Aminoazine amides

Abstract

To provide a novel compound having autotaxin (ATX) inhibitory activity for the treatment of diseases involving ATX, specifically kidney diseases, liver diseases, chronic inflammatory disorders or inflammatory diseases, respiratory diseases, vascular and cardiovascular diseases, fibrotic diseases, and cancers, or a pharmaceutically acceptable salt, a solvate or a salt of the solvate, or a composition including the compound.SOLUTION: The present invention discloses, for example, an aminoazine amide compound represented by the following formula, or a pharmaceutically acceptable salt, a solvate or a salt of the solvate, or a composition including the compound.SELECTED DRAWING: None

Description

[Technical field]

[0001] background Lysophosphatidic acid (LPA) has a significant effect on cell growth, motility, survival and proliferation. LPA levels are controlled in part by a glycoprotein called autotaxin (ATX), which functions as lysophospholipase D to hydrolyze lysophosphatidylcholine (LPC) to LPA. Through its regulation of LPA, ATX is involved in several physiological processes including tumor progression and survival, neurodevelopment, vascular development, fibrosis and lymphocyte trafficking. ATX is also thought to be involved in cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection. Thus, small molecule inhibitors of ATX would be highly beneficial, for example, as cancer treatments. In addition, they can be used to accommodate organ transplants or ameliorate the effects of pruritus. [Background technology]

[0002] ATX is an extracellular enzyme that belongs to the ectonucleotide pyrophosphatase / phosphodiesterase (ENPP2) family and was first isolated from A2058 melanoma cells. ATX was later found to be a glycoprotein called lysophospholipase D, an enzyme that catalyzes the production of lysophosphatidic acid (LPA). The LPA produced is then converted to LPA 1-6ATX acts through a series of six G protein-coupled receptors (GPCRs) known as GPCRs, inducing a wide range of cellular responses including cell proliferation, survival and motility. Increased ATX expression has been detected in chronic liver disease (CLD) and appears to be involved in liver cirrhosis and hepatocellular carcinoma (HCC) (see Kaffe et al. Hepatology 2017 Apr;65(4):1369-1383), as well as cholestatic pruritus associated with liver disease (see Kremer et al. Gastroenterology, 139 (2010):1008-1018). ATX inhibition and the resulting inhibition of downstream LPA signaling have been shown to have therapeutic effects in mouse models of nonalcoholic steatohepatitis (NASH) and may be a potential therapeutic treatment for fibrotic diseases including multiple fibrotic liver diseases and NASH (see Bain et al. J Pharmacol. Exp. Ther. 2017 360(1):1-13). ATX is believed to be involved in the inflammation underlying many chronic diseases such as rheumatoid arthritis, multiple sclerosis, atherosclerosis, organ fibrosis including liver and lung fibrosis, hepatitis, asthma, diabetes and obesity (Sevastou et al. Biochimica et Biophysica Acta, 2013, 1831:42-60, Benesch M. et al. FEBS Lett 2014, 588(16):2712-2727, Park et al. Am. J. Respir. Crit. Care Med., 2013 188:928-940). Increased ATX expression is also found in ulcerative colitis, Crohn's disease and inflammatory bowel disease (see Hozumi et al. Lab. Invest., 2013 93:508-519).ATX inhibition has also shown efficacy in mouse models of inflammation, inflammatory bowel disease (IBD), multiple sclerosis (MS) and pain (see Thirunavukkarasu K. et al. J Pharmacol Exp Ther. 2016 359(1):207-14 and Saga H., https: / / doi.org / 10.1371 / journal / pone / 0093230). Upregulated ATX / LPA signaling leads to increased LPA levels and increased LPA receptor production, which is thought to create an environment that promotes cancer proliferation, migration, metastasis and cancer therapy resistance. ATX / LPA signaling is positively correlated with the invasive and metastatic potential of several cancers, including melanoma, breast cancer, ovarian cancer, thyroid cancer, renal cell carcinoma, lung cancer, neuroblastoma, hepatocellular carcinoma (HCC), and glioblastoma multiforme (see Samadi et al. Biochimie, 2011 93:61-70). ATX is one of many lipid metabolic enzymes that are involved in vascular proliferative diseases, including those that affect the eye, such as age-related macular degeneration (AMD), diabetic retinopathy, and retinopathy of prematurity (ROP) (see Stahl et al. Br J Ophthalmol. 2011 95(11):1496-15010). ATX is also abundant in human aqueous humor and has potential therapeutic importance in the treatment of high intraocular pressure in glaucoma patients (see Iyer et al. https: / / doi.org / 10.1371 / journal.pone.0042627). Recent studies have also shown that adipose-derived ATX is involved in metabolic disorders including obesity and insulin resistance or diabetes (see D'Souza et al. Endocrinology, 2017 158(4):791-803). Summary of the Invention [Problem to be solved by the invention]

[0003] overview The present disclosure relates to certain aminoazine amide compounds, methods of making these compounds, methods of using these compounds, and compositions including these compounds. [Means for solving the problem]

[0004] In some embodiments, the compounds disclosed herein are related to inhibit ATX and thereby inhibit LPA production.In some embodiments, the compounds disclosed herein are related to treatment or prevention in mammals, where the mammals suffer from one or more of renal condition, hepatic condition, inflammatory condition, nervous system disorder, respiratory system disorder, vascular condition, cardiovascular condition, fibrotic disease, cancer, eye condition, metabolic condition, cholestatic pruritus, non-cholestatic pruritus, acute organ transplant rejection, and chronic organ transplant rejection.

[0005] For example, the disclosure provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof, compositions comprising the compound of formula (I) or a pharma- ceutically acceptable salt thereof, and methods of making and using the compound of formula (I) or a pharma- ceutically acceptable salt thereof. The compound of formula (I) or a pharma- ceutically acceptable salt thereof can be used to treat certain diseases, disorders, and conditions, either as a monotherapy or as a component of a combination therapy. ATX inhibitors, such as the compounds of formula (I) or pharma- ceutically acceptable salts thereof, are useful in the treatment of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis; inflammatory diseases, including inflammatory bowel disease, ulcerative colitis and Crohn's disease; chronic inflammatory disorders, including rheumatoid arthritis (RA), multiple sclerosis (MS), idiopathic pulmonary fibrosis (IPF), hepatitis and atherosclerosis; acute inflammatory disorders, such as sepsis; respiratory diseases, including asthma; vascular and cardiovascular diseases, including atherosclerosis; fibrotic diseases, including hepatic, pulmonary, renal and peritoneal fibrosis; renal diseases; chronic It may be useful in the treatment or prevention of conditions, diseases, disorders in which ATX or LPA is implicated, such as liver disease, including cirrhosis, multiple fibrotic liver disease, fatty liver disease, and nonalcoholic steatohepatitis (NASH), as well as cholestatic and other forms of chronic pruritus associated with liver disease, cancer, including melanoma, breast cancer, ovarian cancer, thyroid cancer, renal cell carcinoma, lung cancer, neuroblastoma, hepatocellular carcinoma (HCC), and glioblastoma multiforme, metabolic disorders, including diabetes and obesity, eye diseases, including diabetic retinopathy, ROP, AMD, and glaucoma, and acute and chronic organ transplant rejection.

[0006] Some embodiments include compounds of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate or salt of the solvate.

[0007] In some embodiments, W is [ka] is selected from.

[0008] In some embodiments, X, Y and Z are each independently selected from N and CH. In some embodiments, X is N and Y and Z are each CH.

[0009] In some embodiments, n is 0, 1 or 2. In some embodiments, n is 0 or 1.

[0010] In some embodiments, R 1a and R 1b are each independently: (a) hydrogen; (b) OR a C optionally substituted with 1-6 Alkyl, and (c) C 1-6 In some embodiments, R 1a and R 1b one of which is hydrogen and the other is (a) hydrogen, (b) C optionally substituted with OH 1-4 Alkyl, and (c) C 1-4 In some embodiments, R 1a +R 1b Each pair, together with the carbon atom to which it is connected, is (a) C 1-4 (b) a 4- to 6-membered carbocyclic ring optionally substituted with 1 to 3 groups independently selected from alkyl and OH; or (b) O, S(O) m and N.R. b Forms a 4- to 6-membered heterocycle having one heteroatom selected from the group consisting of:

[0011] In some embodiments, R 2a , R 2b , R 3a , and R 3b are each independently: (a) hydrogen; (b) OR a or NR b R c C optionally substituted with 1-6 Alkyl, (c) C 1-6 Haloalkyl, (d) halogen, (e) OR a , (f) N.R.b R c , and (g) S(O) m C 1-6 In some embodiments, R 2a +R 2b Each pair, together with the carbon atom to which it is connected, is (a) C 1-4 (b) a 4- to 6-membered carbocyclic ring optionally substituted with 1 to 3 groups independently selected from alkyl and OH; or (b) O, S(O) m and N.R. b In some embodiments, R 1a +R 2a and the carbon atoms to which each pair is connected, taken together, are (a) O, S(O) m and N.R. b or (b) a 5- or 6-membered heteroaryl having one heteroatom selected from the group consisting of:

[0012] In some embodiments, R 4a and R 4b are each independently: (a) hydrogen; (b) OR a C optionally substituted with 1-6 Alkyl, and (c) C 1-6 In some embodiments, R 4a and R 4b are each hydrogen.

[0013] In some embodiments, R 5a and R 5b are each independently (a) hydrogen, and (b) C 1-6 is selected from alkyl.

[0014] In some embodiments, R 6 (a)C 1-6 Alkyl, (b) C 1-6 Haloalkyl, (c) (CH2) p C 3-6 Cycloalkyl, (d) OR a , (e)NR b Rc (f) halogens, (g) SF5, (h) CN, (i) S(O) m C 1-6 Alkyl, and (j) C(O)NR b R c In some embodiments, R 6 (a)C 1-4 Alkyl, (b) C 1-4 Fluoroalkyl, (c) (CH2) p C 3-4 Cycloalkyl, (d)OC 1-4 Alkyl, (e)OC 1-4 Fluoroalkyl, (f)NR b R c , (g) halogens, (h) SF5, (i) CN, and (j) S(O). m C 1-6 In some embodiments, R 6 (a)C 1-4 Alkyl, (b) C 1-2 Fluoroalkyl, (c) C 3-4 Cycloalkyl, (d)OC 1-4 Alkyl, and (e) O-C 1-2 fluoroalkyl.

[0015] In some embodiments, R 7 , R 8 and R 9 are each independently (a) hydrogen, and (b) R 6 In some embodiments, R 7 (a)C 1-4 Alkyl, (b) C 1-4 Fluoroalkyl, (c) (CH2) p C 3-4 Cycloalkyl, (d)OC 1-4 Alkyl, (e)OC 1-4 Fluoroalkyl, (f) O(CH2) p C 3-4 Cycloalkyl, (g) NR b R c , (h) halogen, and (i) hydrogen. 7(a)C 1-4 Alkyl, (b) C 1-2 Fluoroalkyl, (c) C 3-4 Cycloalkyl, (d) CH2C 3-4 Cycloalkyl, (e)OC 1-4 Alkyl, (f)OC 1-2 Fluoroalkyl, (g) OCH2C 3-4 cycloalkyl, and (h) azetidinyl.

[0016] In some embodiments, m is 0, 1 or 2.

[0017] In some embodiments, p is 0, 1 or 2.

[0018] In some embodiments, R a is (a) hydrogen, (b) C 1-6 Alkyl, (c) C 1-6 Haloalkyl, and (d) (CH2) p C 3-6 cycloalkyl.

[0019] In some embodiments, R b and R c is (a) hydrogen, (b) -C(O)C 1-6 Alkyl, (c) -SO2C 1-6 Alkyl, (d) halogen, S(O) m C 1-6 C optionally substituted with alkyl 1-6 Alkyl, (e) C 1-6 Haloalkyl, (f) C 3-6 (g) 4- to 6-membered heterocycle, and (h) C(O)OC 1-6 In some embodiments, R b , R c and the atoms to which they are connected, taken together, are O, S(O) m and NH.

[0020] In some embodiments, the compound of Formula (I) has the formula (Ia): [ka] [Wherein W is [ka] is selected from n is 0 or 1; R 6 (a)C 1-4 Alkyl, (b) C 1-4 Fluoroalkyl, (c) (CH2) p C 3-4 Cycloalkyl, (d)OC 1-4 Alkyl, (e)OC 1-4 Fluoroalkyl, (f)NR b R c , (g) halogens, (h) SF5, (i) CN, and (j) S(O)2C 1-4 alkyl; R 7 (a)C 1-4 Alkyl, (b) C 1-4 Fluoroalkyl, (c) (CH2) p C 3-4 Cycloalkyl, (d)OC 1-4 Alkyl, (e)OC 1-4 Fluoroalkyl, (f) O(CH2) p C 3-4 Cycloalkyl, (g) NR b R c (h) halogen, and (i) hydrogen; and R 8 (a)C 1-4 Alkyl, (b) C 3-4 Cycloalkyl, (c)OC 1-4 (c) a substituted or unsubstituted alkyl group; (d) an aryl group selected from the group consisting of (a) an alkyl group, (b) an alkyl group, (c) an alkyl group, (d) an alkyl group, (e) an alkyl group, and (f) an alkyl group; or a pharma- ceutically acceptable salt, solvate, or salt of the solvate thereof.

[0021] Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0022] Some embodiments provide a method for the treatment or prevention of a disease, disorder or condition selected from the group consisting of renal disease, liver disease, chronic inflammatory or inflammatory disorders, autoimmune diseases, respiratory diseases, vascular and cardiovascular diseases, fibrotic diseases, cancer, eye diseases, metabolic diseases, cholestatic and other forms of chronic pruritus, and acute and chronic organ transplant rejection, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt, solvate or salt of a solvate thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt, solvate or salt of a solvate thereof.Some embodiments provide a method for the treatment of a chronic inflammatory disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt, solvate or salt of a solvate thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt, solvate or salt of a solvate thereof. In certain embodiments, the chronic inflammatory disorder is rheumatoid arthritis (RA), multiple sclerosis (MS), idiopathic pulmonary fibrosis (IPF), hepatitis or atherosclerosis.

[0023] Some embodiments provide a method for the treatment or prevention of multiple sclerosis comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula (I) or a pharma- ceutically acceptable salt, solvate or salt of a solvate thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a pharma- ceutically acceptable salt, solvate or salt of a solvate thereof.

[0024] Some embodiments provide a method for inhibiting ATX, comprising contacting a cell with a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or salt of the solvate thereof. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell.

[0025] Some embodiments provide a method for reducing LPA production in a cell, comprising contacting the cell with a compound of formula (I) or a pharma- ceutically acceptable salt, solvate or salt of the solvate thereof.In some embodiments, the cell is a mammalian cell.In some embodiments, the cell is a human cell.

[0026] Detailed Description Some embodiments include compounds of formula (I) [ka] [Wherein W is [ka] is selected from X, Y and Z are each independently selected from N and CH; n is 0, 1 or 2; R 1a and R 1b , R 4a and R 4b are each independently (a) hydrogen, (b) OR a C optionally substituted with 1-6 Alkyl, and (c)C 1-6 Haloalkyl Selected from; R 2a , R 2b , R 3a , and R 3b are each independently (a) hydrogen, (b) ORa or NR b R c C optionally substituted with 1-6 Alkyl, (c)C 1-6 Haloalkyl, (d) halogens, (e) OR a , (f)NR b R c , and (g) S(O) m C 1-6 Alkyl or R 1a +R 1b , or R 2a +R 2b , or R 3a +R 3b represents, together with the carbon atom to which each pair is connected, (a)C 1-4 a 4- to 6-membered carbocyclic ring optionally substituted with 1-3 groups independently selected from alkyl and OH; or (b) O, S(O) m and N.R. b A 4- to 6-membered heterocycle having one heteroatom selected from or R 1a +R 2a , or R 2a +R 3a and the carbon atoms to which each pair is linked, taken together, (a) O, S(O) m and N.R. b or a 5- to 6-membered heterocycle having one heteroatom selected from (b) 5-6 membered heteroaryl Forming; R 5a and R 5b are each independently (a) hydrogen, and (b)C 1-6 Alkyl is selected from R 6 teeth, (a)C1-6 Alkyl, (b)C 1-6 Haloalkyl, (c)(CH2) p C 3-6 Cycloalkyl, (d) OR a , (e)NR b R c , (f) Halogen (g) SF5, (h)CN, (i) S(O) m C 1-6 Alkyl, and (j)C(O)NR b R c is selected from R 7 , R 8 and R 9 are each independently (a) hydrogen, and (b)R 6 Groups classified as is selected from m is 0, 1 or 2; p is 0, 1 or 2; R a teeth, (a) hydrogen, (b)C 1-6 Alkyl, (c)C 1-6 Haloalkyl, and (d)(CH2) p C 3-6 Cycloalkyl is selected from R b and R c teeth, (a) hydrogen, (b) -C(O)C 1-6 Alkyl, (c)-SO2C 1-6 Alkyl, (d) S(O) m C 1-6 C optionally substituted with alkyl 1-6 Alkyl, (e)C 1-6 Haloalkyl, (f)C 3-6 Cycloalkyl, (g) 4- to 6-membered heterocycles, and (h)C(O)OC 1-6 Alkyl are independently selected from; or R b , R c and the atoms to which they are connected, taken together, are O, S(O) m and NH. or a pharma- ceutically acceptable salt, solvate or salt of the solvate thereof.

[0027] In some embodiments, X is N and Y and Z are each CH. In some embodiments, Y is N and X and Z are each CH. In some embodiments, Z is N and X and Y are each CH. In some embodiments, X, Y and Z are each CH. In some embodiments, n is selected from the group consisting of the moiety [C(R 3a )(R 3b )] n (i.e., the nitrogen-containing ring is azetidine). In some embodiments, n is 0 with respect to the moiety [C(R 3a )(R 3b )] n (i.e., the nitrogen-containing ring is pyrrolidine). In some embodiments, n is 1 with respect to the moiety [C(R 3a )(R 3b )] n (i.e., the nitrogen-containing ring is piperidine). 2a , R 2b , R 3a , R 3b , R 4a , R 4b Each is hydrogen. In some embodiments, R 1a , R 1b , R 3a , R 3b , R 4a, R 4b are each hydrogen.

[0028] In some embodiments, R 1a and R 1b are each independently: (a) hydrogen; (b) OR a C optionally substituted with 1-6 Alkyl, and (c) C 1-6 haloalkyl; or R 1a +R 1b together with the carbon atom to which the pair is connected, (a) C 1-4 (b) a 4- to 6-membered carbocyclic ring optionally substituted with 1 to 3 groups independently selected from alkyl and OH; or (b) O, S(O) m and N.R. b R 2a , R 2b , R 3a , R 3b , R 4a and R 4b Each is hydrogen. In some embodiments, R 1a and R 1b one of which is hydrogen and the other is (a) hydrogen, (b) C optionally substituted with OH 1-4 Alkyl, and (c) C 1-4 In some embodiments, R 1a and R 1b In some embodiments, one or both of R 1a and R 1b Either or both of the following are OR a C optionally substituted with 1-6 Alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and t-butyl, each of which may be unsubstituted or substituted with hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, etc. In some embodiments, R 1a and R 1b Either or both of 1-6Haloalkyl, for example, -CF3, -CH2F, -CF2H, -CH2CHF2, -CH2CF3, -CF2Cl, or -CH(CF3)2.

[0029] In some embodiments, R 1a +R 1b together with the carbon atom to which the pair is connected, (a) C 1-4 (b) a 4- to 6-membered carbocyclic ring optionally substituted with 1 to 3 groups independently selected from alkyl and OH; or (b) O, S(O) m and N.R. b In some embodiments, R 1a +R 1b together with the carbon atom to which they are both attached, C 1-4 Forms a 4-6 membered carbocyclic ring optionally substituted with 1-3 groups independently selected from alkyl and OH, e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which may be unsubstituted or substituted with one or more groups selected from OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and t-butyl. In some embodiments, R 1a +R 1b together with the carbon atom to which they are attached form O, S(O) m and N.R. b In some embodiments, the heterocycle is an oxygen-containing heterocycle such as oxetane, tetrahydrofuran, and tetrahydropyran. In some embodiments, the heterocycle is a sulfur-containing heterocycle such as thietane (including oxides and dioxides), tetrahydrothiophene (including oxides and dioxides), and tetrahydrothiopyran (including oxides and dioxides). In some embodiments, the heterocycle is a nitrogen-containing heterocycle such as azetidine, pyrrolidine, and piperidine, wherein each nitrogen atom is unsubstituted or is -C(O)C. 1-6Alkyl (e.g., acetyl, n-propanoyl, isopropanoyl, n-butanoyl, sec-butanoyl, and t-butanoyl), -SO2C 1-6 Alkyl (e.g., methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropanesulfonyl, n-butanesulfonyl, sec-butanesulfonyl, and t-butanesulfonyl), S(O) m C 1-6 C optionally substituted with alkyl 1-6 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, methylsulfonylmethyl, methylsulfonylethyl), C 1-6 Haloalkyl (e.g., 2,2-difluoroethyl and 2,2,2-trifluoroethyl), C 3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), 4- to 6-membered heterocycle (e.g., oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl and piperidinyl), or C(O)OC 1-6 In some embodiments of this paragraph, R 2a , R 2b , R 3a , R 3b , R 4a , R 4b are each hydrogen.

[0030] In some embodiments, R 2a and R 2b One of the groups is hydrogen, and the other group is (a) hydrogen, (b) OR a or NR b R c C optionally substituted with 1-6 Alkyl, (c) C 1-6 Haloalkyl, (d) halogen, (e) OR a , (f) N.R. b R c , and (g) S(O) m C 1-6 alkyl; or R 2a +R2b together with the carbon atom to which the pair is connected, (a) C 1-4 (b) a 4- to 6-membered carbocyclic ring optionally substituted with 1 to 3 groups independently selected from alkyl and OH; or (b) O, S(O) m and N.R. b and R 1a , R 1b , R 3a , R 3b , R 4a and R 4b Each is hydrogen. In some embodiments, R 2a and R 2b In some embodiments, one or both of R 2a and R 2b Either or both of the following are OR a or NR b R c C optionally substituted with 1-6 Alkyl, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and t-butyl, each of which may be unsubstituted or substituted with hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, amino, methylamino, dimethylamino, and the like. In some embodiments, R 2a and R 2b Either or both of 1-6 haloalkyl, for example, -CF, -CHF, -CFH, -CHCHF, -CHCF, -CFCl, or -CH(CF). In some embodiments, R 2a and R 2b One or both of R is halogen, e.g., fluoro, chloro, bromo, or iodo. 2a and R 2b One of the two is OR a (e.g., hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy), or NR b R c (e.g., amino, methylamino, dimethylamino), or S(O) m C 1-6alkyl (eg, methylthio, methylsulfinyl, methylsulfonyl).

[0031] In some embodiments, R 2a +R 2b together with the carbon atom to which they are both attached, C 1-4 Forms a 4-6 membered carbocyclic ring optionally substituted with 1-3 groups independently selected from alkyl and OH, e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which may be unsubstituted or substituted with one or more groups selected from OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and t-butyl. In some embodiments, R 2a +R 2b together with the carbon atom to which they are attached form O, S(O) m and N.R. b In some embodiments, the heterocycle is an oxygen-containing heterocycle such as oxetane, tetrahydrofuran, and tetrahydropyran. In some embodiments, the heterocycle is a sulfur-containing heterocycle such as thietane (including oxides and dioxides), tetrahydrothiophene (including oxides and dioxides), and tetrahydrothiopyran (including oxides and dioxides). In some embodiments, the heterocycle is a nitrogen-containing heterocycle such as azetidine, pyrrolidine, and piperidine, wherein each nitrogen atom is unsubstituted or is -C(O)C. 1-6 Alkyl (e.g., acetyl, n-propanoyl, isopropanoyl, n-butanoyl, sec-butanoyl, and t-butanoyl), -SO2C 1-6 Alkyl (e.g., methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropanesulfonyl, n-butanesulfonyl, sec-butanesulfonyl, and t-butanesulfonyl), S(O) m C 1-6 C optionally substituted with alkyl 1-6Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, methylsulfonylmethyl, methylsulfonylethyl), C 1-6 Haloalkyl (e.g., 2,2-difluoroethyl and 2,2,2-trifluoroethyl), C 3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), 4- to 6-membered heterocycle (e.g., oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl and piperidinyl), or C(O)OC 1-6 In some embodiments of this paragraph, R 1a , R 1b , R 3a , R 3b , R 4a , R 4b are each hydrogen.

[0032] In some embodiments, each R 3a and R 3b is hydrogen.

[0033] In some embodiments, R 4a and R 4b In some embodiments, one or both of R 4a and R 4b Either or both of 1-6 Alkyl (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl).

[0034] In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0035] In some embodiments, W is [ka] In some embodiments, W is selected from: [ka] In some embodiments, W is [ka] In some embodiments, W is [ka] In some embodiments, W is [ka] In some embodiments, W is [ka] is selected from.

[0036] In some embodiments, R 5a and R 5b In some embodiments, one or both of R 5a and R 5b Either or both of 1-6 Alkyl (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl).

[0037] In some embodiments, R 6 -OC 1-6 alkyl, for example, methoxy, ethoxy, n-propyloxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy; in some embodiments, R 6 -OC 1-4 In some embodiments, R 6 -OC 1-6haloalkyl, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy; in some embodiments, R 6 -OC 1-4 Fluoroalkyl or -OC 1-2 In some embodiments, R 6 is -O-(CH2) p C 3-6 Cycloalkyl, for example, cyclobutyloxy, cyclopropyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopropylethoxy, cyclobutylethoxy. In some embodiments, R 6 is C 1-6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl; in some embodiments, R 6 -C 1-4 In some embodiments, R 6 is C 1-6 haloalkyl, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl; in some embodiments, R 6 is C 1-4 Fluoroalkyl or C 1-2 In some embodiments, R 6 is halogen, e.g., fluoro, chloro, bromo, and iodo. In some embodiments, R 6 is (CH2) p C 3-6 Cycloalkyl, for example, cyclobutyl, cyclopropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl. In some embodiments, R 6 is NR b R c For example, amino, methylamino, dimethylamino, azetidine, pyrrolidine, and piperidine. 6is CN. In some embodiments, R 6 is SF5. In some embodiments, R 6 is S(O) m C 1-6 alkyl, for example, methylthio, methylsulfinyl, methylsulfonyl. In some embodiments, R 6 is C(O)NR b R c For example, carboxamide, N-methylcarboxamide, N,N-dimethylcarboxamide, 1-azetidinylcarbonyl.

[0038] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 -OC 1-6 alkyl, for example, methoxy, ethoxy, n-propyloxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy; in some embodiments, R 7 -OC 1-4 In some embodiments, R 7 -OC 1-6 haloalkyl, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy; in some embodiments, R 7 -OC 1-4 Fluoroalkyl or -OC 1-2 In some embodiments, R 7 is -O-(CH2) p C 3-6 Cycloalkyl, for example, cyclobutyloxy, cyclopropyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopropylethoxy, cyclobutylethoxy. In some embodiments, R 7 is C 1-6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl; in some embodiments, R 7 -C1-4 In some embodiments, R 7 is C 1-6 haloalkyl, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl; in some embodiments, R 7 is C 1-4 Fluoroalkyl or C 1-2 In some embodiments, R 7 is halogen, e.g., fluoro, chloro, bromo, and iodo. In some embodiments, R 7 is (CH2) p C 3-6 Cycloalkyl, for example, cyclobutyl, cyclopropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl. In some embodiments, R 7 is NR b R c For example, amino, methylamino, dimethylamino, azetidine, pyrrolidine, and piperidine. 7 is CN. In some embodiments, R 7 is SF5. In some embodiments, R 7 is S(O) m C 1-6 alkyl, for example, methylthio, methylsulfinyl, methylsulfonyl. In some embodiments, R 7 is C(O)NR b R c For example, carboxamide, N-methylcarboxamide, N,N-dimethylcarboxamide, 1-azetidinylcarbonyl.

[0039] In some embodiments, R 8 is hydrogen. In some embodiments, R 8 -OC 1-6alkyl, for example, methoxy, ethoxy, n-propyloxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy; in some embodiments, R 8 -OC 1-4 In some embodiments, R 8 -OC 1-6 haloalkyl, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy; in some embodiments, R 8 -OC 1-4 Fluoroalkyl or -OC 1-2 In some embodiments, R 8 is -O-(CH2) p C 3-6 Cycloalkyl, for example, cyclobutyloxy, cyclopropyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopropylethoxy, cyclobutylethoxy. In some embodiments, R 8 is C 1-6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl; in some embodiments, R 8 -C 1-4 In some embodiments, R 8 is C 1-6 haloalkyl, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl; in some embodiments, R 8 is C 1-4 Fluoroalkyl or C 1-2 In some embodiments, R 8 is halogen, e.g., fluoro, chloro, bromo, and iodo. In some embodiments, R 8 is (CH2) p C 3-6Cycloalkyl, for example, cyclobutyl, cyclopropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl. In some embodiments, R 8 is NR b R c For example, amino, methylamino, dimethylamino, azetidine, pyrrolidine, and piperidine. 8 is CN. In some embodiments, R 8 is SF5. In some embodiments, R 8 is S(O) m C 1-6 alkyl, for example, methylthio, methylsulfinyl, methylsulfonyl. In some embodiments, R 8 is C(O)NR b R c For example, carboxamide, N-methylcarboxamide, N,N-dimethylcarboxamide, 1-azetidinylcarbonyl.

[0040] In some embodiments, R 9 is hydrogen. In some embodiments, R 9 -OC 1-6 alkyl, for example, methoxy, ethoxy, n-propyloxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy; in some embodiments, R 9 -OC 1-4 In some embodiments, R 9 -OC 1-6 haloalkyl, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy; in some embodiments, R 9 -OC 1-4 Fluoroalkyl or -OC 1-2 In some embodiments, R 9 is -O-(CH2) p C 3-6Cycloalkyl, for example, cyclobutyloxy, cyclopropyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopropylethoxy, cyclobutylethoxy. In some embodiments, R 9 is C 1-6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl; in some embodiments, R 9 -C 1-4 In some embodiments, R 9 is C 1-6 haloalkyl, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl; in some embodiments, R 9 is C 1-4 Fluoroalkyl or C 1-2 In some embodiments, R 9 is halogen, e.g., fluoro, chloro, bromo, and iodo. In some embodiments, R 9 is (CH2) p C 3-6 Cycloalkyl, for example, cyclobutyl, cyclopropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl. In some embodiments, R 9 is NR b R c For example, amino, methylamino, dimethylamino, azetidine, pyrrolidine, and piperidine. 9 is CN. In some embodiments, R 9 is SF5. In some embodiments, R 9 is S(O) m C 1-6 alkyl, for example, methylthio, methylsulfinyl, methylsulfonyl. In some embodiments, R 9 is C(O)NR b R cFor example, carboxamide, N-methylcarboxamide, N,N-dimethylcarboxamide, 1-azetidinylcarbonyl.

[0041] In some embodiments, the compound of formula (Ia) [ka] wherein the variables are as defined elsewhere herein. In certain embodiments, compounds are provided having formula (I) having the formula: [ka] n is 0 or 1; R 6 (a)C 1-4 Alkyl, (b) C 1-4 Fluoroalkyl, (c) (CH2) p C 3-4 Cycloalkyl, (d)OC 1-4 Alkyl, (e)OC 1-4 Fluoroalkyl, (f)NR b R c , (g) halogens, (h) SF5, (i) CN, and (j) S(O)2C 1-4 alkyl; R 7 (a)C 1-4 Alkyl, (b) C 1-4 Fluoroalkyl, (c) (CH2) p C 3-4 Cycloalkyl, (d)OC 1-4 Alkyl, (e)OC 1-4 Fluoroalkyl, (f) O(CH2) p C 3-4 Cycloalkyl, (g) NR b R c (h) halogen, and (i) hydrogen; R 8 (a)C 1-4 Alkyl, (b) C 3-4 Cycloalkyl, (c)OC 1-4 (d) halogen; (e) CN; and (f) hydrogen.

[0042] In some embodiments, the compound of Formula (I) is (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; 6-Oxa-1-azaspiro[3.3]heptan-1-yl(2-((3-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone; 2-Oxa-6-azaspiro[3.3]heptan-6-yl(2-((3-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone; (2-((3-(tert-butyl)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-(tert-butyl)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; Azetidin-1-yl(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone; (2-((3,5-bis(trifluoromethyl)benzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (2-((3,5-dichlorobenzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (2-((3,5-dimethoxybenzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (2-((3-methyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; 6-Oxa-1-azaspiro[3.3]heptan-1-yl(2-((1-(3-(trifluoromethoxy) phenyl)ethyl)amino)pyrimidin-5-yl)methanone; 3-(((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)methyl)benzonitrile; (2-((3-chlorobenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-(methylsulfonyl)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-(difluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-(difluoromethyl)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-isopropyl-5-(pentafluorothio)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; 6-Oxa-1-azaspiro[3.3]heptan-1-yl(2-((3-(trifluoromethyl)benzyl)amino)pyrimidin-5-yl)methanone; (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(pyrrolidin-1-yl)methanone; (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(piperidin-1-yl)methanone; (2-((3-cyclobutyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; 6-Oxa-1-azaspiro[3.3]heptan-1-yl(2-((3-(pentafluorothio)benzyl)amino)pyrimidin-5-yl)methanone; (2-((3-bromo-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-fluoro-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-(cyclopropylmethoxy)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-isopropoxy-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-(cyclopropylmethyl)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-methoxy-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-ethoxy-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; 2-((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl) amino)-2,3-dihydro-1H-indene-5-carbonitrile; 6-Oxa-1-azaspiro[3.3]heptan-1-yl(2-((3-(2,2,2-trifluoroethoxy)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethyl)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3,5-dicyclopropylbenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-isopropoxybenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-isopropoxy-5-propylbenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(7-methyl-1,7-diazaspiro[3.5]nonan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2,2-dimethylazetidin-1-yl)methanone; (2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-(difluoromethyl)azetidin-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-oxa-5-azaspiro[3.4]octan-5-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(7-oxa-1-azaspiro[3.5]nonan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.5]nonan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6,6-dioxido-6-thia-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3,5-dichlorobenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3,4-dichlorobenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3,5-diisopropoxybenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3,5-diethoxybenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((2,5-dichlorobenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((2,3-dichlorobenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; Azetidin-1-yl(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-(methoxymethyl)azetidin-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)((S)-2-(methoxymethyl)azetidin-1-yl)methanone; (2-((3,5-diisopropoxybenzyl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-isopropoxybenzyl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (S)-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (R)-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-(azetidin-1-yl)-5-isopropoxybenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-(2-hydroxypropan-2-yl)azetidin-1-yl)(2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone; (2-((3,5-dicyclopropylbenzyl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((3-ethoxy-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-ethoxybenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-(azetidin-1-yl)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (R)-(2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (S)-(2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; 6-Oxa-1-azaspiro[3.3]heptan-1-yl(5-((3-(trifluoromethoxy)benzyl)amino)pyrazin-2-yl)methanone; 6-Oxa-1-azaspiro[3.3]heptan-1-yl(6-((3-(trifluoromethoxy)benzyl)amino)pyridazin-3-yl)methanone; 6-Oxa-1-azaspiro[3.3]heptan-1-yl(6-((3-(trifluoromethoxy)benzyl)amino)pyridin-3-yl)methanone; Azetidin-1-yl(5-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrazin-2-yl)methanone; (5-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrazin-2-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (6-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyridin-3-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (6-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyridin-3-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (6-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; Azetidin-1-yl(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3-hydroxyazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3-fluoroazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3,3-difluoroazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3-hydroxy-3-methylazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3-(methylsulfonyl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2,2-dimethylazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)methanone; tert-Butyl 1-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2,4-dimethylazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(methoxymethyl)pyrrolidin-1-yl)methanone; (S)-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(methoxymethyl)pyrrolidin-1-yl)methanone; (R)-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(methoxymethyl)pyrrolidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-oxa-5-azaspiro[3.4]octan-5-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.4]octan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3-(methoxymethyl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3-((dimethylamino)methyl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(7-oxa-1-azaspiro[3.5]nonan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(methoxymethyl)azetidin-1-yl)methanone; (R)-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(methoxymethyl)azetidin-1-yl)methanone; (S)-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(methoxymethyl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(1-oxa-6-azaspiro[3.3]heptan-6-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2,2-dioxido-2-thia-6-azaspiro[3.3]heptan-6-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6,6-dioxido-6-thia-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.5]nonan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3-methoxyazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3-(dimethylamino)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(hexahydro-1H-furo[3,4-b]pyrrol-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(7-methyl-1,7-diazaspiro[3.5]nonan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(difluoromethyl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(trifluoromethyl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.4]octan-1-yl)methanone; (R)-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.4]octan-1-yl)methanone; (S)-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.4]octan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2,4-dimethylazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)((2R,4R)-2,4-dimethylazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)((2S,4S)-2,4-dimethylazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)((2R,4S)-2,4-dimethylazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.5]nonan-1-yl)methanone; (R)-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.5]nonan-1-yl)methanone; (S)-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.5]nonan-1-yl)methanone; (2-((3-ethyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-methyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-ethyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5,6-dibromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5,6-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (R)-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (S)-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-(((R)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.4]octan-1-yl)methanone; (2-(((R)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.4]octan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (2-(((R)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-hydroxy-6-methyl-1-azaspiro[3.3]heptan-1-yl)methanone; (R)-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-hydroxy-6-methyl-1-azaspiro[3.3]heptan-1-yl)methanone; 2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)((S)-2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; 2-(((R)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)((S)-2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)((R)-2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-(((R)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)((R)-2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((3-(methylsulfonyl)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-(methylsulfonyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; 3-(((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)methyl)-5-(trifluoromethoxy)benzonitrile; 3-(((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)methyl)-5-(trifluoromethoxy)benzamide; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(1,6-diazaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-methyl-1,6-diazaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-ethyl-1,6-diazaspiro[3.3]heptan-1-yl)methanone; (6-cyclobutyl-1,6-diazaspiro[3.3]heptan-1-yl)(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(oxetan-3-yl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-cyclopropyl-1,6-diazaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-isopropyl-1,6-diazaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(2,2,2-trifluoroethyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(2,2-difluoroethyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone; · (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(2-(methylsulfonyl)ethyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone; (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(methylsulfonyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-(methylsulfonyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone; 1-(1-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonyl)-1,6-diazaspiro[3.3]heptan-6-yl)ethanone; 1-(1-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonyl)-1,6-diazaspiro[3.3]heptan-6-yl)ethanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-methyl-1,6-diazaspiro[3.4]octan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-methyl-1,6-diazaspiro[3.5]nonan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-methyl-2,5-diazaspiro[3.4]octan-5-yl)methanone; (2-((3-(azetidin-1-yl)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-ethoxy-5-isopropoxybenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-ethoxy-5-isopropoxybenzyl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((5-isopropoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; and (2-((5-ethoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, or a pharma- ceutically acceptable salt, solvate, or solvate of the salt of any of the foregoing.

[0043] Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0044] Some embodiments provide a method for the treatment or prevention of renal conditions, hepatic conditions, inflammatory conditions, neurological conditions, respiratory conditions, vascular and cardiovascular conditions, fibrotic diseases, cancer, ophthalmic conditions, metabolic conditions, cholestatic and other forms of chronic pruritus, and acute and chronic organ transplant rejection comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt, solvate or salt of a solvate thereof.

[0045] Some embodiments provide a method for the treatment or prevention of multiple sclerosis, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or salt of a solvate thereof.

[0046] Any feature of an embodiment is applicable to all embodiments specified herein. Moreover, any feature of an embodiment can be independently combined with other embodiments described herein, either partially or entirely, in any way, for example, one, two or three or more embodiments can be combined entirely or partially. Moreover, any feature of an embodiment can be arbitrarily selected with respect to other embodiments. Any embodiment of a method can include another embodiment of a compound, and any embodiment of a compound can be configured to carry out a method of another embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless otherwise specified. In the event that there are multiple definitions for a term herein, those in this section shall prevail unless otherwise specified.

[0048] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used unless otherwise indicated. The use of "or" or "and" means "and / or" unless otherwise indicated. Furthermore, the use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting. As used herein, regardless of transitional phrases or the body of the claims, the terms "comprise(s)" and "comprising" are to be construed as having an open-ended meaning. That is, the terms are to be construed as synonymous with the phrases "having at least" or "including at least." When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or ingredients, but may include additional features or ingredients.

[0049] The term "patient" includes mammals, such as mice, rats, cows, sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans. In some embodiments, the patient is a human.

[0050] The term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine, or iodine.

[0051] The term "alkyl" refers to a saturated hydrocarbon chain, which may be a straight or branched chain, containing the specified number of carbon atoms. For example, C 1-6Alkyl indicates that the group may have 1 to 6 (inclusive) carbon atoms in it. In some embodiments, alkyl is C , which represents a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0052] The term "cycloalkyl" refers to a fully saturated monocyclic, bicyclic, tricyclic or other polycyclic hydrocarbon group having a specified number of ring carbon atoms. Polycyclic cycloalkyls can be fused, bridged or spiro ring systems. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and norbornyl. In some embodiments, cycloalkyl is a monocyclic C3-C8 cycloalkyl.

[0053] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by halo. In some embodiments, more than one hydrogen atom (e.g., 2, 3, 4, 5, or 6) is replaced by halo. In these embodiments, the hydrogen atoms may each be replaced by the same halogen (e.g., fluoro), or the hydrogen atoms may be replaced by a combination of different halogens (e.g., fluoro and chloro). "Haloalkyl" also includes alkyl moieties in which all hydrogens are replaced by halo (sometimes referred to herein as perhaloalkyl, e.g., perfluoroalkyl, such as trifluoromethyl). Examples of haloalkyl also include "fluoroalkyl", which is an alkyl group in which one or more hydrogen atoms are replaced by fluorine.

[0054] As referred to herein, the term "alkoxy" refers to a group of the formula -O-(alkyl). Alkoxy can be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 2-pentoxy, 3-pentoxy, or hexyloxy. Similarly, the term "thioalkoxy" refers to a group of the formula -S-(alkyl). The terms "haloalkoxy" and "thiohaloalkoxy" refer to -O-(haloalkyl) and -S-(haloalkyl), respectively.

[0055] In any of the foregoing groups, one or more hydrogen atoms in the alkyl portion of the group may be replaced with deuterium, for example, a deuteromethoxy group (-OCD3) or a deuteromethyl group (-CD3).

[0056] The term "aralkyl" refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. One of the carbons of the alkyl moiety serves as the attachment point of the aralkyl group to another moiety. Non-limiting examples of "aralkyl" include benzyl, 2-phenylethyl, and 3-phenylpropyl groups.

[0057] The term "alkenyl" refers to a straight or branched hydrocarbon chain containing a specified number of carbon atoms and having one or more carbon-carbon double bonds. Alkenyl groups can include, for example, vinyl, allyl, 1-butenyl, and 2-hexenyl. In some embodiments, alkenyl is a C2-C6 alkenyl.

[0058] The term "cycloalkenyl" refers to a partially unsaturated monocyclic, bicyclic, tricyclic or other polycyclic hydrocarbon group. A ring carbon (e.g., saturated or unsaturated) is the point of attachment of the cycloalkenyl substituent. Any atom may be optionally substituted, for example, by one or more substituents. Cycloalkenyl moieties can include, for example, cyclopentenyl, cyclohexenyl, cyclohexadienyl, or norbornenyl.

[0059] The term "alkynyl" refers to a straight or branched hydrocarbon chain containing a specified number of carbon atoms and having one or more carbon-carbon triple bonds. Alkynyl groups can include, for example, ethynyl, propargyl, 1-butynyl, and 2-hexynyl. In some embodiments, the alkynyl is a C2-C6 alkynyl.

[0060] The terms "heterocycle", "heterocyclyl" or "heterocyclic" as used herein, except where noted, refer to a stable 4-, 5-, 6- or 7-membered monocyclic or a stable 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic heterocyclic ring system containing at least one non-aromatic (i.e., saturated or partially unsaturated) ring consisting of carbon atoms and 1-4, preferably up to 3, heteroatoms selected from the group consisting of N, O and S, in which the nitrogen and sulfur atoms may be optionally oxidized as N-oxide, sulfoxide or sulfone, and the nitrogen atom may be optionally quaternized. The heterocycle may be bonded through a ring carbon atom or, where possible, through a ring nitrogen atom. Bicyclic heterocyclic ring systems may be fused, bridged or spiro bicyclic heterocyclic ring systems. In some embodiments, the heterocyclyl is monocyclic having 4 to 7, preferably 4 to 6, ring atoms, in which one or two of the ring atoms are heteroatoms independently selected from the group consisting of N, O, and S. In some embodiments, the heterocyclyl group is bicyclic, in which the second ring can be an aromatic or non-aromatic ring consisting of carbon atoms and 1 to 4, preferably up to 3, heteroatoms independently selected from the group consisting of N, O, and S, or the second ring can be a benzene ring, or a "cycloalkyl" or "cycloalkenyl" as defined herein.Examples of such heterocyclic groups are azetidine, chroman, dihydrofuran, dihydropyran, dioxane, dioxolane, hexahydroazepine, imidazolidine, imidazoline, indoline, isochroman, isoindoline, isothiazolidine, isoxazoline, isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, piperazine, piperidine, dihydropyridine, tetrahydropyridine, dihydropyridazine, pyran, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, tetrahydrofuran, tetrahydropyran, thiamorpholine, tetrahydrothiophene, thiazoline, thiazolidine, thiomorpholine, thietane, thiolane, sulfolane, 1,3-dioxolane, 1,3-oxazolidine, 1,3-thiazolidine, tetrahydrothiopyran ... These include, but are not limited to, thiazoline, 1,3-dioxane, 1,4-dioxane, hexahydrotriazine, tetrahydro-oxazine, tetrahydropyrimidine, perhydroazepine, perhydro-1,4-diazepine, perhydro-1,4-oxazepine, 7-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.2.0]heptane, 7-azabicyclo[4.1.0]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, tropane, 2-oxa-6-azaspiro[3.3]heptane, dihydrobenzofuran, dihydrobenzimidazolyl, dihydrobenzoxazole, and dihydrobenzothiazolyl, and the N-oxides or sulfones or sulfoxides thereof.

[0061] The term "aryl" as used herein is intended to mean any stable monocyclic or bicyclic carbon ring of up to six members in each ring (i.e., a total of 6 to 10 ring atoms), in which at least one ring is aromatic. For example, C6-C aryl, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, or 1H-indenyl. 10 Aryl groups.

[0062] The term "heteroaryl" as used herein, unless otherwise noted, refers to a stable 5-, 6-, or 7-membered monocyclic or a stable 9- or 10-membered fused bicyclic ring system containing at least one aromatic ring consisting of carbon atoms and 1-4, preferably up to 3, heteroatoms selected from the group consisting of N, O, and S, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. In the case of a "heteroaryl" which is a bicyclic group, the second ring need not be aromatic and need not contain a heteroatom. Thus, a bicyclic "heteroaryl" encompasses, for example, a stable 5- or 6-membered monocyclic aromatic ring consisting of carbon atoms and 1-4, preferably up to 3, heteroatoms as defined immediately above, fused to a benzene ring or a second monocyclic "heteroaryl" or "heterocyclyl", "cycloalkyl" or "cycloalkenyl" as defined above. Examples of heteroaryl groups include, but are not limited to, benzimidazole, benzopyrazole, benzisothiazole, benzisoxazole, benzofuran, isobenzofuran, benzothiazole, benzothiophene, benzotriazole, benzoxazole, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, benzimidazole, benzothiadiazole, isoindole, pyrrolopyridine, imidazopyridines such as imidazo[1,2-a]pyridine, pyrazolopyridines, pyrrolopyrimidines, and N-oxides thereof.

[0063] The terms "treating," "treat," or "treatment" generally refer to inhibiting, alleviating, ameliorating, slowing the progression of, or eliminating the named condition once it has been established. In addition to its customary meaning, the terms "prophylaxis," "prophylactic," "preventing," "prevent," or "prevention" also refer to delaying the onset of the named condition, or reducing the risk of developing the named condition or of processes that may result in that condition, or reducing the recurrence of symptoms of the condition.

[0064] The term "therapeutically effective amount" or "effective amount" is an amount sufficient to achieve a beneficial or desired clinical result. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of a disease state.

[0065] As used herein, abbreviations for any protecting groups, amino acids and other compounds follow their common usage, widely accepted abbreviations, or those of the IUPAC-IUB Biochemical Nomenclature Commission (see Biochem. 11:942-944 (1972)) unless otherwise specified.

[0066] Compound forms and salts The compounds of the present disclosure may contain one or more asymmetric centers and may occur as racemates and racemic mixtures, enantiomerically enriched mixtures, single enantiomers, individual diastereomers, and diastereomeric mixtures. The compounds of the present disclosure may exist in the form of isomers (e.g., enantiomers, diastereomers) either by the nature of an asymmetric center or by hindered rotation.

[0067] It will also be understood that when two or more asymmetric centers are present in the compounds of the present disclosure, several diastereomers and enantiomers of the exemplified structures are often possible, and that pure diastereomers and pure enantiomers represent preferred embodiments. Pure stereoisomers, pure diastereomers, pure enantiomers and mixtures thereof are intended to be within the scope of the present disclosure.

[0068] All isomers of the compounds of the present disclosure, whether separated, pure, partially pure, or racemic mixtures, are included within the scope of the present disclosure. The purification of said isomers and the separation of said isomeric mixtures can be achieved by standard techniques known in the art. For example, diastereomeric mixtures can be separated into individual isomers by chromatographic processes or crystallization, and racemates can be separated into their respective enantiomers by either chromatographic processes or resolution on chiral phases.

[0069] The compounds of the present disclosure include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers and mixtures thereof. The compounds of the present disclosure may also be represented in multiple tautomeric forms, and in such cases, the present disclosure expressly includes all tautomeric forms of the compounds described herein, even if only a single tautomeric form may be represented. In addition, when a term used in the present disclosure includes a group that can be tautomerized, all tautomeric forms are expressly included thereunder. For example, hydroxy-substituted heteroaryl groups include, but are not limited to, 2-hydroxypyridine and 2-pyridone, 1-hydroxyisoquinoline and 1-oxo-1,2-dihydroisoquinoline, 2-hydroxypyrimidine and 2-pyrimidone, 2-hydroxyquinoline and 2-quinolinone, 5-hydroxy-1,2,4-oxadiazole and 1,2,4-oxadiazole-5(4H)one, and the like. All such isomeric forms of such compounds are expressly included in the present disclosure.

[0070] The compounds of the present disclosure include not only the compounds themselves, but also their salts, solvates, and solvates of salts, if applicable. For the purposes of the present disclosure, salts are preferably pharma- ceutically acceptable salts of the compounds of the present disclosure. Also included are salts that are not suitable for pharmaceutical use themselves, but can be used, for example, to isolate or purify the compounds of the present disclosure. Salts can be formed, for example, between an anion and a positively charged substituent (e.g., amino) on the compounds described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Similarly, salts can also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on the compounds described herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium.

[0071] As used herein, "pharmaceutical acceptable salt" refers to a derivative in which the parent compound is modified by making its acid or base salt. Examples of pharmaceutical acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. When the compound of the present disclosure is basic, the pharmaceutical acceptable salts include, for example, the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, sulfonic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and, for example, the salts prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenedisulfonic acid, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, camphorsulfonic acid, gluconic acid, mandelic acid, mucic acid, pantothenic acid, oxalic acid, isethionic acid, and the like.

[0072] When the compounds of the present disclosure are acidic, salts can be prepared from pharma- ceutically acceptable non-toxic bases, including inorganic and organic bases.Such salts that can be prepared include lithium, sodium, potassium, magnesium, calcium, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, arginine, lysine, and the like.

[0073] Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; S. M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19; and "Pharmaceutical Salts: Properties, Selection, and Use. A Handbook"; Wermuth, CG and Stahl, PH (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN 3-906390-26-8]; each of which is incorporated herein by reference in its entirety.

[0074] Solvates in the context of the present disclosure are designated as forms of the compounds of the present disclosure that form a complex in the solid or liquid state by stoichiometric coordination with solvent molecules. Hydrates, in which coordination occurs with water, are a specific form of solvate. Hydrates are preferred solvates in the context of the present disclosure. The formation of solvates is described in detail in "Solvents and Solvent Effects in Organic Chemistry"; Reichardt, C. and Welton T.; John Wiley & Sons, 2011 [ISBN: 978-3-527-32473-6], the contents of which are incorporated herein by reference in their entirety. Those skilled in the art will recognize the solvates of the present disclosure.

[0075] The present disclosure also encompasses all suitable isotopic variants of the compounds of the present disclosure, whether radioactive or not. An isotopic variant of a compound of the present disclosure is understood to mean a compound in which at least one atom in the compound of the present disclosure is replaced with another atom of the same atomic number but with an atomic mass different from the atomic mass that normally or preferentially occurs in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include: 2 H (deuterium), 3H (tritium), 13 C. 14 C. 15 N, 17 O. 18 O. 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I and other isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine. Certain isotopic variations of the compounds according to the present disclosure, especially those incorporating one or more radioisotopes, may be useful, for example, for investigating the mechanism of action of an active compound or its biodistribution. Due to their relatively easy preparation and detectability, especially 3 H, 14 C and / or 18 Compounds labeled with F isotopes are suitable for this purpose. In addition, the incorporation of isotopes, such as deuterium, can result in a certain therapeutic benefit, such as an increased half-life in the body or a lower required active dose, as a result of the compound's greater metabolic stability. Such modifications of compounds according to the present disclosure may therefore also constitute preferred embodiments of the present disclosure in some cases. In some embodiments, hydrogen atoms of compounds described herein may be replaced with deuterium atoms. Isotopic variants of compounds according to the present disclosure can be prepared by processes known to those skilled in the art, for example, by the methods described below and in the Examples, by using the corresponding isotopic modifications of certain reagents and / or starting compounds.

[0076] Pharmaceutical Compositions The term "pharmaceutical composition" as used herein is intended to include a product that includes an active ingredient(s) and an inactive ingredient(s) that constitute a carrier, as well as any product that results directly or indirectly from any combination, complex formation or aggregation of two or more components, from the dissociation of one or more components, or from other types of reaction or interaction of one or more components. Thus, the pharmaceutical composition of the present disclosure includes any composition made by mixing a compound of the present disclosure or a pharmaceutically acceptable salt or solvate or solvate of a salt thereof and a pharmaceutically acceptable carrier.

[0077] The term "pharmaceutically acceptable carrier" refers to a carrier or adjuvant that may be administered to a patient, together with a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, or salt of a solvate thereof, which does not destroy its pharmacological activity and is non-toxic when administered in a dosage sufficient to deliver a therapeutic amount of the compound.

[0078] In some embodiments, the compounds of the present application are administered at about 1 mg to 1,000 mg, about 2 mg to 900 mg, about 3 mg to 800 mg, about 4 mg to 700 mg, about 5 mg to 600 mg, about 10 mg to 500 mg, about 50 mg to 400 mg, about 100 mg to 300 mg, about 150 mg to 250 mg, or any value therebetween. In some embodiments, the total daily dose may be divided and administered in portions throughout the day, for example, once a day, twice a day, three times a day, or four times a day. In some embodiments, the total dose may be administered once a week, twice a week, three times a week, four times a week, five times a week, or six times a week.

[0079] In some embodiments, the pharmaceutical composition of the present disclosure for injection comprises pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and sterile powder for reconstitution into sterile injectable solution or dispersion immediately before use.Examples of suitable aqueous or non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyol (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oil (e.g., olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by using coating materials such as lecithin, maintaining the required particle size in the case of dispersion, and using surfactants.

[0080] In some embodiments, pharmaceutical compositions may also contain auxiliary agents such as preservatives, wetting agents, emulsifiers and dispersants. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid. It may be desirable to include isotonic agents such as sugar, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical forms can be caused by including agents that delay absorption, such as aluminum monostearate and gelatin. If desired, and for more effective distribution, the compound can be incorporated into sustained release or targeted delivery systems, such as polymer matrices, liposomes and microspheres.

[0081] In some embodiments, pharmaceutical compositions that are injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use.

[0082] In some embodiments, the solid dosage form of the pharmaceutical composition for oral administration. In some embodiments, oral dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite clay, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0083] Solid pharmaceutical compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0084] The solid dosage forms of the pharmaceutical composition of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulations. These may optionally contain opacifying agents and may be in the form of a formulation that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedded pharmaceutical compositions that can be used include polymeric substances and waxes.

[0085] The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0086] Some embodiments provide liquid dosage forms of the pharmaceutical composition for oral administration.In some embodiments, liquid dosage forms include pharma-ceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, EtOAc, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0087] Besides inert diluents, the oral pharmaceutical compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0088] The compound suspensions may contain, in addition to the active compound, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0089] Pharmaceutical compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compound with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at room temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active compound.

[0090] Dosage forms for topical administration of the compounds or pharmaceutical compositions of the present disclosure include powders, patches, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharma- ceutically acceptable carrier and any needed preservatives, buffers, or propellants, as may be required.

[0091] use Some embodiments provide a method for the treatment or prevention of a disease, disorder or condition selected from the group consisting of renal conditions, hepatic conditions, inflammatory conditions, neurological conditions, respiratory conditions, vascular and cardiovascular conditions, fibrotic diseases, cancer, ophthalmic conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula (I) or a pharma- ceutically acceptable salt, solvate or salt of a solvate thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a pharma- ceutically acceptable salt, solvate or salt of a solvate thereof.

[0092] Renal conditions include, but are not limited to, acute kidney injury and chronic kidney disease with and without proteinuria, including end stage renal disease (ESRD). More specifically, this includes glomerulosclerosis with reduced creatinine clearance and reduced glomerular filtration rate, microalbuminuria, albuminuria and proteinuria, expansion of the reticular mesangial matrix with or without significant cellular hyperplasia (particularly diabetic nephropathy and amyloidosis), focal thrombosis of the glomerular capillaries (particularly thrombotic microangiopathy), global fibrinoid necrosis, ischemic lesions, malignant nephrosclerosis (such as ischemic regression, reduced renal blood flow and renal arteriopathy), swelling and proliferation of intracapillary (endothelial and mesangial) and / or extracapillary cells (crescents) (as in the entity of glomerulonephritis), focal segmental glomerulosclerosis, IgA nephropathy, vasculitis / systemic disease, and acute and chronic renal transplant rejection.

[0093] Hepatic conditions include, but are not limited to, cirrhosis, hepatic congestion, cholestatic liver disease including pruritus, nonalcoholic steatohepatitis, and acute and chronic liver transplant rejection.

[0094] Inflammatory conditions include, but are not limited to, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, abnormal elimination disorders, and the like, as well as inflammatory airway diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or chronic bronchial asthma.

[0095] Further respiratory conditions include, but are not limited to, iatrogenic drug-induced fibrosis, occupational and / or environmental induced fibrosis, systemic diseases and other diffuse parenchymal lung diseases of different etiology, including vasculitis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases, pulmonary alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, genetic diseases (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease), radiation-induced fibrosis, silicosis, asbestos-induced pulmonary fibrosis, or acute respiratory distress syndrome (ARDS).

[0096] Conditions of the nervous system include, but are not limited to, neuropathic pain, schizophrenia, neuroinflammation (eg, astrogliosis), peripheral and / or autonomic (diabetic) neuropathies, multiple sclerosis, and the like.

[0097] Vascular conditions include, but are not limited to, atherosclerosis, thrombotic vascular disease and thrombotic microangiopathy, proliferative arteriopathy (such as swelling and nodular thickening of myointimal cells surrounded by a mucous extracellular matrix), atherosclerosis, decreased vascular compliance (such as stiffness, decreased ventricular compliance and decreased vascular compliance), endothelial dysfunction, and the like.

[0098] Cardiovascular conditions include, but are not limited to, acute coronary syndromes, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmias such as atrial fibrillation, stroke, and other vascular injuries.

[0099] Fibrotic diseases include, but are not limited to, myocardial and vascular fibrosis, renal fibrosis, hepatic fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma, and encapsulating peritonitis.

[0100] Cancer and cancer metastasis include, but are not limited to, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, liver cancer, gastrointestinal cancer, and their progression and metastatic aggressiveness.

[0101] Ocular conditions include, but are not limited to, proliferative and non-proliferative (diabetic) retinopathy, dry and exudative age-related macular degeneration (AMD), macular edema, central arterial / venous occlusion, traumatic injury, glaucoma, etc. In particular, the ocular condition is glaucoma.

[0102] Metabolic conditions include, but are not limited to, obesity and diabetes.

[0103] Thus, the disclosure further provides a method for the treatment or prevention of renal conditions, hepatic conditions, inflammatory conditions, neurological conditions, respiratory conditions, vascular and cardiovascular conditions, fibrotic diseases, cancer, ophthalmic conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt, solvate or salt of a solvate thereof.

[0104] In some embodiments, the condition to be treated is multiple sclerosis, including relapsing-remitting multiple sclerosis, relapsing multiple sclerosis, primary progressive multiple sclerosis, or secondary progressive multiple sclerosis. In some embodiments, administration of a compound of Formula (I) attenuates, reverses, or inhibits demyelination in the treated patient. In some embodiments, administration of a compound of Formula (I) promotes remyelination in the treated patient. In some embodiments, demyelination or remyelination can be monitored by magnetic resonance imaging (MRI), including conventional T1-weighted and T2-weighted imaging, magnetic resonance spectroscopy, diffusion tensor imaging (DTI), magnetization transfer imaging, and separation of the T2 relaxation component. In some embodiments, demyelination or remyelination can be monitored by ultrashort echo time (TE) imaging or 31 This can be monitored by P spectroscopy.

[0105] Administration The compounds and compositions described herein can be administered, for example, orally, parenterally (e.g., by subcutaneously, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques), by inhalation spray, topically, rectally, nasally, bucally, vaginally, via an implantable reservoir, by injection, subdermally, intraperitoneally, transmucosally, or ophthalmically, in dose ranges from about 0.01 mg / kg to about 1000 mg / kg, or any value therebetween (e.g., from about 0.01 to about 100 mg / kg, from about 0.1 to about 100 mg / kg, from about 1 to about 100 mg / kg, from about 1 to about 10 mg / kg, or any value therebetween) every 4 to 120 hours, or any value therebetween. The interrelationship of dosages for animals and humans (based on milligrams per square meter of body surface) is described in Freireich et al., Cancer Chemother. Rep. 50, 219-244 (1966) and is understood by those skilled in the art. Body surface area can be approximately determined from the height and weight of the patient by those skilled in the art. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, NY, 537 (1970). In certain embodiments, the composition is administered by oral administration or by injection. The methods herein contemplate administration of an effective amount of the compound or compound composition to achieve a desired or specified effect. Typically, the pharmaceutical compositions of the present disclosure will be administered about 1 to about 6 times per day or as a continuous infusion. Such administration can be used as a chronic or acute therapy.

[0106] Lower or higher doses than those mentioned above may be required. The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, excretion rate, drug combinations, severity and course of the disease, symptoms or signs, susceptibility of the patient, and the judgment of the treating physician.

[0107] In some embodiments, the dosage form includes a compound of formula (I) (and / or a compound of any of the other formulae described herein) or a salt thereof (e.g., a pharmaceutically acceptable salt) as defined anywhere herein at about 0.001 milligrams to about 2,000 milligrams, or any value therebetween (including about 0.001 milligrams to about 1,000 milligrams, about 0.001 milligrams to about 500 milligrams, about 0.01 milligrams to about 250 milligrams, about 0.01 milligrams to about 100 milligrams, about 0.05 milligrams to about 50 milligrams, and about 0.1 milligrams to about 25 milligrams, or any value therebetween). The dosage form may further include a pharmaceutically acceptable carrier and / or an additional therapeutic agent.

[0108] Appropriate dosage levels can be determined by any suitable method known to those skilled in the medical arts. Preferably, the active agent is administered 1 to 4 times per day for topical administration, or often less frequently if a drug delivery system is used.

[0109] However, the actual dosage level and time course of administration of the active ingredient in the pharmaceutical composition of the present disclosure may be modified so as to obtain an amount of active ingredient effective for achieving the desired therapeutic response for a particular patient, composition and mode of administration without causing toxicity to the patient.Therefore, it may be necessary to deviate from the prescribed amount in appropriate cases, depending in particular on the age, sex, weight, diet and general health of the patient, the route of administration, the individual response to the active ingredient, the nature of the preparation and the time or interval at which administration is performed.Thus, it may be sufficient in some cases to deal with less than the minimum amount mentioned above, while in other cases the prescribed upper limit may have to be exceeded.When administering larger amounts, it may be advisable to divide them into several individual doses per day.

[0110] Use in combination In some embodiments, the compound of formula (I) or its pharma- ceutically acceptable salt, solvate or solvate salt can be co-administered with one or more additional therapeutic agents.Additional therapeutic agents include, but are not limited to, corticosteroids, interferons, monoclonal antibodies, and immunomodulators.For example, methylprednisolone; interferon beta-1a, interferon beta-1b; natalizumab, alemtuzumab, daclizumab, ocrelizumab; glatiramer acetate, mitoxantrone, fingolimod, teriflunomide, cladribine, and dimethyl fumarate.

[0111] In some embodiments, a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or salt of a solvate thereof may be administered to a subject undergoing plasma exchange therapy.

[0112] synthesis The preparation of the compounds of formula (I) of the present disclosure can be carried out in sequential or convergent synthetic routes. The synthesis of the present disclosure is shown in the general scheme below. The skills required to carry out the reaction and purification of the resulting products are known to those skilled in the art. If a mixture of enantiomers or diastereoisomers is produced during the reaction, these enantiomers or diastereoisomers can be separated by methods described herein or known to those skilled in the art, such as (chiral) chromatography or crystallization. The substituents and indices used in the methods of the process description below have the meanings defined herein.

[0113] Compounds of formula (I) may be prepared as illustrated in Scheme 1. A halogenated heteroaryl carboxylic acid or carboxylate 1 is reacted with an amine 2 in the presence of a base, followed by hydrolysis in the case of the carboxylate, to provide an aminoheteroaryl carboxylic acid 3. The acid 3 is coupled with a cyclic amine 4 using standard amide coupling techniques (e.g., with HATU, EDCI, DCC, HOBt / HBTU, an organic base such as triethylamine or diisopropylethylamine) to provide the corresponding compound of formula (I).

[0114] [ka]

[0115] Amines 2 are either commercially available or accessible from commercially available precursors using conventional synthetic methodology. Scheme 2 illustrates the synthesis of amines in which W is an aryl halide and an aryl carboxylate. [ka] Several representative methods for preparing amines 2 are depicted. Aryl halides 5 can be converted to the corresponding aldehydes 6 by treatment with an organolithium reagent (e.g., nBuLi) and dimethylformamide; aldehydes 6 can also be prepared by reducing aryl carboxylates 7 to the corresponding alcohols, e.g., using LiBH4, and oxidizing the latter to aldehydes, e.g., using Dess-Martin periodinane. Reductive amination of 6 (e.g., hydroxylamine, followed by Pd / C and H2) affords amines 2a. Aryl carboxylates 7 can be converted to the corresponding amides 8 using ammonia; reduction of 8, e.g., using lithium aluminum hydride, provides amines 2a.

[0116] [ka]

[0117] The intermediate halides 5, aldehydes 6 and carboxylates 7 are commercially available or may be prepared from commercially available precursors as illustrated in Scheme 3. Metal-catalyzed cross-coupling reactions may be used to introduce various substituents onto the aromatic ring. For example, the formation of a CC bond may be achieved by reacting aryl halides 9 with Grignard reagents in the presence of a nickel catalyst (Kumada reaction), or with organozinc halides in the presence of a palladium catalyst (Negishi reaction), or with boronates or organoboronic acids in the presence of a palladium catalyst (Suzuki-Miyaura reaction); aryl halides 9 may also be converted to arylamines under Buchwald-Hartwig reaction conditions (e.g., in the presence of a palladium catalyst). Nucleophilic substitution reactions may be used to prepare additional intermediates. For example, the phenoxide generated from phenol 10 by treatment with base may be reacted with alkyl-LG (LG=leaving group) to provide the corresponding ether; Grignard reagents may be reacted with benzyl compounds 11 to provide 15. Although various phenyl compounds are shown in the scheme, one skilled in the art will understand that the depicted transformations may be applied to similar substituted indanyl amines. Furthermore, these reactions may be used to convert a suitable compound 3 or a compound of formula (I) (e.g., halo-substituted 3 or halo-substituted formula (I)) to another corresponding compound (e.g., one with alkyl or cycloalkyl substituents). In some cases, it may be advantageous to protect the reactive amino group; for this purpose, a conventional protecting group such as tBoc may be introduced and subsequently removed using well-known synthetic methodologies.

[0118] [ka]

[0119] biological function The utility of the compounds of the present disclosure can be demonstrated by one or more of the following methods or other methods known in the art: Preparation of ATX, LPC, 4-AAP, TOOS, HRP, and CO Autotaxin enzyme (ATX, 25 μg) (Echelon Biosciences, Inc. Cat# E-4000, Salt Lake City, UT) was resuspended in 250 μL of sterile water to a stock solution of 100 μg / mL. Lyso PC 14:0 (LPC, Avanti Polar Lipids, Alabaster, AL) (200 mg) was resuspended in 7.13 mL of sterile water to give a 60 mM stock solution. · 4-Aminoantipyrine (4-AAP, Sigma-Aldrich, St. Louis, MO) was resuspended in 50 mM Tris-HCl (pH 8.0) to obtain a 50 mM stock solution. · 3-(N-ethyl-3-methylanilino)-2-hydroxypropanesulfonic acid sodium salt (TOOS, Sigma-Aldrich) was resuspended in 50 mM Tris-HCl (pH 8.0) to obtain a 30 mM stock solution. Horseradish peroxidase (HRP, Sigma-Aldrich) was resuspended in 50 mM Tris-HCl (pH 8.0) to give a stock solution of 530 U / mL. Choline oxidase (CO, Sigma-Aldrich) (500 U) was resuspended in 2.5 mL of 50 mM Tris-HCl (pH 8.0) to a stock solution of 200 U / mL.

[0120] Preparation of assay working solutions: Assay buffer I: 100 mM Tris-HCl (pH 9.0), 500 mM NaCl, 5 mM MgCl2, 30 μM CoCl2, 0.05% Triton X-100 Assay Buffer II: 4.5 mM 4-AAP, 2.7 mM TOOS, 21.2 U / mL HRP, 3 U / mL CO, 4.5 mM MgCl2 in 50 mM Tris-HCl (pH 8.0)

[0121] Preparation of test compounds: A compound preparation plate (Nunc 249944) was prepared by adding a 30 mM stock solution (in DMSO) of the test compound and performing a serial full log dilution down to 30 nM. 2 μL / well was transferred from the first compound preparation plate to a compound dilution plate (Corning, 3641) and 198 μL of Assay Buffer I was added to make a 10× solution.

[0122] In vitro ATX assay: A 10ng / mL solution of ATX was prepared by diluting in Assay Buffer I and 80μL / well was added to the assay plate (Corning, 3641); negative control wells contained 80μL / well of Assay Buffer I only (no ATX). 10μL / well from the compound dilution plate (containing serially diluted test compounds or DMSO) was added to the assay plate, which was then incubated at 37°C for 15 minutes. A solution of LPC 14:0 was prepared at 3mM in Assay Buffer I and 10μl / well was added to the assay plate for a final concentration of LPC of 0.3mM, which was returned to the 37°C incubator for 4 hours. After the 4 hour incubation, 100μL / well of Assay Buffer II was added to all wells of the assay plate. The plate was incubated at RT for 15 minutes before being read on the FlexStation in absorbance mode at 555nm. Results of the enzyme ATX inhibition assay are provided for compounds of formula (I). IC of "A" 50 Values ​​are less than 100 nM, "B" is greater than or equal to 100 nM but less than 1 μM, and "C" is greater than or equal to 1 μM.

[0123] [Table 1] TIFF2025060769000020.tif81169

[0124] The compounds of formula (I) and their pharma- ceutically acceptable salts or esters thereof as described herein have an IC 50Certain compounds have IC values ​​between 0.0005 μM and 500 μM. 50 Further specific compounds have IC values ​​between 0.0005 μM and 50 μM. 50 More specific compounds have IC values ​​between 0.0005 μM and 5 μM. 50 These results were obtained by using the enzyme assay described above.

[0125] The present disclosure is hereinafter illustrated by examples which are not of a limiting nature. Where preparations are obtained as mixtures of enantiomers, the pure enantiomers can be obtained by the methods described herein or by methods known to those skilled in the art, such as, for example, chiral chromatography or crystallization.

[0126] Abbreviation The following abbreviations may be referenced in the experimental and schemes of this disclosure: [Table 2]

[0127] [Example] All examples and intermediates were prepared under a nitrogen atmosphere unless otherwise noted.

[0128] Intermediates A1 to A26: Intermediates A1 to A26 are commercially available and are listed in the table below: [Table 3]

[0129] Intermediate A27: (3-(tert-butyl)-5-(trifluoromethoxy)phenyl)methanamine hydrochloride [ka] Step 1: Ethyl 3-bromo-5-(trifluoromethoxy)benzoate To a solution of 3-bromo-5-(trifluoromethoxy)benzoic acid (2.0 g, 7.0 mmol, 1.0 eq.) in EtOH (20 mL) was added SOCl2 (1.0 mL, 14 mmol, 2.0 eq.). After stirring at RT for 17 h, the mixture was partitioned between EtOAc and aq. NaHCO3. The aqueous phase was separated and washed once with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified on SiO2 to give ethyl 3-bromo-5-(trifluoromethoxy)benzoate (1.9 g, 85% yield).

[0130] Step 2: Ethyl 3-(tert-butyl)-5-(trifluoromethoxy)benzoate Ethyl 3-bromo-5-(trifluoromethoxy)benzoate (0.9 g, 2.9 mmol, 1.0 eq.) was dissolved in THF (5.8 mL, inhibitor free). Argon gas was bubbled through the solution for 10 min. 1,3-Dicyclohexyl-1H-imidazol-3-ium tetrafluoroborate (92 mg, 0.29 mmol, 10 mol%) and NiCl2·1.5 water (45 mg, 0.29 mmol, 10 mol%, see J. Am. Chem. Soc. 2011, 133, 8478-8481) were added and the mixture was cooled to -10 °C. A 1 M solution of tert-butylmagnesium chloride in THF (5.8 mL, 5.8 mmol, 2.0 eq.) was added dropwise while maintaining the temperature of the mixture below -8 °C. After 1 h, the mixture was partitioned between EtOAc and 10% aq. NH4Cl. The aqueous phase was separated and washed with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified on SiO2 to give ethyl 3-(tert-butyl)-5-(trifluoromethoxy)benzoate (0.68 g, 81% yield).

[0131] Step 3: (3-(tert-butyl)-5-(trifluoromethoxy)phenyl)methanol To a solution of ethyl 3-(tert-butyl)-5-(trifluoromethoxy)benzoate (0.68 g, 2.3 mmol, 1.0 eq.) in THF (5 mL) was added a 1M solution of LiBH4 in THF (5.8 mL, 12 mmol, 5.0 eq.) and the mixture was heated to 50° C. for 5.5 h. The mixture was quenched with 1M HCl and extracted with EtOAc. The organic phase was separated, washed with water, then with brine, dried over MgSO4, filtered and concentrated to give (3-(tert-butyl)-5-(trifluoromethoxy)phenyl)methanol (0.54 g, 94% yield), which was used without further purification.

[0132] Step 4: 3-(tert-butyl)-5-(trifluoromethoxy)benzaldehyde To a solution of (3-(tert-butyl)-5-(trifluoromethoxy)phenyl)methanol (0.54 g, 2.2 mmol, 1.0 eq.) in CHCl was added Dess-Martin periodinane (1.0 g, 2.4 mmol, 1.1 eq.). After 4 h, the mixture was quenched with NaSO and then partitioned between EtOAc and saturated aq. NaHCO. After filtration to remove solids, the organic phase was separated, washed with brine, dried over MgSO, filtered and concentrated. The residue was purified on SiO to give 3-(tert-butyl)-5-(trifluoromethoxy)benzaldehyde (0.34 g, 64% yield).

[0133] Step 5: (3-(tert-butyl)-5-(trifluoromethoxy)phenyl)methanamine hydrochloride To 3-(tert-butyl)-5-(trifluoromethoxy)benzaldehyde (0.34 g, 1.4 mmol, 1.0 eq.) in EtOH (9 mL) at RT was added HONH2·HCl (0.15 g, 2.1 mmol, 1.5 eq.). After 16 h, concentrated HCl (0.58 mL, 7.0 mmol, 5 eq.) and 20% Pd(OH)2 on carbon (0.2 g) were added and the mixture was placed on a Parr shaker at 65 psi for 1 h. The mixture was filtered through a pad of Celite and then concentrated to give (3-(tert-butyl)-5-(trifluoromethoxy)phenyl)methanamine hydrochloride, which was used without further purification. MS (ESI): m / z=248 [M+H] +

[0134] Intermediate A28: (3-cyclobutyl-5-(trifluoromethoxy)phenyl)methanamine hydrochloride [ka] Step 1: Ethyl 3-cyclobutyl-5-(trifluoromethoxy)benzoate A solution of ethyl 3-bromo-5-(trifluoromethoxy)benzoate (0.89 g, 2.9 mmol, 1.0 eq., product of step 1 of intermediate A27) in THF (inhibitor free, 10 mL) was purged with N2 for 10 min. Cyclobutylzinc bromide (8.5 mL, 4.3 mmol, 1.5 eq., 0.5 M in THF) and bis(tri-tert-butylphosphine)palladium (0.15 g, 0.29 mmol, 10 mol%) were added and the mixture was heated to 45 °C for 22 h. After cooling, the mixture was partitioned between EtOAc and aq. NH4Cl. The organic phase was separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified on SiO2 to give ethyl 3-cyclobutyl-5-(trifluoromethoxy)benzoate (0.44 g, 53% yield).

[0135] Step 2: (3-Cyclobutyl-5-(trifluoromethoxy)phenyl)methanamine hydrochloride The title compound was prepared similarly to steps 3-5 of A27 using ethyl 3-cyclobutyl-5-(trifluoromethoxy)benzoate. MS (ESI): m / z=246 [M+H] +

[0136] Intermediate A29: (3-isopropoxy-5-(trifluoromethoxy)phenyl)methanamine [ka] Step 1: 3-Isopropoxy-5-(trifluoromethoxy)benzaldehyde To a solution of 3-hydroxy-5-(trifluoromethoxy)benzaldehyde (0.40 g, 1.9 mmol, 1.0 eq.) in DMF (2 mL) was added 2-iodopropane (0.33 mL, 2.9 mmol, 1.5 eq.) and K2CO3 (0.67 g, 4.9 mmol, 2.5 eq.). The mixture was heated to 70° C. for 20 h, then cooled to RT and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified on SiO2 to give 3-isopropoxy-5-(trifluoromethoxy)benzaldehyde (0.30 g, 62% yield).

[0137] Step 2: (3-isopropoxy-5-(trifluoromethoxy)phenyl)methanamine To 3-isopropoxy-5-(trifluoromethoxy)benzaldehyde (0.3 g, 1.2 mmol, 1.0 eq.) in EtOH (5 mL) at RT was added HONH2·HCl (0.13 g, 1.8 mmol, 1.5 eq.). After 30 min, concentrated HCl (0.50 mL, 6.0 mmol, 5.0 eq.) and 20% Pd(OH)2 on carbon (0.2 g) were added and the mixture was placed under H2 atmosphere at 50 °C for 18 h. The mixture was cooled, filtered through a pad of Celite and concentrated. The residue was purified by reverse phase C chromatography. 18Purification on column gave (3-isopropoxy-5-(trifluoromethoxy)phenyl)methanamine (0.15 g, 50% yield). MS (ESI): m / z=250 [M+H] +

[0138] Intermediates A30-A35: The following intermediates were prepared in a similar manner to Intermediate A29 using the starting material indicated in step 1. [Table 4]

[0139] Intermediate A36: (3-(cyclopropylmethyl)-5-(trifluoromethoxy)phenyl)methanamine [ka] Step 1: 1-Bromo-3-(cyclopropylmethyl)-5-(trifluoromethoxy)benzene To a solution of cyclopropylmagnesium bromide (18 mL, 9 mmol, 1.5 eq., 0.5 M in THF) at 0 °C, CuI (0.11 g, 0.6 mmol, 10 mol%) was added. After stirring for 15 min, a solution of 1-bromo-3-(bromomethyl)-5-(trifluoromethoxy)benzene (2.0 g, 6.0 mmol, 1.0 eq.) in THF (10 mL) was added dropwise via a dropping funnel. The mixture was allowed to warm to RT and stirred for 3 h. In a separate flask, CuI (0.05 g, 0.3 mmol, 5 mol%) was added to a solution of cyclopropylmagnesium bromide (9 mL, 4.5 mmol, 0.75 eq., 0.5 M in THF) at 0 °C. After stirring for 15 min, the freshly prepared reagent was added to the mixture and stirred for 18 h. The mixture was quenched with aq. NH4Cl, then extracted with EtOAc and filtered through a pad of Celite. The filtrate was dried over MgSO4, filtered, concentrated and purified on SiO2 to give 1-bromo-3-(cyclopropylmethyl)-5-(trifluoromethoxy)benzene (1.2 g, 70% yield).

[0140] Step 2: 3-(Cyclopropylmethyl)-5-(trifluoromethoxy)benzaldehyde To a solution of 1-bromo-3-(cyclopropylmethyl)-5-(trifluoromethoxy)benzene (1.2 g, 4.1 mmol, 1.0 eq.) in THF at -78 °C was added n-butyllithium (1.9 mL, 1.1 eq., 2.5 M in hexanes) while maintaining the temperature of the mixture below -70 °C. Once the addition was complete, the mixture was stirred for 15 min, then DMF (0.49 mL, 6.1 mmol, 1.5 eq.) was added while again maintaining the temperature of the mixture below -70 °C. The mixture was quenched with MeOH and partitioned between EtOAc and aq. NH4Cl. The organic layer was separated, washed with brine, dried over MgSO4, filtered, concentrated, and purified on SiO2 to give 3-(cyclopropylmethyl)-5-(trifluoromethoxy)benzaldehyde (0.77 g, 74% yield).

[0141] Step 3: (3-(cyclopropylmethyl)-5-(trifluoromethoxy)phenyl)methanamine The title compound was prepared analogously to step 2 / A29 using 3-(cyclopropylmethyl)-5-(trifluoromethoxy)benzaldehyde. MS (ESI): m / z=246 [M+H] +

[0142] Intermediate A37: (3-isopropyl-5-(trifluoromethoxy)phenyl)methanamine hydrochloride [ka] Step 1: 3-(prop-1-en-2-yl)-5-(trifluoromethoxy)benzaldehyde To 3-bromo-5-(trifluoromethoxy)benzaldehyde (15 g, 56 mmol, 1.0 eq.) in dioxane (112 mL) and water (38 mL) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (14 g, 84 mmol, 1.5 eq.) and K2CO3 (23 g, 170 mmol, 3.0 eq.). N2 was bubbled through the mixture for 15 min. Pd(PPh3)4 (3.2 g, 2.8 mmol, 5 mol%) was added and the reaction vessel was sealed and heated to 85 °C for 20 h. The mixture was cooled to RT and then partitioned between EtOAc and water. The aqueous layer was extracted once with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated. The residue was purified on SiO2 to give 3-(prop-1-en-2-yl)-5-(trifluoromethoxy)benzaldehyde (11 g, 85% yield).

[0143] Step 2: (3-isopropyl-5-(trifluoromethoxy)phenyl)methanamine hydrochloride To 3-(prop-1-en-2-yl)-5-(trifluoromethoxy)benzaldehyde (11 g, 47 mmol, 1.0 eq.) in EtOH (165 mL) at RT was added HONH2·HCl (4.9 g, 71 mmol, 1.5 eq.). After 18 h, concentrated HCl (8.0 mL, 95 mmol, 2.0 eq.) and 20% Pd(OH)2 on carbon (2.2 g) were added and the mixture was placed on a Parr shaker under 60 psi of hydrogen for 18 h. An additional amount of HCl (4 mL, 47 mmol, 1.0 eq.) and 20% Pd(OH)2 on carbon (1.3 g) was added and the mixture was placed on a Parr shaker under 60 psi of hydrogen for 24 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was dissolved in EtOAc, washed twice with saturated NaHCO3, dried over MgSO4, filtered, concentrated, and purified on SiO2. To a solution of the crude mixture (5.4 g) in EtOH (80 mL) was added HCl (4 mL) and 20% Pd(OH)2 on carbon (1.5 g). The mixture was placed on a Parr shaker at 60 psi of hydrogen for 18 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated to give (3-isopropyl-5-(trifluoromethoxy)phenyl)methanamine hydrochloride (6.2 g, 49% yield). MS (ESI): m / z=234 [M+H] +

[0144] Intermediate A38: (3-isopropyl-5-(pentafluorothio)phenyl)methanamine [ka] The title compound was prepared analogously to A37 using 3-bromo-5-(pentafluorothio)benzaldehyde in step 1. MS (ESI): m / z=276 [M+H] +

[0145] Intermediate A39: (3-cyclopropyl-5-(trifluoromethoxy)phenyl)methanamine [ka] Step 1: 3-Cyclopropyl-5-(trifluoromethoxy)benzaldehyde To 3-bromo-5-(trifluoromethoxy)benzaldehyde (2 g, 7.4 mmol, 1.0 eq.) in dioxane (20 mL) was added cyclopropylboronic acid (1.3 g, 15 mmol, 2.0 eq.) and cesium fluoride (3.8 g, 25 mmol, 3.4 eq.). N2 was bubbled through the mixture for 10 min. PdCl2(dppf)·CH2Cl2 (0.60 g, 0.74 mmol, 10 mol%) was added and the reaction vessel was sealed and heated to 90 °C for 18 h. The mixture was partitioned between EtOAc and water and filtered through a pad of Celite. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified on SiO2 to give 3-cyclopropyl-5-(trifluoromethoxy)benzaldehyde (1.6 g, 93% yield).

[0146] Step 2: (3-Cyclopropyl-5-(trifluoromethoxy)phenyl)methanamine To 3-cyclopropyl-5-(trifluoromethoxy)benzaldehyde (0.94 g, 4.1 mmol, 1.0 eq.) in EtOH (9 mL) at RT was added HONH2·HCl (0.43 g, 6.2 mmol, 1.5 eq.). After 1.5 h, concentrated HCl (0.85 mL, 10 mmol, 2.5 eq.) and 10% palladium on carbon (0.2 g, 20 wt%) were added and the mixture was stirred under hydrogen atmosphere for 22 h. An additional amount of HCl (0.85 mL, 10.3 mmol, 2.5 eq.) was added and the mixture was placed on a Parr shaker at 60 psi for 24 h. The mixture was filtered through a pad of Celite, concentrated and purified using reverse phase C chromatography. 18 Purification on column gave (3-cyclopropyl-5-(trifluoromethoxy)phenyl)methanamine (0.87 g, 84% yield) as the formate salt. MS (ESI): m / z=232 [M+H] +

[0147] Intermediate A40: (3-cyclopropyl-5-(trifluoromethyl)phenyl)methanamine [ka] The title compound was prepared analogously to A39 using 3-bromo-5-(trifluoromethyl)benzaldehyde in step 1. MS (ESI): m / z=216 [M+H] +

[0148] Intermediate A41: (3,5-dicyclopropyl-phenyl)methanamine [ka] The title compound was prepared analogously to A39 using 3,5-dibromo-benzaldehyde and 4 eq. of cyclopropylboronic acid in step 1. MS (ESI): m / z=188 [M+H] +

[0149] Intermediate A42: (3-cyclopropyl-5-isopropoxyphenyl)methanamine [ka] Step 1: Methyl 3-cyclopropyl-5-isopropoxybenzoate The title compound was prepared analogously to step 1 / A39 using methyl 3-bromo-5-isopropoxybenzoate.

[0150] Step 2: (3-cyclopropyl-5-isopropoxyphenyl)methanol The title compound was prepared similarly to Step 3 / A27.

[0151] Step 3: 3-Cyclopropyl-5-isopropoxybenzaldehyde The title compound was prepared similarly to step 4 / A27.

[0152] Step 4: (3-cyclopropyl-5-isopropoxyphenyl)methanamine The title compound was prepared as in step 2 / A29 and run on reversed phase C18 After purification on column, (3-cyclopropyl-5-isopropoxyphenyl)methanamine was obtained. MS (ESI): m / z=206 [M+H] +

[0153] Intermediate A43: (3-isopropoxy-5-propylphenyl)methanamine [ka] (3-isopropoxy-5-propylphenyl)methanamine was isolated as a by-product from step 4 of intermediate A42. MS (ESI): m / z=208 [M+H] +

[0154] Intermediate A44: (3-cyclopropyl-5-ethoxyphenyl)methanamine [ka] The title compound was prepared analogously to A42 using methyl 3-bromo-5-ethoxybenzoate in step 1. MS (ESI): m / z=192 [M+H] +

[0155] Intermediate A45: 3-bromo-5-isopropoxyphenyl)methanamine [ka] Step 1: 3-Bromo-5-isopropoxybenzamide To methyl 3-bromo-5-isopropoxybenzoate (1.1 g, 3.9 mmol, 1.0 eq.) was added 15 mL of 7N ammonia in MeOH. The mixture was heated to 50° C. in a pressure vessel for 16 h. An additional 10 mL of 7N ammonia in MeOH was added and heating was continued at 50° C. for 16 h. The mixture was concentrated to remove the solvent and the residue was purified on SiO2 to give 3-bromo-5-isopropoxybenzamide (0.92 g, 92% yield).

[0156] Step 2: (3-bromo-5-isopropoxyphenyl)methanamine Lithium aluminum hydride (2.7 mL, 5.4 mmol, 1.5 eq., 2.0 M in THF) was added to a solution of 3-bromo-5-isopropoxybenzamide (0.90 g, 3.5 mmol, 1.0 eq.) in 10 mL of THF at 0° C. The ice bath was removed and the mixture was heated to 70° C. for 1.5 h. The mixture was then partitioned between EtOAc and water. The aqueous layer was extracted twice more with EtOAc and the combined organic layers were concentrated. The residue was purified by reverse phase C chromatography. 18 After purification on column, (3-bromo-5-isopropoxyphenyl)methanamine (0.26 g, 30% yield) was isolated. MS (ESI): m / z=244 [M+H] +

[0157] Intermediate A46: (3-(azetidin-1-yl)-5-isopropoxyphenyl)methanamine [ka] Step 1: Methyl 3-(azetidin-1-yl)-5-isopropoxybenzoate To methyl 3-bromo-5-isopropoxybenzoate (1.4 g, 4.7 mmol, 1.0 eq.) in toluene (14 mL) was added azetidine hydrochloride (0.88 g, 9.4 mmol, 2 eq.) and Cs2CO3 (6.1 g, 19 mmol, 4.0 eq.). The mixture was purged subsurface with nitrogen for 10 min. Pd(OAc)2 (0.063 g, 0.28 mmol, 0.06 eq.) and Xantphos (0.22 g, 0.38 mmol, 0.08 eq.) were added and the mixture was heated to 100° C. for 18 h, then cooled to RT and partitioned between EtOAc and water. The aqueous layer was extracted once with EtOAc and the combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified on SiO2 to give methyl 3-(azetidin-1-yl)-5-isopropoxybenzoate (0.98 g, 84% yield).

[0158] Step 2: 3-(azetidin-1-yl)-5-isopropoxybenzamide The title compound was prepared analogously to step 1 / A45 using methyl 3-(azetidin-1-yl)-5-isopropoxybenzoate.

[0159] Step 3: 3-(azetidin-1-yl)-5-isopropoxyphenyl)methanamine To a solution of 3-(azetidin-1-yl)-5-isopropoxybenzamide (0.91 g, 3.6 mmol, 1.0 eq.) in THF (18 mL) at 0° C. was added borane (1.1 mL, 11 mmol, 3 eq., 10 M in dimethylsulfide). After the addition was complete, the mixture was heated to 60° C. for 18 h, then cooled to RT and carefully quenched with 2-propanol. The volatiles were removed to provide 3-(azetidin-1-yl)-5-isopropoxyphenyl)methanamine (1.1 g, 100% yield), which was used without further purification. MS (ESI): m / z=221 [M+H] +

[0160] Intermediate A47: (3-(azetidin-1-yl)-5-(trifluoromethoxy)phenyl)methanamine [ka] The title compound was prepared analogously to A46 using methyl 3-bromo-5-(trifluoromethoxy)benzoate in step 1. MS (ESI): m / z=247 [M+H] +

[0161] Intermediate B: B1 to B39 listed in the table below are commercially available:

[0162] [Table 5] TIFF2025060769000040.tif247169

[0163] Intermediate B43: 2-(azetidin-2-yl)propan-2-ol 2,2,2-trifluoroacetate [ka] Step 1: tert-Butyl 2-(2-hydroxypropan-2-yl)azetidine-1-carboxylate To a solution of methyl 1-Boc-azetidine-2-carboxylate (4.3 g, 20 mmol, 1.0 eq.) in diethyl ether (40 mL) at 0° C. was added MeMgBr (40 mL, 120 mmol, 6.0 eq., 3.0 M in Et2O) dropwise over 20 min via an addition funnel. After stirring for 2 h, the mixture was quenched with aqueous NH4Cl and then partitioned between EtOAc and 1 M HCl. The organic layer was separated, washed with water, then brine, dried over MgSO4, filtered, and concentrated to give tert-butyl 2-(2-hydroxypropan-2-yl)azetidine-1-carboxylate (3.0 g, 69% yield), which was used without further purification.

[0164] Step 2: 2-(azetidin-2-yl)propan-2-ol 2,2,2-trifluoroacetate To a solution of tert-butyl 2-(2-hydroxypropan-2-yl)azetidine-1-carboxylate (3.0 g, 14 mmol, 1.0 eq.) in DCM (30 mL) was added trifluoroacetic acid (10 mL, 140 mmol, 10 eq.). After 3 h, the mixture was concentrated in vacuo to give 2-(azetidin-2-yl)propan-2-ol 2,2,2-trifluoroacetate (4.5 g, 94% yield), which was used without further purification. MS (ESI): m / z=116 [M+H] +

[0165] Intermediates B44~B46: The following intermediates were prepared in a similar manner to B43 using the starting materials indicated in step 1.

[0166] [Table 6]

[0167] [Example] Example 1. (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] Procedure A: SNAr with 2-chloropyrimidine-5-carboxylic acid followed by amide coupling Step 1: 2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylic acid To a solution of (3-isopropyl-5-(trifluoromethoxy)phenyl)methanamine hydrochloride (Intermediate A37, 2.8 g, 10 mmol, 1.0 eq.) in N-methyl-2-pyrrolidone (25 mL) were added 2-chloropyrimidine-5-carboxylic acid (1.7 g, 10 mmol, 1.0 eq.) and K2CO3 (7.2 g, 52 mmol, 5.0 eq.) and the mixture was heated to 120° C. for 24 h. After cooling to RT, concentrated HCl (8.4 mL) and water were added and the resulting suspension was stirred for 18 h. After filtration, the crude solid was suspended in EtOAc and 1M HCl. After filtration to remove insoluble material, the organic layer was separated, dried over MgSO4, filtered and concentrated. The resulting solid was suspended in MeOH and then filtered to give 2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylic acid (1.0 g, 28% yield).

[0168] Step 2: (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone To a solution of 2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylic acid (0.12 g, 0.34 mmol, 1.0 eq.) in DMF (2.0 mL) was added 6-oxa-1-azaspiro[3.3]heptane hemioxalate (Intermediate B1, 0.059 g, 0.41 mmol, 1.2 eq.), HATU (0.26 g, 0.68 mmol, 2.0 eq.), and DIPEA (0.30 mL, 1.7 mmol, 5.0 eq.). After 0.5 h, the mixture was directly subjected to reverse phase C chromatography for purification. 18 Loaded onto column to give (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone (0.098 g, 67% yield). MS (ESI): m / z=437 [M+H] +

[0169] Procedure B: SNAr with ethyl 2-chloropyrimidine-5-carboxylate followed by hydrolysis and amide coupling Step 1: Ethyl 2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylate To a solution of (3-isopropyl-5-(trifluoromethoxy)phenyl)methanamine hydrochloride (Intermediate A37, 4.0 g, 15 mmol, 1.0 eq.) in 2-methoxyethanol (32 mL) was added ethyl 2-chloropyrimidine-5-carboxylate (2.8 g, 15 mmol, 1.0 eq.) and DIPEA (7.8 mL, 45 mmol, 3.0 eq.). The mixture was heated to 120° C. for 20 h, then cooled to RT, diluted with water and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified on SiO2 to give ethyl 2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylate (5.0 g, 87% yield).

[0170] Step 2: 2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylic acid To a solution of ethyl 2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylate (5.0 g, 13 mmol, 1.0 eq.) in THF (40 mL) and EtOH (30 mL) was added 3M NaOH (15 mL, 46 mmol, 3.5 eq.). After 16 h, 3M HCl (15 mL, 46 mmol, 3.5 eq.) was added and the resulting suspension was partially concentrated to remove the organics. Filtration provided 2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylic acid (4.5 g, 98% yield).

[0171] Step 3: (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone Prepared according to procedure A, step 2 to give (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone. MS (ESI): m / z=437 [M+H] +

[0172] The examples in the table below were synthesized in a manner similar to Example 1 using the specified components and procedures:

[0173] [Table 7] TIFF2025060769000045.tif226169 TIFF2025060769000046.tif223169 TIFF2025060769000047.tif236169 TIFF2025060769000048.tif229169 TIFF2025060769000049.tif225169 TIFF2025060769000050.tif227169 TIFF2025060769000051.tif236169 TIFF2025060769000052.tif236169 TIFF2025060769000053.tif232169 TIFF2025060769000054.tif238169 TIFF2025060769000055.tif235169 TIFF2025060769000056.tif249169 TIFF2025060769000057.tif57169

[0174] Example 69 and Example 70. 2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone, S enantiomer and R enantiomer [ka] The racemic product of Example 6 was resolved into its two enantiomerically enriched (>99% ee) antipodes by chiral SFC (stationary phase: Lux Cellulose-2 10×250 mm, 5 μm; mobile phase: 50% methanol, CO2 at 100 Bar; flow rate: 10 mL / min). First eluting enantiomer, Example 69; RT: 3.56 min, MS (ESI): m / z=409 [M+H] + Second eluting enantiomer, Example 70; RT: 5.58 min, MS (ESI): m / z=409 [M+H] +

[0175] Example 71. 6-Oxa-1-azaspiro[3.3]heptan-1-yl(5-((3-(trifluoromethoxy)benzyl)amino)pyrazin-2-yl)methanone [ka] The title compound was prepared according to procedure B of Example 1 using ethyl 5-chloropyrazine-2-carboxylate and (3-(trifluoromethoxy)phenyl)methanamine (Intermediate A1) in step 1. MS (ESI): m / z=395 [M+H] +

[0176] Example 72. 6-Oxa-1-azaspiro[3.3]heptan-1-yl(6-((3-(trifluoromethoxy)benzyl)amino)pyridazin-3-yl)methanone [ka] The title compound was prepared according to procedure B of Example 1 using ethyl 6-chloropyridazine-3-carboxylate and (3-(trifluoromethoxy)phenyl)methanamine (Intermediate A1) in step 1. MS (ESI): m / z=395 [M+H] +

[0177] Example 73. 6-Oxa-1-azaspiro[3.3]heptan-1-yl(6-((3-(trifluoromethoxy)benzyl)amino)pyridin-3-yl)methanone [ka] The title compound was prepared according to procedure B of Example 1 using ethyl 6-chloronicotinate and (3-(trifluoromethoxy)phenyl)methanamine (Intermediate A1) in step 1. MS (ESI): m / z=394 [M+H] +

[0178] Example 74. Azetidin-1-yl(5-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrazin-2-yl)methanone [ka] The title compound was prepared according to procedure B of Example 1 using ethyl 5-chloropyrazine-2-carboxylate in step 1 and azetidine hydrochloride (Intermediate B4) in step 3. MS (ESI): m / z=395 [M+H] +

[0179] Example 75. (5-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrazin-2-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] The title compound was prepared according to procedure B of Example 1 using ethyl 5-chloropyrazine-2-carboxylate in step 1. MS (ESI): m / z=437 [M+H] +

[0180] Example 76. (6-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyridin-3-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] The title compound was prepared according to procedure B of Example 1 using ethyl 6-chloronicotinate in step 1. MS (ESI): m / z=436 [M+H] +

[0181] Example 77. (6-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyridin-3-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] The title compound was prepared according to procedure B of Example 1 using ethyl 6-chloronicotinate and (3-cyclopropyl-5-(trifluoromethoxy)phenyl)methanamine (Intermediate A39) in step 1. MS (ESI): m / z=434 [M+H] +

[0182] Example 78. (6-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] The title compound was prepared according to procedure B of Example 1 using ethyl 6-chloronicotinate and 5-chloro-2,3-dihydro-1H-inden-2-amine (Intermediate A18) in step 1. MS (ESI): m / z=370 [M+H] +

[0183] Example 79. (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(1-azaspiro[3.3]heptan-1-yl)methanone [ka] Step 1: Ethyl 2-((3-bromo-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylate To (3-bromo-5-(trifluoromethoxy)phenyl)methanamine (Intermediate A15, 3.0 g, 11 mmol, 1.0 eq.) in 2-methoxyethanol (24 mL) was added ethyl 2-chloropyrimidine-5-carboxylate (2.1 g, 11 mmol, 1.0 eq.) and DIPEA (5.8 mL, 33 mmol, 3.0 eq.). The resulting solution was heated to 120° C. for 22 h, then cooled to RT and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The resulting solid was triturated with hexane and filtered to give ethyl 2-((3-bromo-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylate (4.0 g, 86% yield).

[0184] Step 2: Ethyl 2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylate To ethyl 2-((3-bromo-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylate (2.0 g, 4.8 mmol, 1.0 eq.) in 1,4-dioxane (20 mL) was added cyclopropylboronic acid (1.6 g, 19 mmol, 4.0 eq.) and cesium fluoride (2.5 g, 16 mmol, 3.4 eq.). N2 was bubbled through the mixture for 10 min. PdCl2(dppf)·CH2Cl2 (0.35 g, 0.48 mmol, 10 mol%) was added and the reaction vessel was sealed and heated to 90 °C for 4 h. The mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified on SiO2 to give ethyl 2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylate (1.7 g, 94% yield).

[0185] Step 3: 2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylic acid To a solution of ethyl 2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylate (1.7 g, 4.5 mmol) in THF (12 mL) and EtOH (8 mL) was added 3M NaOH (5.2 mL, 16 mmol, 3.5 eq.). The mixture was stirred at RT for 20 h and then neutralized with 3M HCl (5.2 mL, 16 mmol, 3.5 eq.). The mixture was concentrated to remove organics, then filtered and dried to give 2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylic acid (1.4 g, 90% yield).

[0186] Step 4: (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(1-azaspiro[3.3]heptan-1-yl)methanone To a solution of 2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylic acid (0.050 g, 0.14 mmol, 1.0 eq.) in DMF (1 mL) was added 1-azaspiro[3.3]heptane (Intermediate B14, 0.017 g, 0.17 mmol, 1.2 eq.), HATU (0.059 g, 0.15 mmol, 1.1 eq.), and DIPEA (0.075 mL, 0.42 mmol, 3.0 eq.). After 0.5 h, the mixture was directly subjected to reverse phase C chromatography for purification. 18 Loaded onto column to give (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(1-azaspiro[3.3]heptan-1-yl)methanone (0.056 g, 91% yield). MS (ESI): m / z=433 [M+H] +

[0187] The examples in the table below were synthesized in a manner similar to Example 79, using specific building blocks in step 4:

[0188] [Table 8] TIFF2025060769000069.tif229169 TIFF2025060769000070.tif234169 TIFF2025060769000071.tif234169 TIFF2025060769000072.tif250169 TIFF2025060769000073.tif43169

[0189] Example 116 and Example 117. (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.4]octan-1-yl)methanone, R enantiomer and S enantiomer [ka] The racemic product of Example 97 was resolved into its two enantiomerically enriched (>99% ee) antipodes by chiral SFC (stationary phase: Lux Cellulose-2 4.6 x 250 mm, 5 μm; mobile phase: 5%-55% methanol + 0.1% formic acid, CO2 at 100 Bar; flow rate: 10 mL / min). First eluting enantiomer, Example 116; RT: 3.49 min, MS (ESI): m / z=449 [M+H] + Second eluting enantiomer, Example 117; RT: 4.05 min, MS (ESI): m / z=449 [M+H] +

[0190] Example 118, Example 119 and Example 120 (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2,4-dimethylazetidin-1-yl)methanone, (2S,4S) trans diastereomer and (2R,4R) trans diastereomer, and (2R,4S) cis diastereomer [ka] The mixture of diastereomeric products of Example 93 was resolved into its three diastereoenriched (>99% de) components by chiral SFC (stationary phase: Lux Cellulose-2 10×250 mm, 5 μm; mobile phase: 40% methanol, CO2 at 100 Bar; flow rate: 10 mL / min). The first eluted trans diastereomer, Example 118; RT: 4.20 min, MS (ESI): m / z=421 [M+H] + Second eluting trans diastereomer, Example 119; RT: 5.26 min, MS (ESI): m / z=421 [M+H] + Third eluting cis diastereomer, Example 120; RT: 8.18 min, MS (ESI): m / z=421 [M+H] +

[0191] Example 121 and Example 122. (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.5]nonan-1-yl)methanone, R enantiomer and S enantiomer [ka] The racemic product of Example 108 was resolved into its two enantiomerically enriched (>99% ee) antipodes by chiral SFC (stationary phase: ChiralPak AD 10×250 mm, 5 μm; mobile phase: 55% methanol, CO2 at 100 Bar; flow rate: 10 mL / min). First eluting enantiomer, Example 121; RT: 4.88 min, MS (ESI): m / z=463 [M+H] + Second eluting enantiomer, Example 122; RT: 9.27 min, MS (ESI): m / z=463 [M+H] +

[0192] Example 123. (2-((3-ethyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] The title compound was prepared in analogy to Example 79 using ethylboronic acid in step 2 and 6-oxa-1-azaspiro[3.3]heptane hemioxalate (Intermediate B1) in step 4. MS (ESI): m / z=423 [M+H] +

[0193] Example 124. (2-((5-methyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] The title compound was prepared in analogy to Example 79 using 5-bromo-2,3-dihydro-1H-inden-2-amine hydrobromide (Intermediate A21) in step 1, methylboronic acid in step 2, and 6-oxa-1-azaspiro[3.3]heptane hemioxalate (Intermediate B1) in step 4. MS (ESI): m / z=351 [M+H] +

[0194] Example 125. (2-((5-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] The title compound was prepared in analogy to Example 79 using 5-bromo-2,3-dihydro-1H-inden-2-amine hydrobromide (Intermediate A21) in step 1 and 6-oxa-1-azaspiro[3.3]heptane hemioxalate (Intermediate B1) in step 4. MS (ESI): m / z=377 [M+H] +

[0195] Example 126. (2-((5-ethyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] The title compound was prepared in analogy to Example 79 using 5-bromo-2,3-dihydro-1H-inden-2-amine hydrobromide (Intermediate A21) in step 1, ethylboronic acid in step 2, and 6-oxa-1-azaspiro[3.3]heptane hemioxalate (Intermediate B1) in step 4. MS (ESI): m / z=365 [M+H] +

[0196] Example 127. (2-((5,6-dibromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] Step 1: Ethyl 2-((5,6-dibromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate: The by-product isolated from step 1 of Example 62, obtained from 5,6-dibromo-2,3-dihydro-1H-inden-2-amine present as a contaminant in commercially obtained 5-bromo-2,3-dihydro-1H-inden-2-amine hydrobromide (Intermediate A21), was identified as ethyl 2-((5,6-dibromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate.

[0197] Step 2: 2-((5,6-dibromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid Ethyl 2-((5,6-dibromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate from the previous step was converted to the corresponding carboxylic acid using a method similar to Step 3 of Example 79.

[0198] Step 3: (2-((5,6-dibromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone The title compound was prepared in analogy to step 4 of Example 79 using 2-((5,6-dibromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid and 6-oxa-1-azaspiro[3.3]heptane hemioxalate (Intermediate B1). MS (ESI): m / z=495 [M+H] +

[0199] Example 128. (2-((5,6-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] The title compound was prepared in analogy to Example 79 (steps 2-4) using ethyl 2-((5,6-dibromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (prepared in step 1 of Example 127) in step 2, 2 eq. of methylboronic acid, and 6-oxa-1-azaspiro[3.3]heptane hemioxalate (Intermediate B1) in step 4. MS (ESI): m / z=365 [M+H] +

[0200] Example 129. (R)-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] Step 1: (R)-Ethyl 2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate The title compound was prepared similarly to Step 1 of Example 79 using (R)-5-bromo-2,3-dihydro-1H-inden-2-amine hydrochloride (Intermediate A26).

[0201] Step 2: (R)-Ethyl 2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate To a solution of (R)-ethyl 2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (0.51 g, 1.4 mmol) in DMF (10 mL) was added CuCl (0.28 mL, 2.8 mmol, 2 eq.) and the mixture was stirred at 150° C. for 18 h. The mixture was partitioned between EtOAc and aq. 1N HCl. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give (R)-ethyl 2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (0.440 g, 98% yield).

[0202] Step 3: (R)-2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid The title compound was prepared in a similar manner to step 3 of example 79 using (R)-ethyl 2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate to give (R)-2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid.

[0203] Step 4: (R)-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone The title compound was prepared in a similar manner to step 4 of Example 79 using (R)-2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid and 6-oxa-1-azaspiro[3.3]heptane hemioxalate (Intermediate B1). MS (ESI): m / z=371 [M+H] +

[0204] Example 130. (S)-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] The title compound was prepared in a similar manner to Example 129, using (S)-5-bromo-2,3-dihydro-1H-inden-2-amine hydrochloride (Intermediate A25) in the process. MS (ESI): m / z=371 [M+H] +

[0205] Example 131. (2-(((R)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone [ka] The title compound was prepared in a similar manner to Example 129 using 2-(azetidin-2-yl)propan-2-ol 2,2,2-trifluoroacetate (Intermediate B43) in step 4. MS (ESI): m / z=387 [M+H] +

[0206] Example 132. (2-(((R)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.4]octan-1-yl)methanone [ka] The title compound was prepared in analogy to Example 129 using 6-oxa-1-azaspiro[3.4]octane hemioxalate (Intermediate B22) in step 4. MS (ESI): m / z=385 [M+H] +

[0207] Example 133. (2-(((R)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone [ka] The title compound was prepared in a similar manner to Example 129 using 2-methylazetidine hydrochloride (Intermediate B3) in step 4. MS (ESI): m / z=343 [M+H] +

[0208] Example 134. (R)-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-hydroxy-6-methyl-1-azaspiro[3.3]heptan-1-yl)methanone [ka] The title compound was prepared in analogy to Example 129 using 6-methyl-1-azaspiro[3.3]heptan-6-ol 2,2,2-trifluoroacetate (Intermediate B46) in step 4. MS (ESI): m / z=399 [M+H] +

[0209] Example 135. 2-(((R)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)((S)-2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone [ka] The title compound was prepared in a similar manner to Example 129 using (S)-2-(azetidin-2-yl)propan-2-ol 2,2,2-trifluoroacetate (Intermediate B44) in step 4. MS (ESI): m / z=387 [M+H] +

[0210] Example 136. (2-(((R)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)((R)-2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone [ka] The title compound was prepared in a similar manner to Example 129 using (R)-2-(azetidin-2-yl)propan-2-ol 2,2,2-trifluoroacetate (Intermediate B45) in step 4. MS (ESI): m / z=387 [M+H] +

[0211] Example 137. (2-((3-(methylsulfonyl)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] Step 1: Ethyl 2-((3-(methylsulfonyl)-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylate To a solution of ethyl 2-((3-bromo-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylate (0.21 g, 0.50 mmol, 1.0 eq., prepared in step 1 of Example 79) in DMSO (2 mL) was added trifluoromethanesulfonate copper(I) benzene complex (2:1) (0.013 g, 0.050 mmol, 10 mol%), sodium methanesulfinate (0.18 g, 1.5 mmol, 3.0 eq.), and N,N-dimethylethylenediamine (0.11 mL, 1.0 mmol, 2.0 eq.). The mixture was heated to 130° C. for 18 h, then cooled to RT and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified on SiO2 to give ethyl 2-((3-(methylsulfonyl)-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylate (0.060 g, 29% yield).

[0212] Step 2: 2-((3-(methylsulfonyl)-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylic acid The title compound was prepared in a similar manner to step 3 of example 79.

[0213] Step 3: (2-((3-(methylsulfonyl)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone The title compound was prepared in analogy to step 4 of Example 79 using 2-((3-(methylsulfonyl)-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylic acid and 6-oxa-1-azaspiro[3.3]heptane hemioxalate (Intermediate B1). MS (ESI): m / z=473 [M+H] +

[0214] Example 138. (2-((5-(methylsulfonyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] The title compound was prepared in a manner similar to Example 137, using ethyl 2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (prepared in Step 1 of Example 43) in Step 1. MS (ESI): m / z=415 [M+H] +

[0215] Example 139. 3-(((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)methyl)-5-(trifluoromethoxy)benzonitrile [ka] Step 1: Ethyl 2-((3-cyano-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylate To a solution of ethyl 2-((3-bromo-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylate (0.26 g, 0.61 mmol, 1.0 eq., prepared in step 1 of Example 79) in DMF (3 mL) was added Zn(CN) (0.11 g, 0.92 mmol, 1.5) and the mixture was purged with N for 10 min. After addition of Pd(PPh) (0.035 g, 0.030 mmol, 0.050 eq.), the reaction vessel was sealed and heated to 100° C. for 15 h, then cooled to RT and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over MgSO, filtered and concentrated. The residue was purified on SiO2 to give ethyl 2-((3-cyano-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylate (0.12 g, 55% yield).

[0216] Step 2: 2-((3-cyano-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylic acid The title compound was prepared in a similar manner to step 3 of example 79.

[0217] Step 3: 3-(((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)methyl)-5-(trifluoromethoxy)benzonitrile The title compound was prepared in analogy to step 4 of Example 79 using 2-((3-cyano-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylic acid and 6-oxa-1-azaspiro[3.3]heptane hemioxalate (Intermediate B1). MS (ESI): m / z=420 [M+H] +

[0218] Example 140. 3-(((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)methyl)-5-(trifluoromethoxy)benzamide [ka] The by-product isolated from step 3 of Example 139 was identified as 3-(((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)methyl)-5-(trifluoromethoxy)benzamide. MS (ESI): m / z=438 [M+H] +

[0219] Example 141. (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(1,6-diazaspiro[3.3]heptan-1-yl)methanone [ka] To a solution of the product of Example 92 (0.040 g, 0.074 mmol) in DCM (2 mL) was added TFA (2 mL) and the resulting solution was stirred at RT. After 1 h, the mixture was partitioned between EtOAc and aq. NaHCO3. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated to give (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(1,6-diazaspiro[3.3]heptan-1-yl)methanone (0.032 g, 100% yield). MS (ESI): m / z=434 [M+H] +

[0220] Example 142. (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-methyl-1,6-diazaspiro[3.3]heptan-1-yl)methanone [ka] To a solution of the product of Example 141 (0.25 g, 0.46 mmol) in MeOH (5 mL) and AcOH (0.13 mL, 2.3 mmol, 5 eq.) was added formaldehyde (0.20 mL, 37% w / w in water, 2.3 mmol, 5 eq.), followed by Na(OAc)3BH (0.20 g, 0.93 mmol, 2 eq.). The resulting solution was stirred at RT for 1 h and then treated with additional formaldehyde (0.20 mL, 37% w / w in water, 2.3 mmol, 5 eq.) and Na(OAc)3BH (0.20 g, 0.93 mmol, 2 eq.). After stirring at RT for 30 min, the mixture was partitioned between EtOAc and aq. NaHCO3. The organic layer was washed with water, brine, dried over MgSO4, filtered, concentrated and purified using reverse phase C. 18 Purification on column gave (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-methyl-1,6-diazaspiro[3.3]heptan-1-yl)methanone (0.12 g, 58% yield). MS (ESI): m / z=448 [M+H] +

[0221] Example 143. (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-ethyl-1,6-diazaspiro[3.3]heptan-1-yl)methanone [ka] The title compound was prepared similarly to Example 142 using acetaldehyde. MS (ESI): m / z=462 [M+H] +

[0222] Example 144. (6-Cyclobutyl-1,6-diazaspiro[3.3]heptan-1-yl)(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone [ka] The title compound was prepared similarly to Example 142 using cyclobutanone. MS (ESI): m / z=488 [M+H] +

[0223] Example 145. (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(oxetan-3-yl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone [ka] The title compound was prepared similarly to Example 142 using 3-oxetanone. MS (ESI): m / z=490 [M+H] +

[0224] Example 146. (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-cyclopropyl-1,6-diazaspiro[3.3]heptan-1-yl)methanone [ka] To a solution of the product of Example 141 (0.10 g, 0.24 mmol) in MeOH (5 mL) and AcOH (0.068 mL, 1.2 mmol, 5 eq.) was added (1-ethoxycyclopropoxy)trimethylsilane (0.076 mL, 0.38 mmol, 1.6 eq.) and 4 Å molecular sieves. The mixture was heated to 80° C. for 3 h, then cooled to RT and treated with NaBH3CN (0.040 g, 0.60 mmol, 2 eq.). The mixture was stirred at 40° C. for 18 h, filtered through a pad of Celite and purified using reverse phase C. 18 Purification on column gave (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-cyclopropyl-1,6-diazaspiro[3.3]heptan-1-yl)methanone (0.003 g, 3% yield). MS (ESI): m / z=474 [M+H] +

[0225] Example 147. (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-isopropyl-1,6-diazaspiro[3.3]heptan-1-yl)methanone [ka] To a solution of the product of Example 141 (0.080 g, 0.19 mmol, 1.0 eq.) in DMF (2 mL) was added K2CO3 (0.11 g, 0.76 mmol, 4.0 eq.) and 2-bromopropane (0.087 mL, 0.92 mmol, 5.0 eq.). The mixture was stirred at 60 °C for 3.5 h, then cooled to RT and partitioned between EtOAc and aq. NaHCO3. The organic layer was washed with water, brine, dried over MgSO4, filtered, concentrated and purified using reverse phase C. 18Purification on column gave (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-isopropyl-1,6-diazaspiro[3.3]heptan-1-yl)methanone) (0.01 g, 11% yield). MS (ESI): m / z=476 [M+H] +

[0226] Example 148. (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(2,2,2-trifluoroethyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone [ka] To a solution of the product of Example 141 (0.10 g, 0.24 mmol) in THF (5 mL) at 0° C. was added DIPEA (0.13 mL, 0.72 mmol, 3 eq.) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.077 mL, 0.53 mmol, 2.2 eq.). The resulting solution was stirred at RT for 2 h, then treated with additional 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.077 mL, 0.53 mmol, 2.2 eq.) and stirred at RT for 18 h. The mixture was concentrated and the residue was purified on SiO2 to give (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(2,2,2-trifluoroethyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone (0.060 g, 48% yield). MS (ESI): m / z=516 [M+H] +

[0227] Example 149. (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(2,2-difluoroethyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone [ka] The title compound was prepared similarly to Example 148 using 2,2-difluoroethyl trifluoromethanesulfonate. MS (ESI): m / z=498 [M+H] +

[0228] Example 150. (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(2-(methylsulfonyl)ethyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone [ka] To a solution of the product of Example 141 (0.07 g, 0.16 mmol, 1.0 eq.) in THF (2 mL) was added methyl vinyl sulfone (0.052 g, 0.48 mmol, 3.0 eq.) and DIPEA (0.085 mL, 0.49 mmol, 3.0 eq.). The resulting solution was stirred at RT for 18 h, then concentrated and purified using reverse phase C 18 Purification on column gave (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(2-(methylsulfonyl)ethyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone) (0.041 g, 48% yield). MS (ESI): m / z=540 [M+H] +

[0229] Example 151. (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(methylsulfonyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone [ka] Step 1: (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(1,6-diazaspiro[3.3]heptan-1-yl)methanone The title compound was prepared in a similar manner to Example 141 using tert-butyl 1-(2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate (prepared according to Procedure B using tert-butyl 1,6-diazaspiro[3.3]heptane-6-carboxylate hemioxalate (Intermediate B17) in step 3).

[0230] Step 2: (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(methylsulfonyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone To a solution of (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(1,6-diazaspiro[3.3]heptan-1-yl)methanone) (0.082 g, 0.19 mmol, 1.0 eq.)) in DCM (2 mL) was added TEA (0.13 mL, 0.95 mmol, 5.0 eq.) and methylsulfonyl chloride (0.026 g, 0.23 mmol, 1.2 eq.). The resulting solution was stirred at RT for 18 h, then concentrated and purified using reverse phase C 18 Purification on column gave (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-methylsulfonyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone (0.037 g, 38% yield). MS (ESI): m / z=514 [M+H] +

[0231] Example 152. (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-(methylsulfonyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone [ka] Step 1: (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(1,6-diazaspiro[3.3]heptan-1-yl)methanone The title compound was prepared in analogy to Example 141 using tert-butyl 1-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate (prepared according to Procedure B using 5-chloro-2,3-dihydro-1H-inden-2-amine (Intermediate A18) in Step 1 and tert-butyl 1,6-diazaspiro[3.3]heptane-6-carboxylate hemioxalate (Intermediate B17) in Step 3).

[0232] Step 2: (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-(methylsulfonyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone The title compound was prepared in analogy to step 2 of Example 151 using (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(1,6-diazaspiro[3.3]heptan-1-yl)methanone. MS (ESI): m / z=448 [M+H] +

[0233] Example 153. 1-(1-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonyl)-1,6-diazaspiro[3.3]heptan-6-yl)ethanone [ka] To a solution of the product of Example 141 (0.097 g, 0.22 mmol, 1.0 eq.) in DCM (3 mL) was added DIPEA (0.047 mL, 0.27 mmol, 1.2 eq.) and acetic anhydride (0.023 mL, 0.24 mmol, 1.1 eq.). The resulting solution was stirred at RT for 15 min, concentrated and purified using reverse phase C18 Purification on column gave 1-(1-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonyl)-1,6-diazaspiro[3.3]heptan-6-yl)ethanone (0.048 g, 46% yield). MS (ESI): m / z=476 [M+H] +

[0234] Example 154. 1-(1-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonyl)-1,6-diazaspiro[3.3]heptan-6-yl)ethanone [ka] The title compound was prepared in a similar manner to Example 153 using (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(1,6-diazaspiro[3.3]heptan-1-yl)methanone (prepared in Step 1 of Example 152). MS (ESI): m / z=412 [M+H] +

[0235] Example 155. (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-methyl-1,6-diazaspiro[3.4]octan-1-yl)methanone [ka] Step 1: tert-Butyl 1-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonyl)-1,6-diazaspiro[3.4]octane-6-carboxylate The title compound was prepared analogously to Example 79 using tert-butyl 1,6-diazaspiro[3.4]octane-6-carboxylate (Intermediate B40) in step 4.

[0236] Step 2: (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(1,6-diazaspiro[3.4]octan-1-yl)methanone The title compound was prepared similarly to example 141 using tert-butyl 1-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonyl)-1,6-diazaspiro[3.4]octane-6-carboxylate.

[0237] Step 3: (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-methyl-1,6-diazaspiro[3.4]octan-1-yl)methanone The title compound was prepared in a similar manner to Example 142 using (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(1,6-diazaspiro[3.4]octan-1-yl)methanone. MS (ESI): m / z=462 [M+H] +

[0238] Example 156. (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-methyl-1,6-diazaspiro[3.5]nonan-1-yl)methanone [ka] The title compound was prepared in analogy to Example 155 using tert-butyl 1,6-diazaspiro[3.5]nonane-6-carboxylate (Intermediate B41) in step 1. MS (ESI): m / z=476 [M+H] +

[0239] Example 157. (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-methyl-2,5-diazaspiro[3.4]octan-5-yl)methanone [ka] The title compound was prepared in analogy to Example 155 using tert-butyl 2,5-diazaspiro[3.4]octane-2-carboxylate (Intermediate B42) in step 1. MS (ESI): m / z=462 [M+H] +

[0240] Example 158. (2-((3-(azetidin-1-yl)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] Step 1: Ethyl 2-((3-bromo-5-(trifluoromethoxy)benzyl)(tert-butoxycarbonyl)amino)pyrimidine-5-carboxylate To a solution of ethyl 2-((3-bromo-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carboxylate (1.00 g, 2.38 mmol, 1.0 eq., prepared in step 1 of Example 79) in DCM (20 mL) was added 100 mg of 4-dimethylaminopyridine and BocO (2.6 g, 11.9 mmol, 5.0 eq.). The mixture was stirred at RT for 1 h and then diluted with water. The organic layer was washed with brine, dried over MgSO, filtered and concentrated to provide ethyl 2-((3-bromo-5-(trifluoromethoxy)benzyl)(tert-butoxycarbonyl)amino)pyrimidine-5-carboxylate (1.2 g, 98% yield), which was used without further purification.

[0241] Step 2: 2-((3-bromo-5-(trifluoromethoxy)benzyl)(tert-butoxycarbonyl)amino)pyrimidine-5-carboxylic acid The title compound was prepared analogously to step 3 / example 79 using ethyl 2-((3-bromo-5-(trifluoromethoxy)benzyl)(tert-butoxycarbonyl)amino)pyrimidine-5-carboxylate.

[0242] Step 3: tert-Butyl (5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)(3-bromo-5-(trifluoromethoxy)benzyl)carbamate The title compound was prepared in a similar manner to step 4 of example 79 using 2-((3-bromo-5-(trifluoromethoxy)benzyl)(tert-butoxycarbonyl)amino)pyrimidine-5-carboxylic acid and 6-oxa-1-azaspiro[3.3]heptane hemioxalate (intermediate B1).

[0243] Step 4: (2-((3-(azetidin-1-yl)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone To a solution of tert-butyl (5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl(3-bromo-5-(trifluoromethoxy)benzyl)carbamate (0.13 g, 0.22 mmol, 1.0 eq.) in toluene (3 mL) was added azetidine hydrochloride (42 mg, 0.44 mmol, 2.0 eq.) and sodium tert-butoxide (0.090 g, 0.88 mmol, 4.0 eq.). The mixture was purged subsurface with nitrogen for 10 min and then treated with Pd(OAc)2 (0.003 g, 0.01 mmol, 0.06 eq.) and Xantphos (0.01 g, 0.02 mmol, 0.08 eq.). The reaction vessel was sealed and the mixture was stirred at 100° C. for 18 h, then cooled to RT and diluted with water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase C chromatography. 18Purification on column gave (2-((3-(azetidin-1-yl)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-1-yl)methanone (0.020 g, 20% yield). MS (ESI): m / z=450 [M+H] +

[0244] Example 159. (2-((3-ethoxy-5-isopropoxybenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] Step 1: Ethyl 2-((3-bromo-5-isopropoxybenzyl)amino)pyrimidine-5-carboxylate The title compound was prepared analogously to Step 1 of Example 79 using 3-bromo-5-isopropoxyphenyl)methanamine (Intermediate A45).

[0245] Step 2: Ethyl 2-((3-bromo-5-isopropoxybenzyl)(tert-butoxycarbonyl)amino)pyrimidine-5-carboxylate The title compound was prepared similarly to Step 1 of Example 158 using ethyl 2-((3-bromo-5-isopropoxybenzyl)amino)pyrimidine-5-carboxylate.

[0246] Step 3: Ethyl 2-(tert-butoxycarbonyl)(3-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)amino)pyrimidine-5-carboxylate To a solution of ethyl 2-((3-bromo-5-isoproxy)benzyl)(tert-butoxycarbonyl)amino)pyrimidine-5-carboxylate (0.90 g, 1.8 mmol, 1.0 eq.) in MeCN (9 mL) was added bis(pinacolato)diboron (0.56 g, 2.2 mmol, 1.2 eq.) and KOAc (0.89 g, 9.1 mmol, 5.0 eq.). The mixture was purged subsurface with nitrogen for 10 min, PdCl2(dppf) (0.27 g, 0.36 mmol, 0.2 eq.) was added to the mixture, the reaction vessel was sealed and heated to 80 °C for 18 h. After cooling to RT, the mixture was partitioned between water and EtOAc. The organic phase was separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified on SiO2 to give ethyl 2-(tert-butoxycarbonyl)(3-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)amino)pyrimidine-5-carboxylate (0.89 g, 90% yield).

[0247] Step 4: Ethyl 2-((tert-butoxycarbonyl)(3-hydroxy-5-isopropoxybenzyl)amino)pyrimidine-5-carboxylate To a solution of ethyl 2-(tert-butoxycarbonyl)(3-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)amino)pyrimidine-5-carboxylate (0.89 g, 1.6 mmol, 4.2 eq.) in THF (4.5 mL) and water (4.5 mL) was added NaBO3 tetrahydrate (1.1 g, 6.9 mmol, 4.2 eq.). The mixture was stirred at RT for 30 min, filtered and partitioned between 10% Na2S2O3 and EtOAc. The organic phase was separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified on SiO2 to give ethyl 2-((tert-butoxycarbonyl)(3-hydroxy-5-isopropoxybenzyl)amino)pyrimidine-5-carboxylate (0.56 g, 80% yield).

[0248] Step 5: Ethyl 2-((tert-butoxycarbonyl)(3-ethoxy-5-isopropoxybenzyl)amino)pyrimidine-5-carboxylate The title compound was prepared analogously to Step 1 of Intermediate A29 using ethyl 2-((tert-butoxycarbonyl)(3-hydroxy-5-isopropoxybenzyl)amino)pyrimidine-5-carboxylate and iodoethane.

[0249] Step 6: Ethyl 2-((3-ethoxy-5-isopropoxybenzyl)amino)pyrimidine-5-carboxylate The title compound was prepared analogously to Step 2 of Intermediate B43 using ethyl 2-((tert-butoxycarbonyl)(3-ethoxy-5-isopropoxybenzyl)amino)pyrimidine-5-carboxylate.

[0250] Step 7: 2-((3-ethoxy-5-isopropoxybenzyl)amino)pyrimidine-5-carboxylic acid The title compound was prepared similarly to step 3 of example 79 using ethyl 2-((3-ethoxy-5-isopropoxybenzyl)amino)pyrimidine-5-carboxylate.

[0251] Step 8: (2-((3-ethoxy-5-isopropoxybenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone The title compound was prepared in analogy to step 4 of Example 79 using 2-((3-ethoxy-5-isopropoxybenzyl)amino)pyrimidine-5-carboxylic acid and 6-oxa-1-azaspiro[3.3]heptane hemioxalate (Intermediate B1). MS (ESI): m / z=413 [M+H] +

[0252] Example 160. (2-((3-ethoxy-5-isopropoxybenzyl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone [ka] The title compound was prepared in a similar manner to Example 159 using 2-(azetidin-2-yl)propan-2-ol 2,2,2-trifluoroacetate (Intermediate B43) in step 8. MS (ESI): m / z=429 [M+H] +

[0253] Example 161. (2-((5-isopropoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] The title compound was prepared in analogy to Example 159 using 5-bromo-2,3-dihydro-1H-inden-2-amine hydrobromide (Intermediate A21) in step 1 and 2-iodopropane in step 5. MS (ESI): m / z=395 [M+H] +

[0254] Example 162. (2-((5-ethoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone [ka] The title compound was prepared in analogy to Example 159 using 5-bromo-2,3-dihydro-1H-inden-2-amine hydrobromide (Intermediate A21) in step 1. MS (ESI): m / z=381 [M+H] +

[0255] Example A The compounds of formula (I) can be used, in a manner known per se, as active ingredient for the preparation of tablets of the following composition: Per tablet Active ingredient: 200mg Microcrystalline cellulose 155mg Corn starch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0256] Example B The compounds of formula (I) can be used, in a manner known per se, as active ingredient for the preparation of capsules of the following composition: Per capsule Active ingredient 100.0mg Corn starch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

[0257] In another embodiment, any one of the above-described embodiments can be used alone or in combination with any one or more of the above-described embodiments.

[0258] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be used in practicing the present disclosure. It is intended that the following claims define the scope of the disclosure, and that methods and structures within the scope of these claims and their equivalents are covered thereby.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, W is 【Chemistry 2】 is selected from X, Y and Z are each independently selected from N and CH; n is 0, 1 or 2; R １ａ and R １ｂ , R ４ａ and R ４ｂ are each independently (a) hydrogen, (b) OR ａ C optionally substituted with １－６ Alkyl, and (c) C １－６ Haloalkyl Selected from: R ２ａ , R ２ｂ , R ３ａ , and R ３ｂ are each independently (a) hydrogen, (b) OR ａ Or NR ｂ R ｃ C optionally substituted with １－６ Alkyl, (c) C １－６ Haloalkyl, (d) halogen, (e)OR ａ 、 (f) NR ｂ R ｃ , and (g) S(O) ｍ C １－６ Alkyl or R １ａ +R １ｂ , or R ２ａ +R ２ｂ , or R ３ａ +R ３ｂ represents, together with the carbon atom to which each pair is connected, (a) C １－４ a 4- to 6-membered carbocyclic ring optionally substituted with 1 to 3 groups independently selected from alkyl and OH; or (b) O, S(O) ｍ and N-R ｂ A 4- to 6-membered heterocycle having one heteroatom selected from or R １ａ +R ２ａ , or R ２ａ +R ３ａ and the carbon atoms to which each pair is linked, taken together, (a) O, S(O) ｍ and N-R ｂ or a 5- to 6-membered heterocycle having one heteroatom selected from (b) 5- to 6-membered heteroaryl Forming R ５ａ and R ５ｂ are each independently (a) hydrogen, and (b) C １－６ Alkyl is selected from R ６ teeth, (a) C １－６ Alkyl, (b) C １－６ Haloalkyl, (c) (CH ２ ) ｐ C ３－６ Cycloalkyl, (d)OR ａ 、 (e)NR ｂ R ｃ 、 (f) Halogen (g)SF ５ 、 (h) C.N., (i) S(O) ｍ C １－６ Alkyl, and (j)C(O)NR ｂ R ｃ is selected from R ７ , R ８ and R ９ are each independently (a) hydrogen, (b) C １－６ Alkyl, (c) C １－６ Haloalkyl, (d) (CH ２ ) ｐ C ３－６ Cycloalkyl, (e)OR ａ 、 (f)NR ｂ R ｃ 、 (g) Halogen (h)SF ５ 、 (i) C.N., (j) S(O) ｍ C １－６ Alkyl, and (k)C(O)NR ｂ R ｃ Selected from: m is 0, 1 or 2; p is 0, 1 or 2; R ａ teeth, (a) hydrogen, (b) C １－６ Alkyl, (c) C １－６ Haloalkyl, and (d) (CH ２ ) ｐ C ３－６ Cycloalkyl is selected from R ｂ and R ｃ teeth, (a) hydrogen, (b) -C(O)C １－６ Alkyl, (c) -SO ２ C １－６ Alkyl, (d) S(O) ｍ C １－６ C optionally substituted with alkyl １－６ Alkyl, (e) C １－６ Haloalkyl, (f) C ３－６ Cycloalkyl, (g) a 4- to 6-membered heterocycle, and (h) C(O)OC １－６ Alkyl or R ｂ , R ｃ and the atoms to which they are linked, taken together, are O, S(O) ｍ and NH. or a pharma- ceutically acceptable salt, solvate or salt of the solvate.

2. 2. The compound of claim 1, wherein X is N and Y and Z are each CH.

3. The compound according to any one of claims 1 to 2, wherein n is 0 or 1.

4. R ４ａ and R ４ｂ The compound of any one of claims 1 to 3, wherein each is hydrogen.

5. R １ａ and R １ｂ However, each independently, (a) hydrogen, (b) OR ａ C optionally substituted with １－６ Alkyl, and (c) C １－６ Haloalkyl or R １ａ +R １ｂ together with the carbon atom to which the pair is connected, (a) C １－４ a 4- to 6-membered carbocyclic ring optionally substituted with 1 to 3 groups independently selected from alkyl and OH; or (b) O, S(O) ｍ and N-R ｂ A 4- to 6-membered heterocycle having one heteroatom selected from and R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R ４ａ and R ４ｂ are each hydrogen, The compound according to any one of claims 1 to 3.

6. R １ａ and R １ｂ is hydrogen, and the other is (a) hydrogen, (b) C optionally substituted with OH １－４ alkyl, and (c) C １－４ 6. The compound of claim 5, wherein the alkyl group is selected from fluoroalkyl.

7. R １ａ +R １ｂ together with the carbon atom to which the pair is connected, (a) C １－４ a 4- to 6-membered carbocyclic ring optionally substituted with 1 to 3 groups independently selected from alkyl and OH; or (b) O, S(O) ｍ and N-R ｂ A 4- to 6-membered heterocycle having one heteroatom selected from Forming The compound according to claim 5.

8. R ２ａ and R ２ｂ One of the groups is hydrogen and the other is (a) hydrogen, (b) OR ａ Or NR ｂ R ｃ C optionally substituted with １－６ Alkyl, (c) C １－６ Haloalkyl, (d) halogen, (e)OR ａ 、 (f) NR ｂ R ｃ , and (g) S(O) ｍ C １－６ Alkyl or R ２ａ +R ２ｂ together with the carbon atom to which the pair is connected, (a) C １－４ a 4- to 6-membered carbocyclic ring optionally substituted with 1 to 3 groups independently selected from alkyl and OH; or (b) O, S(O) ｍ and N-R ｂ A 4- to 6-membered heterocycle having one heteroatom selected from and R １ａ , R １ｂ , R ３ａ , R ３ｂ , R ４ａ and R ４ｂ are each hydrogen, The compound according to any one of claims 1 to 3.

9. R ２ａ +R ２ｂ together with the carbon atom to which the pair is connected, O, S(O) ｍ and N-R ｂ The compound according to claim 8, which forms a 4- to 6-membered heterocycle having one heteroatom selected from:

10. W, 【Chemistry 3】 The compound according to any one of claims 1 to 9, selected from:

11. Formula (Ia) 【Chemistry 4】 [In the formula, W is 【Chemistry 5】 is selected from n is 0 or 1; R ６ teeth, (a) C １－４ Alkyl, (b) C １－４ Fluoroalkyl, (c) (CH ２ ) ｐ C ３－４ Cycloalkyl, (d) O.C. １－４ Alkyl, (e) O.C. １－４ Fluoroalkyl, (f)NR ｂ R ｃ 、 (g) halogen, (h)SF ５ 、 (i) CN, and (j) S(O) ２ C １－４ Alkyl Selected from: R ７ teeth, (a) C １－４ Alkyl, (b) C １－４ Fluoroalkyl, (c) (CH ２ ) ｐ C ３－４ Cycloalkyl, (d) O.C. １－４ Alkyl, (e) O.C. １－４ Fluoroalkyl, (f) O(CH ２ ) ｐ C ３－４ Cycloalkyl, (g)NR ｂ R ｃ 、 (h) halogen, and (i) Hydrogen Selected from: R ８ teeth, (a) C １－４ Alkyl, (b) C ３－４ Cycloalkyl, (c) O.C. １－４ Alkyl, (d) halogen, (e) CN, and (f) Hydrogen Selected from 2. The compound of claim 1 having the formula:

12. W, 【Chemistry 6】 and R ６ but, (a) C １－４ Alkyl, (b) C １－２ Fluoroalkyl, (c) C ３－４ Cycloalkyl, (d) O.C. １－４ Alkyl, and (e) O.C. １－２ Fluoroalkyl is selected from R ７ but, (a) C １－４ Alkyl, (b) C １－２ Fluoroalkyl, (c) C ３－４ Cycloalkyl, (d) CH ２ C ３－４ Cycloalkyl, (e) O.C. １－４ Alkyl, (f) O.C. １－２ Fluoroalkyl, (g) OCH ２ C ３－４ Cycloalkyl, and (h) azetidinyl Selected from: The compound of claim 10.

13. W is 【Chemistry 7】 12. The compound of claim 11, wherein

14. R １ａ and R １ｂ However, each independently, (a) hydrogen, (b) OR ａ C optionally substituted with １－６ Alkyl, and (c) C １－６ Haloalkyl or R １ａ +R １ｂ together with the carbon atom to which the pair is connected, (a) C １－４ a 4- to 6-membered carbocyclic ring optionally substituted with 1 to 3 groups independently selected from alkyl and OH; or (b) O, S(O) ｍ and N-R ｂ A 4- to 6-membered heterocycle having one heteroatom selected from Forming The compound according to any one of claims 11 to 13.

15. R １ａ and R １ｂ is hydrogen, and the other is (a) hydrogen, (b) C optionally substituted with OH １－４ alkyl, and (c) C １－４ The compound according to any one of claims 11 to 13, selected from fluoroalkyl.

16. R １ａ +R １ｂ together with the carbon atom to which the pair is connected, O, S(O) ｍ and N-R ｂ forming a 4-6 membered heterocyclic ring having one heteroatom selected from R ｂ but, (a) hydrogen, (b) -C(O)C １－４ Alkyl, (c) -SO ２ C １－４ Alkyl, (d) S(O) ｍ C １－６ C optionally substituted with alkyl １－４ Alkyl, (e) C １－６ Haloalkyl, (f) C ３－４ Cycloalkyl, (g) oxetanyl, and (h) C(O)OC １－４ Alkyl Selected from: The compound according to any one of claims 11 to 13.

17. The compound according to any one of claims 11 to 16, wherein n is 0.

18. below: (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; 6-Oxa-1-azaspiro[3.3]heptan-1-yl(2-((3-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone; 2-Oxa-6-azaspiro[3.3]heptan-6-yl(2-((3-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone; (2-((3-(tert-butyl)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-(tert-butyl)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; Azetidin-1-yl(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone; (2-((3,5-bis(trifluoromethyl)benzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (2-((3,5-dichlorobenzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (2-((3,5-dimethoxybenzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (2-((3-methyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; 6-Oxa-1-azaspiro[3.3]heptan-1-yl(2-((1-(3-(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-5-yl)methanone; 3-(((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)methyl)benzonitrile; (2-((3-chlorobenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-(methylsulfonyl)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-(difluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-(difluoromethyl)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-isopropyl-5-(pentafluorothio)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; 6-Oxa-1-azaspiro[3.3]heptan-1-yl(2-((3-(trifluoromethyl)benzyl)amino)pyrimidin-5-yl)methanone; (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(pyrrolidin-1-yl)methanone; (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(piperidin-1-yl)methanone; (2-((3-cyclobutyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; 6-Oxa-1-azaspiro[3.3]heptan-1-yl(2-((3-(pentafluorothio)benzyl)amino)pyrimidin-5-yl)methanone; (2-((3-bromo-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-fluoro-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-(cyclopropylmethoxy)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-isopropoxy-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-(cyclopropylmethyl)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-methoxy-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-ethoxy-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; 2-((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-5-carbonitrile; 6-Oxa-1-azaspiro[3.3]heptan-1-yl(2-((3-(2,2,2-trifluoroethoxy)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethyl)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3,5-dicyclopropylbenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-isopropoxybenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-isopropoxy-5-propylbenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(7-methyl-1,7-diazaspiro[3.5]nonan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2,2-dimethylazetidin-1-yl)methanone; (2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-(difluoromethyl)azetidin-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-oxa-5-azaspiro[3.4]octan-5-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(7-oxa-1-azaspiro[3.5]nonan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.5]nonan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6,6-dioxido-6-thia-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3,5-dichlorobenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3,4-dichlorobenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3,5-diisopropoxybenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3,5-diethoxybenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((2,5-dichlorobenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((2,3-dichlorobenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; Azetidin-1-yl(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-(methoxymethyl)azetidin-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)((S)-2-(methoxymethyl)azetidin-1-yl)methanone; (2-((3,5-diisopropoxybenzyl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-isopropoxybenzyl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (S)-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (R)-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-(azetidin-1-yl)-5-isopropoxybenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-(2-hydroxypropan-2-yl)azetidin-1-yl)(2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone; (2-((3,5-dicyclopropylbenzyl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((3-ethoxy-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-ethoxybenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-(azetidin-1-yl)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (R)-(2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (S)-(2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; 6-Oxa-1-azaspiro[3.3]heptan-1-yl(5-((3-(trifluoromethoxy)benzyl)amino)pyrazin-2-yl)methanone; 6-Oxa-1-azaspiro[3.3]heptan-1-yl(6-((3-(trifluoromethoxy)benzyl)amino)pyridazin-3-yl)methanone; 6-Oxa-1-azaspiro[3.3]heptan-1-yl(6-((3-(trifluoromethoxy)benzyl)amino)pyridin-3-yl)methanone; Azetidin-1-yl(5-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrazin-2-yl)methanone; (5-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrazin-2-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (6-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyridin-3-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (6-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyridin-3-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (6-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; Azetidin-1-yl(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3-hydroxyazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3-fluoroazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3,3-difluoroazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3-hydroxy-3-methylazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3-(methylsulfonyl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2,2-dimethylazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)methanone; tert-Butyl 1-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2,4-dimethylazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(methoxymethyl)pyrrolidin-1-yl)methanone; (S)-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(methoxymethyl)pyrrolidin-1-yl)methanone; (R)-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(methoxymethyl)pyrrolidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-oxa-5-azaspiro[3.4]octan-5-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.4]octan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3-(methoxymethyl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3-((dimethylamino)methyl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(7-oxa-1-azaspiro[3.5]nonan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(methoxymethyl)azetidin-1-yl)methanone; (R)-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(methoxymethyl)azetidin-1-yl)methanone; (S)-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(methoxymethyl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(1-oxa-6-azaspiro[3.3]heptan-6-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2,2-dioxido-2-thia-6-azaspiro[3.3]heptan-6-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6,6-dioxido-6-thia-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.5]nonan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3-methoxyazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(3-(dimethylamino)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(hexahydro-1H-furo[3,4-b]pyrrol-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(7-methyl-1,7-diazaspiro[3.5]nonan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(difluoromethyl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(trifluoromethyl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.4]octan-1-yl)methanone; (R)-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.4]octan-1-yl)methanone; (S)-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.4]octan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2,4-dimethylazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)((2R,4R)-2,4-dimethylazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)((2S,4S)-2,4-dimethylazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)((2R,4S)-2,4-dimethylazetidin-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.5]nonan-1-yl)methanone; (R)-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.5]nonan-1-yl)methanone; (S)-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.5]nonan-1-yl)methanone; (2-((3-ethyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-methyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-ethyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5,6-dibromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5,6-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (R)-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (S)-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-(((R)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.4]octan-1-yl)methanone; (2-(((R)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.4]octan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (2-(((R)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-methylazetidin-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-hydroxy-6-methyl-1-azaspiro[3.3]heptan-1-yl)methanone; (R)-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-hydroxy-6-methyl-1-azaspiro[3.3]heptan-1-yl)methanone; 2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)((S)-2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; 2-(((R)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)((S)-2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)((R)-2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-(((R)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)((R)-2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((3-(methylsulfonyl)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((5-(methylsulfonyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; 3-(((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)methyl)-5-(trifluoromethoxy)benzonitrile; 3-(((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl)pyrimidin-2-yl)amino)methyl)-5-(trifluoromethoxy)benzamide; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(1,6-diazaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-methyl-1,6-diazaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-ethyl-1,6-diazaspiro[3.3]heptan-1-yl)methanone; (6-cyclobutyl-1,6-diazaspiro[3.3]heptan-1-yl)(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(oxetan-3-yl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-cyclopropyl-1,6-diazaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-isopropyl-1,6-diazaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(2,2,2-trifluoroethyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(2,2-difluoroethyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(2-(methylsulfonyl)ethyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone; (2-((3-isopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(methylsulfonyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone; (2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-(methylsulfonyl)-1,6-diazaspiro[3.3]heptan-1-yl)methanone; 1-(1-(2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonyl)-1,6-diazaspiro[3.3]heptan-6-yl)ethanone; 1-(1-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonyl)-1,6-diazaspiro[3.3]heptan-6-yl)ethanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-methyl-1,6-diazaspiro[3.4]octan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-methyl-1,6-diazaspiro[3.5]nonan-1-yl)methanone; (2-((3-cyclopropyl-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(2-methyl-2,5-diazaspiro[3.4]octan-5-yl)methanone; (2-((3-(azetidin-1-yl)-5-(trifluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-ethoxy-5-isopropoxybenzyl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; (2-((3-ethoxy-5-isopropoxybenzyl)amino)pyrimidin-5-yl)(2-(2-hydroxypropan-2-yl)azetidin-1-yl)methanone; (2-((5-isopropoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone; and (2-((5-ethoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl)methanone, 2. The compound of claim 1 selected from: or a pharma- ceutically acceptable salt, solvate or solvate of the salt of any of the foregoing.

19. 27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

20. 20. A method for the treatment or prevention of a disease, disorder or condition selected from the group consisting of renal disease, liver disease, chronic inflammatory disorders or diseases, respiratory diseases, vascular and cardiovascular diseases, fibrotic diseases, cancer, eye diseases, metabolic diseases, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any of claims 1 to 18 or a pharma- ceutically acceptable salt, solvate or salt of the solvate thereof, or a pharmaceutical composition according to claim 19.

21. A method for the treatment or prevention of a chronic inflammatory disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 18 or a pharma- ceutically acceptable salt, solvate or salt of the solvate thereof, or a pharmaceutical composition according to claim 19.

22. 22. The method of claim 21, wherein the chronic inflammatory disorder is rheumatoid arthritis (RA), multiple sclerosis (MS), idiopathic pulmonary fibrosis (IPF), hepatitis or atherosclerosis.

23. 23. The method of claim 21 or 22, wherein the chronic inflammatory disorder is multiple sclerosis.

24. 20. A method of inhibiting ATX, comprising contacting a cell with a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt, solvate, or salt of the solvate thereof.

25. 25. The method of claim 24, wherein the cell is a mammalian cell.

26. A method for reducing LPA production in a cell, comprising contacting the cell with a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt, solvate, or salt of the solvate thereof.

27. 27. The method of claim 26, wherein the cell is a mammalian cell.

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