WO2012037351A1 - Compounds - Google Patents

Abstract

Compounds, pharmaceutical compositions containing them, and their use treatment of conditions mediated by the TRPC3 and/or TRPC6 ion channels.

Description

COMPOUNDS

FIELD OF THE INVENTION

The present invention relates to 2-(amino)-thiazole-4-carboxamide compounds, pharmaceutical compositions containing them, and their use as TRPC3 and/or TRPC6 ion channel blockers and for the treatment of conditions which benefit from the blockade of the TRPC3 and/or TRPC6 ion channels.

BACKGROUND OF THE INVENTION

Heart failure occurs when the heart can no longer provide adequate blood flow or blood pressure to meet the body's demands. This condition triggers a number of compensatory mechanisms including changes in cardiac function and structure such as ventricular remodeling. Compared to healthy controls, patients with heart failure frequently have ventricular hypertrophy, dilation, and fibrosis. This ventricular remodeling can lead to diastolic dysfunction, systolic dysfunction, pulmonary congestion and edema. The mechanisms that contribute to ventricular remodeling remain unclear but abnormal calcium handling in cardiac myocytes is a dominant, common characteristic of the myocyardium in heart failure.

The transient receptor potential (TRP) superfamily of cation channels is divided into six major families including the "canonical" TRPC family, which contains TRPC1 -7. TRPC3 and TRPC6 channels are composed of 4 subunits in either homomeric or heteromeric conformation. Heterotetramers may form between TRPC channels and possibly with channels from other TRP families (K. Kiselyov, R.L. Patterson, Frontiers in Bioscience 14 (2009), 45-58; M.L. Villereal, Sem Cell Dev Biol 17 (2006), 618-629; J.Y. Park, E.M. Hwang, O. Yarishkin, J.H. Seo, E. Kim, J. Yoo, G.S. Yi, D.G. Kim, N. Park, CM. Ha, J. La, D. Kang, J. Han, U. Oh, S.G. Hong, Biochem Biophys Res Comm 368 (2008), 677-683; X. Ma, S. Qiu, J. Lui., Y. Ma, C.Y. Ngai, B. Shen, C. Wong, Y. Huang, X. Yao, Arterioscler Thromb Vase Biol 30 (2010), 851 -858. TRPC3 and TRPC6 are nonselective, calcium-permeable cation channels that are activated by diacylglycerol and a G-protein coupled receptor- phospholipase C signaling pathway. The channels contribute to changes in the cytosolic free calcium concentration by acting as calcium entry pathways in the plasma membrane or by changing the membrane polarization which modulates calcium entry mediated by alternative pathways (B. Nilius, G. Owslanik, T. Voets, J.A. Peters, Physiol Rev 87 (2007), 165-217). TRPC3 and TRPC6 are widely expressed including in brain, heart, lung, skeletal muscle, adipose, bone, blood vessels, and kidney (A. Riccio, A.D. Medhurst, C. Mattei, R.E. Kelsell, A.R. Calver, A.D. Randall, CD. Benham, M.N. Pangalos, Mol Br Res 109 (2002), 95-104). Considering their tissue distribution and the importance of calcium in all cell types, it is not surprising that TRPC3 and TRPC6 contribute to a variety of cellular functions in myocytes, endothelium, epithelium, chondrocytes, lymphocytes, neuronal cells, and tumors. Some of these cellular functions include hypertrophy, contraction, proliferation, apoptosis, differentiation, chemoattraction, survival, neurotransmission, activation, and migration (B. Nilius, G. Owslanik, T. Voets, J.A. Peters, Physiol Rev 87 (2007), 165-217; J. Abramowitz, L. Birnbaumer, FASEB J 2 (2009), 297-328).

Previous studies have established that maladaptive hypertrophy of cardiac myocytes involves impaired calcium regulation and translates to overall cardiac hypertrophy. Clinical and preclinical studies suggest that increases in TRPC3 and TRPC6 activities contribute to pathological cardiac hypertrophy and heart failure. Cardiac hypertrophy in humans and rats is associated with an increase in cardiac mRNA or protein expression of TRPC3 and TRPC6 by approximately 2-fold (E.W. Bush, D.B. Hood, P.J. Papst, J.A. Chapo, W. Minobe, M.R.

Bristow, E.N. Olson, T.A. McKinsey, J Biol Chem 281 (2006), 33487-33496; K. Kuwahara, Y. Wang, J. McAnally, J.A. Richardson, R. Bassel-Duby, J.A. Hill, E.N. Olson, J Clin Invest 1 16 (2006), 31 14-3125). Cardiac specific over-expression of TRPC3 in mice causes cardiac hypertrophy and dilation, increased mortality, and increased sensitivity to well-established stimulators of cardiac hypertrophy including isoproterenol, angiotensin II, and transverse aortic constriction (H. Nakayama, B.J. Wilkin, I. Bodi, J.D. Molkentin, FASEB J 20 (2006), 1660-1670). Similarly, cardiac specific over-expression of TRPC6 in mice causes cardiac hypertrophy, heart failure, and increased cardiac sensitivity to transverse aortic constriction (K. Kuwahara, Y. Wang, J. McAnally, J.A. Richardson, R. Bassel-Duby, J.A. Hill, E.N.

Olson, J Clin Invest 1 16 (2006), 31 14-3125). Investigators report that TRPC3 or TRPC6 siRNA decreases calcium influx, expression of hypertrophy-associated genes, actin reorganization and protein synthesis in neonatal rat cardiomyocytes treated with angiotensin II or phenylephrine (K. Kuwahara, Y. Wang, J. McAnally, J.A. Richardson, R. Bassel-Duby, J.A. Hill, E.N. Olson, J Clin Invest 1 16 (2006), 31 14-3125; J.S. Brenner, R.E. Domnetsch, PLos ONE 8 (2007), e802; N. Onohara, M. Nishida, R. Inoue, H. Kobayashi, H. Sumimoto, Y. Sato,Y. Mori, T. Nagao, H. Kurose, EMBO J 25 (2006), 5305-5316). Indeed, cardiac- specific expression of dominant negative (dn) TRPC3 and dnTRPC6 attenuates the development of cardiac hypertrophy and dysfunction in response to

phenylephrine/angiotensin II infusion or transverse aortic constriction in transgenic mice. Furthermore, ventricular myocytes from dnTRPC3 and dnTRPC6 transgenic mice have reduced calcium influx (X. Wu, E. Petra, C. Baojun, J.D. Molkentin, Proc Nat Acad Sci (2010) Vol 107, No. 5, 7000-7005 (www.pnas.org/cgi/doi/10.1073/pnas.1001825107)).

These studies suggest that blockade of TRPC3 and TRPC6 would be beneficial in the treatment of cardiac hypertrophy and heart failure.

In addition to cardiac hypertrophy and heart failure, TRPC3 and TRPC6 may play an important role in a variety of other pathophysiological states. Human genetic and preclinical studies indicate that TRPC3 and/or TRPC6 contribute to pulmonary hypertension (Y. Yu, I. Fantozzi, C.V. Remillard, J.W. Landsberg, N. Kunichika,, O. Platoshyn, D.D. Tigno, P.A. Thistlethwaite, L.J. Rubin, J.S-J. Yuan, Proc Natl Acad Sci 101 (2004), 13861 -13866), essential hypertension (F. Thilo, D. Baumunk, H. Krause, M. Schrader, K. Miller, C.

Loddenkemper, A. Zakrzewicz, K. Krueger, W. Zidek, M. Tepel, J Hypertens 27 (2009),

1217-1223; D. Liu, A. Scholze, A. Zhu,,K. Krueger, F. Thilo, A. Burkert, K. Streffer S. Holz, C. Harteneck, W. Zidek, M. Tepel, J Hypertens 24 (2006), 1 105-1 1 14), cardiac arrhythmia (H. Watanabe, M. Murakami, T. Ohba, K. Ono, H. Ito, Circ J 73 (2009) 419-427), asthma (J- H Xiao et al., Am J Respir Cell Mol Biol (2010); 43: 17-25), acute respiratory distress syndrome (D.L. Cioffi et al., "Membrane Receptors, Channels, and Transporters in

Pulmonary Circulation" AEME (2010); 661 :137-154), chronic obstructive pulmonary disease (S. Li, J. Westwick, C. Poll, Cell Calcium 33 (2003), 551-558), pulmonary edema (X. Yao and C.J. Garland. Circ Res (2005); 97:854-863; D.L. Cioffi et al., "Membrane Receptors, Channels, and Transporters in Pulmonary Circulation" AEME (2010); 661 :137-154, G.U. Ahmmed and A.B. Malik. Pflugers Arch-Eur J Phys (2005); 451 :131-142; A. Kerem et al. Circ Res (2010); 106:1 103-1 1 16), focal segmental glomerulosclerosis (N. Mukerji, T.V.

Damodaran, M.P. Winn, Biochem Biophys Acta 1772 (2007), 859-868), other forms of kidney disease (C.C. Moller, C. Wei, M. M. Altintas, J. Li, A. Greka, T. Ohse, J. W. Pippin, M. P. Rastaldi, S. Wawersik, S. Schiavi, A. Henger, m. Kretzler, S. J.Shankland, J. Reiser. J Am Soc Nephrol 18 (2007), 29-36), osteoarthritis (K. Gavenis, C. Schumacher, U.

Schneider, J. Eisfeld, J. Mollenhauer, B. Schmidt-Rohlfing, Mol Cell Biochem. Oct. 4 (2008). ), Duchenne or other muscular dystrophy (C. Vandebrouck, D. Martin, M. Colson-Van Schoor, H. Debaix, P. Gailly, J Cell Biol 158 (2002), 1089-1096; J. Kruger, C. Kunert-Keil, F. Bisping, H. Brinkmeier, Neuromuscular Disorders 18 (2008), 501-513; D.P. Millay et al. Proc Nat Acad Sci (2009); 19023-19028), cystic fibrosis (F. Antigny et al. Am J Res Cell Mol Bio (2010) doi 10.1 165/rcmb.2009-03470C), ovarian cancer (S.L. Yang, Q. Cao, K.C. Zhou, Y.J. Feng, Y.Z. Wang, Oncogene 28 (2009), 1320-1328), breast cancer (E. Aydar, S. Yeo, M. Djamgoz, C. Palmer, Cancer Cell Int 9 (2009), 23), gastric cancer (R. Cai, X. Ding, K. Zhou, Y. Shi, R. Ge, G. Ren, Y. Jin, Y. Wang, Int J Cancer 125 (2009), 2281-2287), esophageal cancer (Y. Shi, X. Ding, Z.H. He, K.C. Zhou, Q. Wang, Y.Z. Wang, Gut 58 (2009), 1443- 1450), or glioma (X. Ding et al., J Natl Cancer Inst 2010; 102: 1052-1068). See also S. Kiyonaka et al., www.pnas.org/cgi/doi/10.1073/pnas.0808793108;

www.pnas.org/cgi/conlenl/fuli/0808793106/DCSuppienientai; PNAS Vol 106, No. 13, Mar 31 , 2009 5400-5405; and Yakugaku Zasshi (2010), 130(3), 303-31 1 Pharmaceutical Society of Japan, CODEN YKKZAJ ISSN: 0031 -6903; AN 2010:857537 CAPLUS. Therefore, blockade of TRPC3 and TRPC6 channels may be useful in the treatment of these and other cardiovascular, respiratory, renal, and musculo-skeletal diseases, and types of cancer.

SUMMARY OF THE INVENTION The present invention relates to the discovery that certain compounds are TRPC3 and/or TRPC6 ion channel blockers (i.e., inhibit TRPC3 and/or TRPC6 ion channel activity), and therefore may be useful in treating diseases to which TRPC3 and/or TRPC6 activity contribute.

In one aspect, the present invention provides for novel compounds of Formula I and salts, e.g. pharmaceutically acceptable salts, thereof:

R4 and R5 are independently selected from hydrogen, halo, (Ci_-6)alkyl, trifluoromethyl, -S0₂phenyl, (C_1-6)alkylthio, -OH, -C0₂(Ci_-6)alkyl, -CO(d_-6)alkyl, phenyl, cyano, and (C_1-6)alkoxy; or R4 and R5, together with the carbon atoms to which they are attached, form a 6- membered, saturated carbocyclic ring optionally substituted with one to three substituents selected from halo, (C_1-6)alkyl, trifluoromethyl, -S0₂phenyl, (C_1-6)alkylthio, -OH,

6)alkyl, -CO(Ci_-6)alkyl, phenyl, cyano, and (Ci_-6)alkoxy;

R6 is an optional substituent independently selected from halo, (Ci_-6)alkyl, trifluoromethyl, -S0₂phenyl, (d_-6)alkylthio, -OH, -C0₂(Ci_-6)alkyl, -CO(Ci_-6)alkyl, phenyl, cyano, and (Ci_-6)alkoxy;

n is an integer of from 0-3;

R2 is H, D, halo, or (C_1-4)alkyl;

R3 is a monocyclic, carbocyclic or heterocyclic ring selected from phenyl and pyridinyl; either of which may be optionally substituted with one to three substituents independently selected from D, (Ci_-6)alkyl, (Ci_-6)alkoxy, halo, trifluoromethoxy,

trifluoromethyl, cyano, -N(R^a)(R^b), morpholinyl, -S0₂R^c, and -S0₂N(R^d)(R^e); or R3 is a bicyclic ring system (A):

wherein: ring (a) is saturated or unsaturated;

X and Y are independently selected from CR', CR'R', C=0, N, NR', O and S;

Z is a 1-3 member linking group wherein the members are independently selected from CR', CR'R', C=0, N, NR', O and S;

p is an integer of from 1 to 3; and

R' is independently selected from H, D, (Ci_-6)alkyl, (Ci_-6)alkoxy, halo,

trifluoromethoxy, trifluoromethyl, cyano, -N(R^a)(R^b), -S0₂R^c, and -S0₂N(R^d)(R^e); and

R^a-R^e are independently selected from H and (Ci_-6)alkyl. In another aspect, the present invention provides for pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect, the invention provides for the use of a compound of Formula I or a pharmaceutically acceptable salt thereof as an antagonist or inhibitor of TRPC3 and/or TRPC6 ion channel activity (e.g. in in vitro or in vivo assays or in a subject in need thereof).

In another aspect, the invention provides for the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for treating a disease, e.g. cardiovascular, respiratory, renal, or musculo-skeletal disease or cancer, to which TRPC3 and/or TRPC6 ion channel activity contribute.

In another aspect, the invention provides for the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for treating cardiac hypertrophy, heart failure, chronic renal failure, pulmonary hypertension, essential hypertension, cardiac arrhythmia, asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary edema, focal segmental glomerulosclerosis, other kidney diseases, osteoarthritis, Duchenne or other muscular dystrophy, cystic fibrosis, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, or glioma.

These and other aspects of the present invention are described further in the following detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

As used herein:

"Alkyl" refers to a monovalent, saturated, linear or branched hydrocarbon group having the specified number of member carbon atoms. For example, Ci_-9 alkyl as used herein refers to an alkyl group having from 1 to 9 member atoms. Branched alkyl groups include hydrocarbon chains having one, two, or three branches. Examples of alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, sec-butyl, t- butyl), pentyl (n-pentyl, isopentyl, neopentyl), and hexyl.

"Alkoxy" or "alkoxyl" refers to a group containing an alkyl radical attached through an oxygen linking atom. Exemplary alkoxy groups include (Ci_-4)alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy and t-butoxy (or methoxyl, ethoxyl, etc.)

"Alkylthio" refers to a group containing an alkyl radical attached through a sulfur linking atom. Exemplary alkylthio groups include (Ci_-4)alkylthio groups such as methylthio-, ethylthio-, n-propylthio-, isopropylthio-, n-butylthio-, s-butylthio-, and t-butylthio-.

"Carbocyclyl" or "carbocyclic" refers to a 3-12 membered monocyclic or fused 8-12 membered bicyclic hydrocarbon ring which may be saturated or unsaturated, and aromatic or non-aromatic. Carbocyclyl includes aryl and cycloalkyi.

"Cycloalkyi" refers to a monovalent, saturated monocyclic hydrocarbon ring having the specified number of carbon atoms in the ring. For example, C_3-7 cycloalkyi refers to a monovalent, saturated monocyclic hydrocarbon ring having 3 to 7 ring carbon atoms.

Examples of cycloalkyi include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

"Aryl" refers to a 6-12 membered monocyclic or fused bicyclic hydrocarbon ring, wherein at least one ring is aromatic. Examples of such groups include phenyl, naphthyl, tetrahydronaphthalenyl and indanyl.

"Heterocyclyl" or "heterocyclic" refers to a 4-7 membered monocyclic ring or a fused 8-12 membered bicyclic ring which may be saturated or unsaturated, aromatic or non- aromatic, containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulphur. Heterocyclyl includes heteroaryl. Examples of such monocyclic rings include pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl,

dihydropyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl,

tetrahydrothiophenyl, tetrahydrothiopyranyl, diazepanyl, and azepanyl. Examples of such bicyclic rings include indolinyl, isoindolinyl, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydro- 1 H-3-benzazepine, tetrahydroisoquinolinyl, benzodioxolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzoxazolyl, 3,4-dihydro-2H-1 ,5-benzodioxepinyl, 2H-1 ,4-benzoxazinyl, and 1 ,2,3,4- tetrahydroquinolinyl.

"Heteroaryl" refers to a 5-6 membered monocyclic aromatic or a fused 8-10 membered bicyclic aromatic ring, containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulphur. Examples of such monocyclic aromatic rings include thienyl, furyl, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, triazinyl, and tetrazinyl. Examples of such fused aromatic rings include quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pteridinyl, cinnolinyl, phthalazinyl, naphthyridinyl, indolyl, isoindolyl, azaindolyl, indolizinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzoimidazolyl, benzooxazolyl,

benzoisooxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, and benzothiadiazolyl.

"D" is deuterium (also referred to as ²H).

"Halogen" and "halo" include fluorine, chlorine, bromine and iodine, and fluoro, chloro, bromo, and iodo, respectively.

"Substituted" in reference to a group indicates that one or more hydrogen atoms attached to a member atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term "substituted" includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is stated that a group may contain one or more

substituents, one or more (as appropriate) member atoms within the group may be substituted. In addition, a single member atom within the group may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group. Where two or more substituents may be present, it is to be understood that each substituent is independently selected from the defined group of substituents, unless otherwise indicated.

"Optionally substituted" or "optional substituent" indicates that a group, such as alkyl, phenyl, cycloalkyl, heterocycloalkyl, heteroaryl, carbocyclic, heterocyclic etc., may be unsubstituted, or the group may be substituted with one or more substituents as defined. With regard to stereoisomers, the compounds of Formula I may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof.

As used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio. It will be recognized that compounds, materials, compositions and dosage forms of the invention may be acceptable in veterinary applications, provided they are suitable for use in contact with the tissues of (non-human) animals without excessive toxicity, irritation, or other problem or complication, within the scope of sound veterinary judgment and commensurate with a reasonable benefit/risk ratio.

The skilled artisan will appreciate that salts of the compounds according to Formula I may be prepared. These salts may be prepared in situ during the isolation and purification of the compound, or by separately treating the purified compound in its free acid or free base form with a suitable base or acid, respectively.

Because of their potential use in medicine, the salts of the compounds of Formula I are preferably pharmaceutically acceptable. Thus the compounds of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts can include acid or base addition salts. For a review on suitable salts see Berge et al, J. Pharm. Sci., 1977, 66, 1-19.

Typically, a pharmaceutical acceptable salt may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent used during preparation.

In certain embodiments, compounds according to Formula I may contain an acidic functional group and are, therefore, capable of forming base addition salts by treatment with a suitable base. Examples of such bases include:

a) hydroxides, carbonates, and bicarbonates of alkali metals or alkaline earth metals, such as sodium, potassium, lithium, calcium, magnesium, aluminium, and zinc,

b) primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2- hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine,

diethanolamine, and cyclohexylamine,

A pharmaceutically acceptable base addition salt can be formed by reaction of a compound of Formula I with a suitable inorganic or organic base (optionally in a suitable solvent such as an organic solvent), to give the base addition salt which is usually isolated for example by crystallisation and filtration.

In certain embodiments, compounds according to Formula I may contain a basic functional group and are therefore capable of forming acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and organic acids. Representative pharmaceutically acceptable acids include hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, sulfonic acid, phosphoric acid, acetic acid, hydroxyacetic acid, phenylacetic acid, propionic acid, butyric acid, valeric acid, maleic acid, acrylic acid, fumaric acid, succinic acid, malic acid, malonic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, tannic acid, formic acid, stearic acid, lactic acid, ascorbic acid, methanesulfonic acid, p-toluenesulfonic acid, oleic acid, lauric acid, and the like.

A pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of Formula I with a suitable inorganic or organic acid, optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration.

Other salts, eg. oxalates, may be used, for example in the isolation of compounds of Formula I, and are included within the scope of this invention.

The invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the salts of the compounds of Formula I.

As used herein, the term "a compound of Formula I" or "the compound of Formula I" refers to one or more compounds according to Formula I.

The compound of Formula I may exist in solid or liquid form. In the solid state, it may exist in crystalline or noncrystalline form, or as a mixture thereof. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed for crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.

The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs.

Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

Accordingly, in some embodiments the invention comprises a novel compound of Formula I:

R4 and R5 are independently selected from hydrogen, halo, (Ci_-6)alkyl,

trifluoromethyl, -S0₂phenyl, (d_-6)alkylthio, -OH, -C0₂(Ci_-6)alkyl, -CO(Ci_-6)alkyl, phenyl, cyano, and (Ci_-6)alkoxy;

or R4 and R5, together with the carbon atoms to which they are attached, form a 6- membered, saturated carbocyclic ring optionally substituted with one to three substituents selected from halo, (Ci_-6)alkyl, trifluoromethyl, -S0₂phenyl, (Ci_-6)alkylthio, -OH, -C0₂(Ci. ₆)alkyl, -CO(C_1-6)alkyl, phenyl, cyano, and (C_1-6)alkoxy; R6 is an optional substituent independently selected from halo, (C_1-6)alkyl, trifluoromethyl, -S0₂phenyl, (C_1-6)alkylthio, -OH, -C0₂(C_1-6)alkyl, -CO(C_1-6)alkyl, phenyl, cyano, and (C_1-6)alkoxy;

n is an integer of from 0-3;

R2 is H, D, halo, or (C_1-4)alkyl;

R3 is a monocyclic, carbocyclic or heterocyclic ring selected from phenyl and pyridinyl; either of which may be optionally substituted with one to three substituents independently selected from D, (Ci_-6)alkyl, (Ci_-6)alkoxy, halo, trifluoromethoxy, trifluoromethyl, cyano, -N(R^a)(R^b), morpholinyl, -S0₂R^c, and -S0₂N(R^d)(R^e); or R3 is a bic clic ring system (A):

wherein: ring (a) is saturated or unsaturated;

X and Y are independently selected from CR', CR'R', C=0, N, NR', O and S; Z is a 1-3 member linking group wherein the members are independently selected from CR', CR'R', C=0, N, NR', O and S;

p is an integer of from 1 to 3; and

R' is independently selected from H, D, (Ci_-6)alkyl, (Ci_-6)alkoxy, halo,

trifluoromethoxy, trifluoromethyl, cyano, -N(R^a)(R^b), -S0₂R^c, and -S0₂N(R^d)(R^e); and

R^a-R^e are independently selected from H and (Ci_-6)alkyl.

In some embodiments, R1 is:

(R6), n wherein R4 and R5 are independently selected from hydrogen, halo, (C_1-6)alkyl, trifluoromethyl, -S0₂phenyl, (C_1-6)alkylthio, -OH, -C0₂(C_1-6)alkyl, -CO(C_1-6)alkyl, phenyl, cyano, and (C_1-6)alkoxy; and R6 and n are as defined in Formula I.

In some such embodiments, R4 and R5 are hydrogen, and n is 0 (R1 is

unsubstituted 1 -piperidinyl:

In other embodiments, R1 is 1 -piperidinyl substituted with 1 -3 substituents

independently selected from halo, (Ci_-6)alkyl, trifluoromethyl, -S0₂phenyl, (Ci_-6)alkylthio, - OH, -C0₂(Ci_-6)alkyl, -CO(Ci_-6)alkyl, phenyl, cyano, and (Ci_-6)alkoxy. In some particular embodiments, the piperidinyl ring is substituted with 2-3 substituents selected from these groups.

In other embodiments, R1 is 1 -piperidinyl substituted with 1 -2 (C_1-6)alkyl groups. In some such embodiments, (C_1-6)alkyl is methyl (in some particular embodiments, 2 methyl groups on the same or different ring carbon atoms, and in more particular embodiments 2,2-; 2,3-; 2,6-; or 4,4-dimethyl). In some embodiments, R1 is 2,3-dimethyl-1-piperidinyl.

In some embodiments, R1 is:

wherein R4 and R5, together with the carbon atoms to which they are attached, form a 6-membered, saturated carbocyclic ring optionally substituted with one to three

substituents selected from halo, (Ci_-6)alkyl, trifluoromethyl, -S0₂phenyl, (Ci_-6)alkylthio, -OH, - C0₂(C_1-6)alkyl, -CO(C_1-6)alkyl, phenyl, cyano, and (C_1-6)alkoxy; and R6 and n are as defined for Formula I.

In some such embodiments, the carbocyclic ring is unsubstituted (R1 is

octa hyd roq u i n ol i n- 1 (2 H )-y I :

In other embodiments, R1 is octahydroquinolin-1 (2H)-yl substituted with 1 -6 substituents independently selected from halo, (C_1-6)alkyl, trifluoromethyl, -S0₂phenyl, (C-i. ₆)alkylthio, -OH, -C0₂(C_1-6)alkyl, -CO(C_1-6)alkyl, phenyl, cyano, and (C_1-6)alkoxy.

In some embodiments, R2 is selected from H, methyl, chloro or fluoro. In some embodiments, R2 is selected from methyl and chloro.

In some embodiments, R3 is selected from phenyl and pyridinyl, either of which may be optionally substituted with one to three substituents independently selected from D, (d. ₆)alkyl, (Ci_-6)alkoxy, halo, trifluoromethoxy, trifluoromethyl, cyano, -N(R^a)(R^b), morpholinyl, - S0₂R^c, and -S0₂N(R^d)(R^e); as defined in Formula I.

In other embodiments, R3 is a bicyclic ring system (A) as defined in Formula I.

In some embodiments, R3 is selected from:

phenyl;

2,3-dihydro-1 ,4-benzodioxin-6-yl;

1 ,3-benzodioxol-5-yl;

2.3- dihydro-1 H-inden-5-yl;

3.4- dihydro-2H-1 ,5-benzodioxepin-7-yl;

1-benzofuran-5-yl; and

1 H-indazol-5-yl;

any of which may be optionally substituted in accordance with the definition of R3 of Formula I.

Accordingly, in some embodiments, R3 is unsubstituted phenyl.

In other embodiments, R3 is phenyl substituted as defined above for R3 (phenyl) of Formula I. In some such embodiments, R3 is phenyl substituted with 1-3 (e.g., 1 -2) substituents independently selected from (Ci_-6)alkyl, halo, (Ci_-6)alkoxy, trifluoromethoxy, - N(R^a)(R^b), and cyano (e.g., methyl, chloro, fluoro, propan-2-yl, propan-2yl-oxy,

dimethylamino, methoxy, trifluoromethoxy, and cyano; in some more particular

embodiments: fluoro, propan-2-yl, propan-2yl-oxy, dimethylamino, trifluoromethoxy, and cyano).

In some embodiments, R3 is phenyl substituted at least in the 2-position (relative to the point of attachment of the aniline N), and optionally further substituted, in accordance with Formula I (e.g. 2,4-substituted phenyl).

In some embodiments, R3 is phenyl substituted with a fluoro in the 2-position (relative to the point of attachment to the aniline N), i.e., R3 is 2-fluorophenyl, optionally further substituted with 1-2 substituents as defined above for R3 (phenyl) of Formula I (i.e., selected from D, (C_1-6)alkyl, (C_1-6)alkoxy, halo, trifluoromethoxy, trifluoromethyl, cyano, - N(R^a)(R^b), morpholinyl, -S0₂R^c, and -S0₂N(R^d)(R^e)). In some such embodiments, R3 is 2- fluorophenyl, optionally further substituted with 1 -2 substituents selected from (C_1-6)alkyl, (C-i. ₆)alkoxy, halo, trifluoromethoxy, trifluoromethyl, cyano, and -N(R^a)(R^b) (e.g., methyl, chloro, fluoro, propan-2-yl, propan-2yl-oxy, dimethylamino, methoxy, trifluoromethoxy, and cyano). In some such embodiments, R3 is selected from 2-fluoro-4-cyanophenyl; 2-fluoro-4- chlorophenyl; 2-fluoro-4-trifluoromethoxyphenyl; 2-fluoro-4-methylphenyl; and 2-fluoro-4- methoxyphenyl.

In some other embodiments, R3 is 1 ,3-benzodioxol-5-yl.

In some other embodiments, R3 is 1 ,3-benzodioxol-5-yl substituted as defined for R3 (bicyclic ring system (A)) in Formula I. In some particular embodiments R3 is 1 ,3- benzodioxol-5-yl substituted with 1-3 substituents independently selected from halo (in particular, fluoro) and D, which may be on the same or different ring carbon atoms. In some embodiments, the 1 -3 substituents on 1 ,3-benzodioxol-5-yl include a fluoro in the 2- position of the benzo ring (relative to the point of attachment of the benzo ring to the N), i.e., R3 is 6- fluoro-1 ,3-benzodioxol-5-yl, optionally further substituted in accordance with Formula I including as more particularly described above. In some other embodiments, R3 is 2,2- difluoro-1 ,3-benzodioxol-5-yl, optionally further substituted in accordance with Formula I including as more particularly described above.

The scope of this invention includes any combination of the alternative definitions for the various groups and substituent groups of Formula I provided throughout the

specification. The compounds of the invention are only those which are contemplated to be "chemically stable" as will be appreciated by those skilled in the art.

In some embodiments, a compound of the invention is a salt (including

pharmaceutically acceptable salts) of a compound of Formula I.

Specific examples of compounds of the present invention include the following:

A/-(2,3-dihydro-1 ,4-benzodioxin-6-yl)-5-methyl-4-[(4-methyl-1-piperidinyl)carbonyl]-1 ,3- thiazol-2-amine

5-fluoro-/V-(4-methylphenyl)-4-[(4-methyl-1 -piperidinyl)carbonyl]-1 ,3-thiazol-2-amine

5-chloro-/V-(4-methylphenyl)-4-[(4-methyl-1-piperidinyl)carbonyl]-1 ,3-thiazol-2-amine

5-chloro-4-[(2,3-dimethyl-1 -piperidinyl)carbonyl]-/V-(6-fluoro-1 ,3-benzodioxol-5-yl)-1 ,3- thiazol-2-amine

[2-(1 ,3-benzodioxol-5-ylamino)-1 ,3-thiazol-4-yl](piperidin-1 -yl)methanone

[2-(1 ,3-benzodioxol-5-ylamino)-1 ,3-thiazol-4-yl](4-methylpiperidin-1-yl)methanone

[2-(1 ,3-benzodioxol-5-ylamino)-1 ,3-thiazol-4-yl](2-methylpiperidin-1-yl)methanone

[2-(1 ,3-benzodioxol-5-ylamino)-1 ,3-thiazol-4-yl](3-methylpiperidin-1-yl)methanone

[2-(1 ,3-benzodioxol-5-ylamino)-1 ,3-thiazol-4-yl](2,3-dimethylpiperidin-1 -yl)methanone

[2-(1 ,3-benzodioxol-5-ylamino)-1 ,3-thiazol-4-yl](octahydroquinolin-1 (2H)-yl)methanone {2-[(2-chlorophenyl)amino]-1 ,3-thiazol-4-yl}(4-methylpiperidin-1 -yl)methanone

(2,3-dimethylpiperidin-1 -yl){2-[(4-methylphenyl)amino]-1 ,3-thiazol-4-yl}methanone

(2,2-dimethylpiperidin-1 -yl){2-[(4-methylphenyl)amino]-1 ,3-thiazol-4-yl}methanone

(4,4-dimethylpiperidin-1 -yl){2-[(4-methylphenyl)amino]-1 ,3-thiazol-4-yl}methanone

[(2R,6S)-2,6-dimethylpiperidin-1-yl]{2-[(4-methylphenyl)amino]-1 ,3-thiazol-4-yl}methan

(2,3-dimethylpiperidin-1 -yl)(2-{[4-(propan-2-yl)phenyl]amino}-1 ,3-thiazol-4-yl)methanon

(2,3-dimethylpiperidin-1 -yl)(2-{[2-fluoro-4-(propan-2-yl)phenyl]amino}-1 ,3-thiazol-4- yl)methanone

(2,3-dimethylpiperidin-1 -yl)(2-{[2-fluoro-4-(propan-2-yloxy)phenyl]amino}-1 ,3-thiazol-4- yl)methanone

(2,3-dimethylpiperidin-1 -yl)(2-{[2-fluoro-4-(propan-2-yloxy)phenyl]amino}-5-methyl-1 ,3- thiazol-4-yl)methanone

{2-[(4-chloro-2-fluorophenyl)amino]-5-methyl-1 ,3-thiazol-4-yl}(2,3-dimethylpiperidin-1- yl)methanone

(2-{[4-(dimethylamino)phenyl]amino}-1 ,3-thiazol-4-yl)(2,3-dimethylpiperidin-1 -yl)m

[5-methyl-2-(phenylamino)-1 ,3-thiazol-4-yl](4-methylpiperidin-1-yl)methanone

{2-[(2-fluorophenyl)amino]-1 ,3-thiazol-4-yl}(4-methylpiperidin-1-yl)methanone

{2-[(2-fluorophenyl)amino]-5-methyl-1 ,3-thiazol-4-yl}(4-methylpiperidin-1-yl)methanone

{2-[(2,4-dichlorophenyl)amino]-5-methyl-1 ,3-thiazol-4-yl}(4-methylpiperidin-1-yl)methan

{2-[(2-chlorophenyl)amino]-5-methyl-1 ,3-thiazol-4-yl}(4-methylpiperidin-1-yl)methanone

{2-[(2,4-dimethylphenyl)amino]-5-methyl-1 ,3-thiazol-4-yl}(4-methylpiperidin-1 -yl)meth

{2-[(2,4-difluorophenyl)amino]-5-methyl-1 ,3-thiazol-4-yl}(4-methylpiperidin-1 -yl)methano

{2-[(4-chloro-2-fluorophenyl)amino]-5-methyl-1 ,3-thiazol-4-yl}(4-methylpiperidin-1- yl)methanone

{2-[(2,5-dichlorophenyl)amino]-5-methyl-1 ,3-thiazol-4-yl}(4-methylpiperidin-1-yl)methan

{2-[(4-chloro-2-fluorophenyl)amino]-5-methyl-1 ,3-thiazol-4-yl}(3-methylpiperidin-1- yl)methanone

{2-[(2,3-dichlorophenyl)amino]-5-methyl-1 ,3-thiazol-4-yl}(3-methylpiperidin-1-yl)methanon {2-[(2,4-difluorophenyl)amino]-1 ,3-thiazol-4-yl}(4-methylpiperidin-1-yl)methanone {2-[(2-fluoro-4-methoxyphenyl)amino]-5-methyl-1 ,3-thiazol-4-yl}(4-methylpiperidin-1- yl)methanone

{2-[(2-fluoro-4-methylphenyl)amino]-5-methyl-1 ,3-thiazol-4-yl}(4-methylpiperidin-1 - yl)methanone

3-fluoro-4-({5-methyl-4-[(4-methylpiperidin-1-yl)carbonyl]-1 ,3-thiazol-2-yl}amino)benzonit

[2-(1 ,3-benzodioxol-5-ylamino)-5-chloro-1 ,3-thiazol-4-yl](2,3-dimethylpiperidin-1- yl)methanone [2-(1 ,3-benzodioxol-5-ylamino)-5-chloro-1 ,3-thiazol-4-yl](3-methylpiperidin-1 -yl)methanone

{2-[(3-methoxyphenyl)amino]-1 ,3-thiazol-4-yl}(4-methylpiperidin-1-yl)methanone

{2-[(3-chlorophenyl)amino]-1 ,3-thiazol-4-yl}(4-methylpiperidin-1 -yl)methanone

{2-[(2,5-difluorophenyl)amino]-1 ,3-thiazol-4-yl}(4-methylpiperidin-1-yl)methanone

{2-[(2-chloro-5-fluorophenyl)amino]-1 ,3-thiazol-4-yl}(2,3-dimethylpiperidin-1-yl)methano

{2-[(2-chloro-4-fluorophenyl)amino]-1 ,3-thiazol-4-yl}(2,3-dimethylpiperidin-1-yl)methano

{2-[(2-chloro-3-fluorophenyl)amino]-1 ,3-thiazol-4-yl}(4-methylpiperidin-1-yl)methanone

(4-methylpiperidin-1-yl){2-[(2,3,4-trifluorophenyl)amino]-1 ,3-thiazol-4-yl}methanone

(4-methylpiperidin-1-yl)(2-{[2-(propan-2-yl)phenyl]amino}-1 ,3-thiazol-4-yl)methanone

[2-(2,3-dihydro-1 H-inden-5-ylamino)-5-methyl-1 ,3-thiazol-4-yl](4-methylpiperidin-1 - yl)methanone

[2-(3,4-dihydro-2H-1 ,5-benzodioxepin-7-ylamino)-5-methyl-1 ,3-thiazol-4-yl](4- methylpiperidin-1 -yl)methanone

(2,3-dimethylpiperidin-1 -yl){2-[(6-fluoro-1 ,3-benzodioxol-5-yl)amino]-1 ,3-thiazol-4- yl}methanone

(2,3-dimethylpiperidin-1 -yl){2-[(6-fluoro-1 ,3-benzodioxol-5-yl)amino]-5-methyl-1 ,3-thiazol-4- yl}methanone

{2-[(2,2-2H2)-1 ,3-benzodioxol-5-ylamino]-1 ,3-thiazol-4-yl}(2,3-dimethylpiperidi

yl)methanone

{2-[(2,2-2H2)-1 ,3-benzodioxol-5-ylamino]-5-methyl-1 ,3-thiazol-4-yl}(2,3-dimeth

yl)methanone

(2,3-dimethylpiperidin-1 -yl){2-[(2,2,6-trifluoro-1 ,3-benzodioxol-5-yl)amino]-1 ,3-thiazol-4- yl}methanone

{2-[(2,2-difluoro-1 ,3-benzodioxol-5-yl)amino]-1 ,3-thiazol-4-yl}(2,3-dimethylpiperidin-1- yl)methanone

2-chloro-4-[(4-{[(2S,3S)-2,3-dimethyl-1-piperidinyl]carbonyl}-1 ,3-thiazol-2- yl)amino]benzonitrile

/V-(3,4-dichlorophenyl)-4-{[(2S,3S)-2,3-dimethyl-1-piperidinyl]carbonyl}-5-methyl-1 ,3-thi 2-amine

4-{[(2S,3S)-2,3-dimethyl-1 -piperidinyl]carbonyl}-/V-[3-fluoro-4-(methyloxy)phenyl]-5-methyl- 1 ,3-thiazol-2-amine

/V-[3-chloro-4-(methyloxy)phenyl]-4-{[(2S,3S)-2,3-dimethyl-1 -piperidinyl]carbonyl}-5-meth 1 ,3-thiazol-2-amine

2-chloro-4-[(4-{[(2S,3S)-2,3-dimethyl-1-piperidinyl]carbonyl}-5-methyl-1 ,3-thiazol-2- yl)amino]benzonitrile 4- {[(2S,3S)-2,3-dimethyl-1 -piperidinyl]carbonyl}-/V-[3-fluoro-4-(methyloxy)ph 2-amine

/V-[3-chloro-4-(methyloxy)phenyl]-4-{[(2S,3S)-2,3-dime

2-amine

5- chloro-4-[(2,3-dimethyl-1 -piperidinyl)carbonyl]-/V-(6-fluoro-1 ,3-benzodioxol-5-yl)-1 ,3- thiazol-2-amine

/V-(4-chloro-2-fluorophenyl)-4-{[(2S,3S)-2,3-dimethyl-1-piperidinyl]carbonyl}-5-methyl-1 ,3- thiazol-2-amine; and salts (including pharmaceutically acceptable salts) thereof.

In some embodiments, a compound of Formula I is not:

{2-[(2,4-dimethylphenyl)amino]-5-methyl-1 ,3-thiazol-4-yl}(4-methylpiperidin-1 -yl)methanone {2-[(3-chlorophenyl)amino]-1 ,3-thiazol-4-yl}(4-methylpiperidin-1 -yl)methanone

(4-methylpiperidin-1-yl){2-[(4-methyl-phenyl)amino]-1 ,3-thiazol-4-yl}methanone

(piperidin-1-yl){2-[(4-methyl-phenyl)amino]-1 ,3-thiazol-4-yl}methanone

{2-[(2-chlorophenyl)amino]-1 ,3-thiazol-4-yl}(piperidin-1 -yl)methanone

{2-[(4-methoxyphenyl)amino]-1 ,3-thiazol-4-yl}(piperidin-1-yl)methanone

(piperidin-1-yl){2-[(3-methyl-phenyl)amino]-1 ,3-thiazol-4-yl}methanone

{2-[(4-methoxyphenyl)amino]-1 ,3-thiazol-4-yl}(4-methylpiperidin-1-yl)methanone

{2-[(3,4-chlorophenyl)amino]-1 ,3-thiazol-4-yl}(piperidin-1 -yl)methanone

[2-(phenylamino)-1 ,3-thiazol-4-yl](4-methylpiperidin-1 -yl)methanone and/or

2-[(2,4-dimethylphenyl)amino]-1 ,3-thiazol-4-yl}(4-methylpiperidin-1-yl)methanone.

The present invention is intended to include novel pharmaceutical compositions and uses of these compounds.

Compound Preparation

The compounds according to Formula I are prepared using conventional organic syntheses. Suitable synthetic routes are depicted below in the following general reaction schemes. All functional groups are as defined in Formula I for corresponding groups unless otherwise defined. For example, "R" is one or more optional substituents on R3=phenyl of Formula I. Starting materials and reagents depicted below in the general reaction schemes are commercially available or can be made from commercially available starting materials using methods known by those skilled in the art. The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts,

Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999). In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.

Scheme 1

Scheme 1 represents a general reaction scheme for preparing general compounds according to Formula I (depicted as compound 1.6). Treatment of thiourea 1.1 with a reagent 1.2 (commercially available or made from commercially available starting materials using methods known to those skilled in the art) in ethanol (or equivalent solvent) at temperatures between 0°C to 80°C provides intermediates 1.3 or 1.4. If R2 = alkyl group such as an ethyl group, then compound 1.3 is treated with base such as NaOH or equivalent and solvent such as ethanol at temperatures between 0°C to 80°C to yield intermediate 1.4. Next, reaction of intermediate 1.4 with an amine 1.5 (commercially available or made from commercially available starting materials using methods known to those skilled in the art), a coupling reagent (such as 1 H-1 ,2,3-benzotriazol-1 -yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) reagent^ and a base (such as DIEA) in a solvent (such as DMF) at temperatures between 0°C to 80°C provides compounds 1.6 according to Formula I.

Scheme 2

Scheme 2 represents an alternative general reaction scheme for preparing certain compounds according to Formula I (depicted as compound 2.6). Treatment of intermediate 2.1 with aniline 2.2 in a solvent (such as ethanol) at temperatures between 0 to 150 °C under standard microwave conditions yields intermediate 2.3. Treatment of intermediate 2.3 with a base (such as LiOH) in a THF/MeOH mixture provides intermediate 2.4. Next, reaction of intermediate 2.4 with an amine 2.5 (commercially available or made from commercially available starting materials using methods known to those skilled in the art), a coupling reagent (such as 1 H-1 ,2,3-benzotriazol-1 -yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) reagent), and a base (such as DIEA) in a solvent (such as DMF) at temperatures between 0°C to 80°C provides compounds 2.6 according to Formula I. Scheme 3

3.3

Selectfluor

solvent

1 ) NCS, solvent

2) TFA, solvent

3.4

Scheme 3 represents a general scheme to incorporate either a chlorine or fluorine group onto the thiazole ring. Treatment of amide 3.1 with BOC₂0 in a solvent and base yields the protected amide 3.2. Treatment of intermediate 3.2 with Selectfluor ® (1- chloromethyl-4-fluoro-1 ,4-diazoniabicyclo [2.2.2] octane bis-(tetrafluoroborate); Air Products & Chemicals Inc.) in a solvent yields the desired fluorinated compound 3.3. Treatment of 3.2 with N-chlorosuccinimide in a solvent followed by TFA deprotection of the BOC protecting group yields the desired chloro compound 3.4. Scheme 4

4.3

Scheme 4 represents an alternative general scheme to incorporate a fluorine or chlorine group onto the thiazole ring. Treatment of amide 4.1 with Selectfluor ® in a solvent such as CH₃CN yields the desired amide 4.2. Chloro analogs 4.3 can be synthesized directly from 4.1 by treatment with NCS in a solvent.

Scheme 5

Scheme 5 represents two general syntheses for thioureas that are used in the synthesis of the desired compounds according to the Formula I described previously.

Treatment of aniline 5.1 with benzoyl isothiocyanate in a solvent such as CH₃CN or CH₂CI₂ yields the intermediate 5.2. Treatment of intermediate 5.2 with a base in a solvent at temperatures between 0 to 100 °C yields thiourea 5.3. Alternatively, reaction of aniline 5.1 with ammonium thiocyanate in an acid such as HCI yields the desired thiourea 5.3.

Anilines that are utilized to make the above thioureas are commercially available or can be made from commercially available starting materials using general methods known by those skilled in the art. For example, Scheme 6 represents the synthesis of certain anilines that may be used in the synthesis of corresponding compounds of Formula I. a) Reaction of 4-fluorocatechol 6.1 with bromochloromethane and base such as Cs₂C0₃ yields intermediate 6.2. Next, treatment of intermediate 6.2 with nitric acid forms the intermediate 6.3 which upon treatment with SnCI₂ yields the desired aniline 6.4. b) Treatment of 4- nitrocatechol 6.5 with Cs₂C0₃ and dibromomethane-d2 yields the intermediate 6.6 which can be transformed via reduction to the desired aniline 6.7.

Biological Activity

The compounds of the invention are TRPC3 and/or TRPC6 blockers or inhibitors, and therefore may be useful for treatment of conditions or diseases to which TRPC3 and/or TRPC6 ion channel activity contribute. The biological activity of compounds of Formula I can be determined using any suitable assay for determining the activity of a candidate compound as a TRPC3 and/or TRPC6 inhibitor, as well as tissue and in vivo models. For example, the biological activity of compounds of Formula I may be demonstrated by one or more of the following tests. a) Liqand-qated assay

TRPC3 and TRPC6 channel opening causes an influx of predominantly calcium and sodium cations that result in a change in the electrical potential across the cell membrane. This change in membrane potential can be monitored using membrane potential dyes. To measure changes in membrane potential, HEK-293-MSRII (macrophage scavenging receptor - MSRII) are transduced with BacMam vector (J. P. Condreay, S.M. Witherspoon, W.C. Clay, T.A. Kost, Proc Nat Acad Sci 96 (1999), 127-132) expressing either human TRPC3 or human TRPC6. For TRPC3, cells are resuspended in DMEM/F12 with 10% FBS to a final density of 300,000 cells/mL when incubated for 24 hours prior to experiments, or to 200,000 cells/mL when incubated for 48 hours prior to experiments. BacMam virus expressing TRPC3 is added at 1 % v/v ratio prior to incubation. For TRPC6, cells are resuspended in DMEM/F12 (Dulbecco's Modified Eagle Medium, Nutrient Mixture F-12, available from Invitrogen Life Science) with 10% FBS (fetal bovine serum) to a final density of 300,000 cells/mL. It has been found that the optimal results for TRPC6 are obtained when 0.5% TRPC6 BacMam virus plus 0.5% muscarinic receptor type 1 BacMam are transduced together.

Cells plus BacMam virus are plated at either 10K/well or 15K/well in 50 μΙ_, as per above into 384-well polystrene plates. Cells are grown for 24 hours or 48 hours at 37°C plus 5% C0₂. Media is aspirated using a Tecan plate washer and replaced with 20 μΙ_ of dye loading buffer (140 mM NaCI, 3 mM KCI, 0.3 mM CaCI₂, 1 mM MgCI₂, 20 mM HEPES ((4-(2- hydroxyethyl)-1-piperazineethanesulfonic acid)), 5 mM D(+)-glucose, pH 7.4). For TRPC3 a final concentration of 0.5x membrane potential dye (Molecular Devices Membrane Blue) is used. For TRPC6, a final concentration of 0.33x is used. Cells with membrane potential dye are then incubated for 1 hour at 37°C, 5% C0₂ prior to beginning the experiments.

To test the effects of compounds on TRPC3 or TRPC6 activity, compounds are first diluted in 100% DMSO to 3x the final concentration to be used in the experiments. Typical dose-response experiments range from 25 μΜ top concentration to 0.14 pM lower concentration. Ten microliters of 3x compound in 1.5% DMSO are added to the 20 μΙ_ of cells incubated with membrane potential dye. Compound addition is performed on a

FLIPRTetra or a FLIPR 384 (MDS Analytical Technologies). After a ten minute incubation with compound, 10 μ L of carbachol is added at 4x the EC₈o (typical EC₈o for TRPC3 = 2 μ M final; EC₈o for TRPC6 = 1 μ M final). The carbachol challenge is designed to measure the inhibitory activity of compounds on receptor-operated TRPC3 and TRPC6 activation. All data is normalized to low controls (buffer alone) or high controls (carbachol ECioo)- Data is analyzed using an XC₅₀ curve fitting module and reported as plC₅₀ or IC₅₀ values. The values are averaged to determine a mean value, for a minimum of 2

experiments.

In some embodiments, compounds of the invention have a mean TRPC3 and/or TRPC6 IC₅₀ of < 10 μΜ (e.g. < 5 μΜ or < 1 μΜ).

The compounds listed in the Examples herein were tested according to the above assay and exhibited mean TRPC3 and TRPC6 IC₅₀'s which were < 10 μΜ (e.g. -0.1 - 10 uM). b) Electrophvsioloqy assay

TRPC3 and TRPC6 channel activation results in ionic current which can be measured using the whole-cell patch-clamp technique. Intracellular AIF₄ ^" is used to activate human TRPC3 or TRPC6 current in transduced HEK293F cells as previously described (R. Kraft, Biochem Biophys Res Commun 361 (2007), 230-6). HEK293F cells are sub-cultured in 6-well plates at 50-70% confluency. BacMam virus expressing the human TRPC3 or human TRPC6 gene is added to the well with volume to volume concentration of 4-12%. Cells are incubated overnight at 37°C and 5% C0₂. The transduced cells are detached from the well using trypsin solution (0.25% trypsin+0.1 % EDTA(ethylenediaminetetraacetic acid)) and stored in culture medium at room temperature for patch-clamp experiments within 5 hours. All current recordings are conducted at room temperature (~22°C). Cells are placed in a small chamber and continuously perfused with an external solution (~3 mL/min).

Electrodes are made from glass capillary tubes and have a resistance of 2-4 ΜΩ when filled with one of the internal solutions. Seal between cell membrane and electrode is made in the external solution containing (in mM) 140 NaCI, 4 KCI, 1 MgCI₂, 0.2 CaCI₂, 10 glucose, 10 HEPES; pH=7.4. After whole-cell configuration is established, the external solution is switched to an EGTA (ethylene glycol tetraacetic acid) containing solution (in mM; 140 NaCI, 4 KCI, 1 MgCI₂, 2 Na₄EGTA, 10 Glucose, 10 HEPES; pH=7.4) to minimize the

desensitization of TRPC3 or TRPC6 current. Cell membrane capacitance is canceled electronically and the series resistance is compensated by about 70%. To activate TRPC3 or TRPC6 current, the pipette solution contains AIF₄ ^" (in mM, 1 10 CsF, 20 CsCI, 10 HEPES, 10 EGTA, 10 NaF; pH=7.2 with addition of 15 μΜ AICI₃). To record TRPC3 or TRPC6 current, a ramp voltage protocol is applied every 10 seconds for as long as the experiment lasts. The ramp protocol is stepped from a holding voltage of -60 mV to -80 mV for 40 ms and then depolarized to +80 mV in 400 ms, and stepped back to holding voltage after spending 40 ms at +80 mV. TRPC3 or TRPC6 current gradually increases as the cell is dialyzed with the internal solution containing AIF₄ ^". For HEK293F cells transduced with 6-12% TRPC3 BacMam, constitutive TRPC3 current is recorded using an internal solution containing (in mM) 130 CsCI, 5 EGTA, 5.5 MgCI₂, 5 Na₂ATP (Na₂adenosine triphosphate), 0.1 Na₃GTP (Na₃guanosine-5'-triphosphate), 5 HEPES; pH = 7.2 or (in mM) 140 CsCI, 5 Na₄EGTA, 10 HEPES; pH = 7.2. Once the control current is stabilized, the recording chamber is perfused with the EGTA external solution containing a test compound. At each drug concentration, sufficient time is allowed for the drug effect to reach steady-state. At the end of the experiment, a positive control compound is applied to the cell to completely block TRPC3 or TRPC6 current. Positive control is either 2-[4-[(2,5- difluorophenyl)methoxy]phenoxy-5-ethoxyaniline (See e.g., WO99/020598), or 4-(3,4- dihydro-2(1 H)-isoquinolinylcarbonyl)-/\/-[4-(methyloxy)phenyl]-1 ,3-thiazol-2-amine

(alternatively named as 3,4-dihydroisoquinolin-2(1 H)-yl{2-[(4-methoxyphenyl)amino]-1 ,3- thiazol-4-yl}methanone; Methanone, (3,4-dihydro-2(1 H)-isoquinolinyl)[2-[(4- methoxyphenyl)amino]-4-thiazolyl]-)), which are commercially available or may be prepared using methods available in the art. For example, 4-(3,4-dihydro-2(1 H)- isoquinolinylcarbonyl)-/V-[4-(methyloxy)phenyl]-1 ,3-thiazol-2-amine is commercially available from Interchim Inc., San Pedro CA; Zelinsky Institute, Newark DE; Ryan Scientific, Inc., Mt. Pleasant SC; ASINEX Corp., Winston-Salem NC; and Aurora Fine Chemicals LLC and ChemDiv, Inc., both of San Diego; CA.

The TRPC3 or TRPC6 current is measured as the average current at +80 mV. The time course of current is plotted for the whole experiment. Percent inhibition = 100 x (1 - l_D/ l_c), where l_D is the current amplitude measured at the end of a particular drug concentration and lc is the control current amplitude measured before drug application. Zero current (background) level is set at the end of positive control compound perfusion or at the very beginning before AIF₄ ^" activated TRPC3 or TRPC6 current. AXOPATCH 200B amplifier and pCLAMP software (version 8, Molecular Devices) are used for data acquisition. The average percent inhibition at each drug concentration is calculated first. Then, the average data are fit using a 4-parameter logistic equation (Origin 7.0 software) to calculate the IC₅₀ values.

Compounds listed in Examples 12, 22, 39 and 40 herein were tested according to the above assay. The compounds listed in Examples 12 and 22 exhibited constitutive TRPC3 IC₅₀'s which were <1 μΜ. The compounds listed in Examples 39 and 40 exhibited mean AIF4^" activated TRPC6 IC₅₀'s which were <1 μΜ. c) Hypertrophy assays

Calcium influx through TRPC3 and TRPC6 channels contributes to cardiomyocyte hypertrophy (N. Frey, E.N. Olson, Annu Rev Physiol 65 (2003), 45-79). A common hypertrophic response in cardiac myocytes is the increased expression of atrial naturietic factor (ANF) which can be modulated by anti-hypertrophic compounds (E. Bush, J. FielitzJ, L. Melvin, M. Martinez-Arnold, T.A. McKinsey, R. Plichta, E.N. Olson, Proc Nat Acad Sci 101 (2004), 2870-5; D.M. Eble, M. Qui, S. Waldschmidt, P.A. Lucchesi, K.L. Byron, A. M.

Samarel, Am J Physiol Cell Physiol 274 (1998), C1226-C1237). The expression of ANF mRNA or protein is measured by quantifying ANF (Nppa/ANF) messenger RNA levels by Real Time -Polymerase Chain Reaction (RT-PCR) or by high content imaging, respectively.

Isolation of neonatal rat ventricular myocytes (NRVM):

As previously described (X. Long, M.O. Boluyt, M.L. Hipolito, M.S. Lundberg, J.S. Zheng, L. O'Neill, C. Cirielli, E.G. Lakatta and M.T. Crow, J Clin Invest 99 (1997), 2635- 2643), NRVM are isolated from cardiac ventricles of 2-3 day old Sprague-Dawley pups and minced with scissors or a Mcllwain tissue chopper to 5 mm cubes. Cells are dissociated from the cubes by incubation in 0.1 % pancreatin in PBS (phosphate buffered saline) at 37°C for 200 minutes with agitation, changing the digestion solution every 20 minutes.

Alternatively, tissue are incubated at 37°C for 120 minutes with agitation, changing the digestion solution every 20 minutes, discarding the first two isolates. Cell isolates are stored on ice until all fractions have been collected. The crude cell isolates are then pooled and resuspended in two aliquots of 12.5 ml. of 1.082 g/ml_ Percoll in DMEM/F12 containing 15 mM HEPES, pH 7.4. After transfer to a centrifuge tube, 12.5 ml. of 1 .062 and 1 .050 g/mL Percoll, respectively, are layered on top. This is spun at 2095 g at 15°C for 30 minutes, and the myocyte-enriched fraction is collected from the 1 .082:1.062 interface. These cells are then washed twice to remove Percoll, and resuspended in ice-cold plating medium (3:1 mix of DMEM:M199 (Media 199, available from Invitrogen Life Science) with 15% fetal bovine serum supplemented with 0.1 % Neutridoma, penicillin, streptomycin and 1 mM L-glutamine). These cells are then used in two different assays of hypertrophic responses: Taqman analysis of ANF gene expression, and high content imaging analysis of ANF protein within NRVM.

ANF protein hypertrophy assay:

To quantify the induction of ANF protein expression in NRVM during hypertrophy, ANF is stimulated with phenylephrine and measured using high content imaging. In high content imaging assays, cells plated on clear-bottom tissue culture dishes are

photomicrographed using an automated system, and these images are analyzed using automated cell-detection, spot-detection and fluorescence intensity algorithms. Six thousand cells are plated in 50 μΙ_ into each well of a 384 well-dish pre-coated with 0.2% gelatin in PBS. Isolated NRVM are allowed to attach during overnight incubation in a humidity-controlled incubator with 5% C0₂. The day after isolation, plating medium is replaced with 45 μΙ_ of serum-free medium containing test compounds, 0.5% DMSO and 0.01 % CHAPS ((3-((3-Cholamidopropyl)dimethylammonio)propanesulfonate), and cells are pre-incubated at 37°C for 40 minutes. Five microliters of 100 μΜ R-phenylephrine (PE) agonist is then added to each well. Cells are incubated for 48 hours directly in a 5% C0₂ incubator at 37°C or are placed inside a humidity-controlling chamber within the incubator. Cells are fixed with 10% formalin for 15 minutes at room temperature, and fixative is washed away using 3 washes of 100 μΙ_ PBS on a BioTek platewasher. After blocking with 50 μΙ_ of 3% BSA (bovine serum albumin) in PBS + 0.1 % Tween-20 for 72 hours at 4°C, the cells are stained with primary antibodies against ANF (Rabbit IgG) in blocking solution. Primary antibodies are washed away using three washes of 100 μΙ_ PBS on a BioTek platewasher, and cells are similarly stained with secondary antibodies (Alexa 488 anti-Rabbit IgG) and washed. Hoechst nuclear dye is included in the secondary staining solution. Plates are then imaged on a Perkin Elmer Opera, with the following settings: 405 nm laser, 1530 μ\Λ , 240 ms, 450 nm/50 nm filter; 488 nm laser, 4000 μ\Ν, 200 ms, 540 nm/75 nm filter; 635 nm laser, 1030 μ\Λ , 1 s, 690 nm/50 nm filter. In some experiments, a GE InCell 1000 fitted with a DAPI/FITC/Texas Red dichroic mirror is used to image the cells using epiflourescence, with the following settings: Hoechst channel, 360 nm/40 nm excitation filter, 460 nm/40 nm emission filter, 100 ms; Alexa 488 channel, 480 nm/40 nm excitation filter, 545 nm/50 nm excitation filter, 150 ms; Alexa 647 channel, 600 nm/50 nm excitation, 700 nm/75 nm emission, 800 ms. Five to eight fields per well are imaged and analyzed. ANF protein content is defined as the number of ANF-positive spots per cell or as the number of ANF- positive spots within 4 microns of the nucleus. Average responses per well are expressed as the percent of response in hypertrophic control wells (i.e. wells treated with 10 μΜ PE and vehicle only) and plotted against the log of the concentration of compound. These dose-response curves are fitted and IC₅o values are calculated using a four-parameter dose- response curve in Graph Pad Prism software.

Compounds listed in Examples 4, 8, 9 and 12 herein were tested according to the above assay, and exhibited plC₅₀ values which were < 10 μΜ (e.g. -5-10 μΜ).

ANF mRNA hypertrophy assay:

To determine compound activity on the agonist-induced increase in ANF mRNA expression, NRVM are stimulated with PE in the presence and absence of test compounds. Isolated NRVM are plated at a seeding density of 10,000 or 25,000 cells/well in 384 or 96 well-dishes precoated with 0.2% gelatin, respectively. Cells are maintained in 50 μΙ_ plating medium containing 3:1 mix of DMEM:M199 and 15% fetal bovine serum supplemented with 0.1 % Neutridoma, penicillin, streptomycin and 1 mM L-glutamine. After overnight incubation in a standard cell culture incubator (37°C and 5% C0₂), the plating medium is replaced with serum free medium (above medium minus the serum) containing the test compounds (0.1 % DMSO final). Following a 45 minute pre-incubation with the compounds at 37°C, the agonist PE is added to the cells at a final concentration of 10 μΜ. 0.1 %DMSO and PE only treated cells serve as controls. The treated cells are returned to the cell culture incubator for 24 hours and then washed with ice-cold PBS. RNA is isolated using the TaqMan® Gene Expression Cells to Ct Kit™ (Life Technologies Corporation). Following the generation of cDNA, RT-PCR is conducted to quantify levels of Nppal ANF mRNA and the internal control Gapdh mRNA using the probes Rn00561661_m1 (Applied Biosystems) and Rn99999916 s1 (Applied Biosystems), respectively. The reaction is run on a 7900HT Fast Real-Time PCR system (Applied biosystems). ANF mRNA expression values are normalized to the internal control GAPDH, and calculated as percent inhibition versus PE treated controls. The values are plotted against the log concentration of the compound to obtain the IC₅₀ values using the four-parameter dose-response curve provided in GraphPad Prism software.

Compounds listed in Examples 4, 8, 9 and 12 herein were tested according to the above assay, and exhibited plC₅₀ values which were <10 μΜ (e.g. -5-10 μΜ).

Methods of Use

The compounds of the invention are TRPC3 and/or TRPC6 inhibitors. These compounds may be particularly useful for treatment of diseases (conditions) mediated at least in part by TRPC3 and/or TRPC6, specifically by inhibition of TRPC3 and/or TRPC6 activity. In some embodiments, such diseases are selected from cardiovascular, respiratory, renal, or musculo-skeletal disease or cancer, to which TRPC3 and/or TRPC6 ion channel activity contribute.

In some embodiments, a compound of the invention is used for treating a condition selected from cardiac hypertrophy, heart failure, chronic renal failure, pulmonary

hypertension, essential hypertension, cardiac arrhythmia, asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary edema, focal segmental glomerulosclerosis, other kidney diseases, osteoarthritis, Duchenne or other muscular dystrophy, cystic fibrosis, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, and glioma. The methods of treatment of the invention comprise administering an effective amount of a compound according to Formula I or a pharmaceutically-acceptable salt thereof to a patient in need thereof.

Thus the present invention provides a method of treating diseases mediated by TRPC3 and/or TRPC6, specifically by inhibition of TRPC3 and/or TRPC6, for example those diseases mentioned herein above, which comprises administering an effective amount of a compound according to Formula I or a pharmaceutically-acceptable salt thereof to a patient (e.g. human) in need thereof.

The invention also provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases mediated by TRPC3 and/or TRPC6, specifically by inhibition of TRPC3 and/or TRPC6, for example those diseases mentioned herein above.

The invention also provides the use of a compound of Formula I, or a

pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diseases mediated by TRPC3 and/or TRPC6, specifically by inhibition of TRPC3 and/or TRPC6, for example those diseases mentioned herein above.

As used herein, "treat" in reference to a condition means at least the mitigation of a disease condition in a patient. The methods of treatment for mitigation of a disease condition include the use of the compounds of the invention in any conventionally acceptable manner, for example for prevention, retardation, prophylaxis, therapy or cure of a disease. Treatment may include (1 ) amelioration or prevention of the condition or one or more of the biological manifestations of the condition, (2) interference with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) alleviation of one or more of the symptoms or effects associated with the condition, or (4) slowing the progression of the condition or one or more of the biological manifestations of the condition.

As indicated above, "treatment" of a condition includes prevention of the condition. The skilled artisan will appreciate that "prevention" is not an absolute term. As used herein, "prevention" refers to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.

As used herein, "effective amount" in reference to a compound of the invention or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. An effective amount of a compound will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.

As used herein, "patient" or "subject" refers to a human or other animal.

The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration. In some embodiments, a compound of the invention is administered intravenously, transdermally, by inhalation, or orally.

The compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are

administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.

Typical daily dosages may vary depending upon the particular route of administration chosen. Typical dosages for oral administration range from 1 mg to 1000 mg per person per dose. Additionally, the compounds of the invention may be administered as prodrugs. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo. Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset 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 or 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.

Methods of treatment of the invention may be achieved using the compounds of the invention as a monotherapy, or in dual or multiple combination therapy with one or more therapeutic agents or therapies. For example, one or more compounds of the invention may be used in combination. One or more compounds of the invention may also be used with one or more other therapeutic agents or therapies. For example, particularly in the treatment of heart failure, a compound of the invention may be used in combination with a loop diuretic (e.g., bumetanide, furosemide, torsemide), thiazide diuretic (e.g.,

chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone), potassium- sparing diuretic (e.g., amiloride, triamterene), arginine vasopressin antagonist (e.g., satavaptan, tolvaptan, lixivaptan, conivaptan), angiotensin receptor blocker (e.g.,

trandolapril, valsartan, candesartan, losartan), angiotensin converting enzyme inhibitor (e.g., captopril, enalapril, lisinopril, ramilpril, perindopril, foxinopril), cardiac glycoside (e.g., digoxin, digitalis), beta adrenergic receptor antagonist (e.g., carvedilol, bisoprolol, metoprolol), beta adrenergic receptor agonist (e.g., dobutamine), phosphodiesterase inhibitor (e.g., sildenafil), aldosterone receptor antagonist (e.g., sprinolactone, eplerenone), hydralazine, nitrate, renin inhibitor (e.g., aliskiren), ryanodine receptor activator, calcium sensitizer, sarcoplasmic reticulum calcium ATPase activator, and/or TRPV4 blocker, which may be administered in effective amounts. One or more compounds from a given class, or from different classes may be used in combination with a compound of the invention. Use in combination includes combination products (e.g. dosage forms) as well as regimens. Accordingly, the compounds may be combined in a single composition, or may be in different compositions which are administered to a patient concurrently or at different times.

The present invention includes the use of a compound of Formula I or salt thereof as an inhibitor (or antagonist/blocker) of TRPC3 and/or TRPC6 ion channel activity (e.g. in in vitro or in vivo assays or in a subject in need thereof). Accordingly, compounds of Formula I may be used to identify compounds which inhibit TRPC3 and/or TRPC6 ion channel activity, for example by using a compound of Formula I as a control compound in an assay or model which measures TRPC3 and/or TRPC6 ion channel activity, including any biological assays described herein.

Compositions

The compounds of the invention will normally, but not necessarily, be formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically-acceptable excipient.

The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection.

Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains an effective amount of a compound of the invention. When prepared in unit dosage form, the

pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg of a compound of the invention.

The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds (including, e.g., those described herein). Conversely, the pharmaceutical compositions of the invention typically contain more than one pharmaceutically-acceptable excipient. However, in certain embodiments, the pharmaceutical compositions of the invention contain one

pharmaceutically-acceptable excipient. Accordingly, unless otherwise stated, an indication of "a" compound of the invention or "a" pharmaceutically acceptable excipient encompasses one or more of such compounds of excipients, respectively.

As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically acceptable material which is included in the composition for a purpose other than pharmaceutical efficacy (this is not intended to exclude materials which may have some biological effect). For example, an excipient may be involved in giving form or consistency to the pharmaceutical composition, such as forming a vehicle or carrier for a compound of the invention. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.

The compound of the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound of the invention (or other compounds) once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.

Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation. Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company, e.g., 18^th Ed.), Remington: The Science and Practice of Pharmacy (Lippincott Williams & Wilkins. e.g., 21 ^st Ed.), The Handbook of Pharmaceutical Additives (Gower Publishing Limited, e.g., 3^rd Ed.), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press, e.g., 6^th Ed.).

The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g.

microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.

All publications referred to herein are incorporated by reference in their entirety.

EXAMPLES

The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

MS and liquid chromatography MS were recorded on a MDS Sciex liquid chromatography / mass spectroscopy system. All mass spectra were performed under electrospray ionization (ESI), chemical ionization (CI), electron impact (El) or by fast atom bombardment (FAB) methods.

HPLC data was recorded on an Agilent 1 100 series HPLC system with C-18 reverse phase column (Eclipse XDB-C18, 4.6 x 250 mm, 5 micron) running a gradient of 1-99% MeCN/H20 (+0.1 % TFA) over 12 minutes.

All reactions were monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acid, p- anisaldehyde solution, aqueous potassium permanganate or potassium iodide / platinum chloride solution in water.

Flash column chromatography was performed on silica gel.

The naming program used is ACD Name Pro 6.02.

In describing the invention, chemical elements are identified in accordance with the Periodic Table of the Elements. Abbreviations and symbols utilized herein are in accordance with the common usage of such abbreviations and symbols by those skilled in the chemical and biological arts. For example, the following abbreviations are used herein: Abbreviation: Meaning:

"aq" Aqueous

"BOP" (Benzotriazol-l-yloxy)tris (dimethylamino)phosphonium

hexafluorophosphate

"°C^: Celsius

"CH₃CN Acetonitrile

"DIEA' /V,/V-Diisopropylethylamine

"DMAP 4-dimethylaminopyridine

"DMF^: Dimethylformamide

"DMSO Dimethylsulfoxide "EtOAc" Ethyl acetate

"Et₂0" Diethylether

"EtOH" Ethanol

"Et₃N" Triethylamine

"g" gram or grams

"h" hour or hours

"HPLC" High Pressure Liquid Chromatography

"L" liter or liters

"LC-MS" Liquid chromatography-Mass spectrometry

"MeOH" Methanol

"mL or ml" milliliter or milliliters

"min" minute or minutes

"mmol" millimole or millimolar

"N" Normal and refers to the number of equivalents of reagent

per liter of solution

"NCS" /V-Chlorosuccinimide

"RT" Room temperature

"TFA" trifluoroacetic acid

"THF" tetrahydrofuran

I ntermed i ates/Reacta nts a) General procedures to prepare thiazole carboxylic acids: Method 1 - 2-[(2-chlorophenyl)a rboxylic acid

Step 1 : ethyl 2-r(2-chlorophenyl)aminol-1 ,3-thiazole-4-carboxylate

To a microwave reaction vessel charged with ethyl 2-bromo-1 ,3-thiazole-4- carboxylate (400 mg, 1.694 mmol) and ethanol (3 mL), 2-chloroaniline (865 mg, 6.78 mmol) was added. The vessel was sealed and heated in a Biotage Initiator to 150 °C for 4 h. The mixture was concentrated to yield a crude mixture of the titled compound and residual aniline (1.3 g). MS (ES) m/e 283 [M+H]+. Step 2: 2-[(2-chlorophenyl)aminol-1 ,3-thiazole-4-carboxylic acid

To a round-bottomed flask charged charged with ethyl 2-[(2-chlorophenyl)amino]-1 ,3- thiazole-4-carboxylate (480 mg, 1 .698 mmol), THF (5 mL), and MeOH (1 mL), solid LiOH (203 mg, 8.49 mmol) was added. The reaction mixture was stirred at RT for 18 h. The mixture was concentrated and diluted with CH₂CI₂ (50 mL) and water (50 mL). The layers were separated and the aqueous layer was collected. Next, the aqueous layer was acidified (pH = 2) with 2 N HCI and the mixture was chilled overnight. The brown solid was then collected by filtration and air dried giving the crude titled compound (200 mg). MS (ES) m/e 255 [M+H]+.

Method 2 - 2-[(2-fluorophenyl)a rboxylic acid

Step 1 : ethyl 2-[(2-fluorophenyl)aminol-1 ,3-thiazole-4-carboxylate

To a round-bottomed flask charged with N-(2-fluorophenyl)thiourea (2.72 g, 16 mmol) and EtOH (50 mL) was added neat ethyl bromopyruvate (4.16 g, 19.20 mmol). The reaction mixture was stirred at 65 °C overnight. The solvent was removed by rotoevaporation to yield the crude titled compound as an orange oil (4.69 g). MS (ES) m/e 267 [M+H]+.

Step 2: 2-r(2-fluorophenyl)aminol-1 ,3-thiazole-4-carboxylic acid

To round-bottomed flask charged with ethyl 2-[(2-fluorophenyl)amino]-1 ,3-thiazole-4- carboxylate (4.26 g, 16 mmol) and EtOH (2.4 mL) was added NaOH (16 mL, 32.0 mmol). The reaction mixture was stirred at 65 °C overnight. The ethanol was removed via rotoevaporation. The resulting material was diluted with H₂0 (10 mL) and extracted with EtOAc (2 x 20 mL). The aq layer was acidified with 2N HCI, chilled in an ice bath, and filtered to collect the titled compound as a brown solid (2 g, 8.39 mmol). MS (ES) m/e 239 [M+H]+. Method 3 - 2-(2,3-dihydro-1 ,4-benzodioxin-6-ylamino)-5-methyl-1 ,3-thiazole-4- carboxylic acid

To a 100-mL round bottomed flask charged with 3-bromo-2-oxobutanoic acid (473 mg, 2.62 mmol) and 1 ,2-Dimethoxyethane (7 ml_), N-(2,3-dihydro-1 ,4-benzodioxin-6- yl)thiourea (500 mg, 2.378 mmol) was added and the reaction mixture was stirred overnight at 50 °C. A white solid formed and the reaction mixture was chilled at 0 °C for 2 h, filtered, washed with hexanes (20 ml_), and dried in vacuo to yield the titled product as a white solid (674 mg, 2.307 mmol, 97 % yield). MS (ES) m/e 293 [M+H]+.

Method 4 - 2-(1 ,3-benzodioxol- -ylamino)-1 ,3-thiazole-4-carboxylic acid

To a round-bottomed flask charged with N-1 ,3-benzodioxol-5-ylthiourea (470 mg, 2.39 mmol) and N-Methyl-2-pyrrolidone (1 1 ml_), 3-bromo-2-oxopropanoic acid (400 mg, 2.39 mmol) was added and the reaction mixture was stirred for 1 h at 60 °C to yield the titled compound as a crude mixture (633 mg, 2.39 mmol, 100%). MS (ES) m/e 265 [M+H]+. b) Preparation of thioureas

Method 1 - A -(2-chloro-3-fluorophenyl)thiourea

To a round-bottomed flask charged with 2-chloro-3-fluoroaniline (2.0 g, 13.74 mmol) and 6N HCI (14 ml, 84 mmol), ammonium thiocyanate (1.044 g, 13.74 mmol) was added and the reaction mixture was heated for 18 h at 80 °C. The reaction mixture was cooled to 0 °C and the resulting solid material was collected via vacuum filtration. The solid was washed with hexanes and dried in vacuo to yield the title compound (2.3 g, 1 1.24 mmol) as a crude mixture. MS m/e 206 [M+1]⁺ Method 2 - N-(2,3-dihydro-1 ,4-benzodioxin-6-yl)thiourea

Step 1 : N-r(2,3-dihydro-1 ,4-benzodioxin-6-ylamino)carbonothioyllbenzamide

To a round-bottomed flask charged with 2,3-dihydro-1 ,4-benzodioxin-6-amine (1 g, 6.62 mmol) and CH₂CI₂ (5 mL), benzoyl isothiocyanate (1 .080 g, 6.62 mmol) was added and the reaction mixture was stirred overnight. The solvent was removed via rotoevaporation to yield the titled compound (2.1 g, 6.6 mmol) as a brown foam. MS m/e 315 [M+1 ]⁺

Step 2: N-(2,3-dihvdro-1 ,4-benzodioxin-6-yl)thiourea

To a round-bottomed flask charged with N-[(2,3-dihydro-1 ,4-benzodioxin-6- ylamino)carbonothioyl]benzamide (2.081 g, 6.62 mmol), EtOH (20 mL), MeOH (10 mL), and H₂0 (0.477 mL, 26.5 mmol), freshly crushed NaOH (0.530 g, 13.24 mmol) was added and the reaction mixture was stirred at 45 °C for 2 h. The volatile solvents were removed via rotoevaporation and H₂0 (30 mL) was added and the mixture was stirred overnight. The mixture was filtered and the white solid was air-dried for 1 h and then under high vacuum for 1 h to yield the titled compound (1 .3 g, 6.18 mmol) as a brown solid. MS m/e 21 1 [M+1]⁺ c) General procedures to prepare anilines

Method 1 : (6-fluoro-1 ,3-benzodioxol-5-yl)

Step l : 5-fluoro-1 ,3-benzodioxole

To a round-bottomed flask charged with 4-fluoro catechol (10.0 g, 78 mmol), bromochloromethane (7.61 mL, 1 17 mmol) and cesium carbonate (38.2 g, 1 17 mmol) were added. The reaction mixture was heated to 100 °C for 3 h and then allowed to cool slowly to RT. The reaction mixture was poured into H₂0 (1 L) to which 1 N HCI (80 mL) (1.0 eq.) had been added. The mixture was stirred for five minutes, and then the aqueous mixture was extracted with Et₂0 (2 x 500 mL). The combined organic layers were washed with H₂0 (2 x 1 L), washed with brine solution (1 x 500 ml_), dried over Na₂S0₄, and filtered. The solvent was removed by rotary evaporation to provide the titled compound (9.28 g, 62.9 mmol, 81 % yield) as a brown oil.

Step 2: 5-fluoro-6-nitro-1 ,3-benzodioxole

To a round-bottomed flask charged with 5-fluoro-1 ,3-benzodioxole (9.28 g, 66.2 mmol) cooled to -30 °C, nitric acid (100ml_, 2238 mmol) which had been cooled to -30 °C was added. The mixture was stirred vigorously and allowed to warm slowly to RT. After 20 minutes at RT, the reaction mixture was poured into ice-water (500 ml_), which caused the product to precipitate. The solid was filtered off and washed with water (1.5L). The solid was air-dried for ½ h and then dried under high vacuum overnight to yield the title compound (9.22 g, 44.8 mmol, 67.7 % yield) as a light tan solid. This material was carried on to the next step without further purification. MS (ES+) m/e 185.9

Step 3: (6-fluoro-1 ,3-benzodioxol-5-yl)amine

In a round-bottomed flask, 5-fluoro-6-nitro-1 ,3-benzodioxole (9.22 g, 49.8 mmol) was dissolved in EtOH (100 ml.) and treated with tin(ll) chloride dihydrate (56.2 g, 249 mmol) at RT. The reaction mixture was heated to 70 °C for 2 h and then was allowed to cool to RT overnight. Then, K₂C0₃ (68.8 g, 498 mmol) and H₂0 (44.9 ml_, 2,490 mmol) were added to the reaction mixture and this was allowed to stir for 20 minutes at RT. A thick orange precipitate formed, which was removed via filtration. The solvent was removed by rotary evaporation to provide the titled compound (6-fluoro-1 ,3-benzodioxol-5-yl)amine (8.58 g, 49.8 mmol, 100 % yield) as a black solid.

Method 2: 1 ,3-benzodioxol-5-amine-d2

Step 1 : 5-nitro-1 ,3-benzodioxole-d2

To a round-bottomed flask charged with 4-nitro-catechol (25 g, 161 mmol) and N- Methyl-2-pyrrolidone (200 ml_), cesium carbonate (79 g, 242 mmol) was added followed by dibromomethane-d2 (1 1.31 ml_, 161 mmol). The reaction mixture was stirred for 10 minutes at RT and then heated to 100°C for 1 h. Additional dibromomethane-d2 (10 grams) was added and stirred at 100°C for an additional 2 h. The reaction mixture was allowed to cool slowly to RT and stir over the weekend. The reaction mixture was then poured into H₂0 (3L) and 2N NaOH (100 mL) and potassium carbonate (10 grams) were added to the mixture. This mixture was stirred for 10 minutes and then the solid was filtered off and placed under high vacuum to provide the titled compound (26.03 g, 151 mmol, 94 % yield) as a light yellow solid. MS (ES+) m/e 169.0

Step 2: 1 ,3-benzodioxol-5-amine-d2

To a round-bottomed flask charged with 5-nitro-1 ,3-benzodioxole-d2 (12.0 g, 71.0 mmol) and EtOH (100 mL), Pd/C 10 %, Degussa wet-type (2.40 g, 22.55 mmol) was added. The atmosphere in the flask was replaced with H₂, and the flask was fitted with a hydrogen- filled balloon. The reaction mixture was allowed to stir at RT overnight. The reaction mixture was then treated with ~50g of Celite and the slurry was filtered through a pad of Celite. The pad was washed with EtOH (500 mL), and the solvent was removed by rotary evaporation to provide the titled compound (10.98 g, 71.0 mmol, 100 % yield) as a brown solid. d) Procedure to resolve racemic 2,3-dimethylpiperidine

(2S,3S)-2,3-dimethylpiperidine

Racemic 2,3-dimethylpiperidine (10 g, 88 mmol) was dissolved in methanol (20 mL) and treated with (2S,3S)-2,3-dihydroxysuccinic acid commonly called D-(-)-tartaric acid (14.58 g, 97 mmol) dissolved in methanol (20 mL) at room temperature. This resulted in a clear solution with no suspended particles, turbidity, or cloudiness. The mixture was allowed to stand at room temperature over the weekend, and small colorless prismatic crystals formed. The crystals were isolated by filtration to provide 7.5 grams of white solid. This solid was transferred to a separatory funnel and treated with 200 mL of 2N NaOH and 200 mL of ether. The layers were separated after vigorous shaking, and the organic phase was dried over sodium sulfate, filtered, and concentrated to provide (2S,3S)-2,3- dimethylpiperidine (3.1 g, 27.1 mmol, 31 %) as a light colorless oil. The enantiomeric excess (ee) of the product (2S,3S)-2,3-dimethylpiperidine was determined by the following procedure. (2S,3S)-2,3-dimethylpiperidine (700 mg, 6.18 mmol) as the product from the aforementioned process, was dissolved in tetrahydrofuran (THF) (10 mL) and treated with triethylamine (0.948 mL, 6.80 mmol) followed by 4-bromobenzoyl chloride (1357 mg, 6.18 mmol) at room temperature. The reaction was stirred at room temperature for ten minutes, after which time HPLC ((Eclipse XDB-C18, 4.6 x 250 mm, 5 micron, 2.5 mL/min, gradient from 1 -99% CH₃CN (0.1 % trifluoroacetic acid) / H₂0 (0.1 % trifluoroacetic acid), 10 minutes plus 2 minute plateau at 99 % CH3CN (0.1 % trifluoroacetic acid)) and LCMS ((SunFire,

C18, 5um, 3.0 x 50 mm, gradient 10 - 100 % CH₃CN in H20 with 0.1 % TFA, 2.5 min)) indicated that the desired product (2S,3S)-(4-bromophenyl)(2,3-dimethylpiperidin-1 - yl)methanone had formed. The reaction mixture was poured into 100 mL of 1 N HCI and extracted with ether (1 x 100 mL). The organic phase was washed with 1 N HCI (1 x 100 mL) and 2N NaOH (1 x 100 mL), dried over sodium sulfate, filtered, and concentrated to a light yellow oil which solidified after being placed under high vacuum overnight to provide (2S,3S)-(4-bromophenyl)(2,3-dimethylpiperidin-1-yl)methanone. This material was analyzed by chiral HPLC (Chiralpak AS-H, 60% isopropanol, 40% hexanes, 1 mL/min) to determine the %ee and compared to a racemic standard of (4-bromophenyl)(2,3-dimethylpiperidin-1 - yl)methanone made from racemic 2,3-dimethylpiperidine.. The product was found to have 91 % ee and corresponds to the second peak of the racemate. To obtain a higher %ee, this entire process was repeated on the enriched (91 %ee) product (2S,3S)-2,3- dimethylpiperidine, resulting in a %ee of greater than 99%.

Example Compounds

Example 1

A -(2,3-dihydro-1 ,4-benzodioxin-6-yl)-5-methyl-4-[(4-methyl-1 -piperidinyl)carbonyl]-1 ,3- thiazol-2-amine

To a test tube charged with 2-(2,3-dihydro-1 ,4-benzodioxin-6-ylamino)-5-methyl-1 ,3- thiazole-4-carboxylic acid (50 mg, 0.171 mmol) in Ν,Ν-Dimethylformamide (DMF) (1 mL), was added DIEA (0.1 19 mL, 0.684 mmol), BOP (91 mg, 0.205 mmol), and 4- methylpiperidine (3.34 mg, 0.222 mmol) and the reaction mixture was stirred overnight at 50 °C. The reaction mixture was then purified by reverse-phase HPLC (Sunfire, 30 x 150 mm, 45 mL/min, A: acetonitrile (0.1 % TFA) B: water (0.1 % TFA), A: 10 to 90% over 25 min, UV detection at 214 nm) to yield the titled compound (15 mg, 0.04 mmol). MS m/e 374 [M+1]⁺ . Example 2

5-fluoro-A -(4-methylphenyl)- -[(4-methyl-1 -piperidinyl)carbonyl]-1 ,3-thiazol-2-amine

Procedure (step 1 ): 1 , 1-dimethylethyl (4-methylphenyl){4-r(4-methyl-1 -piperidinyl)carbonyll- 1 ,3-thiazol-2-yl}carbamate

To a 25-mL round bottom flask charged with N-(4-methylphenyl)-4-[(4-methyl-1- piperidinyl)carbonyl]-1 ,3-thiazol-2-amine (240 mg, 0.76 mmol) in CH2CI2 (5 ml_), was added

BOC anhydride (183 mg, 0.83 mmol), Et₃N (194 uL, 0.83 mmol), and DMAP (19 mg, 0.15 mmol) and the reaction mixture was stirred overnight. The reaction mixture was poured into and extracted with CH2CI2 (2X). The organics were combined and concentrated to yield the titled compound (300 mg) as a dark brown solid.

Procedure (step 2): 5-fluoro-/\/-(4-methylphenyl)-4-r(4-methyl-1 -piperidinyl)carbonyll-1 ,3- thiazol-2-amine

To a round bottom flask charged with 1 , 1-dimethylethyl (4-methylphenyl){4-[(4- methyl-1 -piperidinyl)carbonyl]-1 ,3-thiazol-2-yl}carbamate (100 mg, 0.24 mmol) in CH₃CN (5 ml_), was added Selectfluor (90 mg, 0.25 mmol) and the reaction mixture stirred for 30 h at

80 °C. The reaction mixture was concentrated to 2 ml. and the mixture was purified via HPLC (20-100% CH₃CN/H2O, 0.1 %TFA, 30 x 150 mm Sunfire, 12 min, 45 mL/min) to yield the titled compound (1 1 mg, 0.03 mmol). MS m/e 334 [M+1]⁺

Example 3

5-chloro-A -(4-methylphenyl -4-[(4-methyl-1 -piperidinyl)carbonyl]-1 ,3-thiazol-2 -amine

Procedure (step 1 ): 1 , 1-dimethylethyl {5-chloro-4-r(4-methyl-1-piperidinyl)carbonyll-1 ,3- thiazol-2-yl}(4-methylphenyl)carbamate

To a round bottom flask charged with 1 , 1-dimethylethyl (4-methylphenyl){4-[(4- methyl-1 -piperidinyl)carbonyl]-1 ,3-thiazol-2-yl}carbamate (170 mg, 0.41 mmol) in THF (5 mL), was added NCS (55 mg, 0.41 mmol) and the reaction mixture stirred for 18 h at 40 °C. Additional NCS (45 mg) was added in portions until the reaction went to completion. The reaction mixture was concentrated, redissolved in CH₂CI₂ and poured into H20. The mixture was extracted with CH₂CI₂ and the organics were collected and concentrated to yield the titled compound (120 mg, 0.27 mmol).

Procedure (step 2): 5-chloro-/\/-(4-methylphenyl)-4-[(4-methyl-1 -piperidinyl)carbonyll-1 ,3- thiazol-2-amine

To a round bottom flask charged with 1 ,1 -dimethylethyl {5-chloro-4-[(4-methyl-1- piperidinyl)carbonyl]-1 ,3-thiazol-2-yl}(4-methylphenyl)carbamate (120 mg, 0.27 mmol) in CH₂CI₂ (5 mL), was added TFA (5 mL) and the reaction mixture stirred for 5 h. The reaction mixture was concentrated and the mixture was purified via HPLC (20-100% ACN/H20, 0.1 %TFA, 30 x 150 mm Sunfire, 12 min, 45 mL/min) to yield the titled compound (52.6 mg, 0.135 mmol). MS m/e 350 [M+1 ]⁺

Example 4

5-chloro-4-[(2,3-dimethyl-1 -piperidinyl)carbonyl]-A -(6-fluoro-1 ,3-benzodioxol-5-yl)-1 ,3- thiazol-2-amine

To a vial charged with 4-[(2,3-dimethyl-1 -piperidinyl)carbonyl]-N-(4-fluoro-1 ,3- benzodioxol-5-yl)-1 ,3-thiazol-2-amine (25 mg, 0.66 mmol) in THF (1 mL), was added NCS (9 mg, 0.07 mmol) and the reaction mixture stirred overnight at 40°C. The reaction mixture was concentrated and the mixture was purified via HPLC (53-87% ACN/H20, 0.1 %TFA, 30 x 150 mm Sunfire, 12 min, 45 mL/min) to yield the titled compound (3.5 mg, 0.0085 mmol). MS m/e 412 [M+1 ]⁺

The following table illustrates compounds that were prepared using the general procedures described above. As is appreciated by those skilled in the art, these analogous examples may involve variations in synthetic procedure.

The compounds were prepared using procedures analogous to those described above, and using the corresponding reactants as will be appreciated by those skilled in the art. Preparation utilizes standard amide bond coupling procedures analogous to Example 1 , using coupling partners corresponding to the title compound. Preparation of compounds having chlorine in the 5-position of the thiazole ring utilize a chlorination reaction such as illustrated by Examples 3 and 4.

10

[2-(1 ,3-benzodioxol-5-ylamino)- 1 ,3-thiazol-4-

385 yl](octahydroquinolin-1 (2H)- yl)methanone trifluoroacetate

1 1

{2-[(2-chlorophenyl)amino]-1 ,3- thiazol-4-yl}(4-methylpiperidin-1 - 338 yl)methanone

12

(2,3-dimethylpiperidin-1-yl){2- [(4-methylphenyl)amino]-1 ,3- 330 thiazol-4-yl}methanone

13

(2,2-dimethylpiperidin-1 -yl){2- [(4-methylphenyl)amino]-1 ,3- 330 thiazol-4-yl}methanone

14

(4,4-dimethylpiperidin-1 -yl){2- [(4-methylphenyl)amino]-1 ,3- 330 thiazol-4-yl}methanone

15

[(2R,6S)-2,6-dimethylpiperidin- 1-yl]{2-[(4-methylphenyl)amino]- 330 1 ,3-thiazol-4-yl}methanone 16

(2,3-dimethylpiperidin-1 -yl)(2- {[4-(propan-2-yl)phenyl]amino}- 358 1 ,3-thiazol-4-yl)methanone

17

(2,3-dimethylpiperidin-1 -yl)(2- {[2-fluoro-4-(propan-2-

376 yl)phenyl]amino}-1 ,3-thiazol-4- yl)methanone

18

(2,3-dimethylpiperidin-1 -yl)(2- {[2-fluoro-4-(propan-2-

392 yloxy)phenyl]amino}-1 ,3-thiazol- 4-yl)methanone

19

(2,3-dimethylpiperidin-1 -yl)(2- {[2-fluoro-4-(propan-2-

406 yloxy)phenyl]amino}-5-methyl- 1 ,3-thiazol-4-yl)methanone

20

{2-[(4-chloro-2- fluorophenyl)amino]-5-methyl-

1 ,3-thiazol-4-yl}(2,3- 382

CI dimethylpiperidin-1- yl)methanone

21

(2-{[4-

(dimethylamino)phenyl]amino}- 1 ,3-thiazol-4-yl)(2,3- 359 dimethylpiperidin-1- yl)methanone trifluoroacetate [5-methyl-2-(phenylamino)-1 ,3-? r^_H thiazol-4-yl](4-methylpiperidin-1 - 316 yl)methanone

{2-[(2-fluorophenyl)amino]-1 ,3- thiazol-4-yl}(4-methylpiperidin-1 - 319 yl)methanone

{2-[(2-fluorophenyl)amino]-5- methyl-1 ,3-thiazol-4-yl}(4- 334 methylpiperidin-1-yl)methanone

{2-[(2,4-dichlorophenyl)amino]- 5-methyl-1 ,3-thiazol-4-yl}(4- 384

CI methylpiperidin-1-yl)methanone

{2-[(2-chlorophenyl)amino]-5- methyl-1 ,3-thiazol-4-yl}(4- 350 methylpiperidin-1-yl)methanone

{2-[(2,4-dimethylphenyl)amino]- 5-methyl-1 ,3-thiazol-4-yl}(4- 344 methylpiperidin-1-yl)methanone

40

{2-[(3-chlorophenyl)amino]-1 ,3- thiazol-4-yl}(4-methylpiperidin-1 - 336 yl)methanone

41

{2-[(2,5-difluorophenyl)amino]-

1 ,3-thiazol-4-yl}(4- 338

F methylpiperidin-1-yl)methanone

42

{2-[(2-chloro-5- fluorophenyl)amino]-1 ,3-thiazol-

368

4-yl}(2,3-dimethylpiperidin-1- yl)methanone

43

{2-[(2-chloro-4- fluorophenyl)amino]-1 ,3-thiazol-

368

4-yl}(2,3-dimethylpiperidin-1- yl)methanone

44

{2-[(2-chloro-3- fluorophenyl)amino]-1 ,3-thiazol-

354 4-yl}(4-methylpiperidin-1 - yl)methanone

45

(4-methylpiperidin-1-yl){2- [(2,3,4-trifluorophenyl)amino]- 356

F 1 ,3-thiazol-4-yl}methanone

58

A/-[3-chloro-4-

(methyloxy)phenyl]-4-{[(2S,3S)- 2,3-dimethyl-1 - 397 o piperidinyl]carbonyl}-5-methyl-

/

1 ,3-thiazol-2-amine

59

2-ch loro-4-[(4-{[(2 S, 3S)-2 , 3- dimethyl-1 -piperidinyl]carbonyl}-

389 5-methyl-1 ,3-thiazol-2- yl)amino]benzonitrile

60

4-{[(2S,3S)-2,3-dimethyl-1- piperidinyl]carbonyl}-/V-[3-fluoro-

364 4-(methyloxy)phenyl]-1 ,3- o

/ thiazol-2-amine

61

A/-[3-chloro-4-

(methyloxy)phenyl]-4-{[(2S,3S)- 2,3-dimethyl-1 - 380 o piperidinyl]carbonyl}-1 ,3-thiazol-

/

2-amine

62

5-chloro-4-[(2,3-dimethyl-1- piperidinyl)carbonyl]-/V-(6-fluoro-

412 1 ,3-benzodioxol-5-yl)-1 ,3- thiazol-2-amine Example 63

/V-(4-chloro-2-fluorophenyl)-4-{[(2S,3S)-2,3-dimethyl-1-piperidinyl]carbon

thiazol-2-amine

The title compound was prepared using standard amide bond coupling conditions analogous to Example 1 , using (2S,3S)-2,3-dimethylpiperidine and 2-[(4-chloro-2- fluorophenyl)amino]-5-methyl-1 ,3-thiazole-4-carboxylic acid. As is appreciated by those skilled in the art, this analogous example may involve variations in synthetic procedure. MS m/e 382 [M+1 ]^{+ 1}H NMR (400 MHz, d₆-DMSO) δ ppm 10.1 (bs, 1 H), 8.4 (dd, 1 H), 7.4 (dd, 1 H), 7.2 (dd, 1 H), 4.6 (bm, 0.5H), 4.3 (bd, 0.5H), 3.9 (bm, 0.5H), 3.6 (bd, 0.5H), 3.0 (bm, 0.5H), 2.8 (bm, 0.5H), 2.3 (d, 3H), 1 .7-1 .4 (m, 5H), 1.1 (d, 3H), 0.9 (d, 1 .5H), 0.7 (d, 1 .5H).

Claims

What is claimed is:

1. A compound of Formula I:

(R6)n wherein:

R4 and R5 are independently selected from hydrogen, halo, (Ci_-6)alkyl,

trifluoromethyl, -S0₂phenyl, (C_1-6)alkylthio, -OH, -C0₂(Ci_-6)alkyl, -CO(Ci_-6)alkyl, phenyl, cyano, and (Ci_-6)alkoxy; or R4 and R5, together with the carbon atoms to which they are attached, form a 6- membered, saturated carbocyclic ring optionally substituted with one to three substituents selected from halo, (Ci_-6)alkyl, trifluoromethyl, -S0₂phenyl, (Ci_-6)alkylthio, -OH, -C0₂(Ci. ₆)alkyl, -CO(Ci_-6)alkyl, phenyl, cyano, and (Ci_-6)alkoxy;

R6 is an optional substituent independently selected from halo, (Ci_-6)alkyl, trifluoromethyl, -S0₂phenyl, (d_-6)alkylthio, -OH, -C0₂(Ci_-6)alkyl, -CO(Ci_-6)alkyl, phenyl, cyano, and (C_1-6)alkoxy; and n is an integer of from 0-3;

R2 is H, D, halo, or (C_1-4)alkyl;

R3 is a monocyclic, carbocyclic or heterocyclic ring selected from phenyl and pyridinyl; either of which may be optionally substituted with one to three substituents independently selected from D, (Ci_-6)alkyl, (Ci_-6)alkoxy, halo, trifluoromethoxy,

trifluoromethyl, cyano, -N(R^a)(R^b), morpholinyl, -S0₂R^c, and -S0₂N(R^d)(R^e); or R3 is a bic clic ring system (A):

wherein: ring (a) is saturated or unsaturated;

X and Y are independently selected from CR', CR'R', C=0, N, NR', O and S;

Z is a 1-3 member linking group wherein the members are independently selected from CR', CR'R', C=0, N, NR', O and S; p is an integer of from 1 to 3; and

R' is independently selected from H, D, (Ci_-6)alkyl, (Ci_-6)alkoxy, halo,

trifluoromethoxy, trifluoromethyl, cyano, -N(R^a)(R^b), -S0₂R^c, and -S0₂N(R^d)(R^e); and

R^a-R^e are independently selected from H and (Ci_-6)alkyl.

2. The compound of claim 1 , wherein R1 is 1 -piperidinyl, optionally substituted with 1 -3 substituents independently selected from halo, (Ci_-6)alkyl, trifluoromethyl, -S0₂phenyl, (Ci_ ₆)alkylthio, -OH, -C0₂(Ci_-6)alkyl, -CO(Ci_-6)alkyl, phenyl, cyano, and (Ci_-6)alkoxy.

3. The compound of claim 2, wherein R1 is 1 -piperidinyl, unsubstituted or substituted with 1 -2 methyl groups.

4. The compound of claim 1 , wherein R1 is octahydroquinolin-1 (2H)-yl, optionally substituted with 1 -6 substituents independently selected from halo, (Ci_-6)alkyl,

trifluoromethyl, -S0₂phenyl, (d_-6)alkylthio, -OH, -C0₂(Ci_-6)alkyl, -CO(Ci_-6)alkyl, phenyl, cyano, and (Ci_-6)alkoxy.

5. The compound of any of the preceding claims, wherein R2 is H, methyl, chloro or fluoro.

6. The compound of any of the preceding claims, wherein R3 is selected from:

phenyl;

2,3-dihydro-1 ,4-benzodioxin-6-yl;

1 ,3-benzodioxol-5-yl;

2.3- dihydro-1 H-inden-5-yl;

3.4- dihydro-2H-1 ,5-benzodioxepin-7-yl;

1 -benzofuran-5-yl; and

1 H-indazol-5-yl;

any of which may be optionally substituted as defined for Formula I in claim 1 .

7. The compound of claim 6, wherein R3 is phenyl substituted with 1 -3 substituents independently selected from (Ci_-6)alkyl, halo, (Ci_-6)alkoxy, trifluoromethoxy, -N(R^a)(R^b), and cyano (e.g., methyl, chloro, fluoro, propan-2-yl, propan-2yl-oxy, dimethylamino, methoxy, trifluoromethoxy, and cyano).

8. The compound of claim 6, wherein R3 is 2-fluorophenyl, optionally further substituted with 1 -2 substituents selected from D, (Ci_-6)alkyl, halo, (Ci_-6)alkoxy, trifluoromethoxy, trifluoromethyl, cyano, -N(R^a)(R^b), morpholinyl, -S0₂R^c, and -S0₂N(R^d)(R^e).

9. The compound of claim 6, wherein R3 is selected from 2-fluoro-4-cyanophenyl; 2- fluoro-4-chlorophenyl; 2-fluoro-4-trifluoromethoxyphenyl; 2-fluoro-4-methylphenyl; and 2- fluoro-4-methoxyphenyl.

10. The compound of claim 6, wherein R3 is 1 ,3-benzodioxol-5-yl, unsubstituted or substituted with 1 -3 substituents independently selected from halo (e.g., fluoro) and D.

1 1 . The compound of Formula I according to claim 1 , wherein the compound is selected from the Example Compounds herein, in free base form.

12. A compound of Formula I according to claim 1 , wherein the compound is not:

{2-[(2,4-dimethylphenyl)amino]-5-methyl-1 ,3-thiazol-4-yl}(4-methylpiperidin-1 -yl)methanone {2-[(3-chlorophenyl)amino]-1 ,3-thiazol-4-yl}(4-methylpiperidin-1 -yl)methanone

(4-methylpiperidin-1-yl){2-[(4-methyl-phenyl)amino]-1 ,3-thiazol-4-yl}methanone

(piperidin-1-yl){2-[(4-methyl-phenyl)amino]-1 ,3-thiazol-4-yl}methanone

{2-[(2-chlorophenyl)amino]-1 ,3-thiazol-4-yl}(piperidin-1 -yl)methanone

{2-[(4-methoxyphenyl)amino]-1 ,3-thiazol-4-yl}(piperidin-1-yl)methanone

(piperidin-1-yl){2-[(3-methyl-phenyl)amino]-1 ,3-thiazol-4-yl}methanone

{2-[(4-methoxyphenyl)amino]-1 ,3-thiazol-4-yl}(4-methylpiperidin-1-yl)methanone

{2-[(3,4-chlorophenyl)amino]-1 ,3-thiazol-4-yl}(piperidin-1 -yl)methanone

[2-(phenylamino)-1 ,3-thiazol-4-yl](4-methylpiperidin-1 -yl)methanone and/or

2-[(2,4-dimethylphenyl)amino]-1 ,3-thiazol-4-yl}(4-methylpiperidin-1-yl)methanone.

13. A pharmaceutically acceptable salt of the compound of Formula I according to any of claims 1-12. ition comprising a compound of Formula I:

wherein:

R1 is:

(R6), n

wherein: R4 and R5 are independently selected from hydrogen, halo, (C_1-6)alkyl,

trifluoromethyl, -S0₂phenyl, (C_1-6)alkylthio, -OH, -C0₂(C_1-6)alkyl, -CO(C_1-6)alkyl, phenyl, cyano, and (Ci_-6)alkoxy; or R4 and R5, together with the carbon atoms to which they are attached, form a 6- membered, saturated carbocyclic ring optionally substituted with one to three substituents selected from halo, (Ci_-6)alkyl, trifluoromethyl, -S0₂phenyl, (Ci_-6)alkylthio, -OH, -C0₂(Ci. ₆)alkyl, -CO(Ci_-6)alkyl, phenyl, cyano, and (Ci_-6)alkoxy;

R6 is an optional substituent independently selected from halo, (Ci_-6)alkyl, trifluoromethyl, -S0₂phenyl, (d_-6)alkylthio, -OH, -C0₂(Ci_-6)alkyl, -CO(Ci_-6)alkyl, phenyl, cyano, and (Ci_-6)alkoxy; and n is an integer of from 0-3;

R2 is H, D, halo, or (C_1-4)alkyl;

R3 is a monocyclic, carbocyclic or heterocyclic ring selected from phenyl and pyridinyl; either of which may be optionally substituted with one to three substituents independently selected from D, (C_1-6)alkyl, (C_1-6)alkoxy, halo, trifluoromethoxy,

trifluoromethyl, cyano, -N(R^a)(R^b), morpholinyl, -S0₂R^c, and -S0₂N(R^d)(R^e); or R3 is a bic clic ring system (A):

wherein: ring (a) is saturated or unsaturated;

X and Y are independently selected from CR', CR'R', C=0, N, NR', O and S; Z is a 1-3 member linking group wherein the members are independently selected from CR\ CR'R', C=0, N, NR', O and S; p is an integer of from 1 to 3; and

R' is independently selected from H, D, (Ci_-6)alkyl, (Ci_-6)alkoxy, halo,

trifluoromethoxy, trifluoromethyl, cyano, -N(R^a)(R^b), -S0₂R^c, and -S0₂N(R^d)(R^e); and

R^a-R^e are independently selected from H and (Ci_-6)alkyl; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

15. The composition of claim 14, wherein R1 is 1-piperidinyl, optionally substituted with 1-3 substituents independently selected from halo, (Ci_-6)alkyl, trifluoromethyl, -S0₂phenyl, (C_1-6)alkylthio, -OH, -C0₂(C_1-6)alkyl, -CO(C_1-6)alkyl, phenyl, cyano, and (C_1-6)alkoxy.

16. The composition of claim 15, wherein R1 is 1 -piperidinyl, unsubstituted or substituted with 1 -2 methyl groups.

17. The composition of claim 14, wherein R1 is octahydroquinolin-1 (2H)-yl, optionally substituted with 1-6 substituents independently selected from halo, (Ci_-6)alkyl,

trifluoromethyl, -S0₂phenyl, (d_-6)alkylthio, -OH, -C0₂(Ci_-6)alkyl, -CO(Ci_-6)alkyl, phenyl, cyano, and (Ci_-6)alkoxy.

18. The composition of any of claims 14-17, wherein R2 is H, methyl, chloro or fluoro.

19. The composition of any of claims 14-18, wherein R3 is selected from:

phenyl;

2,3-dihydro-1 ,4-benzodioxin-6-yl;

1 ,3-benzodioxol-5-yl;

2.3- dihydro-1 H-inden-5-yl;

3.4- dihydro-2H-1 ,5-benzodioxepin-7-yl;

1-benzofuran-5-yl; and

1 H-indazol-5-yl; any of which may be optionally substituted as defined for Formula I in claim 1.

20. The composition of claim 19, wherein R3 is phenyl substituted with 1-3 substituents independently selected from (Ci_-6)alkyl, halo, (Ci_-6)alkoxy, trifluoromethoxy, -N(R^a)(R^b), and cyano (e.g., methyl, chloro, fluoro, propan-2-yl, propan-2yl-oxy, dimethylamino, methoxy, trifluoromethoxy, and cyano).

21 . The composition of claim 19, wherein R3 is 2-fluorophenyl, optionally further substituted with 1-2 substituents selected from D, (Ci_-6)alkyl, halo, (Ci_-6)alkoxy,

trifluoromethoxy, trifluoromethyl, cyano, -N(R^a)(R^b), morpholinyl, -S0₂R^c, and -S0₂N(R^d)(R^e).

22. The composition of claim 19, wherein R3 is selected from 2-fluoro-4-cyanophenyl; 2- fluoro-4-chlorophenyl; 2-fluoro-4-trifluoromethoxyphenyl; 2-fluoro-4-methylphenyl; and 2- fluoro-4-methoxyphenyl.

23. The composition of claim 19, wherein R3 is 1 ,3-benzodioxol-5-yl, unsubstituted or substituted with 1-3 substituents independently selected from halo (e.g., fluoro) and D.

24. The composition of claim 14, wherein the compound of Formula I is selected from the Example Compounds herein, in free base form.

25. A method of treating a cardiovascular, respiratory, renal, or musculo-skeletal disease or a cancer which is mediated by TRPC3 and/or C6 ion channels, comprising administering a pharmaceutically effective amount of a compound of Formula I as defined in any of claims 1-12, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

26. A method of treating cardiac hypertrophy, heart failure, chronic renal failure, pulmonary hypertension, essential hypertension, cardiac arrhythmia, asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary edema, focal segmental glomerulosclerosis, other kidney diseases, osteoarthritis, Duchenne or other muscular dystrophy, cystic fibrosis, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, or glioma comprising administering a pharmaceutically effective amount of a compound of Formula I as defined in any of claims 1-12, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

27. A method of treating heart failure, comprising administering a pharmaceutically effective amount of a compound of Formula I as defined in any of claims 1 -12, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

28. A method of inhibiting TRPC3 and/or TRPC6 ion channel activity, comprising administering to a cell, tissue or a subject in need thereof an effective amount of a compound of Formula I as defined in any of claims 1-12, or a pharmaceutically acceptable salt thereof.

29. Use of a compound of Formula I as defined in any of claims 1-12, or a

pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting TRPC3 and/or TRPC6 ion channel activity.

30. Use of a compound of Formula I as defined in any of claims 1-12, or a

pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a cardiovascular, respiratory, renal, or musculo-skeletal disease or a cancer which is mediated by TRPC3 and/or C6 ion channels.

31 . Use of a compound of Formula I as defined in any of claims 1-12, or a

pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cardiac hypertrophy, heart failure, chronic renal failure, pulmonary hypertension, essential hypertension, cardiac arrhythmia, asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary edema, focal segmental glomerulosclerosis, other kidney diseases, osteoarthritis, Duchenne or other muscular dystrophy, cystic fibrosis, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, or glioma.