-methoxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2-(4-methoxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2-(2-chloro-4-fluorophenyl)-N-((R)-1-(5- cyclopropylmethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-N-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethyl)-2(2-fluoro-4-methoxyphenyl)cyclopropanecarboxamide;
(1S*,2S*)-N-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethyl)-2-(2,4,6-trifluorophenyl)cyclopropanecarboxamide;
(1S*,2S*)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-2-(2,4,6-trifluorophenyl)cyclopropanecarboxamide;
(1R*,2R*)-N-((R)-1-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-2(2,4,6-trifluorophenyl)cyclopropanecarboxamide;
(1S*,2S*)-N-1H-indol-4-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2-phenyl-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2-phenyl-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2-phenyl-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2-phenyl-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2-phenyl-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2-(1H-benzo[d]imidazol-2-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2-(1H-benzo[d]imidazol-2-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2-(1H-benzo[d]imidazol-2-yl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2-(phenoxymethyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2-((3-fluorophenoxy)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2-((3-cyanophenoxy)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2-((4-fluorophenoxy)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2((4-cyanophenoxy)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2-(phenoxymethyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2-((3-fluorophenoxy)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2((3-cyanophenoxy)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2-((4-fluorophenoxy)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2-cyanophenoxy)methyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-y1)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2-(4-((3-methyloxetan-3-yl)methoxy)phenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-N-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethyl)-2-(1H-indol-7-yl)cyclopropanecarboxamide;
(1S*,2S*)-2-(phenoxymethyl)-N-((R)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2-(quinolin-2-yl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2-(4-(benzyloxy)phenyl)-N-((S)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2-(4-(benzyloxy)phenyl)-N-((S)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-y1)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2-(2-fluoro-4-methoxyphenyl)-N-((S)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2-(2-fluoro-4-methoxyphenyl)-N-((S)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2-(2-chloro-4-fluorophenyl)-N-((S)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2-(2-chloro-4-fluorophenyl)-N-((S)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1S*,2S*)-2-phenyl-N-((S)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
(1R*,2R*)-2-phenyl-N-((S)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide;
and salts thereof.

4. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof, as claimed in claim 1, and a pharmaceutically acceptable carrier.

5. A pharmaceutical composition as claimed in claim 4, further comprising another pharmacologically active agent.