BR112016004909B1 - SPIROCYCLIC COMPOUNDS AS TRYPTOPHAN HYDROXYLASE INHIBITORS, PHARMACEUTICAL COMPOSITION AND THEIR USES - Google Patents

Abstract

SPIROCYCLIC COMPOUNDS AS TRYPTOPHAN HYDROXYLASE INHIBITORS. The present invention is directed to spirocyclic compounds which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPH1), which are useful in the treatment of diseases or disorders associated with peripheral serotonin including, for example, gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, and low bone mass, as well as serotonin syndrome, and cancer.

Description

FIELD OF INVENTION

[001] The present invention is directed to spirocyclic compounds that are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPH1), which are useful in the treatment of diseases or disorders associated with peripheral serotonin including, for example, gastrointestinal diseases , cardiovascular, pulmonary, inflammatory, metabolic, and low bone mass, as well as serotonin syndrome, and cancer.

BACKGROUND OF THE INVENTION

[002] Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that modulates central and peripheral functions by acting on neurons, smooth muscle, and other cell types. 5-HT is involved in the control and modulation of multiple physiological and psychological processes. In the central nervous system (CNS), 5-HT regulates mood, appetite, and other behavioral functions. In the GI system, 5-HT plays a general prokinetic role and is an important mediator of sensation (e.g., nausea and satiety) between the GI tract and the brain. Dysregulation of the peripheral 5-HT signaling system has been reported to be involved in the etiology of several conditions (see, for example: Mawe, G. M. & Hoffman, J. M. Serotonin Signaling In The Gut-functions, Dysfunctions And Therapeutic Targets. Nature Reviews. Gastroenterology & Hepatology 10, 473-486 (2013); Gershon, M. D. 5-hydroxytryptamine (serotonin) In The Gastrointestinal Tract. Current Opinion in Endocrinology, Diabetes, and Obesity 20, 14-21 (2013); Lesurtel, M., Soll, C., Graf, R. & Clavien, P.- A. Role of Serotonin In The Hepato-gastrointestinal Tract: An Old Molecule For New Perspectives. Cellular And Molecular Life Sciences: CMLS 65, 940-52 (2008)). These include osteoporosis (e.g., Kode, A. et al. FOXO1 Orchestrates The Bone-suppressing Function Of Gut-derived Serotonin. The Journal of Clinical Investigation 122, 3490-503 (2012); Yadav, V. K. et al. Pharmacological Inhibition Of Gut-derived Serotonin Synthesis Is A Potential Bone Anabolic Treatment For Osteoporosis. Nature Medicine 16, 308-12 (2010); Yadav, V. K. et al. Lrp5 Controls Bone Formation By Inhibiting Serotonin Synthesis In The Duodenum. Cell 135, 825-37 ( 2008)), cancer (e.g., Liang, C. et al. Serotonin Promotes The Proliferation Of Serum-deprived Hepatocellular Carcinoma Cells Via Upregulation Of FOXO3a. Molecular Cancer 12, 14 (2013); Soll, C. et al. Serotonin Promotes Tumor Growth In Human Hepatocellular Cancer. Hepatology 51, 1244-1254 (2010); Pai, V. P et al. Altered Serotonin Physiology In Human Breast Cancers Favors Paradoxical Growth And Cell Survival. Breast Cancer Research: BCR 11, R81 (2009) ; Engelman, K., Lovenberg, W. & Sjoerdsma, A. Inhibition Of Serotonin Synthesis By Para-chlorophenylalanine In Patients With The Carcinoid Syndrome. The New England Journal of Medicine 277, 11038 (1967)), cardiovascular (e.g., Robiolio, P. A. et al. Carcinoid Heart Disease: Correlation of High Serotonin Levels With Valvular Abnormalities Detected by Cardiac Catheterization and Echocardiography. Circulation 92, 790-795 (1995).), diabetes (e.g., Sumara, G., Sumara, O., Kim, J. K. & Karsenty, G. Gut-derived Serotonin Is A Multifunctional Determinant To Fasting Adaptation. Cell Metabolism 16, 588600 (2012)) , atherosclerosis (e.g., Ban, Y. et al. Impact Of Increased Plasma Serotonin Levels And Carotid Atherosclerosis On Vascular Dementia. Aterosclerosis 195, 153-9 (2007)), as well as gastrointestinal (e.g., Manocha, M. & Khan, W. I. Serotonin and GI Disorders: An Update on Clinical and Experimental Studies. Clinical and Translational Gastroenterology 3, e13 (2012); Ghia, J.-E. et al. Serotonin Has A Key Role In Pathogenesis Of Experimental Colitis. Gastroenterology 137, 1649-60 (2009); Sikander, A., Rana, S. V. & Prasad, K. K. Role Of Serotonin In Gastrointestinal Motility And Irritable Bowel Syndrome. Clinica Chimica Acta; International Journal of Clinical Chemistry 403, 47-55 (2009); Spiller, R. Recent Advances In Understanding The Role Of Serotonin In Gastrointestinal Motility In Functional Bowel Disorders: Alterations In 5-HT Signaling And Metabolism In Human Disease. Neurogastroenterology and Motility: The Official Journal of The European Gastrointestinal Motility Society 19 Suppl 2, 25-31 (2007); Costedio, M. M., Hyman, N. & Mawe, G. M. Serotonin And Its Role In Colonic Function And In Gastrointestinal Disorders. Diseases of the Colon and Rectum 50, 376-88 (2007); Gershon, M. D. & Tack, J. The Serotonin Signaling System: From Basic Understanding To Drug Development For Functional GI Disorders. Gastroenterology 132, 397-414 (2007); Mawe, G. M., Coates, M. D. & Moses, P. L. Review Article: Intestinal Serotonin Signaling In Irritable Bowel Syndrome. Alimentary Pharmacology & Therapeutics 23, 1067-76 (2006); Crowell, M. D. Role Of Serotonin In The Pathophysiology Of The Irritable Bowel Syndrome. British Journal of Pharmacology 141, 1285-93 (2004)), pulmonary (e.g., Lau, W. K. W. et al. The Role Of Circulating Serotonin In The Development Of Chronic Obstructive Pulmonary Disease. PloS One 7, e31617 (2012); Egermayer, P., Town, G. I. & Peacock, A. J. Role Of Serotonin In The Pathogenesis Of Acute And Chronic Pulmonary Hypertension. Thorax 54, 161-168 (1999)), inflammatory (e.g., Margolis, K. G. et al. Pharmacological Reduction of Mucosal but Not Neuronal Serotonin Opposes Inflammation In Mouse Intestine. Gut doi:10.1136/gutjnl-2013-304901 (2013); Duerschmied, D. et al. Platelet Serotonin Promotes The Recruitment Of Neutrophils To Sites Of Acute Inflammation In Mice. Blood 121, 1008- 15 (2013); Li, N. et al. Serotonin Activates Dendritic Cell Function In The Context Of Gut Inflammation. The American Journal of Pathology 178, 662-71 (2011)), or liver diseases or disorders (e.g., Ebrahimkhani, M. R. et al. Stimulating Healthy Tissue Regeneration By Targeting The 5-HT2B Receptor In Chronic Liver Disease. Nature Medicine 17, 1668-73 (2011)). The large number of pharmaceutical agents that block or stimulate the various 5-HT receptors is likewise indicative of the wide range of medical disorders that have been associated with 5-HT dysregulation (see, for example: Wacker, D. et al. Structural Features For Functional Selectivity At Serotonin Receptors. Science (New York, N.Y.) 340, 615-9 (2013)).

[003] The rate-limiting step in the biosynthesis of 5-HT is the hydroxylation of tryptophan by dioxygen, which is catalyzed by tryptophan hydroxylase (TPH; EC 1.14.16.4) in the presence of the cofactor (6R)-L-erythro - 5,6,7,8-tetrahydrobiopterin (BH4). The resulting oxidized product, 5-hydroxytryptophan (5-HTT) is subsequently decarboxylated by an aromatic amino acid decarboxylase (AAAD; EC 4.1.1.28) to produce 5-HT. Together with phenylalanine hydroxylase (PheOH) and tyrosine hydroxylase (TH), TPH belongs to the pterin-dependent aromatic amino acid hydroxylase family.

[004] Two vertebrate isoforms of TPH, that is, TPH1 and TPH2, have been identified. TPH1 is mainly expressed in the pineal gland and non-neuronal tissues, such as enterochromaffin cells (EC) located in the gastrointestinal (GI) tract. TPH2 (the dominant form in the brain) is expressed exclusively in neuronal cells, such as dorsal raphe or myenteric plexus cells. The peripheral and central systems involved in 5-HT biosynthesis are isolated, with 5-HT being unable to cross the blood-brain barrier. Therefore, the pharmacological effects of 5-HT can be modulated by agents affecting TPH in the periphery, mainly TPH1 in the intestine.

[005] A small number of phenylalanine-derived TPH1 inhibitors are known. One example, p-chlorophenylalanine (pCPA), a very weak and non-selective irreversible inhibitor of TPH, has been shown to be effective in treating chemotherapy-induced emesis, as well as diarrhea, in patients with carcinoid tumor. However, pCPA is distributed centrally and, as a result, its administration has been linked to the onset of depression and other alterations of CNS function in patients and animals. p-Ethynylphenylalanine is a more selective and more potent TPH inhibitor than pCPA (Stokes, A. H. et al. p-Ethynylphenylalanine: A Potent Inhibitor Of Tryptophan Hydroxylase. Journal of Neurochemistry 74, 2067-73 (2000), however it likewise affects central 5-HT production and, like pCPA, is believed to irreversibly interfere with the synthesis of TPH (and possibly other proteins).

[006] More recently, bulkier phenylalanine-derived TPH inhibitors have been reported to reduce intestinal 5-HT concentration without affecting brain 5-HT levels (Zhong, H. et al. Molecular dynamics simulation of tryptophan hydroxylase- 1: binding modes and free energy analysis to phenylalanine derivative inhibitors. International Journal of Molecular Sciences 14, 9947-62 (2013); Ouyang, L. et al. Combined Structure-Based Pharmacophore and 3D-QSAR Studies on Phenylalanine Series Compounds as TPH1 Inhibitors. International Journal of Molecular Sciences 13, 5348-63 (2012); Camilleri, M. LX-1031, A Tryptophan 5-hydroxylase Inhibitor, And Its Potential In Chronic Diarrhea Associated With Increased Serotonin. Neurogastroenterology and Motility: The Official Journal of The European Gastrointestinal Motility Society 23, 193-200 (2011); Cianchetta, G. et al. Mechanism of Inhibition of Novel Tryptophan Hydroxylase Inhibitors Revealed by Co-crystal Structures and Kinetic Analysis. Current chemical genomics 4, 19-26 (2010); Jin, H. et al. Substituted 3-(4-(1,3,5-triazin-2-yl)-phenyl)-2-aminopropanoic Acids As Novel Tryptophan Hydroxylase Inhibitors. Bioorganic & Medicinal Chemistry Letters 19, 5229-32 (2009); Shi, Z.-C. et al. Modulation Of Peripheral Serotonin Levels By Novel Tryptophan Hydroxylase Inhibitors For The Potential Treatment Of Functional Gastrointestinal Disorders. Journal of medicinal chemistry 51, 3684-7 (2008); Liu, Q. et al. Discovery And Characterization of Novel Tryptophan Hydroxylase Inhibitors That Selectively Inhibit Serotonin Synthesis In The Gastrointestinal Tract. The Journal of Pharmacology and Experimental Therapeutics 325, 47-55 (2008)).

[007] There is a current need to selectively reduce intestinal 5-HT levels as a means of treating and preventing 5-HT associated diseases. The TPH1 inhibitors described here are intended to address this need.

SUMMARY OF THE INVENTION

[008] The present invention relates to a TPH-inhibiting compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein the constituent variables are defined herein.

[009] The present invention also relates to a pharmaceutical composition comprising a TPH-inhibiting compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0010] The present invention also relates to a method of inhibiting TPH, such as TPH1, by contacting the TPH enzyme with a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0011] The present invention also relates to a method of decreasing peripheral serotonin in a patient comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0012] The present invention also relates to a method of treating or preventing a disease in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0013] The present invention also relates to a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating or preventing disease in a patient.

[0014] The present invention also relates to the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of disease in a patient.

DETAILED DESCRIPTION compounds

[0015] The present invention relates to a TPH-inhibiting compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein:

[0016] Ring A is C3-10 cycloalkyl, C6-10 aryl, 4- to 10-membered heterocycloalkyl, or 5 to 10-membered heteroaryl; L is O or NR4; W is N or CR5; X is N or CR6; Y is N or CR7; where only one of X and Y is N;

[0017] R1 is H, C1-10 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, - (CR8R9)pOC(O)R10, -(CR8R9)p NR11R12, or -(CR8R9)pC(O)NR11R12, wherein said C1-10 alkyl, C3-10 cycloalkyl, 410-membered heterocycloalkyl, 5-10-membered heteroaryl, and phenyl are each optionally substituted with 1, 2, 3 , 4, or 5 substituents independently selected from F, Cl, Br, CN, C1-4 alkyl, and C1-4 haloalkyl; R2 and R3 are each independently selected from H, C1-4 alkyl, and C1-4 haloalkyl; R4 is H or C1-4 alkyl; R5 and R6 are each independently selected from H, halo, and C1-4 alkyl;

[0018] R7 is H, C1-4 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, heterocycloalkyl 4-10 membered, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-C1-4 alkyl, NR13R14, OR15, C(O )R16, S(O)qR17, wherein said C1-4 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1- 4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-C1-4 alkyl are each optionally substituted by 1, 2, or 3 substituents selected from halo, C1-4 alkyl, C2-6 alkenyl, amino, C1-4 alkylamino, C2-8 dialkylamino, hydroxy, and C1-4 alkoxy; R8 and R9 are each independently selected from H and C1-4 alkyl; R10 is C1-6 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from C1-6 haloalkyl, C3-10 cycloalkyl, ORa, and NRcRd; R11 and R12 are each independently selected from H and C1-6 alkyl; R13 is H or C1-4 alkyl;

[0019] R14 is H, C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 510 membered heteroaryl, or (5-10 membered heteroaryl)-C1-4 alkyl, C(O)Rb1, C(O)ORa1, C(O) NRc1Rd1, S(O)Rb1, S(O)2Rb1, or S(O)2NRc1Rd1, wherein said C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C610 aryl, C6- 10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-C1- 4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O) NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O) 2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; or R13 and R14 together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, halo, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1 , OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1 , NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C37 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 heteroaryl members are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1 , OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S(O)2Rb1 , NRc1S(O)2NRc1Rd1, and S(O)2NRc1Rd1;

[0020] R15 is H, C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 510-membered heteroaryl, or (5-10 membered heteroaryl)-C1-4 alkyl, wherein said C1-4 alkyl, C3-7 cycloalkyl, C3- 7 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 5- heteroaryl 10 member, and (5-10 member heteroaryl)-C1-4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 member heterocycloalkyl, C6 -10 aryl, 5-6 membered heteroaryl, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C (O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, and S( O)2NRc1Rd1;

[0021] R16 is C1-4 alkyl or NR18aR18b wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, heterocycloalkyl of 4 -7 membered, C6-10 aryl, 5-6 membered heteroaryl, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O) NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S(O)2Rb1, NRc1S(O) 2NRc1Rd1, and S(O)2NRc1Rd1;

[0022] R17 is C1-4 alkyl, NR18aR18b, or OR18c, wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, heterocyl 4-7 membered chloalkyl, C6-10 aryl, 5-6 membered heteroaryl, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC (O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S(O)2Rb1, NRc1S (O)2NRc1Rd1, and S(O)2NRc1Rd1;

[0023] R18a and R18b are each independently selected from H and C1-4 alkyl wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl , 4-7 membered heterocycloalkyl, C610 aryl, 5-6 membered heteroaryl, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC( O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc4C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S(O)2Rb1, NRc1S( O)2NRc1Rd1, and S(O)2NRc1Rd1;

[0024] or R18a and R18b together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, halo, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C( O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S( O)2Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C37 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 4-7 membered heteroaryl 5-6 members are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC( O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S( O)2Rb1, NRc1S(O)2NRc1Rd1, and S(O)2NRc1Rd1;

[0025] R18c is H, C1-6 alkyl, C3-10 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 510 membered heteroaryl, or (5-10 membered heteroaryl)-C1-4 alkyl, wherein said C1-6 alkyl, C3-7 cycloalkyl, C3- 10 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 5- heteroaryl 10 member, and (5-10 member heteroaryl)-C1-4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, NO2 , ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C (O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1;

[0026] RA is H, Cy1, halo, C1-6 alkyl, C2-6 alkenyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O )Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O )Rb2, S(O)NRc2Rd2, S(O)2Rb2, or S(O)2NRc2Rd2, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4 , or 5 substituents independently selected from Cy1, halo, C16 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O) ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O) 2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2;

[0027] RB is H, Cy2, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O) ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O) 2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, or S(O)2NRc3Rd3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy2, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3 , C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc1S(O)2Rb3 , NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3;

[0028] RC and RD are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O )NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O )2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 heteroaryl members, 4-10 membered heterocycloalkyl, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C( O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S( O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4;

[0029] Cy1 and Cy2 are each independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy;

[0030] each RCy is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 member heteroaryl, 4-10 heterocycloalkyl members, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C( O)ORa5, NRc5C(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O )2NRc5Rd5, wherein said C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, 510-membered heteroaryl, and 4-10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC (O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S (O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5;

[0031] each Ra, Ra1, Ra2, Ra3, Ra4, and Ra5 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, or (4-10 membered heterocycloalkyl)-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, heterocycloalkyl 4-10 membered, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, and (410 membered heterocycloalkyl)-C1- 4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, halo, CN, ORa6, C(O)Rb6, C(O)NRc6Rd6, C(O )ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(O )2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6;

[0032] each Rb1, Rb2, Rb3, Rb4, and Rb5 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, heteroaryl of 5 -10 membered, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, or (4-membered heterocycloalkyl) -10 members)-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 member heteroaryl, 4-10 member heterocycloalkyl, C6- 10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, and (4-10 membered heterocycloalkyl)-C1-4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, halo, CN, ORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O )Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, NRc6S(O )2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6;

[0033] each Rc, Rd, Rc1, Rd1, Rc2, Rd2, Rc3, Rd3, Rc4, Rd4, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl , C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5- 10 member)-C1-4 alkyl, or (4-10 member heterocycloalkyl)-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, heteroaryl 5-10 membered, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, and (5-10 membered heterocycloalkyl) 4-10 members)-C1-4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, halo, CN, ORa6, SRa6, C(O)Rb6 , C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6 , S(O)NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6;

[0034] or any Rc and Rd together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1- 6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O )ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(O )2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6, wherein said C1-6 alkyl, C37 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-membered heteroaryl -6 members are optionally replaced by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O )Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, NRc6S(O )2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6;

[0035] or any Rc1 and Rd1 together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1- 6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O )ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(O )2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6, wherein said C1-6 alkyl, C37 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-membered heteroaryl -6 members are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O )Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, NRc6S(O )2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6;

[0036] or any Rc2 and Rd2 together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa6, SRa6, C(O)Rb6, C (O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S (O)NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl , C6-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O )NRc6Rd6, C(O)ORa6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, NRc6S(O )2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6;

[0037] or any Rc3 and Rd3 together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1- 6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa6, SRa6, C(O)Rb6, C(O) NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O) NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6- 10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C( O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S( O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6;

[0038] or any Rc4 and Rd4 together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1- 6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa6, SRa6, C(O)Rb6, C(O) NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O) NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6- 10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C( O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S( O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6;

[0039] or any Rc5 and Rd5 together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1- 6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa6, SRa6, C(O)Rb6, C(O) NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O) NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6- 10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C( O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S( O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6;

[0040] each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-membered heterocycloalkyl -7 members, wherein said C1-4 alkyl, C2-4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 member heteroaryl, and 4-7 member heterocycloalkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, and di(C1-4 alkyl)amino; n is 1 or 2; p is 1, 2, or 3; and q is 1 or 2;

[0041] wherein any aforementioned 4-10 or 4-7 membered heterocycloalkyl group optionally comprises 1, 2, or 3 oxo substituents, wherein each oxo substituent that is present is substituted on a carbon atom, nitrogen, or ring-forming sulfur of the 4-10 or 4-7 membered heterocycloalkyl group.

[0042] In some embodiments, the present invention relates to a TPH-inhibiting compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: Ring A is C3-10 cycloalkyl, C6-10 aryl, 4 to 10 membered heterocycloalkyl, or 5 to 10 membered heteroaryl; L is O or NR4; W is N or CR5; X is N or CR6; Y is N or CR7; where only one of X and Y is N;

[0043] R1 is H, C1-10 alkyl, C3-10 cycloalkyl, phenyl, - (CR8R9)pOC(O)R10, -(CR8R9)p NR11R12, or -(CR8R9)pC(O)NR11R12, where the Said C1-10 alkyl, C3-10 cycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from F, Cl, Br, CN, C1-4 alkyl, and C1 -4 halo- alkyl; R2 and R3 are each independently selected from H, C1-4 alkyl, and C1-4 haloalkyl; R4 is H or C1-4 alkyl; R5 and R6 are each independently selected from H, halo, and C1-4 alkyl;

[0044] R7 is H, C1-4 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, heterocycloalkyl 4-10 membered, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-C1-4 alkyl, NR13R14, OR15, C(O)R16 , S(O)qR17, wherein said C1-4 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl , 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-C1-4 alkyl are each optionally substituted by 1, 2, or 3 substituents selected from halo, C1-4 alkyl, C2-6 alkenyl, amino, C1-4 alkylamino, C2-8 dialkylamino, hydroxy, and C1-4 alkoxy; R8 and R9 are each independently selected from H and C1-4 alkyl; R10 is C1-6 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from C1-6 haloalkyl, C3-10 cycloalkyl, ORa, and NRcRd; R11 and R12 are each independently selected from H and C1-6 alkyl; R13 is H or C1-4 alkyl;

[0045] R14 is H, C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 510 membered heteroaryl, or (5-10 membered heteroaryl)-C1-4 alkyl, C(O)Rb1, C(O)ORa1, C(O) NRc1Rd1, S(O)Rb1, S(O)2Rb1, or S(O)2NRc1Rd1, wherein said C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C610 aryl, C6- 10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-C1- 4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O) NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O) 2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1;

[0046] or R13 and R14 together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, halo, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C( O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S( O)2Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C37 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 4-7 membered heteroaryl 5-6 members are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC( O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S( O)2Rb1, NRc1S(O)2NRc1Rd1, and S(O)2NRc1Rd1;

[0047] R15 is H, C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 4-10 member heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 510-membered heteroaryl, or (5-10 membered heteroaryl)-C1-4 alkyl, wherein said C1-4 alkyl, C3-7 cycloalkyl, C3- 7 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 5- heteroaryl 10 member, and (5-10 member heteroaryl)-C1-4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 member heterocycloalkyl, C6 -10 aryl, 5-6 membered heteroaryl, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C (O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, and S( O)2NRc1Rd1;

[0048] R16 is C1-4 alkyl or NR18aR18b wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, heterocycloalkyl of 4 -7 membered, C6-10 aryl, 5-6 membered heteroaryl, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O) NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S(O)2Rb1, NRc1S(O) 2NRc1Rd1, and S(O)2NRc1Rd1;

[0049] R17 is C1-4 alkyl, NR18aR18b, or OR18c, wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, heterocyl 4-7 membered chloalkyl, C6-10 aryl, 5-6 membered heteroaryl, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC (O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S(O)2Rb1, NRc1S (O)2NRc1Rd1, and S(O)2NRc1Rd1;

[0050] R18a and R18b are each independently selected from H and C1-4 alkyl wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl , 4-7 membered heterocycloalkyl, C610 aryl, 5-6 membered heteroaryl, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC( O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc4C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S(O)2Rb1, NRc1S( O)2NRc1Rd1, and S(O)2NRc1Rd1;

[0051] or R18a and R18b together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1 -6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, halo, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C( O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S( O)2Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C37 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 4-7 membered heteroaryl 5-6 members are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC( O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S( O)2Rb1, NRc1S(O)2NRc1Rd1, and S(O)2NRc1Rd1;

[0052] R18c is H, C1-6 alkyl, C3-10 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 510 membered heteroaryl, or (5-10 membered heteroaryl)-C1-4 alkyl, wherein said C1-6 alkyl, C3-7 cycloalkyl, C3- 10 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 5- heteroaryl 10 member, and (5-10 member heteroaryl)-C1-4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, NO2 , ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C (O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1;

[0053] RA is H, Cy1, halo, C1-6 alkyl, C2-6 alkenyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O )Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O )Rb2, S(O)NRc2Rd2, S(O)2Rb2, or S(O)2NRc2Rd2, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4 , or 5 substituents independently selected from Cy1, halo, C16 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O) ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O) 2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2;

[0054] RB is H, Cy2, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O) ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O) 2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, or S(O)2NRc3Rd3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy2, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3 , C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc1S(O)2Rb3 , NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3;

[0055] RC and RD are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O )NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O )2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 heteroaryl members, 4-10 membered heterocycloalkyl, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C( O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S( O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4;

[0056] Cy1 and Cy2 are each independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy;

[0057] each RCy is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 member heteroaryl, 4-10 heterocycloalkyl members, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C( O)ORa5, NRc5C(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O )2NRc5Rd5, wherein said C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, 510-membered heteroaryl, and 4-10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC (O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S (O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5;

[0058] each Ra, Ra1, Ra2, Ra3, Ra4, and Ra5 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, or ( 410-membered heterocycloalkyl)-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, and (4-10 membered heterocycloalkyl)-C1-4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, halo, CN, ORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6;

[0059] each Rb1, Rb2, Rb3, Rb4, and Rb5 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, heteroaryl of 5 -10 membered, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, or (4-membered heterocycloalkyl) -10 members)-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 member heteroaryl, 4-10 member heterocycloalkyl, C6- 10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, and (4-10 membered heterocycloalkyl)-C1-4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, halo, CN, ORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O )Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, NRc6S(O )2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6;

[0060] each Rc, Rd, Rc1, Rd1, Rc2, Rd2, Rc3, Rd3, Rc4, Rd4, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl , C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5- 10 member)-C1-4 alkyl, or (4-10 member heterocycloalkyl)-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, heteroaryl 5-10 membered, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, and (5-10 membered heterocycloalkyl) 4-10 members)-C1-4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, halo, CN, ORa6, SRa6, C(O)Rb6 , C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6 , S(O)NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6;

[0061] or any Rc and Rd together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1- 6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O )ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(O )2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6, wherein said C1-6 alkyl, C37 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-membered heteroaryl -6 members are optionally replaced by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O )Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, NRc6S(O )2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6;

[0062] or any Rc1 and Rd1 together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C (O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S (O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6, wherein said C1-6 alkyl, C37 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and heteroaryl of 5-6 members are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC (O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, NRc6S (O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6;

[0063] or any Rc2 and Rd2 together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1- 6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa6, SRa6, C(O)Rb6, C(O )NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O )NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6 -10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C (O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S (O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6;

[0064] or any Rc3 and Rd3 together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa6, SRa6, C(O)Rb6, C( O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S( O)NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O) NRc6Rd6, C(O)ORa6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, NRc6S(O) 2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6;

[0065] or any Rc4 and Rd4 together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1- 6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa6, SRa6, C(O)Rb6, C(O) NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O) NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6- 10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C( O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S( O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6;

[0066] or any Rc5 and Rd5 together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1- 6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa6, SRa6, C(O)Rb6, C(O) NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O) NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6- 10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C( O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S( O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6;

[0067] each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-membered heterocycloalkyl -7 members, wherein said C1-4 alkyl, C2-4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 member heteroaryl, and 4-7 member heterocycloalkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, and di(C1-4 alkyl)amino; n is 1 or 2; p is 1, 2, or 3; and q is 1 or 2; wherein any aforementioned 4-10 or 4-7 membered heterocycloalkyl group optionally comprises 1, 2, or 3 oxo substituents, wherein each oxo substituent that is present is substituted on a carbon, nitrogen, or sulfur atom of ring formation of 4-10 or 4-7 membered heterocycloalkyl group.

[0068] In some embodiments, L is O.

[0069] In some embodiments, L is NR4.

[0070] In some embodiments, W is CR5; X is N; and Y is CR7.

[0071] In some embodiments, W is N; X is N; and Y is CR7.

[0072] In some embodiments, W is CR5; X is CR6; and Y is N.

[0073] In some embodiments, W is CR5; X is CR6; and Y is CR7.

[0074] In some embodiments, W is N; X is CR6; and Y is CR7.

[0075] In some embodiments, R2 is H and R3 is H.

[0076] In some embodiments, R2 is H and R3 is C1-4 alkyl.

[0077] In some embodiments, R2 is H and R3 is methyl.

[0078] In some embodiments, R2 is H and R3 is C1-4 haloalkyl.

[0079] In some embodiments, R2 is H and R3 is trifluoromethyl.

[0080] In some embodiments, n is 1.

[0081] In some embodiments, n is 2.

[0082] In some embodiments, R1 is H.

[0083] In some embodiments, R1 is C1-10 alkyl, C3-10 cycloalkyl, phenyl, -(CR8R9)pOC(O)R10, -(CR8R9)p NR11R12, or - (CR8R9)pC(O)NR11R12 , wherein said C1-10 alkyl, C3-10 cycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from F, Cl, Br, CN, C1 -4 alkyl, and C1-4 haloalkyl.

[0084] In some embodiments, R1 is C1-10 alkyl.

[0085] In some embodiments, R1 is ethyl.

[0086] In some embodiments, R4 is H.

[0087] In some embodiments, R5 is H.

[0088] In some embodiments, R6 is H.

[0089] In some embodiments, R7 is different from H.

[0090] In some embodiments, R7 is C1-4 alkyl, NR13R14, or OR15.

[0091] In some embodiments, R7 is NR13R14.

[0092] In some embodiments, R7 is NH2.

[0093] In some embodiments, R7 is C1-4 alkyl.

[0094] In some embodiments, R7 is OR15.

[0095] In some embodiments, Ring A is C3-10 cycloalkyl.

[0096] In some embodiments, Ring A is C6-10 aryl.

[0097] In some embodiments, Ring A is phenyl.

[0098] In some embodiments, Ring A is a 4- to 10-membered heterocycloalkyl.

[0099] In some embodiments, Ring A is phenyl, adamantanyl, naphthyl, 1,2,3,4-tetrahydroquinoxalinyl, 3,4-dihydroquinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, or pyridyl.

[00100] In some embodiments, Ring A is a 5- to 10-membered heteroaryl.

[00101] In some embodiments, at least one of RA, RB, RC, and RD is other than hydrogen.

[00102] In some embodiments, at least two of RA, RB, RC, and RD are different from hydrogen.

[00103] In some embodiments, RA is Cy1.

[00104] In some embodiments, RA is C6-10 aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.

[00105] In some embodiments, RA is a 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.

[00106] In some embodiments, RA is a 5- to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00107] In some embodiments, RA is pyrazolyl that is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.

[00108] In some embodiments, RA is 3-methyl-1H-pyrazol-1-yl.

[00109] In some embodiments, RA is C6-10 aryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00110] In some embodiments, RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00111] In some embodiments, RB is H.

[00112] In some embodiments, RB is Cy2, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, c3 c3 d3 b3 c3 d3 b3 c3 d3 NR S(O)2NR R , S(O)R , S(O)NR R , S(O)2R , and S(O)2NR R , wherein said C1- 6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy2, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc1S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3.

[00113] In some embodiments, RB is Cy2.

[00114] In some embodiments, RB is C6-10 aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.

[00115] In some embodiments, RB is halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O) ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O) 2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy2, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O )NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc1S(O )2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3.

[00116] In some embodiments, RB is halo.

[00117] In some embodiments, RC is H.

[00118] In some embodiments, RC is halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C( O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, c4 c4 d4 b4 c4 d4 b4 c4 d4 NR S(O)2NR R , S(O)R , S(O)NR R , S(O)2R , and S(O)2NR R ; wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4.

[00119] In some embodiments, RD is H.

[00120] In some embodiments, RD is halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C( O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S( O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 heteroaryl members, 4-10 membered heterocycloalkyl, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O) ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O) 2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4.

[00121] In some embodiments, the compounds of the invention have Formula IIa:

[00122] In some embodiments, the compounds of the invention have Formula IIb:

[00123] In some embodiments, the compounds of the invention have Formula IIc:

[00124] In some embodiments, the compounds of the invention have Formula IId:

[00125] In some embodiments, the compounds of the invention have Formula IIe:

[00126] In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, L is O.

[00127] In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, L is NR4.

[00128] In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R3 is H.

[00129] In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R2 is CF3 and R3 is H.

[00130] In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R1 is H or C1-10 alkyl.

[00131] In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, RA is Cy1.

[00132] In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, RA is C6-10 aryl or 510-membered heteroaryl, each of which is optionally substituted by 1, 2, 3 , 4, or 5 substituents independently selected from RCy.

[00133] In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, RA is a 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 independent substituents. carefully selected from RCy.

[00134] In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, RA is a 5- to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy .

[00135] In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, RA is C6-10 aryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00136] In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00137] In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, RB is Cy2.

[00138] In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, RB is H, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN , ORa3, C(O)NRc3Rd3, or C(O)ORa3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1 -6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc1S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S (O)2NRc3Rd3.

[00139] In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, RC is H.

[00140] In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, RD is H.

[00141] In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R5 is H.

[00142] In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R6 is H.

[00143] In some embodiments, the compounds of the invention have Formula IIIa or IIIb:

[00144] In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, R2 is CF3.

[00145] In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, R1 is H or C1-10 alkyl.

[00146] In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, RA is Cy1.

[00147] In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, RA is C6-10 aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.

[00148] In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, RA is a 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.

[00149] In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, RA is a 5- to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00150] In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, RA is C6-10 aryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00151] In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00152] In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, RB is Cy2.

[00153] In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, RB is H, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, ORa3, C(O)NRc3Rd3, or C(O)ORa3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-6 haloalkyl, CN, NO2, ORa3 , SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O )NRc3Rd3, NRc3S(O)Rb3, NRc1S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3.

[00154] In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, RC is H.

[00155] In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, RD is H.

[00156] In some embodiments, the compounds of the invention have Formula IV:

[00157] In some embodiments, where the compounds of the invention have Formula IV, R2 is CF3.

[00158] In some embodiments, where the compounds of the invention have Formula IV, R1 is H or C1-10 alkyl.

[00159] In some embodiments, where the compounds of the invention have Formula IV, RA is Cy1.

[00160] In some embodiments, where the compounds of the invention have Formula IV, RA is C6-10 aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.

[00161] In some embodiments, where the compounds of the invention have Formula IV, RA is a 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.

[00162] In some embodiments, where the compounds of the invention have Formula IV, RA is a 5- to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00163] In some embodiments, where the compounds of the invention have Formula IV, RA is C6-10 aryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00164] In some embodiments, where the compounds of the invention have Formula IV, RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00165] In some embodiments, where the compounds of the invention have Formula IV, RB is Cy2.

[00166] In some embodiments, where the compounds of the invention have Formula IV, RB is H, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, ORa3, C(O)NRc3Rd3, or C(O)ORa3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-6 haloalkyl, CN, NO2, ORa3 , SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O )NRc3Rd3, NRc3S(O)Rb3, NRc1S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3.

[00167] In some embodiments, where the compounds of the invention have Formula IV, RC is H.

[00168] In some embodiments, where the compounds of the invention have Formula IV, RD is H.

[00169] In some embodiments, the compounds of the invention have Formula Va:

[00170] In some embodiments, where the compounds of the invention have Formula Va, R2 is CF3.

[00171] In some embodiments, where the compounds of the invention have Formula Va, R1 is H or C1-10 alkyl.

[00172] In some embodiments, where the compounds of the invention have Formula Va, RA is Cy1.

[00173] In some embodiments, where the compounds of the invention have Formula Va, RA is C6-10 aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.

[00174] In some embodiments, where the compounds of the invention have Formula Va, RA is a 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.

[00175] In some embodiments, where the compounds of the invention have Formula Va, RA is a 5- to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00176] In some embodiments, where the compounds of the invention have Formula Va, RA is C6-10 aryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00177] In some embodiments, where the compounds of the invention have Formula Va, RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00178] In some embodiments, where the compounds of the invention have Formula Va, RB is Cy2.

[00179] In some embodiments, where the compounds of the invention have Formula Va, RB is H, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, ORa3, C(O)NRc3Rd3, or C(O)ORa3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-6 haloalkyl, CN, NO2, ORa3 , SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O )NRc3Rd3, NRc3S(O)Rb3, NRc1S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3.

[00180] In some embodiments, the compounds of the invention have Formula Vb:

[00181] In some embodiments, where the compounds of the invention have Formula Vb, R2 is CF3.

[00182] In some embodiments, where the compounds of the invention have Formula Vb, R1 is H or C1-10 alkyl.

[00183] In some embodiments, where the compounds of the invention have Formula Vb, RA is Cy1.

[00184] In some embodiments, where the compounds of the invention have Formula Vb, RA is C6-10 aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.

[00185] In some embodiments, where the compounds of the invention have Formula Vb, RA is a 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.

[00186] In some embodiments, where the compounds of the invention have Formula Vb, RA is a 5- to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00187] In some embodiments, where the compounds of the invention have Formula Vb, RA is C6-10 aryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00188] In some embodiments, where the compounds of the invention have Formula Vb, RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00189] In some embodiments, where the compounds of the invention have Formula Vb, RB is Cy2.

[00190] In some embodiments, where the compounds of the invention have Formula Vb, RB is H, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, ORa3, C(O)NRc3Rd3, or C(O)ORa3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-6 haloalkyl, CN, NO2, ORa3 , SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O )NRc3Rd3, NRc3S(O)Rb3, NRc1S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3.

[00191] In some embodiments, the compounds of the invention have the

[00192] In some embodiments, where the compounds of the invention have Formula VI, R2 is CF3.

[00193] In some embodiments, where the compounds of the invention have Formula VI, R1 is H or C1-10 alkyl.

[00194] In some embodiments, where the compounds of the invention have Formula VI, RB is Cy2.

[00195] In some embodiments, where the compounds of the invention have Formula VI, Cy2 is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00196] In some embodiments, where the compounds of the invention have Formula VI, RB is H, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, ORa3, C(O)NRc3Rd3, or C(O)ORa3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-6 haloalkyl, CN, NO2, ORa3 , SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O )NRc3Rd3, NRc3S(O)Rb3, NRc1S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3.

[00197] In some embodiments, where the compounds of the invention have Formula VI, RC is H.

[00198] In some embodiments, where the compounds of the invention have Formula VI, RD is H.

[00199] In some embodiments, the compounds of the invention have Formula VIA:

[00200] In some embodiments, where the compounds of the invention have Formula VIA, R2 is CF3.

[00201] In some embodiments, where the compounds of the invention have Formula VIA, R1 is H or C1-10 alkyl.

[00202] In some embodiments, where the compounds of the invention have Formula VIA, RB is Cy2.

[00203] In some embodiments, where the compounds of the invention have Formula VIA, Cy2 is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.

[00204] In some embodiments, where the compounds of the invention have Formula VIA, RB is H, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, ORa3, C(O)NRc3Rd3, or C(O)ORa3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-6 haloalkyl, CN, NO2, ORa3 , SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O )NRc3Rd3, NRc3S(O)Rb3, NRc1S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3.

[00205] In some embodiments, the compounds of the invention have Formula VII: where a is 0, 1, 2, or 3.

[00206] In some embodiments, where the compounds of the invention have Formula VII, R2 is CF3.

[00207] In some embodiments, where the compounds of the invention have Formula VII, R1 is H or C1-10 alkyl.

[00208] In some embodiments, where the compounds of the invention have Formula VII, RB is Cy2.

[00209] In some embodiments, where the compounds of the invention have Formula VII, RB is H, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, ORa3, C(O)NRc3Rd3, or C(O)ORa3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-6 haloalkyl, CN, NO2, ORa3 , SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C (O)ORa3, NRc3C(O )NRc3Rd3, NRc3S(O)Rb3, NRc1S(O)2Rb3, NRc3S(O)2 NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3.

[00210] In some embodiments, where the compounds of the invention have Formula VII, RB is H or halo.

[00211] In some embodiments, where the compounds of the invention have Formula VII, RB is halo.

[00212] In some embodiments, where the compounds of the invention have Formula VII, RC is H.

[00213] In some embodiments, where the compounds of the invention have Formula VII, RD is H.

[00214] In some embodiments, where the compounds of the invention have Formula VII, RCy is halo, C1-6 alkyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, CN, NO2, ORa5, SRa5, C( O)Rb5, C(O)NRc5 Rd5, C(O)ORa5, NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5, wherein said C16 alkyl and 4-10 membered heterocycloalkyl are each optional- mind substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O) ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, NRc5S(O) Rb5, NRc5S(O)2Rb5, NRc5S(O) 2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5.

[00215] In some embodiments, the compounds of the invention have Formula VIII: where a is 0, 1, 2, or 3.

[00216] In some embodiments, where the compounds of the invention have Formula VIII, R2 is CF3.

[00217] In some embodiments, where the compounds of the invention have Formula VIII, R1 is H or C1-10 alkyl.

[00218] In some embodiments, where the compounds of the invention have Formula VIII, RB is Cy2.

[00219] In some embodiments, where the compounds of the invention have Formula VIII, RB is H, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, ORa3, C(O)NRc3Rd3, or C(O)ORa3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-6 haloalkyl, CN, NO2, ORa3 , SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C (O)ORa3, NRc3C(O )NRc3Rd3, NRc3S(O)Rb3, NRc1S(O)2Rb3, NRc3S(O)2 NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3.

[00220] In some embodiments, where the compounds of the invention have Formula VIII, RB is H or halo.

[00221] In some embodiments, where the compounds of the invention have Formula VIII, RB is halo.

[00222] In some embodiments, where the compounds of the invention have Formula VIII, RC is H.

[00223] In some embodiments, where the compounds of the invention have Formula VIII, RD is H.

[00224] In some embodiments, where the compounds of the invention have Formula VIII, RCy is halo, C1-6 alkyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, CN, NO2, ORa5, SRa5, C( O)Rb5, C(O)NRc5 Rd5, C(O)ORa5, NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5, wherein said C16 alkyl and 4-10 membered heterocycloalkyl are each optional- mind substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O) ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, NRc5S (O)Rb5, NRc5S(O)2Rb5, NRc5S(O) 2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5.

[00225] In some embodiments, where the compounds of the invention have Formula VIII, a is 0.

[00226] In some embodiments, the chiral carbon to which - C(O)OR1 is attached has an S configuration.

[00227] In some embodiments, the carbon to which -R2 is bonded is pe chiral and has an R configuration.

[00228] It is appreciated that certain aspects of the invention, which are, for clarity, described in the context of separate embodiments, may likewise be provided in combination in a single embodiment. Conversely, various aspects of the invention that are, for brevity, described in the context of a single embodiment, may likewise be provided separately or in any suitable subcombination.

[00229] The term “substituted” means that an atom or group of atoms formally replaces hydrogen as a “substituent” attached to another group. The hydrogen atom is formally removed and replaced with a substituent. A simple divalent substituent, for example oxo, can replace two hydrogen atoms. The term “optionally substituted” means not substituted or substituted. The substituents are independently selected, and the substitution can be at any chemically accessible position. It must be understood that substitution on a given atom is limited by valence. In all definitions, the term “Ci-j” indicates a range that includes the endpoints, where i and j are integers and indicate the number of carbons. Examples include C1-4, C1-6, and the like.

[00230] The term “n-members” where n is an integer typically describes the number of ring-forming atoms in a portion where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1, 2, 3, 4 -tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[00231] In various places in the present specification, various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings may be bonded to the remainder of the molecule on any ring member when permitted by valence. For example, the term "a pyridine ring" or "pyridinyl" may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[00232] For compounds of the invention in which a variable appears more than once, each variable may be a different portion independently selected from the group defining the variable. For example, where a structure is described as having two R groups that are simultaneously present in the same compound, the two R groups may represent different moieties independently selected from the group defined for R.

[00233] When used herein, the term “Ci-j alkyl,” used alone or in combination with other terms, refers to a saturated hydrocarbon group that can be straight or branched chain, having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 10, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl.

[00234] When used here, the term “Ci-j alkoxy,” used alone or in combination with other terms, refers to a group of formula -O-alkyl, in which the alkyl group has i to j carbon atoms. Exemplary alkoxy groups include methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy). In some embodiments, the alkyl group has 1 to 3 carbon atoms or 1 to 4 carbon atoms.

[00235] When used herein, “Ci-j alkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having i to j carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Exemplary alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[00236] When used herein, the term “Ci-j alkylamino” refers to a group of formula -NH(alkyl), in which the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[00237] When used herein, the term “di-Ci-j-alkylamino” refers to a group of formula -N(alkyl)2, in which the two alkyl groups each independently have i to j carbon atoms. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.

[00238] When used here, the term “thio” refers to a group of formula -SH.

[00239] When used herein, the term “Ci-j alkylthio” refers to a group of formula -S-alkyl, where the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[00240] When used here, the term “amino” refers to a group of formula -NH2.

[00241] When used herein, the term “Ci-j aryl,” whether used alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic hydrocarbon (e.g., having 2, 3 or 4 fused rings) having i to j ring-forming carbon atoms, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl is C6-10 aryl. In some embodiments, the aryl group is a naphthalene ring or phenyl ring. In some embodiments, the aryl group is phenyl.

[00242] When used herein, the term “arylalkyl” refers to a group of formula -Ci-j alkyl-(Ci—j aryl). In some embodiments, arylalkyl is C6-10 aryl-C1-3 alkyl. In some embodiments, arylalkyl is C610 aryl-C1-4 alkyl. In some embodiments, arylalkyl is benzyl.

[00243] When used herein, the term “carbonyl,” whether used alone or in combination with other terms, refers to a -C(=O)- group.

[00244] When used here, the term “carboxy” refers to a group of formula -C(=O)OH.

[00245] When used herein, the term “Ci-j cycloalkyl,” whether used alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon moiety having i to j ring-forming carbon atoms, which may optionally contain a or more alkenylene groups as part of the ring structure. Cycloalkyl groups may include mono- or polycyclic ring systems (e.g., having 2, 3 or 4 fused rings). Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings (aryl or heteroaryl) fused to the cycloalkyl ring, for example, benzo or pyrido derivatives of cyclopentane, cyclopentene, cyclohexane, and the like. Where the cycloalkyl group includes a fused aromatic ring, the cycloalkyl group may be attached to an atom in the aromatic or non-aromatic portion. One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized to form carbonyl bonds. In some embodiments, cycloalkyl is C3-10 or C3-7 cycloalkyl, which may be monocyclic or polycyclic. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantanyl and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[00246] When used herein, the term “cycloalkylalkyl” refers to a group of formula -Ci-jalkyl-(Ci-j cycloalkyl). In some embodiments, cycloalkylalkyl is C3-7 cycloalkyl-C1-3 alkyl, wherein the cycloalkyl moiety is monocyclic. In some embodiments, cycloalkylalkyl is C3-7 cycloalkyl-C1-4 alkyl.

[00247] When used herein, “Ci-j haloalkoxy” refers to a group of formula -O-haloalkyl having i to j carbon atoms. An exemplary haloalkoxy group is OCF3. An additional exemplary haloalkoxy group is OCHF2. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[00248] When used herein, the term “halo” refers to a halogen atom selected from F, Cl, I or Br. In some embodiments, “halo” refers to a halogen atom selected from F, Cl , or Br. In some embodiments, the halo group is F.

[00249] When used herein, the term “Ci-j haloalkyl,” used alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms that may be the same or different, where “s” is the number of carbon atoms in the alkyl group, where the alkyl group has i to j carbon atoms. In some embodiments, the haloalkyl group is fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, the haloalkyl group is trifluoromethyl. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms.

[00250] When used herein, the term “heteroaryl,” whether used alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic moiety (e.g., having 2, 3 or 4 fused rings), having one or more members in the heteroatom ring selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl ring, which is monocyclic or bicyclic and which has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl ring, which is monocyclic and which has 1, 2, 3, or 4 members on the heteroatom ring independently selected from nitrogen, sulfur, and oxygen. When the heteroaryl group contains more than one member in the heteroatom ring, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides. Exemplary heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, thiazole, imidazole, furan, thiophene, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole, imidazo[ 1,2-b]thiazole, purine, and the like.

[00251] A 5-membered heteroaryl is a heteroaryl group having five ring-forming atoms comprising carbon and one or more (e.g., 1, 2, or 3) ring atoms independently selected from N, O , and S. Exemplary five-membered heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[00252] A six-membered heteroaryl is a heteroaryl group having six ring-forming atoms in which one or more (e.g., 1, 2, or 3) atoms in the ring are independently selected from N, O, and S Exemplary six-membered heteroaryls include pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

[00253] When used herein, the term “heteroarylalkyl” refers to a group of formula -Ci-j alkyl-(heteroaryl). In some embodiments, heteroarylalkyl heteroaryl-C1-4 alkyl of 5-10 members, wherein the heteroaryl moiety is monocyclic or bicyclic and has 1, 2, 3, or 4 members in the heteroatom ring independently selected from ni- trogen, sulfur and oxygen. In some embodiments, the heteroarylalkyl is 5-6 membered heteroaryl-C1-3 alkyl or 5-6 membered heteroaryl-C1-4 alkyl, wherein the heteroaryl moiety is monocyclic and has 1, 2, 3, or 4 members in the heteroatom ring independently selected from nitrogen, sulfur and oxygen.

[00254] When used herein, the term “heterocycloalkyl”, whether used alone or in combination with other terms, refers to a ring system or non-aromatic ring, which optionally contains one or more alkenylene groups as part of the ring structure, and which has at least one heteroatom ring member independently selected from nitrogen, sulfur and oxygen. When heterocycloalkyl groups contain more than one heteroatom, the heteroatoms may be the same or different. Heterocycloalkyl groups may include mono- or polycyclic ring systems (e.g., having 2, 3 or 4 fused rings), including spiro systems. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings (aryl or heteroaryl) fused to the non-aromatic ring, for example, 1,2,3,4-tetrahydro-quinoline, dihydrobenzofuran and the like. Where the heterocycloalkyl group includes a fused aromatic ring, the heterocycloalkyl group may be attached to an atom in the aromatic or non-aromatic portion. The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group may be oxidized (e.g., have one or two oxo substituents) to form a carbonyl group, or a sulfonyl (or other oxidized bond), or a nitrogen atom. can be quaternized. In some embodiments, the heterocycloalkyl group is 5 to 10 members, which may be monocyclic or bicyclic and which has 1, 2, 3, or 4 members in the heteroatom ring independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heterocycloalkyl group is 5 to 6 members or 5 to 7 members. Examples of heterocycloalkyl groups include 1, 2, 3, 4-tetrahydroquinoline, dihydrobenzofuran, azetidine, azepane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, and pyran. Other examples of heterocycloalkyl groups include 2-oxotetrahydrofuranyl, 2-oxopyrrolidinyl, 2-oxoimidazolidinyl, 1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl, and 2-oxo-1,3-dioxolan-4 -ila.

[00255] When used herein, the term “heterocycloalkylalkyl” refers to a group of formula -Ci-j alkyl-(heterocycloalkyl). In some embodiments, heterocycloalkylalkyl is 5-10 membered heterocycloalkyl-C1-3 alkyl or 5-10 membered heterocycloalkyl-C1-4 alkyl, wherein the heterocycloalkyl moiety is monocyclic or bicyclic and has 1, 2, 3, or 4 members in the heteroatom ring independently selected from nitrogen, sulfur and oxygen. In some embodiments, heterocycloalkylalkyl is a 5-6 membered heterocycloalkyl-C1-4 alkyl in which the heterocycloalkyl moiety is monocyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

[00256] The compounds described here may be asymmetric (for example, having one or more stereocenters). All stereoisomers, such as enantiomers and diastereoisomers, are intended unless otherwise noted. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods of how to prepare optically active forms of optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention can be isolated as a mixture of isomers or as separate isomeric forms.

[00257] The resolution of racemic mixtures of compounds can be carried out by any of the numerous methods known in the art. One example method includes fractional recrystallization using a chiral resolving acid that is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other suitable resolving agents for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine , cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[00258] Resolution of racemic mixtures can also be carried out by elution in a column packed with an optically active resolving agent (for example, dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

[00259] Compounds of the invention may also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond along with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H- imidazole, 1H-, 2H- and 4H- 1, 2, 4-triazole, 1H- and 2H- isoindole, and 1H- and 2H- pyrazole.

[00260] Compounds of the invention may likewise include all isotopes of atoms that occur in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[00261] The term “compound”, when used herein, is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the described structures. Compounds identified herein by name or structure as a particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. Compounds identified herein by name or structure without specifying the particular configuration of a stereocenter are intended to mean all possible configurations at the stereocenter. For example, if a particular stereocenter in a compound of the invention may be R or S, but the name or structure of the compound does not designate which it is, then the stereocenter may be R or S.

[00262] All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated.

[00263] In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By “substantially isolated” it is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation may include, for example, a composition enriched in the compounds of the invention. Substantial separation may include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about at least about 97%, or at least about 99% by weight of the compounds of the invention, or salts thereof. Methods for isolating compounds and their salts are routine in the art.

[00264] The phrase “pharmaceutically acceptable” is used herein to refer to those compounds, materials, compositions, and/or dosage forms that are, within the scope of safe medical diagnosis, suitable for use in contact with the tissues of human beings. humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk relationship.

[00265] The expressions, “ambient temperature” and “room temperature”, when used herein, are understood in the art, and generally refer to a temperature, for example, a reaction temperature, which is about the temperature of the environment in which the reaction is carried out, for example, a temperature of about 20 °C to about 30 °C.

[00266] The present invention also includes pharmaceutically acceptable salts of the compounds described here. When used herein, "pharmaceutically acceptable salts" refer to derivatives of the described compounds in which the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acid residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; Generally, non-aqueous media such as ether, EtOAc, alcohols (e.g., methanol, ethanol, isopropanol, or butanol) or acetonitrile (CH3CN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002).

[00267] The Table below is a key to some abbreviations used throughout. Abbreviations atm atmosphere BOC tert-butyl-oxy-carbonyl CAS# Chemical Abstract Service registration number CBS Corey-Bakshi-Shibata (catalyst) CH3CN Acetonitrile CBZ Carbobenzyloxy DIPEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DME dimethylether DMF dimethylformamide dppf 1,1'-bis(diphenylphosphino)ferrocene EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and enantiomeric excess EtOAc ethyl acetate h hour(s) min minute(s) HOAT 1-hydroxy- 7-azabenzotriazole HOAc acetic acid HPLC high performance liquid chromatography KOAc potassium acetate LAH lithium aluminum hydride LDA lithium diisopropylamide mCPBA 3-meta-chloroperoxybenzoic acid MeOH Methanol MS mass spectrometry MTBE methyl t-butyl ether NH4OH hydroxide ammonium NMP 1-methyl-2-pyrrolidone PAH pulmonary arterial hypertension PE petroleum ether PheOH phenylalanine hydroxylase Prep- preparative thin layer chromatography TLC p-TSA para-toluene sulfonic acid RT room temperature SNAr nucleophilic aromatic substitution TBAF tetrabutylammonium fluoride tBuOH tert- butanol TBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate TEA Triethylamine TFA trifluoroacetic acid TH tyrosine hydroxylase THF Tetrahydrofuran TLC thin layer chromatography TMS Trimethylsilyl TMSI Trimethylsilyl iodide TPH tryptophan hydroxylase

Synthesis

[00268] Procedures for preparing the compounds described here are provided below with reference to Schemes 1-10. Optimal reaction conditions and reaction times may vary depending on the particular reagents used. Unless otherwise specified, solvents, temperatures, pressures and other reaction conditions are readily selected by someone of ordinary skill in the art. Specific procedures are provided in the Examples section. Compounds are named using the “structure to name” function included in ChemDraw® v.12 (Perkin-Elmer).

[00269] Typically, the progress of the reaction can be monitored by thin layer chromatography (TLC) or HPLC-MS if desired. Intermediates and products can be purified by silica gel chromatography, recrystallization, HPLC and/or reversed-phase HPLC. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxy, amino, thio, or carboxy groups) to prevent their undesirable participation in the reactions. The incorporation of such groups, and the methods required to introduce and remove them are known to those skilled in the art (for example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). One or more deprotection steps in the synthetic schemes may be required to ultimately provide the compounds of Formula I. The protecting groups described in the schemes are used as examples, and may be replaced by other compatible alternative groups. Starting materials used in the following schemes can be purchased or prepared by methods described in the chemical literature, or by adaptations thereof, using methods known to those skilled in the art. The order in which the steps are performed may vary depending on the protecting or functional groups introduced and the reagents and reaction conditions used, however, it would be apparent to those skilled in the art.

[00270] Compounds of Formula I can be prepared as generally shown in Scheme 1. Briefly, in step 1, an alcohol (where the ring substituted by RA, RB, RC, RD corresponds to ring A of Formula I) (see, For example, Intermediate 1) in dioxane is treated with the dichlorine heterocycle (e.g., 2-amino-4,6-dichloropyrimidine) in the presence of a base (e.g., Cs2CO3), and heated for several hours (e.g., example, 12-24 h) at reflux. In step 2, a spirocycle of formula B (e.g. (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate) is added to a solution of compound A in a solvent (e.g., dioxane) in the presence of a base (e.g., Na2CO3), and heated at reflux to provide a compound of formula C. In step 3, the amino (P) protecting group (e.g., CBZ or BOC) of a compound of formula C is removed (e.g. with TMSI, transition metal catalyzed hydrogenation, or strong acid depending on the nature of the protecting group). In step 4, a compound of formula D is obtained by ester hydrolysis (e.g. with LiOH in aqueous THF). In some examples, the sequence of steps 3 and 4 may be reversed. Scheme 1

[00271] Alcohols (e.g., Intermediate 1) used in Scheme 1 can be prepared as shown in Scheme 2. Briefly, in step 1, in a solution of base (e.g., potassium t-butoxide) in a solvent (e.g. example, DMSO) 3-methyl pyrazole and an aryl bromide E (eg, 1,4-dibromo-2-fluorobenzene) are added, and the mixture is heated for several hours (eg, 12-24 h) to provide a compound of formula F. In step 2, a compound of formula F is treated with a Grignard reagent (e.g., i-PrMgCl) in a solvent (e.g., THF), then reacted with ethyl trifluoroacetate in a solvent (e.g., THF) to provide a ketone of formula G.

[00272] Alternatively, a ketone of formula G can be obtained by first treating an aromatic fluorine compound of formula E1 with a strong base (for example, LDA), then capturing the aryl lithium intermediate with ethyl ester of trifluoroacetic acid to produce a compound of formula F1 (Step 1a). In a subsequent step 2a, 3-methyl pyrazole can be introduced into a ketone of formula F1 via a SNAr reaction in the presence of base (e.g. K2CO3) under reflux of solvent (e.g. toluene). In step 3, a ketone of formula G is stereospecifically converted to a chiral alcohol of formula H via chiral transfer hydrogenation (e.g. with potassium formate) in the presence of a transition metal catalyst (e.g. potassium dimer). pentamethyl cyclopentadienyl iridium(III) chloride) and a chiral ligand (e.g., (1R,2R)-(-)-N-(4-toluenesulfonyl)-1,2-diphenyl ethylene diamine) in a solvent (e.g., acetonitrile), or alternatively with a borane reagent (e.g., catechol borane) and a chiral catalyst (e.g., (S)-2-methyl-CBS oxazaborolidine) in a solvent (e.g., THF). Alternatively, an alcohol of formula K can be made in a similar aspect starting from a ketone of formula J (step 2c). A ketone of formula J can be prepared in one step (step 2c) by reacting the aryl ester of formula E2 with a nucleophilic silylating agent (e.g., trimethyl(trifluoromethyl) silane) in the presence of a fluoride source ( e.g., TBAF) in an inert solvent (e.g., THF). Scheme 2

[00273] Other types of oxygen or nitrogen linking groups (L groups) can be installed as shown in Scheme 3. Briefly, in step 1, in a spirocyclic compound of B (for example, (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate) in dioxane is added a dihalo heterocycle (e.g. 2-amino-4,6-dichloropyrimidine) in the presence of a base (e.g. , Cs2CO3) under reflux of solvent (e.g., dioxane) to provide a compound of formula M. In step 2, to a compound of formula M in a solvent (e.g., dioxane) is added an alcohol or an amine of formula O (e.g., Intermediate 7 or 16) in the presence of a base (e.g., Cs2CO3). After heating at reflux for several hours (e.g. 12-24 h), a compound of formula P is obtained. In step 3, the amino (P) protecting group (e.g., CBZ or BOC) of a compound of formula P is removed (e.g., with TMSI, transition metal, or acid catalyzed hydrogenation). Then, in step 4, a compound of formula Q is obtained by ester hydrolysis (e.g., with LiOH in aqueous THF). In some examples, the sequence of steps 3 and 4 may be reversed. Scheme 3

[00274] For certain substituents and substitution patterns, palladium-mediated coupling reactions (e.g., Suzuki or Stille reactions) can be used, as shown in Schemes 4a, 4b, and 4c. Briefly, in step 1, to a compound of formula R in a solvent (e.g. aqueous dioxane) a boronic acid or boronate (e.g. phenyl boronic acid) is added in the presence of a palladium catalyst (e.g. PdCl2( dppf)- CH2Cl2) and a base (e.g., KHCO3), and the mixture heated at reflux for several hours (e.g., 12-24) to provide a compound of formula S. In step 3, the amino protecting group ( P) (e.g., CBZ or BOC) from a compound of formula S is removed (e.g., with TMSI, transition metal-catalyzed hydrogenation, or acid). Then, in step 4, a compound of formula T is obtained by ester hydrolysis (e.g. with LiOH in aqueous THF). In some examples, the sequence of steps 2 and 3 may be reversed. A similar set of conditions can be used when starting with a compound of formula U or X, to obtain a compound of formula W or AA, respectively (Schemes 4b and 4c).

[00275] Various substitutions of the central 6-membered ring (e.g., the ring containing W, X, and Y) can be carried out as shown in Scheme 5. Briefly, in step 1, in a solution of a methyl sulfide of formula AB in an inert solvent (e.g. CH2Cl2) an oxidant (e.g. m-CPBA) is added. The solution is stirred at RT for several hours (e.g., 12-24 h) to provide a sulfone of formula AC. In step 2, to a solution of a compound of formula AC in a solvent (e.g. dioxane) a spirocyclic compound of formula B (e.g. (S)-2-benzyl 3-ethyl 2,8-diazaspiro[ 4.5]decane-2,3-dicarboxylate) in the presence of a base (e.g. Cs2CO3), and the mixture is heated for several hours (e.g. 12-24 h) to provide a sulfone of formula AD. In step 3, the ester group is saponified (e.g. with LiOH) in an aqueous or alcoholic solvent (e.g. aqueous THF) to provide an acid of formula AE. In step 4, heating an acid of formula AE in the presence of an alcohol or an amine (e.g. phenol) and a base (e.g. Cs2CO3) for several hours (e.g. 16-24 h) in a solvent ( e.g., dioxane), followed in step 5 by deprotection of the amine (e.g., with TMSI, transition metal-catalyzed hydrogenation, or acid) provides a compound of formula AF. Scheme 5

[00276] Ester group substituents can be introduced by the general method of Scheme 6. Briefly, in step 1, to a solution of an acid of formula AG in an inert solvent (e.g. CH2Cl2) a coupling reagent (e.g. e.g., EDCI and DMAP), followed by an alcohol (e.g., propanol) to provide a compound of formula AH. In step 2, the benzyl groups of the benzyl ester and the N-CBZ group can be removed with reagents such as TMSI or by transition metal catalyzed hydrogenation (e.g., H2 with Pd/C), providing a compound of formula AI. In case the amino protecting group is a BOC, an additional step 3, involving treatment with a strong acid (e.g., TFA), can be used for final deprotection. Scheme 6

[00277] Ethyl esters can generally be prepared according to Scheme 7. Briefly, deprotection of the amino group in a compound of formula AJ can be carried out with the use of a dealkylating agent (for example, TMSI) or through transition metal-catalyzed hydrogenation (e.g., H2 with Pd/C) if the protecting group is CBZ, or with a strong acid (e.g., TFA or HCl), if the protecting group is BOC, to provide AK . It will be recognized by those skilled in the art that many other protective groups can be used alternatively (for example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). Scheme 7

[00278] Various esters can be made through direct alcohol coupling to the acid, as shown in Scheme 8, or through alkylation of the acid, as shown in Scheme 9. Briefly, an amino acid of formula AL is dissolved in a solvent alcoholic (e.g. n-octanol), optionally in the presence of a cosolvent (e.g. toluene), and heated in the presence of acid (e.g. p-TSA) for several hours (e.g. 12-24 h), optionally in the presence of a water capture material (e.g., molecular sieve) or mechanism (e.g., Dean-Stark trap) to produce an ester of formula AM. Alternatively, in step 1, an acid of formula AN is dissolved in a solvent (e.g. DMF) in the presence of a base (e.g. K2CO3) and treated with an alkyl halide (e.g. 2-chloro- ethyl-dimethyl-amine). After heating the solution for several hours (e.g. 12-24 h), an ester of formula AO is obtained. In step 2, removal of the amino protecting group (for example, with an acid such as TFA in an inert solvent such as CH2Cl2 in the case of a BOC protecting group) provides an ester of formula AP. Other compatible deprotection methods apparent to those skilled in the art can be applied to other types of amino protecting groups. Scheme 8

[00279] t-Butyl esters can be made by coupling direct alcohol to the acid, as shown in Scheme 10. Briefly, in step 1, an acid of formula AQ is dissolved in a solvent (e.g., DMF) in the presence of t-butanol, and treated with a coupling agent (e.g., EDCI and DMAP) to provide a compound of formula AR. In step 2, removal of the amino protecting group is achieved as described earlier to provide a compound of formula AS. Scheme 10 Usage Methods

[00280] The compounds of the invention can be used to inhibit the activity of the TPH1 enzyme in a cell by contacting the cell with an inhibiting amount of a compound of the invention. The cell may be from the tissue of a living organism, or it may be in culture, or isolated from a living organism. Additionally, the compounds of the invention can be used to inhibit the activity of the TPH1 enzyme in an animal, individual, or patient by administering an inhibiting amount of a compound of the invention to the cell, animal, individual, or patient. -ent.

[00281] Compounds of the invention can also decrease peripheral serotonin levels in an animal, individual, or patient by administering an effective amount of a compound of the invention to the animal, individual, or patient. In some embodiments, compounds of the invention can selectively decrease levels of peripheral serotonin (e.g., 5-HT in the GI tract) into non-peripheral serotonin (e.g., 5-HT in the CNS). In some embodiments, the selectivity is 2-times or more, 3-times or more, 5-times or more, 10-times or more, 50-times or more, or 100-times or more.

[00282] As TPH1 inhibitors that can decrease peripheral serotonin levels, the compounds of the invention are useful in the treatment and prevention of various diseases associated with abnormal expression or activity of the TPH1 enzyme, or diseases associated with elevated peripheral serotonin levels. or abnormal. In some embodiments, the treatment or prevention includes administering to a patient in need thereof a therapeutically effective amount of a TPH1 inhibitor of the invention.

[00283] Biological assays, some of which are described here, can be used to determine the inhibitory effect of compounds on TPH (such as TPH1) in vitro and/or in vivo. In vitro biochemical assays for human, mouse, and rat TPH1 and human TPH2, PheOH, and TH can be used to measure inhibition of enzyme activity and selectivity between TPH1, TPH2, PheOH, and TH. Furthermore, the efficacy of these compounds can be determined, for example, by measuring their effect on intestinal 5-HT levels in rodents after oral administration.

[00284] Diseases treatable or preventable by administering a TPH1 inhibitor of the invention include bone disease such as, for example, osteoporosis, osteoporotic pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, osteodystrophy, Paget's disease, fractures, and metastasis bone. In some embodiments, the disease is osteoporosis, such as primary type 1 (e.g., postmenopausal osteoporosis), primary type 2 (e.g., senile osteoporosis), and secondary (e.g., steroid or glucocorticoid-induced osteoporosis).

[00285] The present invention also includes methods of treating or preventing bone fracture such as, for example, osteoporotic or traumatic fracture, or surgical fractures associated with an orthopedic procedure (e.g., limb lengthening, bunion removal, a increase in bone formation associated with a prosthesis, bone metastasis, or spinal fusion).

[00286] Other diseases treatable or preventable by the methods of the invention include cardiovascular diseases such as atherosclerosis and pulmonary hypertension (PH), including idiopathic or familial PH, and likewise including PH associated with or brought about by other diseases or conditions. In some embodiments, the PH disease is pulmonary arterial hypertension (PAH).

[00287] The types of PAH treatable according to the methods of the invention include (1) idiopathic (IPAH), (2) familial (FPAH), and (3) associated (APAH) which is the most common type of PAH. The last is PAH which is associated with other medical conditions including, for example, (1) collagen vascular disease (or connective tissue disease) which includes autoimmune diseases such as scleroderma or lupus; (2) congenital lung and heart disease; (3) portal hypertension (e.g., resulting from liver disease); (4) HIV infection; (5) drugs (e.g., appetite suppressants, cocaine, and amphetamines; (6) other conditions including thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, and splenectus - mia. APAH may also be PAH associated with abnormal narrowing of the pulmonary veins and/or capillaries such as in pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis. Another type of PAH is associated with persistent pulmonary hypertension of the newborn born (PPHN).

[00288] Other diseases treatable or preventable by the methods of the invention include metabolic diseases such as diabetes and hyperlipidemia; lung diseases such as chronic obstructive pulmonary disease (COPD), and pulmonary embolism; gastrointestinal diseases such as IBD, colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie syndrome, pancreatic cholera, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, or other gastrointestinal inflammatory conditions; liver diseases such as chronic liver disease; cancers such as liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, and bone cancer (e.g., osteosarcoma, chrondrosarcoma, Ewings sarcoma, osteoblastoma, osteosarcoma osteoid, osteochondroma, enchondroma, chondromyxoid fibroma, aneurysmal bone cyst, unicameral bone cyst, giant cell tumor, and bone tumors); blood diseases (e.g., myeloproliferative syndrome, myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myeloma, and anemia such as aplastic anemia and anemia associated with kidney disease; and blood cancers (e.g., leukemias such as such as acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML)).

[00289] The compounds of the invention are also useful in the treatment and prevention of serotonin syndrome.

[00290] In some embodiments, the present invention includes methods of reducing plasma cholesterol, reducing plasma triglycerides, reducing plasma glycerol, reducing plasma free fatty acids in a patient by administering to said patient a therapeutically effective amount effectiveness of a compound of the invention.

[00291] The compounds of the invention are also useful in the treatment and prevention of inflammatory disease, such as allergic airway inflammation (e.g., asthma).

[00292] When used herein, the term “cell” is intended to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell may be part of a tissue sample taken from an organism such as a mammal. In some embodiments, an in vitro cell may be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

[00293] When used herein, the term “contacting” refers to the joining of the indicated portions in an in vitro system or an in vivo system. For example, "contacting" the enzyme with a compound of the invention includes administering a compound of the present invention to a subject or patient, such as a human, having the TPH1 enzyme, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the TPH1 enzyme.

[00294] When used herein, the term “individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

[00295] When used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human being sought by a researcher. , veterinarian, doctor or other clinician.

[00296] When used herein the term “treating” or “treatment” refers to 1) inhibition of the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or showing the pathology or symptomatology of the disease, condition or disorder (i.e., also stopping the development of the pathology and/or symptomatology), or 2) improving the illness; for example, improving the disease, condition or disorder in an individual who is experiencing or showing the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).

[00297] When used herein, the term “preventing” or “prevention” refers to inhibiting the onset or worsening of the disease; for example, in an individual who may be predisposed to the disease, condition or disorder, but does not yet experience or show the pathology or symptomatology of the disease.

Combination Therapy

[00298] One or more additional pharmaceutical agents or treatment methods can be used in combination with the compounds of the present invention for the treatment or prevention of various diseases, disorders or conditions described herein. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially in separate dosage forms.

[00299] Example pharmaceutical agents that may be useful in a combination therapy for blood disorders such as blood cancers include parathyroid hormone, anti-sclerostin antibodies, cathepsin K inhibitors, and anti-Dickopff 1.

[00300] Example pharmaceutical agents that may be useful in a combination therapy for cancer include leuprolide, goserelin, busserelin, flutamide, nilutamide, ketoconazole, aminoglutethimide, mitoxantrone, estramustine, doxorubicin, etoposide, vinblastine, pa-clitaxel, carboplatin, and vinorelbine. Therapies that can be combined with TPH inhibition include radiation therapy, high-intensity focused ultrasound, or surgery (e.g., removal of diseased tissue). Other drugs for use in cancer treatment include testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, GnRH analogues, temozolomide, bavituximab, cyclophosphamide, fluorouracil, fulvestrant, gefitinib, trastuzumab, IGF-1 antibodies , lapatinib, methotrexate, olaparib, BSI-201, Pazopanib, rapamycin, ribavirin, sorafenib, sunitinib, tamoxifen, docetaxel, vatalinib, bevacizumab, and octreotide.

[00301] Example pharmaceutical agents that may be useful in combination therapy for cardiovascular or pulmonary diseases include endothelin receptor antagonists such as ambrisentan, BMS-193884, bosentan, darusentan, SB-234551, sitaxsentan, tezosentan and macitentan. Anticoagulants such as warfarin, acenocoumarol, phenprocoumon, phenindione, heparin, fondaparinux, argatroban, bivalirudin, lepirudin, and ximelagatran may also be useful in combination therapy. Pharmaceutical agents for combination therapy also include calcium channel blockers such as amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, lercanidipine, phenylalkylamines, verapamil, galopamil, diltiazem, and menthol. Prostacyclins such as epoprostenol, iloprost and treprostinil can also be combined with the TPH inhibitors of the invention. Other pharmaceutical agents for combination therapy in cardiovascular or pulmonary diseases include PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil; diuretics such as furosemide, ethacrynic acid, torasemide, bumetanide, hydrochlorothiazide, spironolactone, mannitol, nitric oxide or nitric oxide releasers, and soluble guanylate cyclase stimulators, such as riociguat. Still other pharmaceutical agents for combination therapy include APJ receptor agonists (WO 2013/111110); IP receptor agonists (WO 2013/105057; WO 2013/105066; WO 2013/105061; WO 2013/105063; WO 2013/105065; WO 2013/105058); and PDGF receptor inhibitors (WO 2013/030802).

[00302] Example pharmaceutical agents that may be useful in combination therapy for metabolic disorders include HSL inhibitors such as those described in International Patent Publications WO2006/074957; WO2005/073199; WO2004/11 1031; WO2004/111004; WO2004/035550; WO2003/051841; WO2003/051842; and WO2001/066531.

[00303] Example pharmaceutical agents that may be useful in combination therapy for bone disorders and diseases include bisphosphonates such as etidronate, clodronate, tiludronate, pamidronate, neridronate, olpadronate, alendronate, ibandronate, risedronate, cídronate, zoledronate, and similar. Serotonin receptor modulators, such as agonists or antagonists of 5-HT1B, 5-HT2A, and 5-HT2B, may also be useful in combination therapy for bone disease. Other useful agents for combination therapy include selective serotonin reuptake inhibitors (SSRI), anti-serotonin antibodies, and beta blockers such as IPS339, ICIl 18,551, butaxamine, metipranolol, nadol, oxprenolol, pembutolol, pindolol, propranolol, timolol , and sotalol. Other agents useful for combination therapy for treating bone disorders, such as osteoporosis, include teriparatide, strontium ranelate, raloxifene, and denosumab. Administration, Pharmaceutical Formulations, Dosage Forms

[00304] The compounds of the invention can be administered to patients (animals and humans) in need of such treatment in appropriate dosages that will provide prophylactic and/or therapeutic efficacy. The dose required for use in the treatment or prevention of any particular disease or disorder will typically vary from patient to patient depending, for example, on the particular compound or composition selected, the routine of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medications or special diets currently being followed by the patient, and other factors. The appropriate dosage can be determined by the treating physician.

[00305] A compound of this invention can be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in unit dosage formulations containing conventional, non-toxic, pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration may involve subcutaneous injections, intravenous or intramuscular injections or infusion techniques.

[00306] The duration of treatment may be as long as deemed necessary by a treating physician. The compositions can be administered one to four or more times per day. A treatment period may end when a desired result, for example, a particular therapeutic effect, is obtained. Or a period of treatment may be continued indefinitely.

[00307] In some embodiments, pharmaceutical compositions can be prepared as solid dosage forms for oral administration (e.g., capsules, tablets, pills, tablets, powders, granules and the like). A tablet can be prepared by compression or molding. Compressed tablets may include one or more binders, lubricants, glidants, inert diluents, preservatives, disintegrants, or dispersing agents. Tablets and other solid dosage forms, such as capsules, pills and granules, may include coatings, such as enteric coatings.

[00308] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration may include, for example, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Suspensions may include one or more suspending agents

[00309] Dosage forms for transdermal administration of an object composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, plasters and inhalants.

[00310] Compositions and compounds of the present invention can be administered by aerosol, which can be administered, for example, by a sonic nebulizer.

[00311] Pharmaceutical compositions of this invention suitable for parenteral administration include a compound of the invention together with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions. Alternatively, the composition may be in the form of a sterile powder that can be reconstituted into a dispersion or sterile injectable solutions just before use.

[00312] The invention will be described in greater detail by means of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to produce essentially the same results. The compounds of the Examples were found to be inhibitors of TPH1 as described below.

EXAMPLES

[00313] The compounds described here can be prepared in various ways based on the teachings contained herein and synthetic procedures known in the art. In describing the synthetic methods described below, it should be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and preparation procedures, may be chosen to be the conditions standard for this reaction unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present in various portions of the molecule must be compatible with the proposed reagents and reactions. Substitutes not compatible with the reaction conditions will be evident to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are commercially available or are readily prepared by standard methods from known materials.

[00314] 1H NMR spectra were acquired on one or more of three instruments: (1) Agilent UnityInova 400 MHz spectrometer equipped with a 5mm Automation Triple Broadband (ATB) probe (the ATB probe was simultaneously tuned to 1H, 19F and 13C); (2) Agilent UnityInova 500 MHz spectrometer; or (3) Varian Mercury Plus 400 MHz spectrometer. Various NMR probes were used with the 500 MHz NMR spectrometer, including equally 3 mm and 5 mm 1H, 19F, and 13C probes and a 3 mm X1H19F NMR probe (normal -mente X is tuned to 13C). For typical 1H NMR spectra, the pulse angle was 45 degrees, 8 scans were summed, and the spectral width was 16 ppm (-2 ppm to 14 ppm). Typically, a total of about 32,768 complex points were collected during the acquisition time of 5.1 seconds, and the recycle delay was set at 1 second. Spectra were collected at 25 °C. 1H NMR spectra were typically processed with 0.3 Hz line broadening and zero loading at about 131072 points before Fourier transformation. Chemical shifts were expressed in ppm in relation to tetramethylsilane. The following abbreviations are used here: br = broad sign, s = singlet, d = doublet, dd = double doublet, ddd = double doublet, dt = double triplet, t = triplet, td = triple doublet, tt = triplet triple q = quartet, m = multiplet.

[00315] Liquid chromatography - mass spectrometry (LCMS) experiment to determine retention times and associated mass ions was performed using one or more of the following Methods A, B, and C: Method A: Waters BEH C18, 3, 0 x 30 mm, 1.7 μm, was used at a temperature of 50oC and a flow rate of 1.5 mL/min, 2 μL injection, mobile phase: (A) water with 0.1% acid formic and 1% acetonitrile, mobile phase (B) MeOH with 0.1% formic acid; retention time given in minutes. Details of Method A: (I) conducted on a G1312B Binary Pump with G1315C UV/Vis diode array detector and Agilent 6130 mass spectrometer in positive and negative ion electrospray mode with UV PDA detection with a gradient of 15-95 % of (B) in a linear gradient of 2.2 min (II) maintained for 0.8 min at 95% of (B) (III) decrease from 95-15% of (B) in a linear gradient of 0, 1 min (IV) maintained for 0.29 min in 15% (B); Method B: An Agilent Zorbax Bonus RP, 2.1 x 50mm, 3.5 μm, was used at a temperature of 50oC and a flow rate of 0.8 mL/min, 2 μL injection, mobile phase: ( A) water with 0.1% formic acid and 1% acetonitrile, mobile phase (B) MeOH with 0.1% formic acid; retention time given in minutes. Method Details: (I) conducted on a G1312B Binary Pump with G1315C UV/Vis diode array detector and Agilent 6130 mass spectrometer in positive and negative ion electrospray mode with UV detection at 220 and 254 nm with a gradient of 5-95% of (B) in a 2.5 min linear gradient (II) maintained for 0.5 min at 95% of (B) (III) decreasing from 95-5% of (B) in a 0.1 min linear gradient (IV) maintained for 0.29 min in 5% (B). Method C: An API 150EX mass spectrometer connected to a Shimadzu LC-10AT LC system with a diode array detector was used. The spectrometer had an electrovaporization force operating in positive and negative ion mode. LC was performed using an Agilent ZORBAX XDB 50 x 2.1 mm C18 column and a flow rate of 0.5 mL/minute. Solvent A: 95% water, 5% acetonitrile containing 0.01% formic acid; Solvent B: acetonitrile. The gradient was shown as below. 0-0.5 min: 2% solvent (B); 0.5-2.5 min: 2% solvent B to 95% solvent (B); 2.5-4.0 min: 95% solvent (B); 4.0-4.2 min: 95% solvent (B) to 2% solvent B; 4.26.0 min: 2% solvent (B).

[00316] Microwave experiments were performed using a Biotage Initiator™, which uses a single-mode resonator and dynamic field tuning. Temperatures of 40-250 °C have been achieved, and pressures of up to 20 bars have been reached.

[00317] Preparative HPLC purification was performed using a Genesis C18 reversed phase column (C18) or a Phenomenex C6-phenyl (C6 Ph) column (100 x 22.5 mm i.d. with 7 micron particle size, UV detection at 230 or 254 nm, flow rate 5-15mL/min), eluting with gradients from 100-0 to 0-100% water/acetonitrile or water/MeOH containing 0.1% formic acid. The fractions containing the required product (identified by LCMS analysis) were pooled, the organic fraction removed by evaporation, and the remaining aqueous fraction lyophilized, to produce the product.

[00318] Chiral HPLC was performed using a Chiralpak AD column, 4.4 mm x 250 mm, particle size 5 microns

[00319] Compounds requiring column chromatography were purified manually or completely automatically using a Biotage SP1TM Flash Purification system with Touch Logic ControlTM or a Combiflash Companion® with Isolute® SPE cartridge on pre-packaged silica gel, Biotage cartridge SNAP or Redisep® Rf cartridge respectively. Preparation of alcohols and amines

[00320] The chiral alcohols represented below are shown in their absolute configuration (unless otherwise shown). Its enantiopurity (%ee) can be determined using Mosher ester analysis and analyzed as described in the literature (Dale, J. A. & Mosher, H. S. Nuclear Magnetic Resonance Enantiomer Regents. Configurational Correlations Via Nuclear Magnetic Resonance Chemical Shifts Of Diastereomeric Mandelate, O -Methylmandelate, and alpha-Meth-oxy alpha-Trifluoromethylphenylacetate (MTPA) Esters. J. Am. Chem. Soc, 95, 512-519 (1973)). The chiral alcohols of the invention are preferably enantiomerically enriched, for example, to >95% ee. Representative Mosher ester preparation

[00321] In a solution of (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (46 mg, 0.20 mmol, Intermediate 3) pyridine (138 mg, 1.7 mmol) was added followed by the addition of (S or R)-a-methoxy-a-trifluoromethyl-phenylacetyl chloride (10 mg, 0.40 mmol). The reaction was stirred for 12 h, then the material was purified directly in silica gel chromatography (EtOAc/heptane) to provide the “Mosher ester” which was analyzed by 1H NMR for enantiomeric purity. Intermediate 1: (R)-1-(4-Bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethanol

[00322] Step 1: Potassium t-Butoxide (16.3 g, 145 mmol) was dissolved in DMSO (100 mL). To this solution was added 3-methyl pyrazole (10.4 g, 120 mmol) and the reaction was heated at 50 °C for 30 min. 1,4-Dibromo-2-fluorobenzene (31 g, 120 mmol) was then added, and the reaction stirred at 50 °C for 16 h. The reaction was cooled at RT and extracted with water and EtOAc, washed with brine, dried over Na2SO4, and then filtered and concentrated in vacuo. Purification by column chromatography on normal phase silica gel (EtOAc/heptane) provided 1-(2,5-dibromophenyl)-3-methyl-1H-pyrazole.

[00323] Step 2: 1-(2,5-dibromophenyl)-3-methyl-1H-pyrazole (23.0 g, 73 mmol) from Step 1 was dissolved in 200 mL of THF and cooled to 0 °C. I-propyl magnesium chloride (2.0 M in THF, 40 mL) was added dropwise, and the reaction was stirred for 45 min, then ethyl trifluoroacetate (10.5 mL) was added. The reaction was stirred for 30 min at 0 °C, then 10% HCl was added dropwise (400 mL). The reaction was extracted with water and EtOAc, washed with brine, dried over Na2SO4, filtered, and then concentrated in vacuo. Purification by column chromatography on normal phase silica gel (EtOAc/heptane) provided 1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2 -trifluoroethanone.

[00324] Step 3: METHOD A: Pentamethylcyclopentadienyl iridium (III) chloride dimer (CAS# 12354-84-6) (10.4 mg) and (1R,2R)-(-)-N-(4 - toluenesulfonyl)-1,2-diphenyl ethylene diamine (CAS# 144222-34-4) (9.2 mg) were combined in water (120 mL), then heated at 50 °C for 5 h to provide the “Complex of iridium”. 1-[4-Bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethanone (16 g, 48 mmol) was dissolved in acetonitrile (120 mL) in which the Iridium complex and potassium formate (3.1 g, 3.7 mmol) were added. The reaction mixture was heated at 50 °C for 8 h. The reaction mixture was then cooled at RT, partitioned between water and EtOAc, and extracted. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Recrystallization from hot heptane (200 mL) provided the title compound.

[00325] METHOD B: Alternatively, trifluoromethyl (or other pro-chiral) ketones of formula G or J (scheme 2) were asymmetrically reduced as follows (see for example: Corey, EJ & Link, JO A General, Catalytic , and Enantioselective Synthesis is Alpha-amino Acids. J. Am. Chem. Soc, 114, 1906-1908 (1992)): Catechol borane (95 mL, 1 M in THF) and (S)-2-methyl-CBS oxazaborolidine (2.6 g, 9.6 mmol) were mixed in a jacketed glass reactor. The mixture was stirred at RT for 20 min, then the jacket was cooled to -78 °C. At a reaction temperature of -65 °C, 1-[4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethanone (16 g, 48 mmol) in THF (150 mL) was added dropwise over 2 h. The reaction was then heated to -36 °C and maintained at this temperature for 22 h. Then, the reaction was quenched with 3 N NaOH (100 mL) while maintaining a reaction temperature of <-25 °C. The reaction was then heated to 0 °C and H2O2 (30%, 100 mL) was added over 30 min, then heated at RT for 4 h. The reaction mixture was quenched with 1N NaOH, extracted with ether, washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by normal phase silica gel chromatography (EtOAc/heptane) provided the product as a viscous oil. Intermediate 2: (R)-1-(5-Bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethanol

[00326] Step 1: Diisopropylamine (4.40 mL, 31.4 mmol) was dissolved in THF (28 mL) and cooled to -40 °C. Then, n-butyllithium (12.6 mL, 2.5 M in hexanes, 31.4 mmol) was added dropwise, and the reaction was stirred at -40 °C for 1 h, then cooled to -78 °C. A solution of 1-bromo-4-fluoro-benzene (5g, 28.6 mmol) in THF (6.0 mL) was added, and the reaction was stirred at -78 °C for 1 h. Trifluoroacetic acid ethyl ester (3.73 mL, 31.4 mmol) in THF (6.0 mL) was then added, and the reaction was slowly warmed to 0 ° C in one hour. The reaction was quenched with NH4Cl (sat aq), and extracted with EtOAc, washed with brine and dried over Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography on normal phase silica gel (EtOAc/heptane) provided 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone.

[00327] Step 2: 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (2.20 g, 8.12 mmol) from Step 1, K2CO3 (1.68 g, 12.2 mmol), and 3-methyl-1H-pyrazole (1.33 g, 16.2 mmol) were stirred in toluene (10 mL). The reaction was then heated to 110 °C for 16 h. The reaction was cooled, and water and EtOAc were added. The toluene-EtOAc layer is removed in vacuo, and then the reaction is extracted with water and EtOAc, washed with brine and dried over Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography on normal phase silica gel (EtOAc/heptane) provided 1-[5-bromo-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2- trifluoro-ethanone.

[00328] Step 3: The title compound was prepared using iridium complex-catalyzed hydrogenation as described by Intermediate 1, (R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1 -yl)phenyl)-2,2,2-trifluoroethanol. Intermediate 3: (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol

[00329] Step 1: Potassium t-Butoxide (3.9 g, 0.33 mmol) was dissolved in DMSO (25 mL). To this solution was added 3-methyl pyrazole (2.7 g, 0.33 mmol), and the reaction was heated at 50 °C for 30 min. 1-Bromo-4-chloro-2-fluorobenzene (4.6 g, 0.22 mmol) was then added, and the reaction was stirred at 50 °C for 16 h. The reaction was cooled at RT and extracted with water and EtOAc, washed with brine and dried over Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography on normal phase silica gel (EtOAc/heptane) provided 1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole and 1-(2-bromo-5-chlorophe -nil)-5-methyl-1H-pyrazole as a 4:1 mixture that was used in the next step directly.

[00330] Step 2: The mixture from Step 1 (8 g, 0.39 mmol) was dissolved in 160 mL of THF and cooled to 0 °C. I-propyl magnesium chloride (2.0 M in THF, 23 mL) was added dropwise, and the reaction stirred for 45 min, then ethyl trifluoroacetate (6 mL) was added. The reaction was stirred for 30 min at 0 °C, then 10% HCl was added dropwise (40 mL). The reaction was extracted with water and EtOAc, washed with brine and dried over Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography on normal phase silica gel (EtOAc/heptane) provided 1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2 -trifluoroethanone as a white solid.

[00331] Step 3: The title compound was prepared using iridium complex-catalyzed hydrogenation, as described by Intermediate 1 (R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1 -yl)phenyl)-2,2,2-trifluoroethanol. Intermediate 4: (R)-1-(5-chloro-2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl) pyrrolidin-2-one

[00332] In a solution of (R)-1-(4)-2,2,2-trifluoroethanol (300 mg, 1.04 mmol) in toluene (7 mL) pyrrolidin-2-one (89 mg, 1.04 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (74 mg, 0.52 mmol), CuI (50 mg, 0.26 mmol) and K2CO3 (360 mg, 2 .6 mmol). The reaction was heated in a sealed tube at 130 oC for 12 h, and then cooled at RT. The solids were filtered, and the product was purified by chromatography on normal phase silica gel (EtOAc:petroleum ether) to provide the title compound as a white solid. Intermediate 5: (R)-2,2,2-Trifluoro-1-(2-methyl-1H-benzo[d]imidazol-4-yl)ethanol

[00333] Step 1: 4-Bromo-2-methyl-1H-benzimidazole (500 mg, 2.37 mmol) was dissolved in THF (8 mL) and cooled to -78 °C. n-Butyllithium (2.3 mL, 2.5 M in hexanes, 5.7 mmol) was added dropwise, and the reaction was stirred at -78 °C for 30 min. Trifluoroacetic acid ethyl ester (339 μL, 2.8 mmol) was added, and the reaction was stirred at 0 °C for 1 h. The reaction was quenched with HCl (2N, 4 mL), then extracted with water and EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography on normal phase silica gel (CH2Cl2/MeOH/NH4OH) provided 2,2,2-trifluoro-1-(2-methyl-1H-benzoimidazol-4-yl)-ethanone.

[00334] Step 2: The title compound was prepared using iridium complex-catalyzed hydrogenation, as described by Intermediate 1 (R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1 -yl)phenyl)-2,2,2-trifluoroethanol. Intermediate 6: 1-(4-Chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethanol

[00335] Step 1: Mixture of 1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole/1-(2-bromo-5-chlorophenyl)-5-methyl-1H-pyrazole ( Intermediate 3, step 1) (1.00 g, 3.68 mmol) was dissolved in THF (6 mL) and cooled to 0 °C. I-propyl magnesium chloride (2.76 mL, 2.0 M in THF, 5.52 mmol) was added dropwise and allowed to heat at RT for 30 min. The reaction was then cooled to -15 °C. Acetyl chloride (481 μL, 5.5 mmol) was added, and the reaction was heated at RT for 3 h. The reaction was quenched with HCl (2N, 4 mL), then extracted with water and EtOAc, washed with brine and dried over Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography on normal phase silica gel (EtOAc/heptane) provided 1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-ethanone.

[00336] Step 2: 1-[4-Chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-ethanone (400 mg, 1.70 mmol) from Step 1 was dissolved in MeOH (10 mL ) and cooled to 0 °C. NaBH4 (129 mg, 3.41 mmol) was added in portions, then the reaction was heated at RT, stirred for 30 min, then quenched with acetone. MeOH was removed in vacuum, then the residue was partitioned between water and EtOAc and extracted several times. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography on normal phase silica gel (CH2Cl2/MeOH/NH4OH) provided the title compound. Intermediate 7: 1-(2,6-dibromophenyl)ethanol

[00337] In a solution of 1-(2,6-dibromophenyl)-2,2,2-trifluoroethanone (CAS# 1208078-23-2) (3 g, 9 mmol) in EtOH (50 mL) was added NaBH4 (340 mg, 9 mmol) at 5 oC. The reaction was heated at RT for 1 h, then extracted with EtOAc NaHCO3, brine and dried over Na2SO4, filtered and concentrated in vacuo to give 1-(2,6-dibromophenyl)-2,2,2-trifluoroethanol as an oil. light yellow. Intermediate 8: 1-(2,5-dibromophenyl)ethanol

[00338] This compound was made as described above by Intermediate 7, 1-(2,6-dibromophenyl)-2,2,2-trifluoroethanol, starting with 1-(2,5-dibromophenyl)-2,2,2- trifluoroethanone to give a light yellow oil. Intermediate 9: (4-Chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)methanol

[00339] Step 1: Mixture of 1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole/1-(2-bromo-5-chlorophenyl)-5-methyl-1H-pyrazole (Intermediate 3 , step 1) (1.00 g, 3.68 mmol) was dissolved in THF (6 mL) then cooled to 0 °C. I-propyl magnesium chloride (2.76 mL, 2.0 M in THF, 5.52 mmol) was added dropwise, and the reaction was heated at RT for 30 min. The reaction was then cooled to -15 °C and paraformaldehyde (166 mg, 5.5 mmol) was added. The reaction mixture was allowed to warm at RT and stirred for 1 h. DMF (500 mL) was added, and the reaction was stirred for an additional 1 h. The reaction was quenched with HCl (2N, 4 mL), diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography on normal phase silica gel (EtOAc/heptane) provided 4-chloro-2-(3-methyl-pyrazol-1-yl)-benzaldehyde.

[00340] Step 2: 4-Chloro-2-(3-methyl-pyrazol-1-yl)-benzaldehyde (446 mg, 2.03 mmol) from Step 1 was dissolved in MeOH (14 mL) and cooled to 0° W. NaBH4 (175 mg, 4.61 mmol)) was added in portions. The reaction mixture was allowed to warm at RT, and after 90 min it was quenched with acetone. MeOH was removed in vacuum. The residue was partitioned between water and EtOAc and then extracted. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography on normal phase silica gel (EtOAc/heptane) provided the title compound.

[00341] Using the procedure described by Intermediate 3, (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol, the following Alcohols (Intermediates 10-15) shown in the Table below were prepared starting with appropriately substituted 1-bromo-2-fluorobenzene. Intermediate 16: (2-Phenoxy-6-(piperidin-1-yl)phenyl)methanamine

[00342] Step 1: In a solution of phenol (415 mg, 4.5 mmol) in 60 mL of DMF, NaH (60%, 6.0 mmol) was added at 0 oC. The reaction was stirred for 1 h, then 2-fluoro-6-(piperidin-1-yl)benzonitrile (CAS# 646989-68-6) (612 mg, 3.0 mmol) was added, and the reaction stirred for 48 hours on RT. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, then concentrated in vacuo. Purification by column chromatography on normal phase silica gel (EtOAc/heptane) provided 2-phenoxy-6-(piperidin-1-yl)benzonitrile as an off-white solid.

[00343] Step 2: In 2-phenoxy-6-(piperidin-1-yl)benzonitrile (250 mg, 0.9 mmol) from Step 1 in 20 mL of MeOH were added Raney Nickel (5%) and NH4OH ( 2 mL). The reaction was stirred under 1 atm of H2 at RT for 2 h. The solid was filtered, and the filtrate was concentrated in vacuo to provide the title compound as a viscous oil. Intermediate 17: (R)-1-(4-Chloro-2-(2-methoxyethoxy)phenyl)-2,2,2-trifluoroethanol

[00344] Step 1: 1-Bromo-4-chloro-2-(2-methoxy-ethoxy)-benzene (CAS# 1245563-20-5) (5.00 g, 18.8 mmol) was dissolved in THF ( 30 mL) and cooled to 0 oC. i-Propylmagnesium bromide (11.3 mL, 2.0 M in THF, 22.6 mmol) was added dropwise, and the reaction was stirred at 10 °C for 30 min, then heated at RT for 16 h . The reaction was then cooled to -15 °C and trifluoroacetic acid ethyl ester (3.37 mL, 28.2 mmol) was added. The reaction was stirred at 10 °C for 1 h. The reaction was quenched with HCl (2 N, 38 mL) at 0 oC. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, then concentrated in vacuo. Purification by column chromatography on normal phase silica gel (EtOAc/heptane) provided 1-(4-chloro-2-(2-methoxyethoxy)phenyl)-2,2,2-trifluoroethanone.

[00345] Step 2: The title compound was prepared using Iridium complex-catalyzed hydrogenation as described by Intermediate 1 (R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl )phenyl)-2,2,2-trifluoroethanol. Intermediate 18: (R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethanol

[00346] In a solution of (R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol (300 mg, 1.1 mmol) in dioxane (12 mL) acid was added boronic phenyl (185 mg, 1.5 mmol), Pd2(dppf)Cl2 (35 mg, 0.07 mmol) and Na2CO3 (3 mL, 2.0 M, aq). The reaction was heated at 90 oC for 2 h, then cooled at RT and concentrated in vacuo. The residue was taken up in CH2Cl2, washed with brine and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4. Purification by normal phase silica gel column (EtOAc/hexanes) to provide a white solid. Intermediate 19: (R)-1-(4-chloro-2-(5-chlorothiophen-2-yl)phenyl)-2,2,2-trifluoroethanol

[00347] This compound was made in the same way as described by Intermediate 18 (R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethanol to provide a white solid. Intermediate 20:(R)-2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)ethanol

[00348] Step 1: To the solution of 2-chloro-6-methylnicotinic acid (5 g, 29.1 mmol) in CH2Cl2 (40 mL) was added oxalyl dichloride (8.1 g, 63.8 mmol) at 0 oC, and the reaction mixture was stirred for 2 h. The mixture was concentrated and 40 mL of methanol was then added at 0°C, and the reaction mixture was stirred at RT for 12 h. The mixture was then concentrated in vacuo and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide methyl 2-chloro-6-methylnicotinate which is used without further purification as a light yellow solid.

[00349] Step 2: In a solution of 3-methyl-1H-pyrazole (1.1 g, 13.4 mmol) in DMF (5 ml) sodium hydride (1.0 g, 60% in oil) was added at 0 oC. The reaction mixture was stirred for 1 h at 0°C and then a solution of methyl 2-chloro-6-methylnicotinate (4.3 g, 23.16 mmol) in DMF (5 mL) was added dropwise to the reaction mixture at 0 oC. After addition, the mixture was heated to 80°C and stirred for 12 h. After this moment, the mixture was poured into ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo, and then column purified on normal phase silica gel (EtOAc/heptate) to give methyl 6-methyl-2-(3-methyl- 1H-pyrazol-1-yl)nicotinate as a brown semisolid.

[00350] Step 3: In a solution of methyl 6-methyl-2-(3-methyl-1H-pyrazol-1-yl)nicotinate (3.7 g, 16 mmol) and trimethyl(trifluoromethyl)silane (11 .4 g, 80.2 mmol) in toluene (60 ml), was added dropwise at -78oC, and then tetrabutyl ammonium fluoride solution (1.6 mL, 1.0 M in THF) was added dropwise to the reaction mixture at -78oC. After addition, the mixture was slowly heated to RT and stirred for 12 h. The reaction mixture was concentrated, and the resulting residue was dissolved in methanol (30 mL). 6N HCl (30 mL) was added to the reaction mixture, and the resulting mixture was stirred for 2 h. The reaction mixture was concentrated, adjusted to pH 6 with sat. and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo, and column purified on normal phase silica gel (EtOAc/heptate) to give 2,2,2-trifluoro-1-(6-methyl- 2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)ethanone as a brown semisolid.

[00351] Step 4: The solution of (S)-(-)-2-Butyl-CBS-oxaza-borolidine solution (3.0 ml 1.0 M in toluene) and catecholborane (30 ml 1.0 M in THF ) was stirred at RT for 30 min. The mixture was then cooled to -70 oC and 2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)ethanone (1 g, 2.9 mmol) in THF (16 mL) was added dropwise. After addition, the reaction mixture was warmed to -32°C and stirred for 12 h. After this point, 3N NaOH (18 mL) was added, followed by H2O2 (18 mL), and the temperature of the reaction mixture was increased to RT for 30 min, and then extracted with ethyl. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo and column purified on normal phase silica gel (EtOAc/heptate) to provide the title compound as a yellow solid. Intermediate 38: (R)-1-(5-bromo-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethanol

[00352] Step 1: The solution of 2,4-dibromo-benzoic acid, (2.3 g, 18.8 mmol), phenyl boronic acid (5 g, 17.9 mmol), Pd2(dba)3 (818 mg, 8.9 mmol) and LiOH (1.65 g, 39.3 mmol) in a 1:1 mixture of NMP/water (100 mL) was heated at 70 oC for 2 d. After this time, the reaction mixture was cooled at RT, and the reaction mixture was adjusted to pH = 4-5 with 3N HCl. The mixture was then extracted with ethyl acetate, and the combined organic layers were washed with brine. , dried in Na2SO4, filtered and concentrated in vacuo and purified by column on normal phase silica gel (EtOAc/PE10:1 to 1:1) to provide 5-bromo-[1,1'-biphenyl]-2 acid -carboxylic as a colorless oil.

[00353] Step 2: In a solution of 5-bromo-[1,1'-biphenyl]-2-carboxylic acid (5 g, 18.2 mmol) in MeOH (30 mL) SOCl2 (10 mL) was added dropwise the drop. The reaction mixture was heated at 70oC for 2 h, then cooled at RT. The mixture was concentrated, adjusted to pH=7-8 with saturated aqueous NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo and column purified on normal phase silica gel (EtOAc/PE 50:1) to provide methyl 5-bromo-[1,1'-biphenyl ]-2-carboxylate as a colorless oil.

[00354] Step 3: The solution of methyl 5-bromo-[1,1'-biphenyl]-2-carboxylate (2.2 g, 6.9 mmol) in THF (50 mL) was cooled to 0 oC. LiAlH4 (380 mg, 10 mmol) was added slowly. The reaction mixture was stirred at RT for 2 h, after which water (1 mL) was added slowly to quench the reaction. The solid was removed by filtration, and the filtrate was concentrated in vacuum to provide (5-bromo-[1,1'-biphenyl]-2-yl)methanol as a white solid, which was used directly without further purification.

[00355] Step 4: In a solution of (5-bromo-[1,1'-biphenyl]-2-yl)methanol (2.0 g, 8.4 mmol) in CH2Cl2 (30 mL) was added Dess-Martin periodinane (4.3 g, 10 mmol). The reaction mixture was stirred at RT for 2 h, and then the solids were filtered, and the resulting filtrate was concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc:PE = 1:50) provided 5-bromo-[1,1'-biphenyl]-2-carbaldehyde as a colorless oil.

[00356] Step 5: In a solution of 5-bromo-[1,1'-biphenyl]-2-carbaldehyde (1.9 g, 7.3 mmol) TMSCF3 (1.2 g, 8.7 mmol) was added ) in THF (20 mL) and cooled to 0 oC. To this solution was added TBAF (1.46 mL, 1M in THF), and the reaction mixture was heated at RT for 3 h. After this point, the mixture was treated with 3N HCl (5 mL) and stirred for 12 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and column purified on normal phase silica gel (EtOAc:PE = 1:10) to provide 1-(5-bromo-[1,1 '-biphenyl]-2-yl)-2,2,2-trifluoroethanol as a colorless oil.

[00357] Step 6: In a solution of 1-(5-bromo-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethane (1.8 g, 5.5 mmol) in CH2Cl2 (30 mL) was added Dess-Martin Periodinane (3g, 7.1 mmol). The reaction mixture was stirred at RT for 2 h, and then the solids were filtered. The resulting filtrate was concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc:PE = 1:50) provided 1-(5-bromo-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethanone as a colorless oil.

[00358] Step 7: 1-(5-Bromo-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethanone (1.3 g, 3.9 mmol) in CH3CN (10 mL ) was reduced to chiral alcohol using the chiral iridium catalyst (METHOD A) at RT. The reaction mixture was then charged with potassium formate (725 mg, 8.6 mmol), and the mixture was stirred at 40 °C for 12 h. Then, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and column purified on normal phase silica gel (EtOAc:PE = 1:10) to provide the title compound as a colorless oil.

[00359] Using the procedure described by Intermediate 3, (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol, the following Alcohols (Intermediates 39-42) shown in the Table below were prepared starting with the appropriately substituted pyrazole. Intermediate 43: (R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol Br GPa

[00360] The dimer solution of dichloro(pentamethylcyclopentadienyl) iridium (III) ([Cp*IrCl2]2, 14 mg, 0.02 mmol) and (1R,2R)-(-)-(4-toluenesulfonyl) -1,2-diphenylethylenediamine (14 mg, 0.04 mmol) in water (7 mL) was prepared at RT. The resulting mixture was heated at 40 oC for 3 h to provide a homogeneous orange solution. To this catalyst solution active at 40 oC was added potassium formate (143mg, 171mmol), and a solution of 1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanone (CAS# 1033805- 23-0.98 mg, 0.34 mmol) in CH3CN (70 mL). The reaction mixture was then stirred at 40 oC for 2 h, and then cooled to RT, and the layers were separated. The aqueous layer was extracted with MTBE, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to provide the title compound, which was used without further purification.

[00361] The following alcohols and amines in the table below are useful in preparing compounds of the invention. They are commercially available or can be prepared by known synthetic procedures. CAS registration numbers are provided for each. No. = Intermediate Numbers; Ex# = Used in the preparation of the following example(s) Preparation of boronic acids and esters

[00362] Boronic acids and esters used in biaryl couplings are commercially available or can be easily synthesized from the corresponding bromide using routine synthetic methods. The following Intermediate 34 is a representative example. Intermediate 34: 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one

[00363] In a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (200 mg, 0.89 mmol) in 5 mL of acetonitrile, pinacoldiboron (300 mg, 1. 2 mmol), Pd(dppf)2Cl (30 mg, 0.09 mmol), KOAc (250 mg, 2.1 mmol) and triethyl amine (1mL). The reaction was heated at 87 oC for 24 h, then cooled at RT. The solids were filtered, and the solvent was removed in vacuo, then extracted with EtOAc, water, brine and dried over Na2SO4. The solvent was removed in vacuo to give an off-white solid, which was used without further purification. Preparation of spirocyclic amino esters Intermediate 35: (S)-2-Benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate

[00364] Step 1: (3S)-8-Tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate [Example 24 in Pat. US No. 2012/0101280] (50 g, 160 mmol) in CH2Cl2 (500 mL), and Et3N (51.7 g, 512 mmol) was cooled to 0 oC. Benzyl chloroformate (34.1 g, 205 mmol) was added dropwise, and the mixture was stirred at 0°C for 3h. The reaction mixture was washed with water, extracted with CH2Cl2, dried over Na2SO4 and concentrated in vacuo to provide (S)-2-benzyl 8-tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane- 2,3,8-tricarboxylate as a light yellow oil, which was used directly without further purification.

[00365] Step 2: In a solution of (S)-2-benzyl 8-tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3,8-tricarboxylate (79 g, 160 mmol, Step 1) in CH2Cl2 (400 mL) TFA (182 g, 1600 mmol) was added dropwise during RT. The reaction mixture was stirred for 3 h, then concentrated in vacuo. The residue was quenched with saturated NaHCO3 and solid NaHCO3 was added until no further gas evolution was noted. The mixture was extracted with EtOAc, and the combined organic layers were concentrated in vacuo. Purification by column chromatography on normal phase silica gel (CH2Cl2/MeOH/NH4OH) provided the title compound as a pale yellow solid. Intermediate 36: (S)-2-Tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate

[00366] Step 1: (S)-2-Benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (2.4 g, 6.9 mmol) in HCl/dioxane (50 mL, 3.3N) was stirred for 2 h at RT. The solvent was then removed in vacuum to provide (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate hydrochloride, which was used directly without further purification.

[00367] Step 2: In a solution of (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate hydrochloride and BOC2O (1.5 g, 6.9 mmol) in EtOH (50 mL) Pd/C (10%, 2.4 g) and HOAc (cat.) were added. The mixture was degassed and covered under H2, then stirred at 45oC at 3.51 kg/cm2 (50 psi) H2 for 12 h. The solid was filtered, and the filtrate concentrated in vacuo to provide the title compound as a viscous solid. Intermediate 37: Methyl 3,9-diazaspiro[5.5]undecane-2-carboxylate o

[00368] In a solution of 3,9-diazaspiro[5.5]undecane-2-carboxylic acid, 3-[(4-methoxyphenyl)methyl]-9-(phenylmethyl)-methyl ester [CAS# 1314388-32-3] (50 mg, 0.12 mmol) in MeOH (2 mL) and water (2 mL) was added a catalytic amount of TFA. The mixture was hydrogenated using an H-cube mechanism under 2 cycles of 80oC / 80 bar. The reaction mixture was cooled at RT, then concentrated in vacuum to provide the title compound as a white solid, which is used directly. General synthetic methods Methods for removing protecting group from N-Carbobenzyloxy (N-CBZ)

[00369] Method A- Hydrogenation in Pd/C: In a solution of compound protected by N-CBZ (1 eq.) in EtOAc, HOAc (100 μL) and 5% (w/w) Pd/C were added (5 mol%). The reaction mixture was degassed, covered under H2 (flask) 3 times, then stirred at RT for 2 h. The reaction was then filtered through a celite pad, which was rinsed with 1:9 MeOH:EtOAc. The filtrate was concentrated in vacuo. The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (H2O:HOAc: 99:1 to MeOH:AcOH99:1).

[00370] Method B- Dealkylation with TMSI: In a solution of compound protected by N-CBZ (1 eq.) in CH3CN, a solution of TMSI (2.2 eq.) in CH3CN (0.2 M) was added. The reaction mixture was stirred at RT for 2 h, then quenched with 1N HCl at pH1. The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (H2O:HOAc: 99:1 to MeOH:AcOH 99:1).

[00371] General ester hydrolysis with lithium hydroxide: In a solution of an ethyl ester compound (1 eq) in THF (0.18 M) and water (1.4 M) LiOH-H2O (10 eq) was added . The mixture was stirred at RT for 1 h. Water was added, and the pH was adjusted to 6.5 with 1 N HCl. THF was removed in vacuo, then the solid was precipitated, washed with water and dried in vacuo to yield the corresponding carboxylic acid.

[00372] The compounds of the examples were isolated in neutral hybrid form or as a salt of TFA or HCl. Example 1u: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl) acid -[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaes- pyro[4.5]decane-3-carboxylic acid

[00373] Step 1: In a solution of (R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (160 mg, 0.2 mmol, Intermediate 1) in dioxane (2 mL) were added 2-amino-4,6-dichloropyrimidine (100 mg, 0.16 mmol) and Cs2CO3 (48 g, 0.16 mmol). The reaction was heated at 80 °C for 16 h, cooled at RT and filtered. The solvent was removed in vacuo, and the residue was dissolved in a mixture of CH2Cl2 and heptane, concentrated to half volume, filtered and concentrated again in vacuo. Purification by chromatography on normal phase silica gel (CH2Cl2/Heptane) provided 4-[(1R)-1-[4-bromo-2-(3-methylpyrazol-1-yl)phenyl]-2, 2,2-Trifluoroethoxy]-6-chloro-pyrimidin-2-amine as an off-white solid.

[00374] Step 2: In a solution of 4-[(1R)-1-[4-bromo-2-(3-methyl-pyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy] -6-chloro-pyrimidin-2-amine (125 mg, 0.3 mmol, Step 1) in dioxane (3 mL) was added (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane- 2,3-dicarboxylate (95 mg, 0.3 mmol) and Na2CO3 (182 mg, 0.35 mmol). The reaction was heated at 90 °C for 130 h, then cooled at RT, filtered, and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-( 3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

[00375] Step 3: In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino- 6-((R)-1-(4-bromo-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) were added phenylboronic acid (143 mg, 0.8 mmol), PdCl2(PPh3)2 (41 mg, 0.058 mmol) and Cs2CO3 (390 mg, 1 .2 mmol). The reaction was heated at 60 oC for 16 h, then cooled at RT, filtered through celite and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)- 2,2,2-trifluoro-1- (3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane -2,3-dicarboxylate as a white solid.

[00376] Step 4: The solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)- 2,2,2-trifluoro-1-(3-(3-methyl -1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate ( 240 mg, 0.4 mmol, Step 3) in EtOAc (5 mL) was hydrogenated using an H-Cube mechanism and a 10% (w/w) Pd/C cartridge at a flow rate of 1.0 mL /min in RT. Purification on normal phase silica gel (EtOAc/heptane) provided (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl -1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4.5]decane-3-carboxylate.

[00377] Step 5: In a solution of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazole -1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (50 mg, 0.08 mmol) From Step 4 in THF (2.0 mL) and water (0.2 mL), lithium hydroxide monohydrate (58 mg, 0.05 mmol) was added. The reaction mixture was stirred at RT for 2 h, then the solution was neutralized with 1 N HCl and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptane) provided the title compound as an off-white solid as the hybrid form. Example 1m: acid (S)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[ 1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00378] Step 1: In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino- 6-((R)-1-(4-bromo-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (Step 2, Example 1u) (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) were added (3,4-dimethylphenyl)boronic acid (120 mg, 0.8 mmol), PdCl2(PPh3)2 (41 mg, 0.058 mmol) and Cs2CO3 (390 mg, 1.2 mmol). The reaction was heated at 60 oC for 16 h, then cooled at RT, filtered through celite and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl -3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaespiro[4.5]decane-2,3-dicarboxylate as a white solid.

[00379] Step 2: The solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1- (3',4'-dimethyl-3-(3-methyl -1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane -2,3-dicarboxylate (220 mg, 0.3 mmol) in EtOAc (5 mL) was hydrogenated using an H-Cube mechanism and a 10% (w/w) Pd/C cartridge at a flow rate of 1.0 mL/min at RT. Purification on normal phase silica gel (EtOAc/heptane) provided (S)-ethyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl -1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3 -carboxylate.

[00380] Step 3: In a solution of (S)-ethyl 8-(2-amino-6-((R)-1- (3',4'-dimethyl-3-(3-methyl-1H-pyrazole -1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (50 mg, 0.08 mmol) from Step 2 in THF (2.0 mL) and water (0.2 mL), lithium hydroxide monohydrate (58 mg, 0.05 mmol) was added. The reaction mixture was stirred at RT for 2 h, then the solution was neutralized with 1 N HCl and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptane) provided the title compound as an off-white solid as the hybrid form. Example 1cq: acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(hydroxymethyl)-4'-methyl-3-( 3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00381] Step 1: In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino- 6-((R)-1-(4-bromo-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (Step 2, Example 1u) (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added (3-(hydroxymethyl)-4-methylphenyl)boronic acid (CAS# 1451391-54-0; 120 mg , 0.7 mmol), PdCl2(PPh3)2 (41 mg, 0.058 mmol) and Cs2CO3 (390 mg, 1.2 mmol). The reaction was heated at 60 oC for 16 h, then cooled at RT, filtered through celite and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro- 1-(3'-(hydroxymethyl)-4'-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]- 4-yl)ethoxy)pyrimidin-4- il)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

[00382] Step 2: The solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)- 2,2,2-trifluoro-1-(3'-(hydroxymethyl) -4'-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[ 4.5]decane-2,3-dicarboxylate (200 mg, 0.24 mmol) in EtOAc (5 mL) was hydrogenated using an H-Cube mechanism and a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. Purification on normal phase silica gel (EtOAc/heptane) provided (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(hydroxymethyl) -4'-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate.

[00383] Step 3: In a solution of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(hydroxymethyl)-4'- methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5] decane-3-carboxylate (50 mg, 0.08 mmol) from Step 2 in THF (2.0 mL) and water (0.2 mL), lithium hydroxide monohydrate (58 mg, 0.05 mL) was added. mmol). The reaction mixture was stirred at RT for 2 h, then the solution was neutralized with 1 N HCl and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptane) provided the title compound as an off-white solid as the hybrid form. Example 1cr: acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-(hydroxymethyl)-3'-methyl-3-( 3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00384] The title compound was made as described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(hydroxymethyl)-4' acid -methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5 ]de-cane-3-carboxylic acid (Example 1cq) using (4-(hydroxymethyl)-3-methylphenyl)boronic acid (CAS# 1218790-88-5).

[00385] Using the generic scheme below, the following examples from Table 1a were prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1- (3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3 -carboxylic (Example 1u). Boronic acid was generally used to prepare the analogues below, however, where it was unavailable, the corresponding boronate was used. Example 1cp: (S)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-(trifluoromethyl)-1H-pyrazol-1-yl) acid -[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00386] The title compound was prepared as described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-) acid pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 1u) starting with acid ( S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diaza-spiro[4.5]decane-3-carboxylic acid (Example 10d). 1H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (br. s., 4 H) 1.91 - 2.01 (m, 1 H) 2.18 - 2.27 (m, 1 H ) 2.33 (d, J=11.71 Hz, 6 H) 2.88 - 3.00 (m, 1 H) 3.08 - 3.19 (m, 1 H) 3.38 - 3.56 (m, 2 H) 3.58 - 3.75 (m, 2 H) 3.85 - 3.98 (m, 1 H) 5.65 (s, 1 H) 6.55 - 6.70 (m , 1 H) 6.92 - 7.04 (m, 1 H) 7.19 - 7.28 (m, 1 H) 7.38 - 7.46 (m, 1 H) 7.46 - 7.53 (m, 1 H) 7.72 (s, 1 H) 7.83 (s, 2 H) 8.22 - 8.35 (m, 1 H) LCMS (MH+): 690. Example 2: acid (S )-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(piperidin-4- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4.5]decane-3-carboxylic acid

[00387] Step 1: The solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)- 2,2,2-trifluoro-1-(2-(3-methyl -1H-pyrazol-1-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2, 3-dicarboxylate (Example 1f) (150 mg, 0.15 mmol) in MeOH (5 mL) was hydrogenated in an H-Cube mechanism using a 10% (w/w) Pd/C cartridge at a flow rate of 1.0 mL/min at RT. The resulting eluent was concentrated in vacuo, and the product was purified by column chromatography using an Isco Gold reversed-phase silica cartridge (100% CH2Cl2 at 90:9:1 CH2Cl2:MeOH:conc. NH4OH) to give (S )-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4 - (1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaes- pyro[4.5]decane-2,3-dicarboxylate.

[00388] Step 2: Hydrolysis of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)- 2,2,2-trifluoro-1-(2-(3-methyl- 1H-pyrazol-1-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3 -dicarboxylate using the general LiOH method gave the title compound as an off-white solid. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.49 - 1.69 (m, 4 H) 2.00 - 2.18 (m, 3 H) 2.21 - 2.35 (m, 1 H) 2.38 (s, 3 H) 2.92 - 3.05 (m, 1 H) 3.08 (d, J=0.44 Hz, 2 H) 3.10 - 3.18 (m, 2 H) 3.25 (d, J=11.71 Hz, 1 H) 3.38 - 3.72 (m, 7 H) 4.09 (t, J=7.88 Hz, 1 H) 5, 69 (s, 1 H) 6.41 (d, J=2.29 Hz, 1 H) 6.74 (q, J=6.80 Hz, 1 H) 7.34 (d, J=1.12 Hz, 1 H) 7.43 (d, J=8.15 Hz, 1 H) 7.71 (d, J=8.44 Hz, 1 H) 7.91 (d, J=2.20 Hz, 1 H). LCMS (MH+): 613. Example 3a: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazole) acid -1-yl)-4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00389] Step 1: In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino- 6-((R)-2,2,2-trifluoro-1-(2-(3- methyl-1H-pyrazol-1-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane -2,3-dicarboxylate (320 mg, 0.413 mmol) in CH2Cl2 (5.0 mL) was added methanesulfonyl chloride (47 mg, 0.41 mmol) and triethylamine (94 mg, 0.83 mmol), and the reaction was stirred for 1.5 h at RT, and then concentrated in vacuo. The product was purified by column chromatography using an Isco Gold reverse phase silica cartridge (100% CH2Cl2 to 90:9:1 CH2Cl2:MeOH:NH4OH conc.) to provide (S)-2-benzyl 3-ethyl 8 -(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)-1 ,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.

[00390] Step 2: The solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)- 2,2,2-trifluoro-1-(2-(3-methyl -1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[ 4.5]decane-2,3-dicarboxylate (290 mg, 0.340 mmol, Step 1) in MeOH (10 mL) was hydrogenated in an H-Cube mechanism using a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. The resulting eluent was concentrated in vacuo, and the product was purified by column chromatography using an Isco Gold reversed-phase silica cartridge (100% CH2Cl2 at 90:9:1 CH2Cl2:MeOH:conc. NH4OH) to give (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1 -(methylsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4.5]decane-3-carboxylate.

[00391] Step 3: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazole -1-yl)-4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the general method of LiOH gave the title compound as an off-white solid. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.53 - 1.65 (m, 4 H) 1.80 (qd, J=12.57, 3.98 Hz, 2 H) 1.94 - 2.02 (m, 2 H) 2.02 - 2.12 (m, 1 H) 2.31 (dd, J=13.42, 9.27 Hz, 1 H) 2.38 (s, 3 H ) 2.67 - 2.94 (m, 3 H) 2.86 (s, 3 H) 3.07 - 3.28 (m, 2 H) 3.37 - 3.74 (m, 4 H) 3 .78 - 3.92 (m, 2 H) 4.08 (dd, J=9.15, 7.20 Hz, 1 H) 5.71 (s, 1 H) 6.39 (d, J=2 .29 Hz, 1 H) 6.64 - 6.82 (m, 1 H) 7.31 (d, J=1.71 Hz, 1 H) 7.42 (dd, J=8.25, 1, 76 Hz, 1 H) 7.67 (d, J=8.10 Hz, 1 H) 7.89 (d, J=2.29 Hz, 1 H). LCMS (MH+): 693.

[00392] Using the generic scheme below, the following examples from Table 2a can be prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1 acid -(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4.5]decane-3-carboxylic acid (Example 3a). Example 4: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methoxy-4'-(methoxycarbonyl)-3-(3-) acid methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00393] Step 1: In a solution of acid (S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10 m ) (135 mg, 0.18 mmol) in dioxane (2 mL) were added (3-methoxy-4-(methoxycarbonyl)phenyl) boronic acid (84 mg, 0.4 mmol) and Cs2CO3 (48 mg, 0.16 mmol). The reaction was heated at 80 °C for 16 h, cooled at RT and filtered. The solvent was removed in vacuum. Purification by chromatography on normal phase silica gel (CH2Cl2/Heptane) provided acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3' -methoxy-4'-(methoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2- ((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid.

[00394] Step 2: Deprotection by N-CBZ was carried out using method B to produce acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-( 3'-methoxy-4'-(methoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.66 (d, J=5.47 Hz, 4 H) 2.03 - 2.17 (m, 1 H) 2.42 (s, 4 H ) 3.16 - 3.30 (m, 2 H) 3.47 - 3.81 (m, 4 H) 3.89 (s, 3 H) 3.97 (s, 3 H) 4.26 - 4 .45 (m, 1 H) 6.40 - 6.52 (m, 1 H) 6.82 - 6.96 (m, 1 H) 7.30 - 7.37 (m, 1 H) 7.40 (s, 1 H) 7.76 (s, 1 H) 7.80 - 7.93 (m, 4 H) 7.99 - 8.09 (m, 1 H). LCMS: 696.7. Example 5a: acid (S)-8-(2-amino-6-((R)-1-(3'-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00395] The title compound was made according to the procedures described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methoxy-acid) 4'-(methoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8 -diazaspiro[4.5]decane-3-carboxylic acid (Example 4). 1H NMR (400 MHz, MeOH-d4): δ ppm 1.42 (t, J=7.13 Hz, 3 H) 1.61 (br. s., 4 H) 2.02 - 2.14 (m , 1 H) 2.28 - 2.40 (m, 1 H) 2.42 (s, 3 H) 3.06 - 3.19 (m, 1 H) 3.21 - 3.30 (m, 1 H) 3.40 - 3.60 (m, 2 H) 3.62 - 3.80 (m, 2 H) 4.01 - 4.19 (m, 1 H) 4.41 (d, J=7 .22 Hz, 2 H) 5.76 (s, 1 H) 6.45 (d, J=2.34 Hz, 1 H) 6.79 - 6.92 (m, 1 H) 7.60 (s , 1 H) 7.70 (d, J=1.56 Hz, 1 H) 7.80 (d, J=1.56 Hz, 1 H) 7.84 (s, 1 H) 7.90 - 7 .97 (m, 1 H) 8.02 (d, J=2.15 Hz, 1 H) 8.05 (s, 1 H) 8.31 (s, 1 H) 680.7. LCMS (MH+): 578.7. Example 5b: acid (S)-8-(2-amino-6-((R)-1-(4'-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00396] The title compound was made according to the procedures described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methoxy-acid) 4'-(methoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8 -diazaspiro[4.5]decane-3-carboxylic acid (Example 4). 1H NMR (400 MHz, MeOH-d4): δ ppm 0.88 (m, 4H), 1.30 (d, J = 17.4 Hz, 10H), 1.40 (t, J = 7.1 Hz , 4H), 1.59 (d, J = 5.8 Hz, 5H), 2.05 (dd, J = 13.5, 7.2 Hz, 1H), 2.35 (m, 5H), 3 .11 (d, J = 11.7 Hz, 1H), 3.24 (d, J = 11.7 Hz, 1H), 3.49 (ddd, J = 28.1, 12.7, 5.7 Hz, 2H), 3.66 (dd, J = 13.2, 7.3 Hz, 3H), 4.07 (t, J = 8.1 Hz, 1H), 4.38 (q, J = 7 .1 Hz, 2H), 4.82 (d, J = 9.7 Hz, 1H), 4.91 (s, 2H), 5.75 (s, 1H), 6.42 (d, J = 2 .4 Hz, 1H), 6.83 (q, J = 6.5 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.81 (m, 4H), 8, 00 (d, J = 2.4 Hz, 1H), 8.10 (m, 2H). LCMS (MH+): 681. Example 6: (S)-8-(2-amino-6-((R)-1-(4-(3-carboxypropyl)-2-(3-methyl-1H-pyrazole) acid -1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00397] Step 1: In a solution of 9-borabicyclo[3.3.1]nonane (2.0 mL, 0.5 M in THF, 1.0 mmol) methyl but-3-enoate (100 μL, 1 .0 mmol) and stirred at RT for 2 h to prepare the 9-BBN/butane solution.

[00398] Step 2: In a solution of acid (S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro [4.5]decane-3-carboxylic acid (product of Step 3, Example 10 m ) (250 mg, 0.32 mmol) in THF (2 mL) were added sequentially PdCl2(dppf)CH2Cl2 (8 mg, 0.01 mmol), NaOEt (66 mg, 1 mmol), and the 9-BBN solution /butene prepared from Step 1. The reaction was heated to 65 °C for 2 h, then cooled at RT. The reaction was extracted with EtOAc, brine and dried over Na2SO4 and concentrated in vacuo. The product was purified by column chromatography using an Isco Gold reverse phase silica cartridge (100% CH2Cl2 at 90:9:1 CH2Cl2:MeOH:NH4OH conc.) to provide (S)-2-benzyl 3-ethyl 8 -(2-amino-6-((R)-2,2,2-trifluoro- 1-(4-(4-methoxy-4-oxobutyl)-2-(3-methyl-1H-pyrazol-1-yl )phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.

[00399] Step 3: Deprotection by N-CBZ was carried out using method B to provide (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-( 4-(4-methoxy-4-oxobutyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate as an off-white solid.

[00400] Step 4: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(4-methoxy-4-oxobutyl )-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate was performed using the general method of LiOH providing the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.40 - 1.61 (m, 4 H) 1.76 - 1.93 (m, 3 H) 2.24 (t, J=7.35 Hz, 2 H) 2.27 - 2.37 (m, 4 H) 2.58 - 2.74 (m, 2 H) 3.10 (br. s., 2 H) 3.53 (br. s ., 4 H) 4.42 (br. s., 1 H) 5.71 (br. s., 1 H) 6.00 (br. s., 2 H) 6.38 (d, J=2 .20 Hz, 1 H) 7.00 (q, J=6.87 Hz, 1 H) 7.29 (d, J=1.51 Hz, 1 H) 7.32 - 7.41 (m, 1 H) 7.60 (s, 1 H) 8.05 (d, J=2.29 Hz, 1 H) 8.94 (br. s., 1 H) 10.20 (br. s, 1 H) 12.14 (br. s., 1 H). LCMS (MH+): 618.6. Example 7: (S)-8-(2-amino-6-((R)-1-(4-(2-carboxyethyl)-2-(3-methyl-1H-pyrazol-1-yl) acid phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4.5]decane-3-carboxylic acid

[00401] The title compound was made as described for acid (S)-8-(2-amino-6-((R)-1-(4-(3-carboxypropyl)-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 6). 1H NMR (400 MHz, MeOH-d4):δ ppm 1.56 (t, J=5.54 Hz, 4 H) 1.97 (s, 2 H) 2.04 (dd, J=13.30, 7.10 Hz, 1 H) 2.29 (dd, J=13.67, 9.18 Hz, 1 H) 2.35 (s, 3 H) 2.59 - 2.68 (m, 2 H) 2.97 (t, J=7.49 Hz, 2 H) 3.06 - 3.13 (m, 1 H) 3.23 (d, J=11.86 Hz, 1 H) 3.39 - 3 .55 (m, 2 H) 3.57 - 3.75 (m, 2 H) 4.06 (dd, J=9.05, 7.30 Hz, 1 H) 5.72 (s, 1 H) 6.36 (d, J=2.29 Hz, 1 H) 6.71 (q, J=6.61 Hz, 1 H) 7.28 (d, J=1.61 Hz, 1 H) 7, 37 (dd, J=8.20, 1.46 Hz, 1 H) 7.62 (d, J=8.10 Hz, 1 H) 7.83 (d, J=2.25 Hz, 1 H) . LCMS (MH+): 604. Example 9: (S)-8-(2-amino-6-((R)-1-(4-(3-ethoxy-3-oxopropyl)-2-(3-methyl) acid -1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00402] Step 1: In a solution of acid (S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10 m ) (240 mg, 0.33 mmol) in ethanol (8 mL) were added (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate ( 110 mg, 0.49 mmol), PdCl2(PPh3)2 (20 mg, 0.049 mmol) and KHCO3 (170 mg, 0.05 mmol). The reaction was heated at 80 °C for 2 h, cooled at RT and filtered. The solvent was removed in vacuum. Purification by chromatography on normal phase silica gel (CH2Cl2/ heptane) provided acid ((S)-8-(2-amino-6-((R)-1-(4-((E)-3- ethoxy-3-oxoprop-1-en- 1-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2- ((((2E,4Z)-2-vinylexa-2,4-dien-1-yl)oxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as a white solid.

[00403] Step 2: In an acid solution ((S)-8-(2-amino-6-((R)-1- (4-((E)-3-ethoxy-3-oxoprop-1- en-1-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((((2E,4Z) -2-vinylexa-2,4-dien-1-yl)oxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (180 mg, 0.15 mmol) in MeOH (5 mL) was hydrogenated in an H-Cube mechanism using a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. The resulting eluent was concentrated in vacuum, and the product was purified by Column chromatography using an Isco Gold reversed phase silica cartridge (100% CH2Cl2 at 90:9:1 CH2Cl2:MeOH:NH4OH conc.) to provide the title compound as a white solid. 1H NMR (400 MHz, MeOH- d4):δ ppm 1.14 (t, J=7.15 Hz, 3 H) 1.50 - 1.68 (m, 4 H) 1.94 - 1.99 (m, 2 H) 2.04 (dd, J=13.45, 7.20 Hz, 1 H) 2.30 (dd, J=13.47, 9.27 Hz, 1 H) 2.35 (s, 3 H) 2.66 ( t, J=7.54 Hz, 2 H) 2.97 (t, J=7.52 Hz, 2 H) 3.07 - 3.14 (m, 1 H) 3.23 (d, J=11 .76 Hz, 1 H) 3.39 - 3.72 (m, 4 H) 4.01 - 4.11 (m, 3 H) 5.70 (s, 1 H) 6.36 (d, J= 2.34 Hz, 1 H) 6.72 (q, J=6.72 Hz, 1 H) 7.27 (d, J=1.61 Hz, 1 H) 7.35 (dd, J=8, 15, 1.61 Hz, 1 H) 7.62 (d, J=8.05 Hz, 1 H) 7.83 (d, J=2.34 Hz, 1 H). LCMS (MH+): 632.1 Example 10d: (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-) acid yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00404] Step 1: In a solution of (1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethanol (40 g, 138 mmol) in dioxane (400 mL) 4,6-dichloropyrimidin-2-amine (113 g, 690 mmol) and Cs2CO3 (132 g, 405 mmol) were added. The mixture was heated for 24 h at 80°C. The reaction was then cooled at RT and filtered. The solvent was removed in vacuo, then CH2Cl2 and heptane were added. The volume of solvent was reduced until a solid precipitated. The solid was filtered, and the procedure repeated several times to yield 4-chloro-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2 -trifluoroethoxy]pyrimidin-2-amine as a white solid.

[00405] Step 2: In a solution of 4-chloro-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy] pyrimidin-2-amine (57.3 g, 137 mmol, Step 1) in dioxane (500 mL) was added (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (48 g, 124.9 mmol) and NaHCO3 (31.5 g, 375 mmol). After 5 h, an additional amount of NaHCO3 (31.5 g, 375 mmol) was added, and the reaction mixture was heated at 90 oC for 36 h. The reaction was then cooled at RT and filtered. Purification by column on normal phase silica gel (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-( 3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

[00406] Step 3: Deprotection by N-CBZ was carried out using method B to provide (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3 -methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaes-piro[4.5]decane-3-carboxylate as an off-white solid.

[00407] Step 4: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2- (3-methyl-1H-pyrazol-1-yl)phenyl )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4.5]decane-3-carboxylate using the general LiOH method provided the title compound as an off-white solid.

[00408] Using the generic scheme below, the following examples from Table 3a were prepared as described above for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-() acid 3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) . Example 10o: (S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2 acid ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-3-carboxylic acid

[00409] The title compound was prepared as described for acid (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(5-bromo- [1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethanol (Intermediate 38). 1H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 7.7 Hz, 2H), 1.61 (q, J = 6.5, 5.3 Hz, 4H), 2 .06 (dd, J = 13.5, 7.4 Hz, 1H), 2.36 (dd, J = 13.5, 9.1 Hz, 1H), 3.15 (d, J = 11.9 Hz, 1H), 3.26 (d, J = 11.7 Hz, 1H), 3.47 (ddt, J = 21.7, 13.4, 5.8 Hz, 2H), 3.63 (m , 2H), 4.18 (t, J = 8.2 Hz, 1H), 6.63 (q, J = 6.8 Hz, 1H), 7.50 (m, 7H). LCMS (MH+): 607. Example 10p: (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-(trifluoromethyl)-1H-pyrazole acid -1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00410] The title compound was prepared as described for acid (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(4-chloro- 2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (Intermediate 39). 1H NMR (400 MHz, MeOH-d4): δ ppm 1.53 (d, J=5.08 Hz, 4 H) 1.77 - 1.87 (m, 1 H) 2.03 - 2.20 ( m, 1 H) 2.75 (s, 1 H) 2.99 (s, 1 H) 3.37 -3.53 (m, 2 H) 3.54 - 3.66 (m, 2 H) 3 .66 - 3.77 (m, 1 H) 5.56 (s, 1 H) 6.53 - 6.70 (m, 1 H) 6.96 (d, J=2.34 Hz, 1 H) 7.62 (dd, J=4.30, 2.34 Hz, 2 H), 7.76 (s, 1 H) 8.25 (d, J=1.37 Hz, 1 H). LCMS (MH+): 620. Example 10pa: (S)-8-(2-amino-6-((R)-1-(2-(3-(tert-butyl)-1H-pyrazol-1 acid -yl)-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4.5]decane-3-carboxylic acid

[00411] The title compound was prepared as described for acid (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(2-(3 -(tert-butyl)-1H-pyrazol-1-yl)-4-chlorophenyl)-2,2,2-trifluoroethanol (Intermediate 40). 1H NMR (400 MHz, MeOH-d4): δ ppm 1.40 (s, 9 H) 1.51 - 1.68 (m, 4 H) 1.99 - 2.12 (m, 1 H) 2, 25 - 2.41 (m, 1 H) 3.05 - 3.16 (m, 1 H) 3.20 -3.28 (m, 1 H) 3.38 - 3.55 (m, 2 H) 3.56 - 3.73 (m, 2 H) 4.00 - 4.16 (m, 1 H) 5.57 (s, 1 H) 6.52 (d, J=2.34 Hz, 1 H ) 7.15 - 7.28 (m, 1 H) 7.44 - 7.53 (m, 1 H) 7.56 (d, J=1.95 Hz, 1 H) 7.68 - 7.79 (m, 1 H) 7.95 (d, J=2.34 Hz, 1 H). LCMS (MH+): 609. Example 10q: (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-isopropyl-1H-pyrazol-1-yl) acid )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaes-piro[4.5]decane-3-carboxylic acid

[00412] The title compound was prepared as described for acid (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(4-chloro- 2-(3-isopropyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (Intermediate 41). 1H NMR (400 MHz, MeOH-d4): δ ppm 1.36 (dd, J=6.93, 1.07 Hz, 6 H) 1.57 (br. s., 4 H) 1.86 - 2 .03 (m, 1 H) 2.15 - 2.30 (m, 1 H) 2.86 - 3.00 (m, 1 H) 3.02 - 3.19 (m, 2 H) 3.39 - 3.55 (m, 2 H) 3.57 - 3.73 (m, 2 H) 3.82 - 3.98 (m, 1 H) 5.63 (s, 1 H) 6.40 - 6 .56 (m, 1 H) 6.93 - 7.10 (m, 1 H) 7.54 (s, 2 H) 7.67 - 7.78 (m, 1 H) 7.91 - 8.02 (m, 1 H). LCMS (MH+): 595. Example 10r: (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-cyclopropyl-1H-pyrazol-1) acid -yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4.5]decane-3-carboxylic acid

[00413] The title compound was prepared as described for acid (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(4-chloro- 2-(3-cyclopropyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (Intermediate 42). 1H NMR (400 MHz, MeOH-d4): δ ppm 0.77 - 0.90 (m, 2 H) 0.95 - 1.08 (m, 2 H) 1.49 - 1.65 (m, 4 H) 1.80 - 1.95 (m, 1 H) 1.99 - 2.10 (m, 1 H) 2.10 - 2.24 (m, 1 H) 2.74 - 2.85 (m , 1 H) 3.00 - 3.11 (m, 1 H) 3.38 - 3.69 (m, 4 H) 3.72 - 3.84 (m, 1 H) 5.56 - 5.70 (m, 1 H) 6.29 - 6.38 (m, 1 H) 6.89 - 7.05 (m, 1 H) 7.52 (s, 2 H) 7.67 - 7.77 (m , 1 H) 7.86 - 7.98 (m, 1 H). LCMS (MH+): 593. Example 11: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(6-methyl-2-(3-methyl) acid -1H-pyrazol-1-yl)pyridin-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaes- piro[4.5]decane-3-carboxylic acid

[00414] The title compound was prepared as described for acid (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (S)-2,2,2-trifluoro -1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)ethanol (Intermediate 20) Example 12a: (S)-8-(2-amino-6) acid -((R)-1-(4-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5]decane-3-carboxylic acid

[00415] Step 1: In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino- 6-((R)-1-(4-bromo-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (300 mg, 0.388 mmol, see the Example 1u) in EtOH:H2O (15 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (90 mg, 0.58 mmol), KHCO3 (389 mg, 3 .88 mmol) and PdCl2(PPh3)2 (41 mg, 0.058 mmol). The reaction mixture was heated at 80 °C for 1 h, then cooled at RT. The reaction was diluted with water, extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification with a 40 g Isco RediSep silica cartridge (EtOAc:heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1 -(2-(3-methyl-1H-pyrazol-1-yl)-4-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

[00416] Step 2: Deprotection by N-CBZ was carried out using method A, which similarly reduced the olefin, to provide (S)-2-benzyl 3-ethyl 8-(2-amino-6-(( R)-1-(4-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5 ]decane-2,3-dicarboxylate as a white solid.

[00417] Step 3: Hydrolysis of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1- (4-ethyl-2-(3-methyl-1H-pyrazol- 1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate using the general LiOH method provided the title compound as a solid white.

[00418] Using the same scheme below, the following examples from Table 4a were prepared as described above for (S)-8-(2-amino-6-((R)-1-(4-ethyl-2-() acid 3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 12a). Example 13: acid (3S)-8-(2-amino-6-((1R)-1-(4-(1,2-dihydroxyethyl)- 2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00419] Step 1: In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino- 6-((R)-2,2,2-trifluoro-1-(2-(3- methyl-1H-pyrazol-1-yl)-4-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (product of Step 1, Example 12b) (373 mg, 0.518 mmol) in 4:1 acetone:H2O (20 mL) was added OsO4 (313 μL of a 4% (w/w) aqueous solution, 325 mg, 0.0518 mmol) and N-methylmorpholine- N-oxide (214 μL of a 50% (w/w) aqueous solution, 242 mg, 1.04 mmol). The reaction was stirred at RT for 24 h, concentrated in vacuo, and the residue was purified by chromatography on a 50 g Isco Gold Redi-Sep reversed-phase silica cartridge (H2O:HOAc: 99:1 to EtOH:HOAc 99 :1). A second purification on a 40 g Isco RediSep silica cartridge eluting (CH2Cl2100% to 90:9:1 CH2Cl2:EtOH:NH4OH) provided (3S)-2-benzyl 3-ethyl 8-(2-amino-6-( (1R)-1-(4-(1,2-dihydroxyethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl )-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

[00420] Step 2: Deprotection by N-CBZ was carried out using method A to provide (3S)-ethyl 8-(2-amino-6-((1R)-1-(4-(1,2-di -hydroxy-ethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3 -carboxylate as a white solid.

[00421] Step 3: Hydrolysis of (3S)-ethyl 8-(2-amino-6-((1R)-1-(4-(1,2-dihydroxyethyl)-2-(3-methyl-1H -pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the general LiOH method gives the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.49 - 1.66 (m, 4 H) 2.05 (dd, J=13.50, 7.20 Hz, 1 H) 2.31 ( dd, J=13.45, 9.20 Hz, 1 H) 2.38 (s, 3 H) 3.04 - 3.28 (m, 2 H) 3.38 - 3.76 (m, 6 H ) 4.08 (dd, J=8.98, 7.27 Hz, 1 H) 4.67 - 4.79 (m, 1 H) 5.72 (d, J=2.15 Hz, 1 H) 6.39 (d, J=2.29 Hz, 1 H) 6.77 (q, J=6.65 Hz, 1 H) 7.45 (s, 1 H) 7.52 (d, J=8 .20 Hz, 1 H) 7.71 (d, J=8.15 Hz, 1 H) 7.88 (dd, J=4.20, 2.34 Hz, 1 H). LCMS (MH+): 592. Example 14: (S)-8-(2-amino-6-((R)-1-(4-cyano-2-(3-methyl-1H-pyrazol-1) acid -yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-3-carboxylic acid

[00422] Step 1: In a solution of (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (730 mg, 1.0 mmol) ZnCN2 ( 280 mg, 2.4 mmol), Zn (64 mg, 1.0 mmol), DMA (10 mL) and Pd(P-t-Bu3)2 (78 mg, 0.15 mmol). The reaction mixture was heated in a sealed bottle at 115oC for 2 h, then cooled at RT, filtered and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptate) provided (3S)- 2-benzyl 3-ethyl 8-(2-amino-6-(1-(4-cyano-2-(3-methyl- 1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a viscous oil.

[00423] Step 2: Deprotection by N-CBZ was performed via Method A to provide (3S)-ethyl 8-(2-amino-6-(1-(4-cyano-2-(3-methyl-1H - pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4.5]decane-3-carboxylate as an off-white solid.

[00424] Step 3: Hydrolysis of (3S)-ethyl 8-(2-amino-6-(1-(4-cyano-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the general LiOH method provides the title compound as an off-white solid. 1H NMR (400 MHz, MeOH-d4):δ ppm 1.47 - 1.71 (m, 4 H) 1.95 - 2.10 (m, 1 H) 2.20 - 2.33 (m, 1 H) 2.36 (s, 3 H) 2.96 - 3.24 (m, 2 H) 3.35 - 3.54 (m, 2 H) 3.55 - 3.79 (m, 2 H) 3.92 - 4.13 (m, 1 H) 5.65 (s, 1 H) 6.42 (d, J=2.15 Hz, 1 H) 6.95 (q, J=6.72 Hz , 1 H) 7.70 - 7.91 (m, 3 H) 7.97 (d, J=2.25 Hz, 1 H). LCMS (MH+): 556. Example 15: (S)-8-(2-amino-6-((R)-1-(4-carbamoyl-2-(3-methyl-1H-pyrazol-1-yl) acid )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaes-piro[4.5]decane-3-carboxylic acid

[00425] Step 1: In a solution of (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(1-(4-cyano-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (150 mg, 0.2 mmol, see Ex. 14 ) in toluene (10 mL) acetaldehyde oxime (240 mg, 4 mmol) and InCl3 (44 mg, 0.2 mmol) were added. The reaction was heated at 110 oC for 3 h, then cooled at RT and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptate) provided (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(1-(4-carba-moyl-2-(3- methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

[00426] Step 2: Deprotection by N-CBZ was performed via Method A to provide (3S)-ethyl 8-(2-amino-6-(1-(4-carbamoyl-2-(3-methyl -1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.

[00427] Step 3: Hydrolysis of (3S)-ethyl 8-(2-amino-6-(1-(4-carbamoyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the general LiOH method provides the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.56 (t, J=4.98 Hz, 5 H) 2.03 (dd, J=13.47, 7.03 Hz, 1 H) 2 .23 - 2.33 (m, 2 H) 2.35 - 2.39 (m, 3 H) 3.04 - 3.12 (m, 1 H) 3.22 (d, J=11.71 Hz , 1 H) 3.37 - 3.72 (m, 5 H) 4.05 (dd, J=9.20, 7.05 Hz, 1 H) 5.70 (s, 1 H) 6.40 ( d, J=2.39 Hz, 1 H) 6.82 - 6.92 (m, 1 H) 7.80 (d, J=8.10 Hz, 1 H) 7.87 - 7.97 (m , 4 H). LCMS (MH+): 575. Example 16: (S)-8-(2-amino-6-((R)-1-(4-carboxy-2-(3-methyl-1H-pyrazol-1-yl) acid )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-3-carboxylic acid

[00428] Step 1: In a solution of (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(1-(4-cyano-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (0.35 g, 0.50 mmol, see Ex 14) in MeOH (5 mL) and water (1 mL) LiOH-H2O (0.20 g, 5 mmol) was added. The mixture was heated at 50oC overnight. The reaction was then cooled at RT, and the reaction was acidified with 6N HCl at pH=1. Concentration in vacuum followed by purification by reversed-phase HPLC (MeOH/water/HOAc) afforded (3S)-8-(2-amino-6-(1-(4-carboxy-2-(3-methyl-1H-) pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as a white solid.

[00429] Step 2: Deprotection by N-CBZ was carried out using Method A to provide the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4):δ ppm 1.57 (t, J=5.42 Hz, 4 H) 2.03 (dd, J=13.42, 7.42 Hz, 1 H) 2 .25 - 2.35 (m, 2 H) 2.37 (s, 2 H) 3.04 -3.13 (m, 1 H) 3.16 - 3.25 (m, 1 H) 3.38 - 3.75 (m, 5 H) 4.06 (dd, J=9.03, 7.32 Hz, 1 H) 5.72 (s, 1 H) 6.39 (d, J=2.29 Hz, 1 H) 6.78 - 6.89 (m, 1 H) 7.76 (d, J=8.15 Hz, 1 H) 7.90 (d, J=2.34 Hz, 1 H) 7.95 (d, J=1.42 Hz, 1 H) 8.04 (dd, J=8.13, 1.59 Hz, 1 H). LCMS (MH+): 576. Example 17: (S)-8-(2-amino-6-((R)-1-(4-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1) acid -yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00430] Step 1: In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino- 6-((R)-1-(4-bromo-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (1.50 g, 1.94 mmol, See Ex. 1u) in THF (20 mL), MeOH (10 mL) and water (10 mL) LiOH-H2O (0.80 g, 19.4 mmol) was added, and the reaction was stirred at RT for 4 h. The pH of the reaction mixture was adjusted to 6.5 with 6N HCl, and the organic solvents were removed in vacuo to provide a white solid which was filtered. The reaction mixture was then partitioned between water and EtOAc and extracted. The combined organic layers were washed with brine, dried over Na2SO4, filtered and then concentrated in vacuo to provide (2S)-8-[2-amino-6-[(1R)-1-[4-bromo-2- (3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-4-yl]-3-benzyloxycarbonyl-3,8-diazaspiro[4.5]decane-2-carboxylic acid as a white solid, which is used directly without further purification.

[00431] Step 2: In a solution of acid (2S)-8-[2-amino-6-[(1R)-1-[4-bromo-2-(3-methylpyrazol-1-yl)phenyl]- 2,2,2-trifluoro-ethoxy]pyrimidin-4-yl]-3-benzyloxycarbonyl-3,8-diazaspiro[4.5]decane-2-carboxylic acid (74 mg, 0.10 mmol, Step 2) in EtOH (4 mL) KHCO3 (84 mg, 1.0 mmol) was added. The reaction mixture was degassed, adjusted with a 1 atm CO balloon, then treated with PdCl2(PPh3)2 (14 mg, 0.02 mmol). The reaction was degassed once again with 1 atm CO, and then heated at 80 oC for 12 h. The reaction was cooled at RT, concentrated in vacuo, and the residue was partitioned between water and EtOAc and extracted. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column on normal phase silica gel (CH2Cl2/AcOH/EtOH) provided acid (2S)-8-[2-amino-6-[(1R)-1-[4-ethoxycarbonyl-2-(3-methylpyrazole -1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-4-yl]-3-benzyloxycarbonyl-3,8-diazaspiro[4.5]decane-2-carboxylic acid as a white solid.

[00432] Step 3: Deprotection by N-CBZ was carried out using Method A to provide the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.37 (t, J=7.13 Hz, 3 H) 1.58 (d, J=4.30 Hz, 4 H) 1.97 (s , 2 H) 2.04 (dd, J=13.47, 7.27 Hz, 1 H) 2.30 (dd, J=13.59, 9.25 Hz, 1 H) 2.38 (s, 3 H) 3.05 - 3.27 (m, 2 H) 3.39 - 3.76 (m, 4 H) 3.99 - 4.10 (m, 1 H) 4.37 (q, J= 7.13 Hz, 2 H) 5.68 (s, 1 H) 6.41 (d, J=2.34 Hz, 1 H) 6.84 (q, J=6.67 Hz, 1 H) 7 .83 (d, J=8.10 Hz, 1 H) 7.94 (d, J=2.34 Hz, 1 H) 7.99 (d, J=1.61 Hz, 1 H) 8.09 (dd, J=8.27, 1.68 Hz, 1 H). LCMS (MH+): 604. Example 18a: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(((1,1,1) acid ,3,3,3-hexafluoro-2-methylpropan-2-yl)oxy)carbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2, 8-diazaspiro[4.5]de-cane-3-carboxylic acid

[00433] Step 1: In a solution of acid (S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10 m ) (1.2 g, 1.6 mmol) in DMF (16 mL) benzyl bromide (0.27 g, 1.6 mmol) and NaHCO3 (0.67 g, 8.0 mmol) were added. The reaction was then heated to 60 oC for 2h, cooled at RT and stirred for 12h. The precipitate was filtered, washed with EtOAc, and the filtrate concentrated in vacuo. The residue was partitioned between water and EtOAc and extracted. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptane) provided (S)-dibenzyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl -1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-2,3-dicarboxylate as the white solid.

[00434] Step 2: In a solution of (S)-dibenzyl 8-(2-amino-6-((R)- 1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate from Step 1 (415 mg, 0.50 mmol) in 1.4 -dioxane (8 mL) and water (4 mL) KHCO3 (420 mg, 5.0 mmol) was added, and the reaction was degassed with 1 atm CO. Then, PdCl2(PPh3)2 (140 mg, 0.10 mmol) was added, and the reaction mixture was treated with 1 atm CO (flask). The reaction mixture was heated at 80 oC for 12 h, then cooled at RT and concentrated in vacuo. The residue was partitioned between water and EtOAc and extracted. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by normal phase silica gel column (CH2Cl2/MeOH/NH4OH) provided 4-[(1R)- 1-[2-amino-6-[(2S)-2,3-bis(benzyloxycarbonyl)-3 ,8-diazaspiro[4.5]decan-8-yl]pyrimidin-4-yl]oxy-2,2,2-trifluoro-ethyl]-3-(3-methylpyrazol-1-yl)benzoic acid as a white solid.

[00435] Step 3: In a solution of 4-[(1R)-1-[2-amino-6-[(2S)-2,3-bis(benzyloxycarbonyl)-3,8-diazaspiro[4.5]decan acid -8-yl]pyrimidin-4-yl]oxy-2,2,2-trifluoroethyl]-3-(3-methylpyrazol-1-yl)benzoic acid (80 mg, 0.1 mmol) in CH2Cl2 (4 mL ) DMAP (73 mg, 0.6 mmol), (CF3)2MeCOH (108 mg, 0.6 mmol) were added, followed by EDCI (114 mg, 0.6 mmol). The reaction mixture was stirred at RT for 12 h, diluted with CH2Cl2 and washed with water. The aqueous solution was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptane) provided dibenzyl (2S)-8-[2-amino-6-[(1R)-2,2,2-trifluoro-1-[2-(3 -methylpyrazol-1-yl)-4-[2,2,2-trifluoro-1-methyl-1-(trifluoromethyl)ethoxy]carbonyl-phenyl]ethoxy]pyrimidin-4-yl]-3,8-diazaspiro[4.5 ]decane-2,3-dicarboxylate as a white solid.

[00436] Step 4: Deprotection by N-CBZ was carried out using Method A to provide the title compound as a white solid.

[00437] Using the generic scheme below, the following examples from Table 5a were prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1- (4-(((1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl)oxy)carbonyl)-2-(3-methyl-1H-pyrazol-1-yl) phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 18a). Example 19a: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl) acid -5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-3-carboxylic acid

[00438] Step 1: In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino- 6-((R)-1-(5-bromo-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (500 mg, 0.65 mmol) in 4:1 EtOH:H2O (25 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (150 mg, 0.971 mmol), KHCO3 (648 mg, 6.47 mmol) and PdCl2(PPh3)2 (68 mg, 0.097 mmol). The reaction mixture was heated to 80°C for 1.75 h, then cooled to RT and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification through a 40 g Isco RediSep silica cartridge eluting (EtOAc/heptate) provides (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2 ,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane -2,3-dicarboxylate as an off-white solid.

[00439] Step 2: Deprotection by N-CBZ was performed via Method B to provide (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-( 2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4.5]decane-3-carboxylate as an off-white solid.

[00440] Step 3: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazole -1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-3-carboxylate using the general LiOH method provided the title compound as a white solid.

[00441] Using the generic scheme below, the following examples from Table 6a were prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1- (2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 19a).

[00442] Using the generic scheme below, the following examples from Table 7a can be prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1 acid -(2-(3-methyl-1H-pyrazol-1-yl)-5-vinyl-phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 19a) , by replacing the alkylidene borolane with a boronic acid or ester. Example 20: acid (S)-8-(2-amino-6-((R)-1-(2'-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00443] The title compound was made using the procedure described for acid (S)-8-(2-amino-6-((R)-1-(3'-(ethoxycarbonyl)-3-(3-methyl-1H -pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4.5]decane -3-carboxylic acid (Example 5a) starting with (S)-8-(2-amino-6-((R)-1-(5-bromo-2-(3-methyl-1H-pyrazol-1-yl) acid )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid. 1H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J=7.15 Hz, 3 H) 1.60 (t, J=5.54 Hz, 4 H) 2.06 (dd , J=13.50, 7.25 Hz, 1 H) 2.33 (dd, J=13.42, 9.27 Hz, 1 H) 2.40 (s, 3 H) 3.08 - 3, 28 (m, 2 H) 3.39 - 3.73 (m, 4 H) 3.74 - 3.98 (m, 2 H) 4.08 (dd, J=9.08, 7.32 Hz, 1 H) 5.74 (s, 1 H) 6.42 (d, J=2.34 Hz, 1 H) 6.88 (q, J=6.75 Hz, 1 H) 7.38 (dd, J=7.71, 0.93 Hz, 1 H) 7.45 - 7.56 (m, 4 H) 7.58 - 7.65 (m, 1 H) 7.82 (dd, J=7, 69, 1.20 Hz, 1 H) 7.95 (d, J=2.34 Hz, 1 H). LCMS (MH+): 680. Example 21: (S)-8-(2-amino-6-((R)-1-(4'-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-) acid 1-yl)-[1,1'-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00444] The title compound was made using the procedure described for acid (S)-8-(2-amino-6-((R)-1-(3'-(ethoxycarbonyl)-3-(3-methyl-1H -pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4.5]decane -3-carboxylic acid (Example 5) starting with (S)- 8-(2-amino-6-((R)-1-(5-bromo-2-(3-methyl-1H-pyrazol-1-yl) )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]de-cane-3-carboxylic acid. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.41 (t, J=7.15 Hz, 3 H) 1.58 (br. s., 4 H) 2.05 (dd, J=13 .50, 7.15 Hz, 1 H) 2.30 (dd, J=13.42, 9.18 Hz, 1 H) 2.40 (s, 3 H) 3.03 - 3.28 (m, 2 H) 3.37 - 3.76 (m, 4 H) 4.07 (dd, J=9.13, 7.22 Hz, 1 H) 4.39 (q, J=7.13 Hz, 2 H) 5.78 (s, 1 H) 6.42 (d, J=2.25 Hz, 1 H) 6.86 - 7.01 (m, 1 H) 7.53 (d, J=8, 30 Hz, 1 H) 7.66 - 7.77 (m, 2 H) 7.84 (dd, J=8.30, 2.20 Hz, 1 H) 7.94 (d, J=2.29 Hz, 1 H) 7.99 (d, J=1.51 Hz, 1 H) 8.06 - 8.17 (m, 2 H). LCMS (MH+): 680. Example 22a: (S)-8-(2-amino-6-((R)-1-(5-ethyl-2-(3-methyl-1H-pyrazol-1) acid -yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-3-carboxylic acid

[00445] Step 1: (S)-Ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1 -yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (100 mg, 0.171 mmol) in MeOH (2 mL) was hydrogenated by via an H-Cube mechanism using a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. The catalyst was filtered, and the filtrate was concentrated in vacuo. The residue was lyophilized from 1:1 H2O:CH3CN to give (S)-ethyl 8-(2-amino-6-((R)-1-(5-ethyl-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid, which was used directly in the next step.

[00446] Step 2: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(5-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the general LiOH method provided the title compound as a white solid.

[00447] Using the same generic scheme below, the following examples from Table 8a can be prepared as described above for (S)-8-(2-amino-6-((R)-1-(5-ethyl-2) acid -(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid ( Example 22a). Example 23: (S)-8-(2-amino-6-((R)-1-(5-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2 acid ,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00448] Step 1: In a solution of acid (S)-8-(2-amino-6-((R)-1-(5-bromo-2-(3-methyl-1H-pyrazol-1-yl )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10 m ) (180 mg, 0.24 mmol) in ethanol (2 mL) Pd(PPh3)2Cl2(34 mg, 0.048 mmol), KHCO3 (242 mg, 2.4 mmol) were added. A CO flask was fitted, and the reaction mixture was heated to 80 °C for 20 h, then cooled at RT. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by column on normal phase silica gel (CH2Cl2/MeOH/AcOH) provided acid (S)-8-(2-amino-6-((R)-1- (5-(ethoxycarbonyl)-2-(3 -methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro [4.5]decane- 3-carboxylic as an off-white solid.

[00449] Step 2: Deprotection by N-CBZ of (S)-8-(2-amino-6-((R)-1-(5-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazole) acid -1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid was carried out by means of Method A to provide the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.34 (t, J=7.10 Hz, 3 H) 1.51 - 1.71 (m, 4 H) 1.90 (dd, J= 13.28, 9.18 Hz, 1 H) 2.26 - 2.40 (m, 4 H) 3.13 (br. s., 2 H) 3.66 (br. s., 4 H) 4 .29 - 4.52 (m, 4 H) 6.07 (s, 1 H) 6.47 (d, J=2.39 Hz, 1 H) 7.48 (d, J=6.05 Hz, 1 H) 7.72 (d, J=8.40 Hz, 1 H) 8.15 (dd, J=8.40, 1.95 Hz, 1 H) 8.19 - 8.29 (m, 2 H) 8.96 (d, J=5.56 Hz, 1 H) 10.36 (d, J=4.49 Hz, 1 H). LCMS (MH+): 604. Example 24: (S)-8-(2-amino-6-((R)-1-(5-carboxy-2-(3-methyl-1H-pyrazol-1-yl) acid )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4.5]decane-3-carboxylic acid

[00450] Hydrolysis of acid (S)-8-(2-amino-6-((R)-1-(5-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl) -2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 23) using the general LiOH method provides the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.45 - 1.65 (m, 4 H) 1.83 - 1.95 (m, 1 H) 2.26 - 2.38 (m, 4 H) 3.12 (br. s., 2 H) 3.61 (br. s., 4 H) 4.36 - 4.51 (m, 1 H) 5.93 (br. s., 1 H ) 6.46 (d, J=2.39 Hz, 1 H) 7.40 (m, J=5.80 Hz, 1 H) 7.67 (d, J=8.35 Hz, 1 H) 8 .11 (dd, J=8.35, 1.95 Hz, 1 H) 8.21 (d, J=2.39 Hz, 1 H) 8.25 (s, 1 H) 8.93 (m, J=4.40 Hz, 1 H) 10.09 (br. s., 1 H). LCMS (MH+): 576. Example 25: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(hydroxymethyl)-2- acid (3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00451] Step 1: In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino- 6-((R)-1-(4-bromo-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (386 mg, 0.50 mmol) in DMF (10 mL) and Et3N (0.35 mL, 2.5 mmol) (n-octyl)3SiH (368 mg, 1.0 mmol) was added. The mixture was degassed under a 1 atm CO balloon and PdCl2(PPh3)2 (72 mg, 0.10 mmol) was added, then degassed again with 1 atm CO and heated at 80 oC for 12 h. The reaction was cooled to RT and concentrated in vacuo. The residue was diluted with water, then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Normal phase column chromatography on silica gel (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-( 4-formyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a solid light yellow contaminated with about 25% of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl -1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a byproduct. The mixture was used directly in the next step.

[00452] Step 2: In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-formyl-2 -(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (36 mg, 0.05 mmol ) in dichloroethane (2 mL) NaCNBH3 (1M in THF, 1 mL, 0.5 mmol) was added, followed by a few drops of HOAc. The mixture was stirred at RT for 3 h, then concentrated in vacuo. The residue was dissolved in MeOH and purified on reverse phase HPLC (MeOH/H2O/HOAc) to give (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)- 2.2, 2-trifluoro-1-(4-(hydroxymethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane -2,3-dicarboxylate as a sticky solid, which was used without further purification.

[00453] Step 3: Deprotection by N-CBZ was performed via Method B to provide (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-( 4-(hydroxymethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4.5]decane-3-carboxylate as a white solid.

[00454] Step 4: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(hydroxymethyl)-2-(3 -methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the general LiOH method provided the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4):δ ppm 1.57 (t, J=5.15 Hz, 4 H) 1.91 - 2.12 (m, 7 H) 2.30 (dd, J= 13.23, 9.42 Hz, 1 H) 2.36 (s, 3 H) 3.07 - 3.26 (m, 2 H) 3.39 - 3.54 (m, 2 H) 3.58 - 3.70 (m, 2 H) 3.99 - 4.13 (m, 1 H) 4.65 (s, 2 H) 5.71 (s, 1 H) 6.37 (d, J=2 .34 Hz, 1 H) 6.74 (q, J=6.65 Hz, 1 H) 7.39 (s, 1 H) 7.45 (d, J=8.20 Hz, 1 H) 7, 68 (d, J=8.10 Hz, 1 H) 7.84 (d, J=2.34 Hz, 1 H). LCMS (MH+): 562. Example 26: acid (S)-8-(2-amino-6-((R)-1-(4-((dimethylamino)methyl)- 2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00455] Step 1: In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-formyl-2 -(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (166 mg, 0.23 mmol , see Ex. 25) in dichloroethane (4 mL) and HOAc (10 mg) were added NaBH(OAc)3 (242 mg, 1.15 mmol) and Me2NH (2M in THF, 0.58 mL, 1.15 mmol ). The reaction mixture was stirred at RT for 20 h, then concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and purified by reverse phase HPLC (MeOH/H2O/HOAc) to provide (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)- 1-(4-((dimethylamino)methyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diaza - spiro[4.5]decane-2,3-dicarboxylate as a white solid.

[00456] Step 2: Deprotection by N-CBZ was carried out using Method A to provide (S)-ethyl 8-(2-amino-6-((R)-1-(4-((dimethylamino) methyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.

[00457] Step 3: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(4-((dimethylamino)methyl)-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the general LiOH method gave the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.66 - 1.81 (m, 4 H) 2.10 (dd, J=13.62, 8.54 Hz, 1 H) 2.38 ( s, 3 H) 2.49 (dd, J=13.62, 8.88 Hz, 1 H) 2.88 (s, 3 H) 2.90 (s, 3 H) 3.58 - 3.90 (m, 4 H) 4.37 - 4.49 (m, 2 H) 4.56 (t, J=8.69 Hz, 1 H) 6.37 (br. s., 1 H) 6.43 (d, J=2.34 Hz, 1 H) 7.06 - 7.12 (m, 1 H) 7.71 - 7.78 (m, 2 H) 7.85 (d, J=8.10 Hz, 1 H) 7.98 (d, J=2.39 Hz, 1 H). LCMS (MH+): 589. Example 27: (S)-8-(6-((R)-1-(4-Bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- acid 2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-3-carboxylic acid

[00458] Step 1: In a solution of 1(R)-1-[4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethanol (15, 7 g, 46.3 mmol, Intermediate 1) in dioxane (200 mL) were added 4,6-dichloro-2-methylpyrimidine (30.6 g, 51 mmol) and Cs2CO3 (61.2 g, 187 mmol). The reaction mixture was heated at 80 °C for 30 h, then cooled at RT and filtered. The residue was concentrated in vacuo and purified by column chromatography on normal phase silica gel (CH2Cl2/heptane) to give (R)- 4-(1-(4-bromo-2-(3-methyl-1H-pyrazol- 1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-chloro-2-methylpyrimidine as a white solid.

[00459] Step 2: In a solution of (R)-4-(1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy) -6-chloro-2-methylpyrimidine (21 g) in dioxane (200 ml) was added (S)-2-benzyl 3-ethyl 2,8-diazaes-pyro[4.5]decane-2,3-dicarboxylate (15 g ) and Na2CO3 (14 g). The reaction was heated at 90 °C for 48 h, then cooled at RT, filtered and concentrated in vacuo. Purification of the residue by column chromatography on normal phase silica gel (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(6-((R)-1-(4-bromo-2-( 3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an almost white solid.

[00460] Step 4: Deprotection by N-CBZ was carried out using Method A to provide (S)-ethyl 8-(6-((R)-1-(4-bromo-2-(3-methyl-1H - pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-3-carboxylate as an off-white solid.

[00461] Step 5: Hydrolysis of (S)-ethyl 8-(6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2, 2,2-Trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diaza-spiro[4.5]decane-3-carboxylate using the general LiOH method provided the title compound as an off-white solid. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.64 (br. s., 4 H) 2.10 (d, J=7.03 Hz, 1 H) 2.28 (s, 3 H) 2.35 (dd, J=13.37, 9.27 Hz, 1 H) 2.39 (s, 3 H) 3.10 - 3.20 (m, 1 H) 3.28 (d, J= 11.91 Hz, 1 H) 3.45 - 3.67 (m, 2 H) 3.75 (br. s., 2 H) 4.10 (dd, J=8.98, 7.22 Hz, 1 H) 6.17 (s, 1 H) 6.43 (d, J=2.15 Hz, 1 H) 7.01 (d, J=6.44 Hz, 1 H) 7.58 - 7, 75 (m, 3 H) 8.03 (d, J=2.15 Hz, 1 H). LCMS (MH+): 609. Example 28: (S)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- acid 2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-3-carboxylic acid

[00462] The title compound was prepared as described above for (S)-8-(6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl acid )-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (by substitution of 1(R)-1-[4 -bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl]- 2,2,2-trifluoroethanol with 1(R)-1-[4-chloro-2-(3-methyl-1H- pyrazol-1-yl)phenyl]-2,2,2-trifluoroethanol, Intermediate 3) and obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.34 - 1.54 (m, 4 H) 1.82 (dd, J=13.01, 6.76 Hz, 1 H) 1.99 - 2.08 (m, 1 H) 2.11 (s, 3 H) 2.30 (s, 3 H) 2.92 (d, J=11.52 Hz, 1 H) 3.06 (d, J =11.52 Hz, 1 H) 3.42 - 3.65 (m, 4 H) 3.70 (dd, J=8.91, 7.00 Hz, 1 H) 6.15 (s, 1 H ) 6.42 (s, 1 H) 7.43 (q, J=6.93 Hz, 1 H) 7.54 - 7.61 (m, 1 H) 7.64 (d, J=2.10 Hz, 1 H) 7.70 (d, J=8.44 Hz, 1 H) 8.19 (d, J=2.39 Hz, 1 H) 8.70 (br. s., 1 H). LCMS (MH+): 565. General Biaryl Coupling Procedures (Suzuki) Biaryl Coupling Method A

[00463] Step 1: In a mixture of acid (S)-2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-bromo-2-(3-methyl- 1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10 m) (150 mg, 0.2 mmol), an arylboronic acid (0.4 mmol), Pd(N,N-dimethylμ-alaninate)2 (3.42 mg, 0.01 mmol) and K3PO4 (128 mg, 0.6 mmol) water (3.0 mL) and EtOH (3.0 mL) were added. The mixture was stirred at 50°C for 12 h. The reaction was then cooled at RT, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The target biaryl compounds were purified by normal phase silica gel column (CH2Cl2:MeOH). Step 2: Subsequent deprotection by N-CBZ via method A provided the final target spirocyclic amino acids. Biaryl Coupling Method B

[00464] Step 1: In a mixture of acid (S)-2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-bromo-2-(3-methyl- 1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10 m) (150 mg, 0.2 mmol), an arylboronic acid (0.4 mmol), Pd(OAc)2 • (1,1,3,3-tetramethyl-2-N-butylguanidine)2 (5.7 mg, 0.01 mmol) and K2CO3 (83.5 mg, 0.61 mmol) were added to water (1.0 mL) and dioxane (3.0 mL). The reaction mixture was stirred at 44°C for 24 h. The reaction mixture was then cooled at RT, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The target biaryl compounds were purified by normal phase silica gel column (CH2Cl2:MeOH).

[00465] Step 2: Subsequent N-CBZ deprotection via method A provided the target final spirocyclic amino acids.

[00466] Using the generic scheme below and employing biaryl coupling method A, the following examples in Table 9 were prepared.

[00467] Using the above generic scheme with biaryl coupling method B, the following examples from Table 10 were prepared. Table 10. Example 30a: 8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)- acid 2-phenoxypyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-3-carboxylic acid

[00468] Step 1: In a solution of (R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethanol (5.00 g, 17, 2 mmol) and 4,6-dichloro-2-(methylthio)pyrimidine (3.36 g, 17.2 mmol) in dioxane (250 mL) was added to Cs2CO3 (16.8 g, 51.6 mmol). The reaction mixture was then heated to 70 °C for 90 h, then cooled at RT. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (EtOAc:heptane) provided 4-chloro-6-[(R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2 ,2,2-trifluoroethoxy]-2-methylsulfanylpyrimidine as a white solid.

[00469] Step 2: In a solution of 4-chloro-6-[(R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy] -2-methylsulfanylpyrimidine (4g, 8.95 mmol) in CH2Cl2 (200 mL) was added m-CPBA (4.2 g of a 77% (w/w) source, 18.8 mmol), and the reaction was stirred at RT for 15 h. The reaction was then diluted with saturated NaHCO3 and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (EtOAc:heptane) provided 4-chloro-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2 ,2,2-trifluoroethoxy]-2-methylsulfonylpyrimidine as an off-white solid.

[00470] Step 3: In a solution of 4-chloro-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy] -2-methylsulfonylpyrimidine (2.49 g, 5.17 mmol) in dioxane (100 mL) was added 2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (1.8 g, 5.2 mmol), Cs2CO3 (5.06 g, 15.5 mmol), and the reaction mixture was heated at 100 °C for 1.5 h. The reaction mixture was cooled to RT, quenched with brine and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (EtOAc:heptane) provided (S)-2-benzyl 3-ethyl 8-(6-((R)-1-(4-chloro-2-(3-methyl -1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid (1.3 g) in addition to (S)-2-benzyl 3-ethyl 8-(4-chloro-6-((R)-1-(4-chloro-2-(3-methyl-1H -pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

[00471] Step 4: In a solution of 2-benzyl 3-ethyl 8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl) -2,2,2-trifluoroethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (2.10 g, 2.65 mmol) in 2:1 THF:H2O (90 mL) LiOH (127 mg, 5.3 mmol) was added, and the reaction was stirred at RT for 21 h, after which additional LiOH (65 mg, 2.6 mmol) was added. , and the reaction was stirred for another 8 h. The reaction was then quenched with 1N HCl at pH<1 and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give 2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-chloro-2-(3-methyl-) 1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-3-carboxylic acid as a solid almost white, which was used directly without further purification.

[00472] Step 5: In a solution of acid 2-((benzyloxy)carbonyl)-8- (6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (300 mg, 0.393 mmol) in 1.4 -dioxane (10 mL) phenol (74 mg, 0.79 mmol), Cs2CO3 (512 mg, 1.5 mmol) were added, and the reaction was heated at 70 °C for 21 h. The reaction was then cooled at RT, diluted with water, acidified to pH<1 with 1N HCl and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification on a 50 g Isco Gold RediSep reversed phase silica cartridge (H2O:HOAc : 99:1 MeOH:HOAc 99:1) provided 2-((benzyloxy)carbonyl)-8-(6-((R) acid -1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-phenoxypyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid.

[00473] Step 6: Deprotection by N-CBZ was carried out using Method B to provide the title compound as an off-white solid.

[00474] Using the generic scheme below, the following examples from Table 11a were prepared as described above for 8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol- 1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-phenoxypyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 30a). Example 31: 8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)- acid 2-(cyclohexylamino)pyrimidin-4-yl)-2,8-diaza-spiro[4.5]decane-3-carboxylic acid

[00475] The title compound was prepared as described above by replacing the alcohol in Step 5 of Example 30a with cyclohexyl amine. 1H NMR (400 MHz, MeOH-d4):δ ppm 0.99 - 1.95 (m, 14 H), 2.02 - 2.37 (m, 2 H), 2.38 (s, 3 H) , 3.07 - 3.29 (m, 2 H), 3.41 - 3.77 (m, 5 H), 4.09 (dd, J = 9.10, 7.15 Hz, 1 H), 5.60 (s, 1 H), 6.39 (d, J = 2.39 Hz, 1 H), 6.87 - 7.21 (m, 1 H), 7.49 (dtd, J = 4 .48, 2.26, 2.26, 2.12 Hz, 2 H), 7.70 (d, J = 9.03 Hz, 1 H), 7.87 (d, J = 2.34 Hz, 1 H). LCMS (MH+): 650. Example 32: (S)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- acid 2,2,2-trifluoroethoxy)-2-(cyclobutanecarboxamido)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00476] Step 1: In a solution of acid (S)-8-(2-amino-6-((R)-1- (4-chloro-2-(3-methyl-1H-pyrazol-1-yl )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10 m ) (300 mg, 0.412 mmol) in pyridine (1.0 mL) was added cyclobutanecarbonyl chloride (54 mg, 0.045 mmol). The reaction mixture was stirred at RT for 3 h, then diluted with EtOAc and washed with 0.5 N HCl. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification on a 40 g Isco RediSep silica cartridge (EtOAc/heptane) provides (S)-2-benzyl 3-ethyl 8-(6-((R)-1-(4-chloro-2-(3-methyl -1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(cyclobutanecarboxamido)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3 -dicarboxylate as an off-white solid.

[00477] Step 2: The title compound was prepared by removing N-CBZ using general method B to provide a white solid. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.66 (d, J = 4.30 Hz, 4 H), 1.78 - 1.99 (m, 2 H), 2.03 - 2, 38 (m, 6 H), 2.39 (s, 3 H), 3.12 - 3.32 (m, 2 H), 3.47 - 3.90 (m, 5 H), 4.10 ( dd, J = 9.10, 7.20 Hz, 1 H), 6.03 (s, 1 H), 6.41 (d, J = 2.34 Hz, 1 H), 6.82 - 6, 98 (m, 1 H), 7.45 - 7.57 (m, 2 H), 7.73 (d, J = 8.49 Hz, 1 H), 7.97 (d, J = 2.34 Hz, 1H). LCMS (MH+): 649. Example 33: (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(2-oxopyrrolidin-1-yl)phenyl acid )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaes-piro[4.5]decane-3-carboxylic acid

[00478] The title compound was prepared as described for acid (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(5-chloro- 2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)pyrrolidin-2-one. 1H NMR (DMSO-d6): δ ppm 1.23 (m, 1H), 1.40 (m, 4H), 1.81 (dd, J = 13.2, 6.9 Hz, 1H), 2, 07 (m, 4H), 2.45 (d, J = 8.1 Hz, 2H), 2.91 (d, J = 11.5 Hz, 3H), 3.06 (d, J = 11.6 Hz, 1H), 3.47 (d, J = 6.9 Hz, 3H), 3.66 (m, 3H), 5.54 (s, 1H), 6.09 (s, 2H), 6, 74 (q, J = 6.9 Hz, 1H), 7.55 (m, 3H). LCMS (MH+): 570. Example 34c: (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)- acid 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00479] Step 1: In a solution of (R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol (Intermediate 43) (400 mg, 1.4 mmol) in dioxane (25 mL) 4,6-dichloropyrimidin-2-amine (1.1 g, 7 mmol) and Cs2CO3 (1.3 g, 4 mmol) were added. The mixture was heated for 24 h at 80°C. The reaction was then cooled at RT and filtered. The solvent was removed in vacuo, then CH2Cl2 and heptane were added. The volume of solvent was reduced until a solid precipitated. The solid was filtered, and the procedure repeated several times to provide (R)-4-(1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine as a white solid.

[00480] Step 2: In a solution of (R)-4-(1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine (100 mg, 0 .24 mmol, Step 1) in dioxane (5 mL) were added (S)-2-benzyl 3-ethyl 2,8-diazaes-piro[4.5]decane-2,3-dicarboxylate (100 mg, 0.29 mmol ) and NaHCO3 (300 mg, 3.5 mmol). After 5 h, an additional amount of NaHCO3 (300 mg, 3.5 mmol) was added, and the reaction mixture was heated at 90 oC for 36 h. The reaction was then cooled at RT and filtered. Purification by column on normal phase silica gel (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

[00481] Step 3: In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-2,3-dicarboxylate (100 mg, 0.13 mmol) in 10:1 dioxane:water (5 mL) were added phenyl boronic acid (33 mg, 0.27 mmol), KHCO3 (27 mg, 0.3 mmol) and PdCl2(dppf)-CH2Cl2 (6 mg, 0.007 mmol). The reaction was heated to 100 oC for 15 h, cooled at RT and concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1, 1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.

[00482] Step 4: Deprotection by N-CBZ was carried out using method B to provide (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1 '-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as an off-white solid.

[00483] Step 5: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the general LiOH method provided the title compound as an off-white solid as the hybrid form. Example 34u: (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-sulfamoyl-[1,1'-biphenyl]-2-yl)-2 acid, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00484] Step 1: In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2, 2-Trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-2,3-dicarboxylate (500 mg, 0.688 mmol) in 10:1 dioxane:water (11 mL) was added 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (195 mg, 0.7 mmol), KHCO3 (207 mg, 2.06 mmol) and PdCl2(dppf )-CH2Cl2 (56 mg, 0.069 mmol). The reaction was heated to 100 oC for 15 h, cooled at RT and concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'- sulfamoyl-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a nearly solid white.

[00485] Step 2: Deprotection by N-CBZ was carried out using method B to provide (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-sulfa - moyl-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaes- pyro[4.5]decane-3-carboxylate as a solid white.

[00486] Step 3: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-sulfamoyl-[1,1'-biphenyl]-2- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-3-carboxylate using the general LiOH method provided the title compound as an off-white solid.

[00487] Using the generic scheme below, the following examples from Table 12a can be prepared as described above for (S)-8-(2-amino-6-((R)-1-(5-chloro-3' acid -sulfamoyl-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 34u ). Example 35: (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(ethoxycarbonyl)-[1,1'-biphenyl]-2-yl acid )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-3-carboxylic acid

[00488] The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(2'-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazole) acid -1-yl)- [1,1'-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaes- piro[4.5]decane-3-carboxylic acid (Example 20) starting with (S)-8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl acid )-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.29 - 1.38 (m, 3 H) 1.47 - 1.72 (m, 4 H) 1.91 (dd, J=13.28 , 9.18 Hz, 1 H) 2.35 (dd, J=13.25, 8.61 Hz, 1 H) 3.14 (br. s., 2 H) 3.65 (br. s., 4 H) 4.30 - 4.40 (m, 2 H) 4.40 - 4.50 (m, 1 H) 5.90 (br. s., 1 H) 6.59 (q, J=6 .67 Hz, 1 H) 7.11 (br. s., 1 H) 7.44 (t, J=1.22 Hz, 1 H) 7.66 (s, 2 H) 7.70 - 7, 79 (m, 2 H) 8.08 (dt, J=6.37, 2.14 Hz, 1 H) 8.14 (br. s., 1 H) 8.98 (d, J=5.61 Hz, 1 H) 10.36 (d, J=5.08 Hz, 1 H). LCMS (MH+): 634. Example 36: (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(2-methoxyethoxy)phenyl)-2 acid, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]de-cane-3-carboxylic acid

[00489] The title compound was prepared as described for acid (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(4-bromo- 2-(2-methoxyethoxy)phenyl)-2,2,2-trifluoroethanol is obtained as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.44 - 1.66 (m, 4 H) 1.83 - 1.95 (m, 1 H) 2.34 (dd, J=13.08 , 8.79 Hz, 1 H) 3.14 (br. s., 2 H) 3.33 (s, 3 H) 3.42 - 3.65 (m, 4 H) 3.67 - 3.79 (m, 2 H) 4.19 - 4.27 (m, 1 H) 4.27 - 4.36 (m, 1 H) 4.48 (t, J=6.49 Hz, 1 H) 5, 74 (s, 1 H) 6.99 (q, J=6.78 Hz, 1 H) 7.07 - 7.16 (m, 1 H) 7.27 (s, 1 H) 7.43 (d , J=8.35 Hz, 1 H) 8.93 (d, J=5.42 Hz, 1 H) 9.81 (br. s., 1 H). LCMS (MH+): 560. Example 36b: (S)-8-(6-((R)-1-(2-(1H-benzo[d]imidazol-1-yl)-4-chlorophenyl)-2 acid ,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00490] Step 1: In a solution of (R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol (1 g, 3.5 mmol) and 1H-benzo[d]imidazole (408 mg, 3.5 mmol) in toluene (24 mL) were added sequentially, CuI (131 mg, 0.69 mmol), K2CO3 (1.19 g, 8.63 mmol) and (1R,2R)-N1 ,N2-dimethylcyclohexane-1,2-diamine (196 mg, 1.38 mmol). The reaction mixture was purged with N2, and then heated to 130 oC in a sealed tube for 12 h. Later, the reaction was cooled at RT. The solid was removed by filtration, and the filtrate was concentrated and purified by flash column (EtOAc in hexane = 0 to 50%) to provide -(R)-1-(2-(1H-benzo[d]imidazol-1- yl)-4-chlorophenyl)-2,2,2-trifluoroethanol as a white solid.

[00491] Steps 2-5: The title compound was made as described for Example 10d (Steps 1-4) to provide a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.59 (m, 4H), 2.05 (dt, J = 13.7, 6.9 Hz, 1H), 2.33 (dt, J = 14.5, 8.5 Hz, 1H), 3.13 (dd, J = 11.7, 7.6 Hz, 1H), 3.26 (m, 2H), 3.49 (m, 3H), 3.63 (m, 2H), 4.10 (q, J = 7.0, 5.2 Hz, 1H), 5.48 (d, J = 3.9 Hz, 1H), 6.43 (p , J = 6.4 Hz, 1H), 7.22 (dd, J = 7.8, 4.0 Hz, 1H), 7.38 (m, 2H), 7.61 (dd, J = 5, 3, 2.2 Hz, 1H), 7.81 (m, 3H), 8.54 (s, 1H). LCMS (MH+): 603. Example 36c: (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(1H-indazol-1-yl)phenyl)- acid 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00492] The title compound was prepared as described for (S)-8-(6-((R)-1-(2-(1H-benzo[d]imidazol-1-yl)-4-chlorophenyl)- acid 2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 36b) starting with 1H-indazole and obtained as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.57 (m, 5H), 2.05 (dd, J = 13.4, 7.1 Hz, 1H), 2.32 (dd, J = 13.5, 9.2 Hz, 1H), 3.12 (d, J = 11.7 Hz, 1H), 3.24 (d, J = 11.7 Hz, 1H), 3.52 (dddd, J = 44.5, 25.8, 14.0, 7.1 Hz, 5H), 4.13 (dd, J = 9.1, 7.1 Hz, 1H), 4.92 (s, 1H) , 6.68 (q, J = 6.5 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.46 (m, 2H), 7.72 (m, 5H) , 8.39 (s, 1H). LCMS (MH+): 603. Example 36d: (S)-8-(2-amino-6-((R)-1-(4-bromo-2-(piperazin-1-yl)phenyl)-2 acid, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]de-cane-3-carboxylic acid

[00493] Step 1: The mixture of 4-bromo-2-fluorobenzoic acid (2 g, 9.1 mmol), benzyl piperazine-1-carboxylate (2.4 g, 10.9 mmol) and K2CO3 (2.5 g, 18.26 mmol) in DMF (40 mL) was stirred at 150°C for 36 h. The reaction was then cooled at RT and extracted with ethyl acetate, 3N HCl, brine, dried over Na2SO4, filtered and concentrated in vacuo to give 2-(4-((benzyloxy)carbonyl)piperazin-1-yl acid )-4-bromobenzoic as yellow oil, which was used without further purification.

[00494] Step 2: In a mixture of 2-(4-((benzyloxy)carbonyl)piperazin-1-yl)-4-bromobenzoic acid (2 g, 9.1 mmol) in THF (20 mL) was BH3/THF (1.0 M, 40 mL) was added dropwise at 0 oC. The mixture was refluxed for 2 h, then cooled at RT, quenched with H2O and extracted with ethyl acetate, 3N HCl, brine, then dried over Na2SO4, filtered and concentrated. Purification by normal phase silica gel (ethyl acetate/hexanes) provided benzyl 4-(5-bromo-2-(hydroxymethyl)phenyl)piperazine-1-carboxylate as a white solid.

[00495] Steps 3-10: The title compound was prepared as described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(5-(methylsulfonyl) acid )-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 54d) following Steps 4-11. 1H NMR (MeOH-d4): δ ppm 0.90 (dt, J = 16.0, 8.0 Hz, 1H), 1.31 (s, 2H), 1.62 (t, J = 5.6 Hz, 5H), 2.03 (dd, J = 13.6, 6.9 Hz, 1H), 2.30 (dd, J = 13.4, 9.1 Hz, 1H), 2.76 (dd , J = 10.1, 6.3 Hz, 2H), 3.08 (m, 8H), 3.22 (d, J = 11.6 Hz, 1H), 3.47 (s, 1H), 3 .54 (m, 1H), 3.65 (dd, J = 13.9, 6.8 Hz, 2H), 4.01 (t, J = 8.0 Hz, 1H), 5.56 (s, 1H), 7.31 (q, J = 6.9 Hz, 1H), 7.41 (dd, J = 8.4, 1.9 Hz, 1H), 7.50 (m, 2H). LCMS (MH+): 615. Example 36e: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-iso-propoxy-3-() acid piperazin-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00496] The title compound was prepared starting with (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-(4-((benzyloxy)carbonyl)piperazin- 1-yl)-4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (intermediate from Step 8, Example 36d ] by means of a Suzuki coupling with (4-isopropoxyphenyl)boronic acid as described for example 54b. 1H NMR (MeOH-d4): δ ppm 0.90 (m, 1H), 1.33 (m, 8H ), 1.40 (s, 1H), 1.59 (q, J = 5.7 Hz, 4H), 2.06 (dd, J = 13.7, 7.0 Hz, 1H), 2.31 (dd, J = 13.5, 9.2 Hz, 1H), 3.11 (m, 3H), 3.26 (d, J = 11.7 Hz, 1H), 3.51 (m, 10H) , 4.09 (dd, J = 9.3, 6.8 Hz, 1H), 4.64 (p, J = 6.0 Hz, 1H), 5.56 (s, 1H), 6.98 ( m, 2H), 7.32 (q, J = 7.0 Hz, 1H), 7.53 (m, 4H), 7.64 (d, J = 8.2 Hz, 1H). LCMS (MH+) : 671. Example 36f: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-iso-propoxy-3-morpholino-[1, 1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4.5]decane-3-carboxylic acid

[00497] The title compound was prepared as described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-isopropoxy-3-(piperazine) acid -1-yl)- [1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 36e) replacing morpholine with benzyl piperazine-1-carboxylate. 1H NMR (MeOH-d4): δ ppm 1.32 (d, J = 6.0 Hz, 7H), 1.58 (d, J = 6.0 Hz, 4H), 1.98 (m, 1H) , 2.25 (dd, J = 13.3, 9.0 Hz, 1H), 2.83 (m, 2H), 2.99 (d, J = 11.5 Hz, 1H), 3.19 ( m, 3H), 3.32 (s, 1H), 3.48 (ddt, J = 18.5, 8.9, 5.0 Hz, 2H), 3.62 (s, 2H), 3.92 (m, 5H), 4.63 (h, J = 6.0 Hz, 1H), 4.88 (m, 1H), 5.54 (s, 1H), 6.97 (m, 2H), 7 .41 (m, 2H), 7.54 (m, 4H). LCMS (MH+): 672

[00498] Example 36g: (S)-8-(6-((R)-1-([1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)-2-amino acid pyrimidin-4-yl)-2,8-diazaspiro[4.5]de-cane-3-carboxylic acid

[00499] The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-sulfamoyl-[1,1'-biphenyl] acid -2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 34u) starting with 1-(2-bromophenyl)- 2,2,2-trifluoroethanone. 1H NMR (MeOH-d4): δ ppm 1.58 (d, J = 5.4 Hz, 4H), 2.00 (dd, J = 13.4, 7.1 Hz, 1H), 2.27 ( dd, J = 13.3, 9.2 Hz, 1H), 3.02 (d, J = 11.6 Hz, 1H), 3.19 (d, J = 11.5 Hz, 1H), 3, 30 (q, J = 1.8 Hz, 3H), 3.45 (td, J = 14.5, 6.3 Hz, 1H), 3.61 (m, 2H), 3.99 (m, 1H ), 5.46 (s, 1H), 6.67 (q, J = 6.8 Hz, 1H), 7.26 (dd, J = 6.2, 2.4 Hz, 1H), 7.45 (m, 7H), 7.70 (d, J = 7.3 Hz, 1H). LCMS (MH+): 528. Example 37: (3S)-8-(6-(1-((1r,3r,5S,7S)-adamantan-2-yl)ethoxy)-2-aminopyrimidin-4-yl acid )-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00500] Step 1: The solution of adamantan-1-yl-methanol (100 mg, 0.60 mmol) in THF (5 mL) was cooled to 0 °C. 15-Crown-5 ether (99 mg, 0.5 mmol) and NaH (60% in oil, 92 mg, 2.4 mmol) were added sequentially. The reaction was heated at RT for 1 h, cooled to 0 °C and 4,6-dichloro-pyrimidin-2-ylamine (247 mg, 1.5 mmol) was added. The reaction was heated to 65 °C for 16 h, cooled at RT, quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by normal phase chromatography (EtOAc/heptane) provided 4-(adamantan-1-ylmethoxy)-6-chloro-pyrimidin-2-ylamine as a white solid.

[00501] Step 2: 4-(Adamantan-1-ylmethoxy)-6-chloro-pyrimidin-2-yl-amine (89 mg, 0.30 mmol), (S)-2-benzyl 3-ethyl 2.8 -diazaspiro[4.5] decane-2,3-dicarboxylate (157 mg, 0.45 mmol) and NaHCO3 (76 mg, 0.9 mmol) were dissolved in dioxane (1.5 mL) and heated to 95 °C for 64 h. Then, the reaction was cooled at RT, quenched with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) gives (S)-2-benzyl 3-ethyl 8-(6-(adamantan-1-ylmethoxy)-2-aminopyrimidin-4-yl)-2,8 -diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid. Step 3: Deprotection by N-CBZ was performed via Method B to provide (S)-ethyl 8-(6-(adamantan-1-ylmethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[ 4.5]decane-3-carboxylate asa white solid.

[00502] Step 4: Hydrolysis of (S)-ethyl 8-(6-(adamantan-1-ylmethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the General LiOH method provides the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.12 (d, J=6.25 Hz, 3 H) 1.42 - 1.76 (m, 17 H) 1.82 - 2.02 ( m, 4 H) 2.34 (dd, J=13.32, 8.59 Hz, 1 H) 3.12 (br. s., 2 H) 3.67 (br. s., 4 H) 4 .35 - 4.48 (m, 1 H) 5.85 (br. s., 1 H) 8.97 (br. s., 1 H) 10.44 (br. s., 1 H). LCMS (MH+): 456. Example 38: (S)-8-(6-((1r,3r,5S,7S)-adamantan-2-ylmethoxy acid)-2-aminopyrimidin-4-yl)-2,8 -diazaspiro[4.5]decane-3-carboxylic acid

[00503] The title compound was made as described above for (3S)-8- (6-(1-((1r,3r,5S,7S)-adamantan-2-yl)ethoxy)-2-aminopyrimidin-4- il)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 37) using (1r,3r,5r,7r)-adamantan-2-ylmethanol. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.39 - 1.76 (m, 16 H) 1.83 - 2.01 (m, 4 H) 2.34 (dd, J=13.18 , 8.44 Hz, 1 H) 3.13 (br. s., 2 H) 3.69 (br. s., 4 H) 3.79 (s, 2 H) 4.42 (br. s. , 1 H) 5.83 (br. s., 1 H) 8.97 (br. s., 1 H) 10.40 (br. s., 1 H). LCMS (MH+): 442. Example 39a: 8-(4-Amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[ acid 4.5]decane-3-carboxylic acid

[00504] Step 1: In a solution of 4,6-dichloro-1,3,5-triazin-2-amine (1.6 g) in isopropanol (14 mL) 2-benzyl 3-ethyl 2,8 was added -diazaspiro[4.5]decane-2, 3-dicarboxylate (1.28 g, 3.7 mmol) and Et3N (7 mL). The solution was heated at reflux for 72 h, then cooled at RT and concentrated in vacuo. Purification by normal phase chromatography (CH2Cl2/MeOH = 50/1) provided 2-benzyl 3-ethyl 8-(4-amino-6-chloro-1,3,5-triazin-2-yl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate as a colorless oil.

[00505] Step 2: In a solution of 2-benzyl 3-ethyl 8-(4-amino-6-chloro-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane- 2,3-dicarboxylate (265 mg, 0.56 mmol) in isopropanol (3 mL) were added naphthalen-2-ylmethanamine (105 mg, 0.67 mmol) and Et3N (1.4 mL). The reaction mixture was heated at reflux for 12 h, then cooled at RT and concentrated in vacuo. Purification by normal phase chromatography (CH2Cl2/MeOH) provided 2-benzyl 3-ethyl 8-(4-amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin-2-yl )-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

[00506] Step 3: Hydrolysis of 2-benzyl 3-ethyl 8-(4-amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin-2-yl)-2,8 -diazaspiro[4.5]decane-2,3-dicarboxylate using the general LiOH method gave 8-(4-amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin- acid 2-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as a white solid.

[00507] Step 4: Deprotection by N-CBZ was carried out using Method B to provide the title compound as a white solid.

[00508] Using the generic scheme below, the following examples from Table 13a were prepared as described above for 8-(4-amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin-2 -yl)-2,8-diazaspiro [4.5]de-cane-3-carboxylic acid (Example 39a). Example 40: 8-(4-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2 acid -trifluoroethoxy)-1,3,5-triazin-2-yl)-2,8-diazaes-

[00509] Step 1: In a solution of (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (380 mg, 1.3 mmol) into 10 mL of THF was added NaH (60 mg, 1.4 mmol), and the reaction was stirred at RT for 30 min. After this moment, 2-benzyl 3-ethyl 8-(4-amino-6-chloro-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate ( product from Step 1, Example 39a) (570 mg, 1.2 mmol) was added, and the reaction was heated at 50 ° C for 12 h. After this moment, the reaction was cooled at RT, quenched with methanol and concentrated in vacuo. Chromatography on normal phase silica gel (EtOAc/heptane) provided 2-benzyl 3-ethyl 8-(4-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazole - 1-yl)phenyl)-2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

[00510] Step 2: Deprotection by N-CBZ was carried out using Method B to provide ethyl 8-(4-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H - pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)-2,8-diazaes- piro[4.5]decane-3-carboxylate as a solid white.

[00511] Step 3: Hydrolysis of ethyl 8-(4-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2, 2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the general LiOH method provided the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.55 (br. s., 4 H) 1.98 (s, 1 H) 2.02 - 2.15 (m, 1 H) 2.30 (dd, J=13.42, 9.27 Hz, 1 H) 2.36 (s, 3 H) 3.10 (d, J=11.71 Hz, 1 H) 3.23 - 3.28 ( m, 1 H) 3.40 - 4.01 (m,4 H) 4.08 (dd, J=9.27, 6.88 Hz, 1 H) 6.39 (d, J=2.25 Hz , 1 H) 7.36 - 7.63 (m, 3 H) 7.76 (d, J=8.54 Hz, 1 H) 7.91 (d, J=2.10 Hz, 1 H). LCMS (MH+): 567. Example 41a: (S)-8-(2-amino-6-((2-(piperidin-1-yl)benzyl)amino)pyrimidin-4-yl)-2 acid, 8-diazaspiro[4.5]decane-3-carboxylic acid

[00512] Step 1: In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-chloropyrimidin-4-yl)-2,8-diazaspiro [4.5]decane-2,3- dicarboxylate (200 mg, 0.6 mmol) and [2-(1-piperidinyl)phenyl]methanamine (CAS#: 72752-54-6) (105 mg, 0.8 mmol) in i-PrOH (2 mL) was diisopropylethyl amine (0.5 mL) is added. The reaction was heated to 120 °C for 2 h followed by heating to 140 °C for 1 h under microwave conditions, then cooled at RT and concentrated in vacuum. Purification by column on normal phase silica gel (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((2-(piperidin-1-yl)benzyl)amino) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

[00513] Step 2: Deprotection by N-CBZ was carried out using Method B to provide (S)-ethyl 8-(2-amino-6-((2-(piperidin-1-yl)benzyl)amino )pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.

[00514] Step 3: Hydrolysis of (S)-ethyl 8-(2-amino-6-((2-(piperidin-1-yl)benzyl)amino)pyrimidin-4-yl)-2,8-diazaspiro[ 4.5]decane-3-carboxylate using the general LiOH method provided the title compound as a white solid.

[00515] Using the generic scheme below, the following examples from Table 14a were prepared as described above for (S)-8-(2-amino-6-((2-(piperidin-1-yl)benzyl)amino acid) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 41a). Example 42a: (S)-8-(2-amino-6-((R)-1-(3'-chloro-[1,1'-biphenyl]-2-yl)-2,2,2- acid trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00516] The title compound was made as described for acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(ethoxycarbonyl)-[1,1'- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 35) starting with (S)-2- benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5 ]decane-2,3-dicarboxylate. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.43 (h, J = 8.5, 6.5 Hz, 4H), 1.80 (dd, J = 13.3, 7.4 Hz, 1H), 2.12 (dd, J = 13.2, 9.0 Hz, 1H), 2.48 (d, J = 1.8 Hz, 1H), 2.95 (d, J = 11.7 Hz, 1H), 3.08 (d, J = 11.7 Hz, 1H), 3.37 (d, J = 16.1 Hz, 1H), 3.48 (d, J = 11.2 Hz, 3H), 3.79 (m, 2H), 5.57 (s, 1H), 6.62 (q, J = 6.9 Hz, 1H), 7.27 (dd, J = 5.8, 3 .3Hz, 1H), 7.51 (m, 7H). LCMS (MH+): 563. Example 42b: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-[1, 1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]de-cane-3-carboxylic acid

[00517] The title compound was made as described for acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(ethoxycarbonyl)-[1,1'- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 35) starting with (S)-2 -benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[ 4.5]decane- 2,3-dicarboxylate. 1H NMR (400 MHz, DMSO-d6): δ ppm0.89 (m, 1H), 1.30 (d, J = 16.3 Hz, 3H), 1.60 (q, J = 5.9 Hz, 4H), 2.05 (dd, J = 13.4, 7.2 Hz, 1H), 2.32 (dd, J = 13.4, 9.1 Hz, 1H), 3.11 (d, J = 11.7 Hz, 1H), 3.24 (d, J = 11.7 Hz, 1H), 3.47 (ddt, J = 20.6, 13.4, 6.5 Hz, 2H), 3 .64 (ddt, J = 15.8, 10.8, 5.2 Hz, 2H), 4.07 (dd, J = 9.2, 7.1 Hz, 1H), 5.51 (s, 1H ), 6.68 (q, J = 6.9 Hz, 1H), 7.25 (m, 4H), 7.48 (m, 3H), 7.71 (m, 1H). LCMS (MH+): 546. Example 43: (S)-8-(5-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- acid 2,2,2-trifluoroethoxy)pyridazin-3-yl)-2,8-diazaspiro[4.5]de-cane-3-carboxylic acid

[00518] Step 1: In (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (1.00 g, 3 .44 mmol, Intermediate 3) in 1,4-dioxane (100 mL) were added 3,5-dichloropyridazine (512 mg, 3.44 mmol) and Cs2CO3 (3.36 g, 10.3 mmol). The reaction mixture was then heated at 100°C for 182 h. During this time, the reaction was loaded with additional 3,5-dichloropyridazine (2.56 g, 17.2 mmol) at t = 86 h. Then, the reaction mixture was cooled at RT, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (EtOAc/heptane) provided 3-chloro-5-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2 ,2,2-trifluoroethoxy]pyridazine as a 3:2 mixture of (R)-3-chloro-5-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl) -2,2,2-trifluoroethoxy)pyridazine and (R)-5-chloro-3-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2 ,2-trifluoroethoxy)pyridazine, respectively.

[00519] Step 2: In a solution of the mixture of (R)-3-chloro-5-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2, 2,2-trifluoroethoxy)pyridazine/(R)-5-chloro-3-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyridazine from step 1 in 1,4-dioxane (19 mL) were added 2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (980 mg, 2.83 mmol) , Cs2CO3 (2.30 g, 7.07 mmol), Pd2(dba)3 (432 mg, 0.471 mmol) and rac-BINAP (587 mg, 0.940 mmol), and the reaction mixture was heated at 60 ° C for 60 H. Then, the reaction mixture was cooled at RT, filtered through celite, washed with EtOAc, and the filtrate concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(5-((R)-1-(4-chloro-2-(3- methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazin-3-yl)-2,8-diazaes-piro[4.5]decane-2,3-dicarboxylate as a white solid.

[00520] Step 3: Deprotection by N-CBZ was carried out using Method B to provide acid (S)-8-(5-((R)-1-(4-chloro-2-(3-methyl-1H -pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazin-3-yl)-3-(ethoxycarbonyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid as a white solid .

[00521] Step 4: Hydrolysis of acid (S)-8-(5-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethoxy)pyridazin-3-yl)-3-(ethoxycarbonyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid using the general LiOH method provided the title compound as a nearly solid white. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.66 - 1.80 (m, 4 H), 2.11 (dd, J = 13.45, 7.05 Hz, 1 H), 2, 30 - 2.40 (m, 1 H), 2.36 (s, 3 H), 3.16 (d, J = 11.81 Hz, 1 H), 3.25 - 3.35 (m, 1 H), 3.37 - 3.65 (m, 4 H), 4.03 - 4.19 (m, 1 H), 6.39 (d, J = 2.34 Hz, 1 H), 6, 63 (d, J = 2.39 Hz, 1 H), 6.95 (q, J = 6.39 Hz, 1 H), 7.43 - 7.57 (m, 2 H), 7.76 ( d, J = 8.35 Hz, 1 H), 8.22 (d, J = 2.39 Hz, 1 H), 8.63 (d, J = 2.49 Hz, 1 H). LCMS (MH+): 551 Example 44: acid (S)-8-(4-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1- yl)phenyl)ethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid and Example 45: (S)-8-(4-((R)-1-( 4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00522] Step 1: In a solution of 2-chloro-4-nitropyridine (200 mg, 1.00 mmol) in 1,4-dioxane (6 mL) (R)-1-(4-chloro-2) was added - (3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (368 mg, 1.27 mmol) and Cs2CO3 (828 mg, 2.54 mmol). The reaction was heated at 80 oC for 12 h, then cooled at RT, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptane) provided (R)-2-chloro-4-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl) -2,2,2-trifluoroethoxy)pyridine as an off-white solid.

[00523] Step 2: In a solution of (R)-2-chloro-4-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2, 2-trifluoroethoxy)pyridine (227 mg, 0.57 mmol) in 1,4-dioxane (5 mL) was added 2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate ( 237 mg, 0.68 mmol), Cs2CO3 (557 mg, 1.71 mmol), BINAP (142 mg, 0.23 mmol) and Pd2(dba)3. The reaction was heated to 60 oC for 3 d, then cooled at RT, and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptane) provided 2-benzyl 3-ethyl 8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol- 1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

[00524] Step 3: Hydrolysis of 2-benzyl 3-ethyl 8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2 ,2,2-trifluoroethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate using the general LiOH method gave 2-((benzyloxy)carbonyl)-8-( 4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridin-2-yl)-2,8 -diazaspiro[4.5]decane-3-carboxylic acid.

[00525] Step 4: Deprotection by N-CBZ was carried out using Method A followed by purification by normal phase silica gel (EtOAc: heptane) also providing the title compounds as white solids (120 mg and 75 mg for the analogue of des-chlorine). 8-(4-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyridin-2-yl)-2,8 -diazaspiro[4.5]decane-3-carboxylic acid: 1H NMR (400 MHz, MeOH-d4): δ ppm 1.52 - 1.76 (m, 4 H) 1.95 - 2.15 (m, 1 H) 2.23 - 2.37 (m, 1 H) 2.39 (s, 3 H) 2.87 (s, 1 H) 3.05 - 3.16 (m, 1 H) 3.19 - 3, 27 (m, 1 H) 3.38 - 3.72 (m, 4 H) 3.77 - 4.13 (m, 1 H) 6.39 (d, J=2.44 Hz, 1 H) 6 .44 - 6.52 (m, 1 H) 6.79 (d, J=2.20 Hz, 1 H) 6.83 - 6.97 (m, 1 H) 7.43 - 7.51 (m , 1 H) 7.54 (d, J=2.05 Hz, 1 H) 7.66 (d, J=8.74 Hz, 1 H) 7.81 - 8.00 (m, 2 H). LCMS (MH+): 550. 8-(4-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyridin-2 - il)-2,8-diazaspiro[4.5]decane-3-carboxylic acid: 1H NMR (400 MHz, MeOH-d4): δ ppm 1.47 - 1.71 (m, 4 H) 1.95 - 2, 04 (m, 1 H) 2.21 - 2.31 (m, 1 H) 2.39 (s, 3 H) 2.73 (s, 1 H) 3.02 (d, J=11.52 Hz , 1 H) 3.14 - 3.22 (m, 1 H) 3.37 - 4.03 (m, 4 H) 6.36 (d, J=2.34 Hz, 1 H) 6.43 - 6.51 (m, 1 H) 6.72 - 6.85 (m, 2 H) 7.30 - 7.51 (m, 3 H) 7.52 - 7.61 (m, 1 H) 7, 67 (d, J=7.86 Hz, 1 H) 7.81 (d, J=2.34 Hz, 1 H) 7.86 - 7.91 (m, 1 H). LCMS (MH+): 516. Example 46: 8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2 acid, 2-trifluoroethoxy)-6-phenoxypyrimidin-2-yl)-2,8-diazaespiro[4.5]decane-3-carboxylic acid

[00526] Step 1: In a solution of 2-benzyl 3-ethyl 8-(4-chloro-6-((R)- 1-(4-chloro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (byproduct of Step 3, Example 30a) (250 mg, 0.347 mmol ) in 1,4-dioxane (9.0 mL) phenol (1.00 g, 10.6 mmol) and Cs2CO3 (3.65 g, 11.2 mmol) were added. The reaction was heated at 80°C for 12 h, then cooled at RT, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification on a 12 g Isco RediSep silica cartridge (EtOAc/heptane) provided 2-benzyl 3-ethyl 8-(4-((R)-1-(4-chloro-2-(3-methyl-1H -pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-phenoxypyrimidin-2-yl)-2,8-diazaes-pyro[4.5]decane-2,3-dicarboxylate as an off-white solid .

[00527] Step 2: Deprotection by N-CBZ was carried out using Method A to provide (ethyl 8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol- 1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-phenoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.

[00528] Step 3: Hydrolysis of ethyl 8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)-6-phenoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the general LiOH method provided the title compound as an off-white solid. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.36 (br. s., 4 H), 1.90 - 1.99 (m, 1 H), 2.11 - 2.21 (m, 1 H), 2.26 (s, 3 H), 2.92 - 3.17 (m, 2 H), 3.24 - 3.60 (m, 4 H), 3.96 (dd, J = 9.13, 6.88 Hz, 1 H), 5.44 (d, J = 2.29 Hz, 1 H), 6.27 - 6.33 (m, 1 H), 7.00 (d, J = 8.00 Hz, 2 H), 7.08 - 7.16 (m, 1 H), 7.24 - 7.32 (m, 2 H), 7.38 (dd, J = 8.44 , 1.90 Hz, 1 H), 7.44 (d, J = 2.00 Hz, 1 H), 7.54 - 7.62 (m, 1 H), 7.64 (d, J = 8 .49 Hz, 1 H), 7.81 (d, J = 2.25 Hz, 1 H). LCMS (MH+): 642. Example 47: (3S)-8-(2-amino-6-(1-(2,6-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl acid )-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00529] The title compound was prepared as described for acid (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with 1-(2,6-dibromophenyl)-2 ,2,2-trifluoroethanol. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, 1H), 1.62 (q, J = 5.7 Hz, 4H), 2.06 (m, 1H), 2.33 (dd, J = 13.5, 9.2 Hz, 1H), 3.13 (d, J = 11.7 Hz, 1H), 3.26 (d, J = 11.7 Hz, 1H), 3 .49 (m, 2H), 3.65 (dq, J = 10.7, 5.4 Hz, 2H), 4.09 (dd, J = 9.2, 7.2 Hz, 1H), 5, 56 (s, 1H), 7.15 (t, J = 8.0 Hz, 1H), 7.28 (q, J = 8.0 Hz, 1H), 7.69 (m, 2H). LCMS (MH+): 611. Example 48: (S)-8-(2-amino-6-((R)-1-(2,5-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4 acid -yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00530] The title compound was prepared as described for acid (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with 1-(2,5-dibromophenyl)-2 ,2,2-trifluoroethanol. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.62 (q, J = 5.8, 5.2 Hz, 4H), 2.06 (dd, J = 13.5, 7.2 Hz, 1H), 2.34 (dd, J = 13.4, 9.2 Hz, 1H), 3.13 (d, J = 11.7 Hz, 1H), 3.26 (d, J = 11.8 Hz, 1H), 3.50 (m, 2H), 3.66 (ddt, J = 15.0, 10.7, 5.2 Hz, 2H), 4.09 (dd, J = 9.2, 7.2 Hz, 1H), 4.83 (s, 1H), 5.58 (s, 1H), 6.97 (q, J = 6.6 Hz, 1H), 7.47 (dd, J = 8.6, 2.4 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H). LCMS (MH+): 611. Example 49: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(methylsulfonyl)-4) acid -propyl-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4.5]decane-3-carboxylic acid

[00531] Step 1: In a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromo-5-chlorophenyl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (660 mg, 0.95 mmol) in dioxane (12 mL) acid (3-( methylsulfonyl)phenyl)boronic acid (285 mg, 1.43 mmol), Pd2(dppf)Cl2 (70 mg, 0.095 mmol) and Na2CO3 (6.0 mL, 2.0 M, aq). The reaction was heated at 90oC for 2 h, then cooled at RT and concentrated in vacuo. The residue was taken up in CH2Cl2, washed with brine and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4. Purification by column on normal phase silica gel (EtOAc/heptane) provided (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(4-chloro-3 '-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-di - carboxylate as a white solid.

[00532] Step 2: In a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(4-chloro-3'-(methylsulfonyl)- [1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (500 mg, 0.65 mmol) in DMF (10 mL) were added tributyl(prop-1-enyl)stannan (258 mg, 0.78 mmol), Pd(t-Bu3P) 2 (33 mg, 0.065 mmol) and CsF (217 mg, 1.43 mmol). The reaction was heated to 130 oC in a sealed tube for 3 h, then cooled at RT. The reaction mixture was partitioned between water and CH2Cl2 and extracted. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptane) provided (S)-2-tert-butyl 3-ethyl 8-(2-amino-6- ((R)-2,2,2-trifluoro- 1-(3'-(methylsulfonyl)-4-(prop-1-en-1-yl)-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

[00533] Step 3: In a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'- (methylsulfonyl)-4-(prop-1-en-1-yl)-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 2,3-dicarboxylate (200 mg, 0.26 mmol) in EtOH (10 mL) was added 10% Pd/C (200 mg), and the reaction mixture was stirred under 1 atm H2 for 12 h. The solids were filtered, and the filtrate was concentrated to provide (S)-2-tert-butyl-3-ethyl-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3 '-(methylsulfonyl)-4-propyl-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-2,3- dicarboxylate as a white solid, which is used directly without further purification.

[00534] Step 4: In a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'- (methylsulfonyl)-4-propyl-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate in CH2Cl2 (4 mL ) TFA (2.0 mL) was added dropwise at 0 oC. The reaction mixture was stirred at RT for 2 h, then concentrated in vacuo. The pH was adjusted to 7-8 with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by normal phase silica gel column (CH2Cl2/MeOH) provided the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4): δ ppm 8.41 (m, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.79 (t, J = 7.8 Hz , 1H), 7.73-7.71 (m, 1H), 7.53 (s, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6.61 (q, J = 6.7 Hz, 1H), 5.61 (s, 1H), 4.10 (t, J = 8.4 Hz, 1H), 3 .72-3.63 (m, 2H), 3.55-3.46 (m, 2H), 3.26 (m, 1H), 3.21 (s, 3H), 3.16-3.13 (m, 1H), 2.66 (t, J = 7.6 Hz, 2H), 2,382.32 (m, 1H), 2.10-2.05 (m, 2H), 1.65-1, 60 (m, 3H). LCMS (MH+): 649. Example 50: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(methylsulfonyl)-4) acid -((E)-prop-1-en-1-yl)-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3 -carboxylic

[00535] The title compound was prepared as described for (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(methylsulfonyl)-4-(prop-1-en-1-yl)-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaes-piro[4.5 ]decane-2,3-dicarboxylate (Example 49) by omitting the olefin hydrogenation reaction from Step 3. 1H NMR (400 MHz, CD3OD-d4): δ ppm 8.46-8.42 (m, 1H), 8.06-8.03 (m, 1H), 7.82-7.71 (m, 2H), 7.64 (s, 1H), 7.45 (dd, J1 = 8.2 Hz, J2 = 33.2 Hz, 1H), 7.25 (dd, J1 = 7.9 Hz, J2 = 23.9 Hz, 1H), 6.64-6.62 (m, 1H), 6.49- 6, 45 (m, 1H), 6.39-5.86 (m, 1H), 5.62 (d, J = 5.3 Hz, 1H), 4.12-4.08 (m, 1H), 3 .70-3.62 (m, 2H), 3.54-3.45 (m, 2H), 3.29-3.26 (m, 1H), 3.22-3.21 (m, 3H) , 3.16-3.13 (m, 1H), 2.37-2.31 (m, 1H), 2.10-2.05 (m, 1H), 1.911.87 (m, 3H), 1 .62 (m, 4H). LCMS (MH+): 647. Example 51a: (S)-8-(6-((R)-1-([1,1':4',1''-terphenyl]-2'-yl)- acid 2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00536] Step 1: In a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(2,5-dibromophenyl)-2,2, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (660 mg, 0.95 mmol) in dioxane (12 mL) was added phenyl boronic acid (290 mg, 2.4 mmol), Pd2(dppf)Cl2 (70 mg, 0.095 mmol) and Na2CO3 (6.0 mL, 2.0 M, aq). The reaction mixture was heated at 90 oC for 2 h, then cooled at RT, concentrated in vacuo and extracted with CH2Cl2. The combined organic layers were washed with brine and dried over Na2SO4. Purification by column on normal phase silica gel (EtOAc/heptane) provided (S)-2-tert-butyl 3-ethyl 8-(6-((R)-1-([1,1':4',1 ''-terphenyl]-2'-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaes- piro[4.5]decane-2,3-dicarboxylate as a solid white.

[00537] Step 2: In a solution of (S)-2-tert-butyl 3-ethyl 8-(6-((R)- 1-([1,1':4',1''-terphenyl] -2'-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (550 mg, 0.75 mmol) in CH2Cl2 (4 mL) was added TFA (2.0 mL) dropwise at 0 oC. The reaction mixture was stirred at RT for 2 h and concentrated in vacuo. The pH was adjusted to 7-8 with a saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column on normal phase silica gel (CH2Cl2/MeOH) provided (S)-ethyl 8-(6-((R)-1-([1,1':4',1''-terphenyl]- 2'-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.

[00538] Step 3: Hydrolysis of (S)-ethyl 8-(6-((R)-1-([1,1':4',1''-terphenyl]-2'-yl)-2, 2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the general LiOH method provided the title compound as a white solid. 1H NMR (400 MHz, CD3OD-d4):δ ppm 7.91 (s, 1H), 7.70 (dd, J1= 6.08 Hz,J= 1.88 Hz,1H),7.62 (m .2H), 7.56-7.44 (m, 7H), 7.39-7.35 (m, 2H), 6.72 (q, J = 6.52 Hz, 1H), 5.48( s, 1H), 4.18 (q, J = 6.96 Hz, 2H), 3.67 (m, 1H), 3.58 (m, 2H), 3.41(m, 2H), 2, 98 (d,J = 10.96 Hz, 1H), 2.69 (d,J = 11.24 Hz,1H), 2.12-2.06 (m,1H), 1.83-1.78 (m, 1H), 1.52 (m, 4H). LCMS (MH+): 604.5 Example 51b: (S)-8-(6-((R)-1-([1,1':3',1''-terphenyl]-2'-yl) acid -2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00539] The title compound was prepared as described for (S)-8-(6-((R)-1-([1,1':4',1''-terphenyl]-2'-yl) acid -2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 51a) starting with (S)-2-tert-butyl 3 -ethyl 8-(2-amino-6-((R)-1-(2,6-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5 ]decane-2,3-dicarboxylate (product of Step 4, example 63ao). 1H NMR (400 MHz, CD3OD-d4): δ ppm 1.32 (dd, J = 15.5, 7.9 Hz, 1H), 1.70 (dd, J = 7.9, 4.3 Hz, 5H), 2.12 (m, 1H), 2.49 (ddd, J = 12.3, 9.0, 2.6 Hz, 1H), 3.25 (dd, J = 11.9, 2, 2 Hz, 1H), 3.60 (s, 9H), 4.48 (t, J = 8.6 Hz, 1H), 6.89 (q, J = 7.8 Hz, 1H), 7.21 (d, J = 7.6 Hz, 2H), 7.42 (m, 14H). LCMS (MH+): 604. Example 52a: (S)-8-(2-amino-6-((R)-1-(3,4-dimethyl-3''-(methylsulfonyl)-[1) acid ,1':3',1''-terphenyl]-4'-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00540] Step 1: In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(methylsulfonyl)-[1 ,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (product of Step 1, Example 34w) (273 mg, 0.34 mmol) in 1,4-dioxane (5 mL) were added (3,4-dimethylphenyl)boronic acid (77 mg, 0.51 mmol), KHCO3 (341 mg, 3, 40 mmol) and Pd(PCy3)2 (34 mg, 0.051 mmol). The reaction was heated at 100 oC for 44 h. The reaction was loaded with additional Pd(PCy3)2 (68 mg, 0.10 mmol) at t = 16 and 39 h. Then, the reaction was cooled at RT and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification on a 12 g Isco RediSep silica cartridge (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(3,4-dimethyl -3''-(methylsulfonyl)-[1,1':3',1''-terphenyl]-4'-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

[00541] Step 2: Deprotection by N-CBZ was performed using Method B to provide (S)-ethyl 8-(2-amino-6-((R)-1-(3,4-dimethyl-3' '-(methylsulfonyl)-[1,1':3',1''-terphenyl]-4'-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4.5]decane-3-carboxylate as a white solid.

[00542] Step 3: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(3,4-dimethyl-3''-(methylsulfonyl)-[1,1 ':3',1''-terphenyl]-4'-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the general method of LiOH gave the title compound as an off-white solid.

[00543] Using the generic scheme below, the following examples from Table 16a were prepared as described above for (S)-8-(2-amino-6-((R)-1-(3,4-dimethyl-3) acid ''-(methylsulfonyl)-[1,1':3',1''-terphenyl]-4'-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[ 4.5]decane-3-carboxylic acid (Example 52a). Example 53: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(methylsulfonyl)-5-((E)-prop-1 acid -en-1-yl)-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00544] Step 1: In a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (600 mg, 0.89 mmol) in dioxane (12 mL) acid (3-( methylsulfonyl)phenyl) boronic acid (275 mg, 1.3 mmol), Pd2(dppf)Cl2 (65 mg, 0.095 mmol) and Na2CO3 (6.0 mL, 2.0 M, aq). The reaction was heated at 90 oC for 2 h, then cooled at RT and concentrated in vacuo. The residue was taken up in CH2Cl2, washed with brine and dried over Na2SO4. Purification by column on normal phase silica gel (EtOAc/heptane) yields (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3 '-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4.5]decane-2,3-di - carboxylate as a white solid.

[00545] Step 2: In a solution (S)-2-tert-butyl 3-ethyl 8-(2-amino-6- ((R)-1-(5-chloro-3'-(methylsulfonyl)-[ 1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (500 mg, 0 .65 mmol) in DMF (10 mL) were added tributyl(prop-1-enyl)stannan (258 mg, 0.78 mmol), Pd(t-Bu3P) 2 (33 mg, 0.065 mmol) and CsF (217 mg , 1.43 mmol). The reaction was heated to 130 oC in a sealed tube for 3 h, then cooled at RT and partitioned between water and CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptane) provided (S)-2- tert -butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro- 1-(3'-(methylsulfonyl)-5- ((E)-prop-1-en-1-yl)-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaes-pyro[4.5]decane-2,3-dicarboxylate as a white solid.

[00546] Step 3: In a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'- (methylsulfonyl)-5-((E)-prop-1-en-1-yl)-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[ 4.5]decane-2,3-dicarboxylate in CH2Cl2 (4 mL) was added TFA (2.0 mL) dropwise at 0 oC. The reaction mixture was stirred at RT for 2 h, then concentrated in vacuo. The pH was adjusted to 7-8 with a saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column on normal phase silica gel (CH2Cl2/MeOH) provided (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'- ( methylsulfonyl)-5-((E)-prop-1-en-1-yl)-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5 ]decane-3-carboxylate as a white solid.

[00547] Step 4: Hydrolysis of acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(methylsulfonyl)-5-( (E)-prop-1-en-1-yl)-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3 -carboxylic acid using the general LiOH method gave the title compound as an off-white solid. 1H NMR (400 MHz, CD3OD-d4): δ ppm 8.40 (s, 1 H), 8.02 (d, 1 H,J=7.4 Hz), 7.50 (m, 3 H), 7.40 (m, 1 H), 7.20 (m, 1 H), 6.58 (m, 1 H), 5.58 (m, 1 H), 4.09 (m, 1 H), 3.55 (m, 2 H), 3.48 (m, 2 H), 3.21 (m, 4 H), 3.10 (m, 1 H), 2.59 (m, 2 H), 2 .29 (m, 1 H),1.95 (m, 1 H), 1.86 (m, 3 H), 1.30 (m, 4 H). LCMS (MH+): 646. Example 54a: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(methylsulfonyl)-5) acid -propyl-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4.5]decane-3-carboxylic acid

[00548] Step 1: In a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'- (methylsulfonyl)-5-((E)-prop-1-en-1-yl)-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[ 4.5]decane-2,3-dicarboxylate (product of Step 2, Example 53) (200 mg, 0.26 mmol) in EtOH (10 mL) is added 10% Pd/C (200 mg), and the reaction mixture was stirred under 1 atm H2 for 12 h. The solids were filtered, and the filtrate was concentrated in vacuo to provide (S)-2-tert-butyl-3-ethyl-8-(2-amino-6-((R)-2,2,2-trifluoro-1- (3'-(methylsulfonyl)-5-propyl-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid that is used directly without further purification.

[00549] Step 2: In a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'- (methylsulfonyl)-5-propyl-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate in CH2Cl2 (4 mL ) TFA (2.0 mL) was added dropwise at 0 oC. The reaction mixture was stirred at RT for 2 h, then concentrated in vacuo. The pH was adjusted to 7-8 with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column on normal phase silica gel (CH2Cl2/MeOH) provided (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-( methylsulfonyl)-5-propyl-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.

[00550] Step 3: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(methylsulfonyl)-5-propyl -[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the general LiOH method gives the title compound as a nearly solid white. 1H NMR (400 MHz, CD3OD-d4): δ ppm 8.40 (s, 1 H), 8.02 (d, 1 H,J=7.8 Hz), 7.60 (m, 3 H), 7.29 (m, 1 H), 7.08 (s, 1 H), 6.58 (m, 1 H), 5.56 (s, 1 H), 4.00 (m, 1 H), 3.55 (m, 2 H), 3.48 (m, 2 H), 3.31 (m, 4 H), 3.30 (m, 1 H), 2.59 (m, 2 H), 2 .29 (m, 1 H),1.95 (m, 1 H), 1.54 (m, 6 H), 0.95 (m, 3 H). LCMS (MH+): 649. Example 54b: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-iso-propoxy-[1,1 ':3',1''-terphenyl]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00551] Step 1: In a solution of (S)-ethyl 8-(2-amino-6-((R)-1-(5-bromo-[1,1'-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (350 mg, 0.56 mmol) in CH2Cl2 (20 mL) was added Boc2O (436 mg, 2.0 mmol) and Et3N (306 mg, 3.03 mmol) at 0 oC. The reaction mixture was stirred at RT for 3 h, then concentrated in vacuo and purified on normal phase silica gel (ethyl acetate/hexanes) to provide (S)-2-tert-butyl 3-ethyl 8-(2- amino-6-((R)-1-(5-bromo-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4.5]decane-2,3-dicarboxylate as a yellow solid.

[00552] Step 2: The solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6- ((R)-1-(5-bromo-[1,1'-biphenyl] -2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (150 mg, 0.2 mmol), 4-isopropoxyphenyl acid boronic acid (44 mg, 0.25 mmol) and Pd(dppf)Cl2 (15 mg, 0.02 mmol) in dioxane (3.0 mL) / aqueous Na2CO3 solution (3.0 mL, 2.0 M, aq .) was stirred at 90 oC for 2 h. The aqueous layer was extracted with CH2Cl2, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/Hex = 10 to 50%) to provide (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2, 2,2-trifluoro-1-(4-isopropoxy-[1,1':3',1''-terphenyl]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5 ]decane-2,3-dicarboxylate as a white solid.

[00553] Step 3: In a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy -[1,1':3',1''-terphenyl]-4'- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (130 mg, 0.164 mmol) in CH2Cl2 (4 mL) TFA (1 mL) was added, and the reaction mixture was stirred at 25 oC for 12 h. The mixture was concentrated and neutralized to pH 7-8 with saturated aqueous NaHCO3. The aqueous layer was extracted with CH2Cl2, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro- 1-(4-isopropoxy-[1,1':3',1''-terphenyl]-4'- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a light yellow solid, which is used without further purification.

[00554] Step 4: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1': 3',1''-terphenyl]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-3-carboxylate using the general LiOH method gave the title compound as an almost white solid. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (d, J = 6.0 Hz, 6H), 1.58 (m, 4H), 2.04 (dd, J = 13.4, 7.2 Hz, 1H), 2.32 (dd, J = 13.4, 9.2 Hz, 1H), 3.11 (d, J = 11.7 Hz, 1H), 3.24 (d, J = 11.7 Hz, 1H), 3.45 (ddd, J = 21.2, 10.1, 6.4 Hz, 2H), 3.60 (td, J = 12.4, 11.2, 6.0 Hz, 2H), 4.08 (dd, J = 9.1, 7.1 Hz, 1H), 4.62 (p, J = 6.1 Hz, 1H), 6.67 (q, J = 6.8 Hz, 1H), 6.95 (m, 2H), 7.54 (m, 9H), 7.72 (d, J = 8.3 Hz, 1H). LCMS (MH+): 663. Example 54c: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-prop-poxy-[1,1 ':3',1''-terphenyl]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaes- pyro[4.5]decane-3-carboxylic acid

[00555] The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1 ':3',1''-ter-phenyl]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 54b) by substitution of acid 4 -propoxyphenyl boronic acid by 4-isopropoxyphenyl boronic acid in Step 2. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.04 (t, J = 7.4 Hz, 3H), 1.57 (m, 4H) , 1.80 (h, J = 6.7 Hz, 2H), 1.99 (dd, J = 13.3, 7.3 Hz, 1H), 2.27 (dd, J = 13.3, 9 .1 Hz, 1H), 3.02 (d, J = 11.6 Hz, 1H), 3.18 (d, J = 11.5 Hz, 1H), 3.30 (d, J = 3.2 Hz, 1H), 3.45 (q, J = 15.9, 11.4 Hz, 2H), 3.60 (s, 2H), 3.97 (dt, J = 13.1, 7.3 Hz , 3H), 4.88 (m, 1H), 5.47 (s, 1H), 6.66 (q, J = 6.9 Hz, 1H), 6.97 (d, J = 8.3 Hz , 2H), 7.54 (m, 9H), 7.72 (m, 1H). LCMS (MH+): 662. Example 54d: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1) acid ,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaes- piro[4.5]decane-3-carboxylic acid

[00556] Step 1: In a mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (5 g, 21.3 mmol) in anhydrous methanol (100 mL) concentrated sulfuric acid (0.5 mL) was added . The resulting solution was stirred for 18 h at reflux. Upon cooling, the mixture was concentrated under reduced pressure, dissolved in CH2Cl2 and washed with NaHCO3 solution and brine. The organic phase was dried over sodium sulfate and concentrated to provide methyl 2-chloro-4-(methylsulfonyl)benzoate as a white solid.

[00557] Step 2: In a mixture of methyl 2-chloro-4-(methylsulfonyl)benzoate (2.2 g, 8.9 mmol), PhB(OH)2 (1.31 g, 10.8 mmol ), DME (12 mL) and 2M Na2CO3 (6 mL) Pd(PPh3)4 (515 mg) was added. The mixture was heated for 20 min at 160 oC in a microwave reactor, and then extracted with EtOAc, dried over sodium sulfate and concentrated in vacuo. Purification on normal phase silica gel (hexane/EtOAc) provided methyl 5-(methylsulfonyl)-[1,1'-biphenyl]-2-carboxylate as a white solid.

[00558] Step 3: In a solution of CaCl2 (1.52 g, 13.78 mmol) in EtOH (50 mL) at RT was added methyl 5-(methylsulfonyl)-[1,1'-biphenyl]- 2- carboxylate (2 g, 6.9 mmol) in THF (50 mL) followed by addition of NaBH4 (1.0 g, 27.6 mmol). The reaction was stirred at RT for 24 h, then concentrated in vacuo and extracted with ethyl acetate, 5% HCl and brine. Purification on normal phase silica gel provided (5-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)methanol as a white solid.

[00559] Step 4: In a solution of (5-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)methanol (1 g, 3.8 mmol) in CH2Cl2 (50 mL) periodinane was added. Dess-Martin (2.4 g, 5.71 mmol). The reaction was stirred for 2 h at RT, then concentrated in vacuo and purified directly on normal phase silica gel to give 5-(methylsulfonyl)-[1,1'-biphenyl]-2-car-baldehyde as a white solid. .

[00560] Step 5: In a solution of 5-(methylsulfonyl)-[1,1'-biphenyl]-2-carbaldehyde (1 g, 3.8 mmol) was added TMS-CF3 (1.0 g, 7, 7 mmol) in THF (10 mL). The reaction was cooled to 0°C and TBAF (0.57 mL, 0.57 mmol) was added dropwise. The reaction mixture was stirred for 2 h, then 3N HCl (2 mL) was added to the mixture, and the reaction mixture was stirred for an additional 30 min. The mixture was extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification on normal phase silica gel provided 2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)ethanol as a white solid.

[00561] Step 6: In a mixture of 2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)ethanol (720 mg, 2.2 mmol)) in CH2Cl2 (50 mL) Dess-Martin periodinane (1.1 g, 2.6 mmol) was added. The reaction was stirred for 2 h at RT, then concentrated in vacuo and purified directly on normal phase silica gel to give 2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1'-biphenyl ]-2-yl)ethanone as a white solid.

[00562] Step 7: Chiral reduction of 2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)ethanone using iridium complex-catalyzed hydrogenation as described by Intermediate 1, (R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol, gave (R)-2,2, 2-trifluoro-1-(5-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)ethanol as a white solid.

[00563] Steps 8-11: The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H) acid -pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d), Steps 1- 4. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.63 (q, J = 5.7, 4.9 Hz, 4H), 2.10 (m, 1H), 2.36 (dd, J = 13.5, 9.2 Hz, 1H), 3.23 (d, J = 31.0 Hz, 5H), 3.50 (dddd, J = 18.0, 13.4, 9.5, 5, 1 Hz, 2H), 3.66 (ddt, J = 15.9, 10.6, 4.6 Hz, 2H), 4.16 (dd, J = 9.2, 7.2 Hz, 1H), 6.78 (q, J = 6.7 Hz, 1H), 7.57 (m, 5H), 7.86 (d, J = 1.9 Hz, 1H), 8.01 (m, 2H), 8.17 (s, 1H). LCMS (MH+): 607. Example 54e: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-fluoro-4-propoxy-[1) acid ,1':3',1''-terphenyl]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaes- piro[4.5]decane-3-carboxylic acid

[00564] The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1 ':3',1''-ter-phenyl]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 54b) by substitution of acid 4 -isopropoxyphenyl boronic acid in Step 2 with (3-fluoro-4-propoxyphenyl)boronic acid (CAS# 192376-68-4). 1H NMR (400 MHz, MeOH-d4): δ ppm 0.86 (m, 1H), 1.05 (t, J = 7.4 Hz, 3H), 1.26 (s, 1H), 1.59 (s, 4H), 1.83 (h, J = 7.1 Hz, 2H), 2.06 (dd, J = 13.4, 7.2 Hz, 1H), 2.33 (m, 1H) , 3.10 (d, J = 11.9 Hz, 1H), 3.23 (d, J = 12.0 Hz, 1H), 3.43 (s, 2H), 3.60 (s, 2H) , 4.02 (t, J = 6.5 Hz, 2H), 4.12 (s, 1H), 6.62 (d, J = 6.8 Hz, 1H), 7.09 (t, J = 8.7 Hz, 1H), 7.34 (s, 1H), 7.43 (m, 4H), 7.50 (s, 3H), 7.60 (m, 1H), 7.76 (m, 2H). LCMS (MH+): 681. Example 54f: (S)-8-(2-amino-6-((R)-1-(3,4-dimethyl-[1,1':3',1'') acid - terphenyl]-4'-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaes- piro[4.5]decane-3-carboxylic acid

[00565] The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1 ':3',1''-ter-phenyl]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 54b) by substitution of acid 4 -isopropoxyphenyl boronic acid in Step 2 with 3,4-dimethylphenyl boronic acid. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.62 (s, 4H), 2.06 (dd, J = 13.5, 7.6 Hz, 1H), 2.29 (d, J = 9.7 Hz, 5H), 2.37 (m, 1H), 3.17 (d, J = 11.8 Hz, 1H), 3.26 (d, J = 11.7 Hz, 1H), 3 .63 (d, J = 14.2 Hz, 2H), 4.27 (t, J = 8.3 Hz, 1H), 6.66 (q, J = 6.8 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 7.36 (m, 2H), 7.49 (m, 5H), 7.64 (dd, J = 8.2, 2.0 Hz, 1H) , 7.74 (d, J = 8.2 Hz, 1H). LCMS (MH+): 633. Example 54g: (S)-8-(6-((R)-1-([1,1':3',1''-terphenyl]-4'-yl)- acid 2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00566] The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1 ':3',1''-ter-phenyl]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 54b) by substitution of phenyl acid boronic acid by 4-isopropoxyphenyl boronic acid in Step 2. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.62 (s, 4H), 2.06 (dd, J = 13.5, 7.7 Hz, 1H), 2.38 (dd, J = 13.5, 9.1 Hz, 1H), 3.16 (d, J = 11.8 Hz, 1H), 3.26 (d, J = 11 .8 Hz, 1H), 3.47 (s, 2H), 3.62 (s, 2H), 4.26 (t, J = 8.4 Hz, 1H), 6.68 (q, J = 6 .9Hz, 1H), 7.35 (m, 1H), 7.47 (m, 4H), 7.53 (s, 3H), 7.66 (m, 3H), 7.77 (d, J = 8.2 Hz, 1H). LCMS (MH+): 604. Example 54h: (R)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)- acid 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00567] The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl acid )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 34c) using (R)-2-benzyl 3-ethyl 8-( 2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 2,3-dicarboxylate. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.59 (d, J = 5.5 Hz, 4H), 2.03 (dd, J = 13.4, 7.1 Hz, 1H), 2 .31 (dd, J = 13.4, 9.2 Hz, 1H), 3.09 (d, J = 11.8 Hz, 1H), 3.23 (d, J = 11.6 Hz, 1H) , 3.46 (dt, J = 15.3, 8.2 Hz, 2H), 3.62 (s, 2H), 4.06 (dd, J = 9.1, 7.1 Hz, 1H), 5.49 (s, 1H), 6.64 (q, J = 6.9 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.46 (m, 5H), 7.53 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H). LCMS (MH+): 562. Example 54i: (R)-8-(2-amino-6-((S)-1-(5-chloro-[1,1'-biphenyl]-2-yl)- acid 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00568] The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1) acid -yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 34c) using (R)-2-benzyl 3- ethyl 8-(2-amino-6-((S)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[ 4.5]decane-2,3-dicarboxylate. 1H NMR (400 MHz, MeOH-d4): δ ppm 7.70 (d, J = 8.5 Hz, 1H), 7.59 - 7.44 (m, 4H), 7.47 - 7.40 ( m, 2H), 7.32 (d, J = 2.2 Hz, 1H), 6.61 (q, J = 6.5 Hz, 1H), 4.51 (t, J = 8.7 Hz, 1H), 3.72 - 3.59 (m, 1H), 3.56 (s, 1H), 3.28 (s, 1H), 2.49 (dd, J = 13.6, 8.9 Hz , 1H), 2.10 (dd, J = 13.6, 8.4 Hz, 1H), 1.71 (dt, J = 16.0, 6.6 Hz, 4H), 1.28 (s, 0H).LCMS (MH+): 562. Example 54j: (S)-8-(2-amino-6-((S)-1-(5-chloro-[1,1'-biphenyl]-2- acid il)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00569] The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1) acid -yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 34c) using (S)-2-benzyl 3- ethyl 8-(2-amino-6-((S)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[ 4.5]decane-2,3-dicarboxylate. 1H NMR (400 MHz, MeOH-d4): δ ppm 7.70 (d, J = 8.5 Hz, 1H), 7.61 - 7.42 (m, 6H), 7.32 (d, J = 2.3 Hz, 1H), 6.66 (q, J = 6.7 Hz, 1H), 4.25 (dd, J = 9.0, 7.6 Hz, 1H), 3.72 - 3, 60 (m, 1H), 3.29 (d, J = 11.7 Hz, 1H), 3.18 (d, J = 11.8 Hz, 1H), 2.40 (dd, J = 13.5 , 9.2 Hz, 1H), 2.09 (dd, J = 13.5, 7.6 Hz, 1H), 1.64 (s, 2H).LCMS (MH+): 562. Example 54k: acid ( S)-8-(2-amino-6-((S)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00570] The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H) acid -pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaes- piro[4.5]decane-3 -carboxylic acid (Example 1m) using (S)-2-benzyl 3-ethyl 8-(2-amino-6-((S)-1-(4-chloro-2-(3-methyl-1H-pyrazole -1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.58 (s, 6H), 2.04 (dd, J = 13.4, 7.2 Hz, 1H), 2.30 (d, J = 11.1 Hz, 9H), 2.40 (s, 3H), 3.10 (d, J = 11.8 Hz, 1H), 3.23 (d, J = 11.7 Hz, 1H), 3 .48 (s, 2H), 3.66 (d, J = 15.7 Hz, 3H), 4.08 (t, J = 8.2 Hz, 1H), 6.41 (d, J = 2, 4 Hz, 1H), 6.77 (q, J = 6.5 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 8.0 Hz , 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.73 (m, 2H), 7.97 (d , J = 2.4 Hz, 1H). LCMS (MH+): 635. Example 54l: (R)-8-(2-amino-6-((S)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazole) acid -1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00571] The title compound was prepared as described above for acid (R)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H -pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaes- piro[4.5]decane-3 -carboxylic acid (Example 1m) using (R)-2-benzyl 3-ethyl 8-(2-amino-6-((S)-1-(4-chloro-2-(3-methyl-1H-pyrazole -1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate. 1H NMR (400 MHz, MeOH-d4): δ ppm 7.97 (d, J = 2.3 Hz, 0H), 7.79 - 7.69 (m, 0H), 7.61 (d, J = 1.6 Hz, 0H), 7.45 (s, 0H), 7.42 - 7.35 (m, 0H), 7.21 (d, J = 7.9 Hz, 0H), 6.77 ( q, J = 6.5 Hz, 0H), 6.41 (d, J = 2.3 Hz, 0H), 4.10 (t, J = 8.2 Hz, 0H), 3.68 (dd, J = 13.9, 6.3 Hz, 0H), 3.58 - 3.43 (m, 0H), 3.24 (d, J = 11.7 Hz, 0H), 3.11 (d, J = 11.8 Hz, 0H), 2.42 - 2.27 (m, 1H), 2.05 (dd, J = 13.5, 7.2 Hz, 0H), 1.59 (d, J = 11.4 Hz, 0H), 1.59 (s, 0H).. LCMS (MH+): 635. Example 54m: acid (R)-8-(2-amino-6-((R)-1-( 3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- il)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00572] The title compound was prepared as described above for (R)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl- 1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (Example 1m) using (R )-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate. 1H NMR (400 MHz, MeOH-d4): δ ppm 7.97 (d, J = 2.4 Hz, 1H), 7.79 - 7.68 (m, 2H), 7.60 (d, J = 1.7 Hz, 1H), 7.44 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6 .76 (q, J = 6.7 Hz, 1H), 6.41 (d, J = 2.3 Hz, 1H), 5.75 (s, 1H), 3.98 (t, J = 8, 1 Hz, 1H), 3.64 (d, J = 15.5 Hz, 3H), 3.47 (s, 2H), 3.33 - 3.27 (m, 6H), 3.17 (d, J = 11.6 Hz, 1H), 3.01 (d, J = 11.6 Hz, 1H), 2.39 (s, 3H), 2.34 - 2.18 (m, 8H), 1, 99 (dd, J = 13.4, 7.1 Hz, 1H), 1.56 (s, 5H). LCMS (MH+): 635. Example 55an: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methoxy-[1, 1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]de-cane-3-carboxylic acid

[00573] Step 1: In a solution of (R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol (150 mg, 0.60 mmol) in dioxane (10 mL) was added 4, 6-dichloropyrimidin-2-amine (120 mg g, 0.71 mmol) and Cs2CO3 (290 mg, 0.88 mmol), and the reaction mixture was heated at 80oC for 30 h. Then, the reaction was cooled at RT. EtOAc was added, and the organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptane) provided (R)-4-(1-(4-bromophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine as an oil, colorless.

[00574] Step 2: In a solution of (R)-4-(1-(4-bromophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine (19 mg, 0.50 mmol) in dioxane (25 ml) was added (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (175 mg, 0.50 mmol) and sodium bicarbonate (210 mg, 0.25 mmol), and the reaction mixture was heated at 100 °C for 48 h. Then, the reaction mixture was cooled at RT and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column on normal phase silica gel (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromophenyl)-2, 2,2-trifluoroethoxy)-pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as white solid.

[00575] Step 3: In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy) -pyrimidin-4-yl)-2,8-diazaes-pyro[4.5]decane-2,3-dicarboxylate (190 mg, 0.27 mmol) was added to NaOH (100 mg, 0.26 mmol) in 15 mL THF /EtOH/H2O (2/1/2.5), and the reaction was stirred for 12 h at RT. Then, the reaction mixture was concentrated in vacuo to remove most organic solvents, and the pH was adjusted to 6 with 1 N HCl. EtOAc was added, and the organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to give acid (S)-8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2- ( benzyloxycarbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as a white solid, which was used without further purification.

[00576] Step 4: In a solution of (S)-8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl acid )-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (80 mg, 0.12 mmol) in dioxane (1 mL)/Na2CO3 (1.0 mL, 2 M, aq ) (3-methoxyphenyl)boronic acid (22 mg, 0.14 mmol) and Pd(dppf)2 (8 mg, 0.01 mmol) were added. The reaction flask was degassed and charged again with argon through a balloon 3 times, and the reaction mixture was refluxed for 4 h. Then, the reaction was cooled at RT, concentrated in vacuum, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by reversed-phase silica gel column (H2O/NH4OH/MeOH) provides the acid (S)-8-(2-amino-6-((S)-2,2,2-trifluoro-1- (3'-methoxy-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3 -carboxylic acid as a white solid.

[00577] Step 5: Deprotection by N-CBZ was carried out using Method A to provide the title compound as an isolated off-white solid as the hybrid form.

[00578] Using the generic scheme below, the following examples from Table 17a were prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1- (3'-methoxy-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 55an) using the appropriate boronic or boronate. In some cases, the Cy coupling reaction was performed prior to removal of ethyl ester and N-CBz (see alternative Steps 3a and 4a) as noted in the schematic. In the cases of example 55al and 55am, racemic 1-(4-bromophenyl)-2,2,2-trifluoroethanol was used as opposed to (R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol for all other examples. Example 56: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1,2,3,4-tetrahydroquinoxalin-6-yl) acid phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4.5]decane-3-carboxylic acid

[00579] Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(1,2,3,4-tetrahydroquinoxalin-6-yl)ethoxy )pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (a byproduct from the N-CBZ deprotection of Example 55bi) using the general LiOH method provided the title compound as a almost white solid. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.54 - 1.72 (m, 4 H) 2.07 - 2.14 (m, 1 H) 2.29 - 2.41 (m, 1 H) 3.09 - 3.18 (m, 1 H) 3.22 - 3.29 (m, 1 H) 3.36 - 3.42 (m, 4 H) 3.43 - 3.58 (m , 2 H) 3.60 - 3.80 (m, 2 H) 4.03 - 4.17 (m, 1 H) 5.49 - 5.65 (m, 1 H) 6.50 - 6.67 (m, 2 H) 6.77 - 6.92 (m, 2 H) 7.43 - 7.63 (m, 4 H). LCMS (MH+): 585. Example 57: (S)-8-(2-amino-6-((R)-1-(3,4-dihydroquinazolin-6-yl)-2,2,2 acid -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00580] Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(3,4-dihydroquinazolin-6-yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (a byproduct from the N-CBZ deprotection of Example 55bk) using the general LiOH method provided the title compound as an off-white solid . 1H NMR (400 MHz, MeOH-d4) δ ppm 1.54 - 1.66 (m, 4 H) 1.98 - 2.08 (m, 1 H) 2.23 - 2.34 (m, 1 H ) 3.02 - 3.11 (m, 1 H) 3.17 - 3.25 (m, 1 H) 3.37 - 3.54 (m, 2 H) 3.55 - 3.72 (m, 2 H) 3.97 - 4.08 (m, 1 H) 4.62 - 4.70 (m, 2 H) 5.50 - 5.58 (m, 1 H) 6.56 - 6.66 ( m, 1 H) 6.86 - 6.93 (m, 1 H) 7.19 - 7.24 (m, 1 H) 7.25 - 7.31 (m, 1 H) 7.38 - 7, 44 (m, 1 H) 7.51 - 7.57 (m, 2 H) 7.57 - 7.64 (m, 2 H). LCMS (MH+): 583 Example 58: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(1,2,3,4-tetrahydroquinazolin) acid -6-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4.5]de-cane-3-carboxylic acid

[00581] Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(3,4-dihydroquinazolin-6-yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (a byproduct from the N-CBZ deprotection of Example 55bk) using the general LiOH method provided the title compound as an off-white solid . 1H NMR (400 MHz, MeOH-d4) δ ppm 1.57 - 1.68 (m, 4 H) 1.93 - 2.03 (m, 1 H) 2.18 - 2.30 (m, 1 H ) 2.90 - 3.01 (m, 1 H) 3.12 - 3.19 (m, 1 H) 3.43 - 3.75 (m, 4 H) 3.86 - 3.95 (m, 1 H) 4.00 - 4.07 (m, 2 H) 4.15 - 4.23 (m, 2 H) 5.45 - 5.64 (m, 1 H) 6.56 - 6.67 ( m, 2 H) 7.17 - 7.23 (m, 1 H) 7.27 - 7.33 (m, 1 H) 7.49 - 7.55 (m, 2 H) 7.55 - 7, 62 (m, 2 H). LCMS (MH+): 585. Example 59a: (S)-8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4 acid -il)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00582] Deprotection by N-CBZ was performed using Method B with (S)-8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy acid ) pyrimidin-4-yl)-2-(benzyloxycarbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (75 mg, product of Step 3, Example 55an) providing the title compound as a solid white. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.50 - 1.68 (m, 4 H) 1.96 (s, 2 H) 2.04 (dd, J=13.35, 7.20 Hz, 1 H) 2.31 (dd, J=13.35, 9.10 Hz, 1 H) 3.07 - 3.26 (m, 2 H) 3.35 - 3.55 (m, 2 H ) 3.55 - 3.73 (m, 2 H), 4.06 (dd, J=9.13, 7.17 Hz, 1 H) 5.52 (s, 1 H) 6.57 (q, J=7.11 Hz, 1 H) 7.41 (d, J=8.44 Hz, 2 H) 7.51 - 7.58 (m, 2 H); LCMS (MH+): 531. Example 59b: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(naphthalen-2-yl)ethoxy)pyrimidin acid 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00583] The title compound was made as described for Example 10e, starting with (R)-2,2,2-trifluoro-1-(naphthalen-2-yl)ethanol. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.20 (dt, J = 12.5, 5.3 Hz, 2H), 1.47 (m, 3H), 1.88 (dd, J = 12.4, 8.0 Hz, 1H), 2.57 (s, 1H), 2.69 (s, 1H), 2.80 (d, J = 12.4 Hz, 1H), 3.36 ( m, 3H), 3.97 (dt, J = 12.3, 5.2 Hz, 2H), 6.05 (s, 1H), 6.37 (m, 3H), 7.53 (m, 2H ), 7.77 (dd, J = 7.5, 1.5 Hz, 1H), 7.93 (m, 4H); LCMS (MH+): 562.

[00584] Example 59c: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-fluoroquinolin-6-yl)-2- acid methylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00585] Step 1: In a solution of 4-bromo-2-methylbenzoic acid (5.0 g, 23.2 mmol) in DMF (50 mL) potassium carbonate (6.4 g, 46.4 mmol) was added ) and iodomethane (6.6 g, 46.479 mmol). The mixture was stirred at RT for 12 h then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by normal phase silica gel column provided methyl 4-bromo-2-methylbenzoate as a colorless oil.

[00586] Step 2: In a solution of methyl 4-bromo-2-methylbenzoate (2 g, 8.7 mmol) in THF (20 mL) LAH (663 mg, 17.5 mmol) was added at 0°C. The mixture was stirred at RT for 1h, then diluted with NaOH (1.0M, 10 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by normal phase silica gel column provided (4-bromo-2-methylphenyl)methanol as a colorless oil.

[00587] Step 3: To the solution of (4-bromo-2-methylphenyl)methanol (1.8 g, 8.1 mmol) in CH2Cl2 (20 mL) was added Dess-Martin Periodinane (5.1 g, 12 .1 mmol) at 0°C. The mixture was stirred at RT for 1h, then diluted with water, and the solid was removed by filtration. The filtrate was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by normal phase silica gel column provided 4-bromo-2-methylbenzaldehyde as a yellow oil.

[00588] Step 4: In a solution of 4-bromo-2-methylbenzaldehyde (1.5 g, 7.5 mmol) in THF (20 mL) TMSCF3 (2.2 g, 15.5 mmol) was added at 0 °C, and then TBAF (1.1 mL, 1.0 M in THF). The mixture was stirred at RT for 1h, then diluted with HCl (3.0M, 10 mL), stirred at RT for 1h and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by normal phase silica gel column provided 1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanol as an off-white solid.

[00589] Step 5: In a solution of 1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanol (1.8 g, 6.7 mmol) in CH2Cl2 (20 mL) Peri- Dess-Martin odinane (3.4 g, 8.1 mmol) at 0°C. The mixture was stirred at RT for 2h, then diluted with water (10 mL) and filtered. The filtrate was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by normal phase silica gel column provided 1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanone as a yellow oil.

[00590] Step 6: The chiral reduction of 1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanone using iridium complex-catalyzed hydrogenation as described by Intermediate 1, (R)-1 -(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol gives (R)-1-(4-bromo-2-methylphenyl)- 2,2,2-trifluoroethanol.

[00591] Step 7: The title compound was prepared as described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methoxy-[ 1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 55an) Steps 4-5. 3-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolone was used as the Suzuki coupling pair (CAS# 1251731-31-3). 1H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.59 (s, 4H), 2.04 (dd, J = 13.5, 7.0 Hz, 1H) , 2.31 (dd, J = 13.3, 9.3 Hz, 1H), 2.65 (s, 3H), 3.10 (d, J = 11.7 Hz, 1H), 3.23 ( d, J = 11.5 Hz, 1H), 3.47 (t, J = 14.3 Hz, 2H), 3.63 (t, J = 13.8 Hz, 2H), 4.07 (t, J = 8.1 Hz, 1H), 5.56 (s, 1H), 6.87 (q, J = 7.0 Hz, 1H), 7.63 (d, J = 4.6 Hz, 3H) , 8.01 (d, J = 8.9 Hz, 1H), 8.12 (m, 3H), 8.80 (m, 1H). LCMS (MH+): 611. Example 59d: (S)-8-(2-amino-6-((R)-1-(2-ethyl-4-(3-fluoroquinolin-6-yl)phenyl acid )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-3-carboxylic acid

[00592] Step 1: In a solution at 0 oC of LDA (10.7 mL, 21.39 mmol) in THF (20 mL) 4-bromo-2-methylbenzoic acid (2 g, 9.3 mmol) was added in THF (5 mL). The mixture was stirred at 0°C for 1 h, cooled to -70°C, and then Mel (2.3 mL, 37.20 mmol) was added dropwise. The mixture was allowed to warm to 0°C, stirred for 3 h, then quenched with H2O, and the pH was adjusted to 1-2 with 3N HCl. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by normal phase silica gel column provided 4-bromo-2-ethylbenzoic acid as a white solid.

[00593] Step 2: The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-) acid fluoroquinolin-6-yl)-2-methylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 59c) starting with 4-bromo-2-ethylbenz- zoic acid in place of 4-bromo-2-methylbenzoic acid. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, 1H), 1.41 (t, J = 7.5 Hz, 3H), 1.59 (q, J = 6.1, 5.6 Hz, 4H), 2.04 (dd, J = 13.5, 7.1 Hz, 1H), 2.32 (dd, J = 13.4, 9.1 Hz, 1H), 3, 01 (dt, J = 12.1, 7.0 Hz, 2H), 3.12 (d, J = 11.6 Hz, 1H), 3.24 (d, J = 11.8 Hz, 1H), 3.48 (dt, J = 21.5, 6.9 Hz, 2H), 3.62 (m, 2H), 4.08 (dd, J = 9.1, 7.0 Hz, 1H), 4 .94 (s, 15H), 5.56 (s, 1H), 7.00 (q, J = 6.9 Hz, 1H), 7.67 (m, 3H), 8.11 (m, 5H) , 8.80 (d, J = 2.8 Hz, 1H). LCMS (MH+): 626. Example 60: 9-(2-Amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2 ,2,2-trifluoroethoxy)pyrimidin-4-yl)-3,9-diazaspiro[5.5]undecane-2-carboxylic acid

[00594] Step 1: In a solution of methyl 3,9-diazaspiro[5.5]undecane-10-carboxylate (30 mg, 0.14 mmol) in dioxane (2 mL) / i-PrOH (2 mL) was added 4-chloro-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-2-amine (92 mg, 0.22 mmol), and the reaction was heated to 100oC under microwaves for 3 h. The reaction was cooled to RT and concentrated in vacuo. The residue was purified by reverse phase HPLC (MeOH/H2O/0.5% TFA) to provide methyl 9-(2-amino-6-((R)-1-(4-chloro-2-(3- methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-3,9-diazaspiro[5.5]undecane-2-carboxylate as an off-white solid.

[00595] Step 2: Hydrolysis of methyl 9-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-3,9-diazaspiro[5.5]undecane-2-carboxylate using the general LiOH method provides the title compound as an off-white solid. 1H NMR (400 MHz, MeOH-d4): δ ppm 1.22 - 1.37 (m, 1 H) 1.30 - 1.30 (m, 1 H) 1.46 - 1.68 (m, 4 H) 1.68 - 1.90 (m, 2 H) 2.29 (dd, J=12.59, 6.83 Hz, 1 H) 2.37 (d, J=1.90 Hz, 3 H ) 3.07 - 3.24 (m, 2 H) 3.59 - 3.90 (m, 4 H) 4.03 - 4.19 (m, 1 H) 6.29 - 6.38 (m, 1 H) 6.40 (d, J=2.29 Hz, 1 H), 6.88 - 7.02 (m, 1 H) 7.52 - 7.61 (m, 2 H) 7.65 - 7.74 (m, 1 H) 7.89 (d, J=2.34 Hz, 1 H). LCMS (MH+): 581. Example 61: (S)-8-(2-Amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4 acid -il)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00596] Step 1: Mixture of 4-bromophenol (173 mg, 1.00 mmol), 4-chloro-6-(chloromethyl)pyrimidin-2-amine (CAS#: 92311-35-8) (178 mg, 1 .16 mmol) and K2CO3 (175 mg, 1.00 mmol) in DMF (5 mL) was heated at 100°C for 12 h. The reaction was cooled at RT, concentrated in vacuo, and the residue taken up in EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification on normal phase silica gel (EtOAc/petroleum ether) provided 4-((4-bromophenoxy)methyl)-6-chloropyrimidin-2-amine as a white solid.

[00597] Step 2: The mixture of 4-((4-Bromophenoxy)methyl)-6-chloropyrimidin-2-amine (454 mg, 1.4 mmol), (S)-2-benzyl 3-ethyl 2 ,8-diazaes-piro[4.5]decane-2,3-dicarboxylate (500 mg, 1.44 mmol) and NaHCO3 (605 mg.7 mmol) in dioxane (5 mL) was heated at 100°C for 12 h. The reaction was cooled at RT, concentrated in vacuo and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification on normal phase silica gel (EtOAc/petroleum ether) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((4-bromophenoxy)methyl)pyrimidin-4-yl)- 2,8-diaza-spiro[4.5]decane-2,3-dicarboxylate as a white solid.

[00598] Step 3: In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((4-bromophenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[ 4.5]decane-2,3-dicarboxylate (550 mg, 0.9 mmol) in acetonitrile (5 mL) was added TMSI (705 mg, 3.5 mmol) dropwise at 0°C. The mixture was stirred at 0°C for 2 h, then concentrated in vacuo. The residue was dissolved in CH2Cl2 (20 mL) followed by sequential addition of Et3N (267 mg, 2.6 mmol) and (BOC)2O (285 mg, 1.3 mmol). The reaction mixture was stirred at RT for 16 h then concentrated in vacuo. Purification on normal phase silica gel (CH2Cl2/MeOH) yields (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((4-bromophenoxy)methyl)pyrimidin-4-yl)- 2,8-diaza-spiro[4.5]decane-2,3-dicarboxylate as a light yellow solid.

[00599] Step 4: The mixture of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((4-bromophenoxy) methyl)pyrimidin-4-yl)-2,8- acid diazaspiro[4.5] decane-2,3-dicarboxylate (350 mg, 0.56 mmol), 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole (285 mg, 1.1 mmol) and Pd(dppf)Cl2 (62 mg, 0.09 mmol) in dioxane (5mL)/aq. Na2CO3 solution. (2.0 M, 5 mL) was heated at 90oC for 4 h. The reaction was cooled to RT, the solids filtered, and the solution concentrated in vacuo. Purification on normal phase silica gel (CH2Cl2/MeOH) provided (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((4-(3-methyl-1H-indazol-6- yl)phenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a brown solid.

[00600] Step 5: In a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy) methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (150 mg, 0.19 mmol) in CH2Cl2 (5 mL) was added TFA (3 mL), and the resulting mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuum, and the resulting material partitioned between CH2Cl2 and saturated NaHCO3, and extracted. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification by prep TLC. (CH2Cl2/MeOH) provided (S)-ethyl 8-(2-amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate as a brown solid.

[00601] Step 6: In a solution of (S)-ethyl 8-(2-amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl) pyrimidin-4 -yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (70 mg, 0.11 mmol) in MeOH (3 mL) is added 4N NaOH (3 mL), and the reaction mixture was stirred at RT for 4 h. The reaction mixture was then concentrated in vacuo. The residue was diluted with water (5 mL), and the pH adjusted to 6-7. The solid precipitate was collected by filtration, and the filter cake was washed with cold water, then dried to provide the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.72-7.70 (d, 1 H), 7.61-7.59 (d, 3 H), 7.31-7.30 (d , 1 H), 7.06-7.04 (d, 2 H), 6.14 (s, 1 H), 4.76 (s, 2 H), 3.87-3.83 (q, 1 H), 3.46-3.41 (m, 4 H), 3.08-3.06 (d, 1 H), 2.98-2.95 (d, 1 H), 2.43 (s , 1 H), 2.16-2.13 (m, 1 H), 1.82-1.80 (m, 1 H), 1.44 (m, 4 H). LCMS (MH+): 514. Example 62: (S)-8-(2-amino-6-((5-chloro-3'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl) acid methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

[00602] Step 1: The mixture of (2-bromo-4-chlorophenyl)methanol (173 mg, 1. mmol), 4-chloro-6-(chloromethyl)pyrimidin-2-amine (178 mg, 1.16 mmol ) and K2CO3 (175 mg, 1.00 mmol) in DMF (5 mL) was heated at 100 °C for 12 h. The reaction was cooled at RT, concentrated in vacuo and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification on normal phase silica gel (EtOAc/petroleum ether) provided 4-((2-bromo-4-chlorobenzyl)oxy)-6-chloropyrimidin-2-amine as a white solid.

[00603] Step 2: The mixture of 4-((2-bromo-4-chlorobenzyl)oxy)-6-chloro-pyrimidin-2-amine (300 mg, 1.1 mmol), (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (400 mg, 1.2 mmol) and NaHCO3 (550 mg, 7 mmol) in dioxane (5 mL) was heated to 100 °C for 12 hours. The reaction was cooled at RT, concentrated in vacuo and extracted with EtOAc. The combined organic layers were washed with brine, water, dried over Na2SO4 and concentrated in vacuo. Purification on normal phase silica gel (EtOAc/petroleum ether) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((2-bromo-4-chlorobenzyl)oxy)pyrimidin-4 -il)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

[00604] Step 3: In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((2-bromo-4-chlorobenzyl)oxy)pyrimidin-4-yl)-2, 8-diazaspiro[4.5]decane-2,3-dicarboxylate (500 mg, 0.8 mmol) in acetonitrile (5 mL) was added TMSI (705 mg, 3.5 mmol) dropwise at 0 oC. The reaction mixture was stirred at 0°C for 2 h, then concentrated in vacuo. The residue was dissolved in CH2Cl2 (20 mL), followed by sequential addition of Et3N (267 mg, 2.6 mmol) and (BOC)2O (285 mg, 1.3 mmol). The reaction mixture was stirred at RT for 16 h, then concentrated in vacuo. Purification on normal phase silica gel (CH2Cl2/MeOH) provided (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((2-bromo-4-chlorobenzyl)oxy)pyrimidin -4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a light yellow solid.

[00605] Step 4: The mixture of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((2-bromo-4-chlorobenzyl) oxy)pyrimidin-4-yl)-2 ,8-diazaspiro[4.5]decane-2,3-dicarboxylate (300 mg, 0.4 mmol), (3-(methylsulfonyl)phenyl)boronic acid (280 mg, 1 mmol) and Pd(dppf)Cl2 (62 mg , 0.09 mmol) in dioxane (5mL)/aq. (2.0 M, 5 mL) was heated at 90 oC for 4 h. The reaction was then cooled at RT, the solids filtered, and the filtrate concentrated in vacuo. Purification on normal phase silica gel (CH2Cl2/MeOH) provided (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((5-chloro-3'-(methylsulfonyl)-[1 ,1'-biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4.5]decane-2,3-dicarboxylate as an off-white solid.

[00606] Step 5: In a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((5-chloro-3'-(methylsulfonyl)-[1,1'- biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (200 mg, 0.25 mmol) in CH2Cl2 (5 ml) was added TFA ( 3 mL), and the resulting mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between CH2Cl2 and saturated NaHCO3. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification by prep TLC. (CH2Cl2/MeOH) provided (S)-ethyl 8- (2-amino-6-((5-chloro-3'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)methoxy) pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as an off-white solid.

[00607] Step 6: In a solution (S)-ethyl 8-(2-amino-6-((5-chloro-3'- (methylsulfonyl)-[1,1'-biphenyl]-2-yl)methoxy )pyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-3-carboxylate (100 mg, 0.13 mmol) in MeOH (3 mL) was added 4N NaOH (3 mL), and the mixture was stirred at RT for 4 h. The reaction mixture was then concentrated in vacuo. The residue was diluted with water (5 mL), and the pH adjusted to 6-7. The solid precipitate was collected by filtration, the filter cake was washed with cold water, then dried to provide the title compound as an isolated off-white solid as the hybrid form. 1H NMR (400 MHz, MeOH-d4): δ ppm 7.94 (m, 2 H), 7.59-7.57 (m, 3 H), 7.44-7.40 (m, 1 H) , 7.33 (m, 1 H), 5.33 (m, 1 H), 4.07 (m, 1 H), 3.59 (m, 2 H), 3.45 (m, 2 H) , 3.30 (m, 1 H), 3.15 (m, 1 H),2.32 (m, 1 H), 2.06 (m, 1 H), 1.61 (s, 4 H) .LCMS (MH+): 573.

[00608] The following esters were isolated as a TFA or HCl salt formed during the HPLC purification procedure used to isolate the final compounds. Example 63bd: (S)-ethyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[ 1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate

[00609] The solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(3',4'-di-methyl-3-(3-methyl- 1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 2,3-dicarboxylate (from Step 3, Example 1m, 220 mg, 0.3 mmol) in EtOAc (5 mL) was hydrogenated using Method A using an H-Cube mechanism and a Pd/C cartridge at 10% (w/w) with a flow rate of 1.0 mL/min at RT. Purification on normal phase silica gel (EtOAc/heptane) provided (S)-ethyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl -1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane - 3-carboxylate. Example 63kp: (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(hydroxymethyl)-4'-methyl-3-( 3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

[00610] The title compound was prepared as described for (S)-ethyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H- pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-car- boxylate (Example 63bd) using Method A to remove the N-CBz group. Example63i: (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

[00611] In a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1- (5-chloro-[1,1'-biphenyl]-2-yl )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-2,3-dicarboxylate (from Step 3, Example 34c, 315 mg, 0.43 mmol) in acetonitrile (300 mL) TMSI (0.13 mL, 0.9 mmol) was added [Method B]. The reaction mixture was then heated at RT for an additional 30-40 min, then cooled to 0-5°C and 2M HCl in diethyl ether (0.5 mL) was added. The reaction mixture was allowed to warm at RT, and then concentrated in vacuo. Normal phase silica gel chromatography gives the title compound as an off-white solid.

[00612] Ethyl ester prodrugs in Table 18a were prepared by removing the N-CBZ group by method A or method B, as shown below. Example 64a: (S)-Octyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2 ,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

[00613] In a flask equipped with a Dean Stark trap, acid (2S)-8-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1) was added. -yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]-3,8-diazaspiro[4.5]de-cane-2-carboxylic acid (1 g, 1.78 mmol), toluene (25 mL ) and p-toluenesulfonic acid monohydrate (336 mg, 1.77 mmol), and n-octanol (690 mg, 5.30 mmol). The reaction mixture was heated at reflux for 48 h, cooled at RT and concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (CH2Cl2/MeOH/NH4OH) provided the title compound as a white solid.

[00614] Applying the generic scheme below, the following examples from Table 19a were prepared as described above for (S)-octyl 8-(2-amino-6-((R)-1-(4-chloro-2-( 3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (Example 64a), using the appropriate alcohol. Example 65a: (S)-Tert-butyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2 ,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

[00615] Step 1: In a mixture of (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl) acid )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (2.8 g, 4.1 mmol) in t-BuOH (50 mL) BOC2O (3.5 g, 16.5 mmol) and DMAP (0.201 g, 1.65 mmol) were added, and the reaction was heated at 50 ° C for 45 min. Then, the reaction was cooled to RT and concentrated in vacuum. Purification on a 220 g Isco RediSep silica cartridge (EtOAc/heptane) provided (S)-2-benzyl 3-tert-butyl 8-(2-amino-6-((R)- 1-(4-chloro -2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an almost white solid.

[00616] Step 2: In a solution of (S)-2-benzyl 3-tert-butyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl- 1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (1.35 g, 1 .7 mmol) in EtOAc (130 mL) 5% (w/w) Pd/C (130 mg) was added. The solution was degassed, charged with 1 atm H2 (flask) and stirred at RT for 3.5 h. Then, the solids were filtered through celite, washed with EtOAc/methanol, and the filtrate was concentrated in vacuo. Purification on a 220 g Isco RediSep silica cartridge (CH2Cl2/MeOH/NH4OH) provided the title compound as an off-white solid.

[00617] Applying the generic scheme below, the following examples from Table 20a were prepared as described above for (S)-tert-butyl 8-(2-amino-6-((R)-1-(4-chloro-2 -(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (Example 65 ). Example 66a: (S)-2-(Dimethylamino)ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

[00618] Step 1: In a mixture of (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl) acid )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (85 mg, 0.16 mmol) in THF (10 mL) was added BOC2O (4 g, 18.6 mmol) in THF (10 mL), and the reaction mixture was stirred at RT for 16 h. Then, the reaction was diluted with CH2Cl2, cooled to 0 oC and the pH adjusted to 2 with 2 N HCl. The reaction mixture was then extracted with CH2Cl2 and concentrated in vacuo to provide acid (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid which was used directly without further purification.

[00619] Step 2: In a solution of acid (S)-8-(2-amino-6-((R)-1- (4-chloro-2-(3-methyl-1H-pyrazol-1-yl )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (1.6 g, 2.45 mmol ) in DMF (24 mL) (2-chloroethyl)-dimethyl-amine hydrochloride (535 mg, 3.7 mmol) and K2CO3 (1.0 g, 7.4 mmol) were added, and the reaction mixture was heated at 65 °C for 16 h. Then, the reaction was cooled at RT, partitioned between EtOAc and water and extracted. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by prep HPLC column chromatography. (CH2Cl2/MeOH/NH4OH) gave (S)-2-tert-butyl 3-(2-(dimethylamino)ethyl) 8-(2-amino-6-((R)-1-(4-chloro-2) acid -(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a solid almost white.

[00620] Step 3: In a solution of (S)-2-tert-butyl 3-(2-(dimethylamino)ethyl) 8-(2-amino-6-((R)-1-(4- chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicar - boxylate (1.4 g, 1.86 mmol) in CH2Cl2 (9 mL) TFA (4.5 mL) was added, and the reaction was stirred at RT for 2 h. Then, the reaction was concentrated in vacuum, and the residue was partitioned between CH2Cl2 and aqueous NaHCO3, and extracted. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by prep HPLC column chromatography. (CH2Cl2/EtOH/NH4OH) gave the title compound as an off-white solid.

[00621] Applying the generic scheme below, the following examples from Table 21a were prepared as described above for (S)-2-(dimethylamino)ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3 -carboxylate (Example 66a), using the appropriate alkylating agent. Example 67a: (S)-isopropyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[ 1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

[00622] In a solution of the compound of Example 1m (400 mg, 0.53 mmol) in propan-2-ol (5 mL) thionyl chloride (2 drops) was added at 0oC. The mixture was heated at RT, and then heated at reflux for 2 h. Then, the reaction mixture was cooled at RT, concentrated and neutralized with saturated aqueous NaHCO3 solution at pH 7-8. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by flash column (0~10% MeOH in DCM) on silica gel to provide the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4): δ ppm 7.96 (d, J = 2.3 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.70 (dd , J = 8.2, 1.8 Hz, 1H), 7.59 (d, J = 1.8 Hz, 1H), 7.43 (s, 1H), 7.37 (d, J = 7, 8 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.76 (q, J = 6.8 Hz, 1H), 6.41 (d, J = 2.3 Hz , 1H), 5.74 (s, 1H), 5.01 (m, 1H), 3.76 (dd, J = 8.7, 7.0 Hz, 1H), 3.61 - 3.42 ( m, 4H), 2.88 (d, J = 11.1 Hz, 1H), 2.72 (d, J = 11.0 Hz, 1H), 2.39 (s, 3H), 2.31 ( s, 3H), 2.29 (s, 3H), 2.05 (dd, J = 13.1, 8.9 Hz, 1H), 1.71 (dd, J = 13.0, 7.0 Hz , 1H), 1.50 (m, 4H), 1.24 (dd, J = 6.2, 3.9 Hz, 6H). LCMS (MH+): 679.

[00623] Applying the generic scheme below, the following examples from Table 22 were prepared as described above for (S)-isopropyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro[4.5]decane-3-carboxylate (Example 67a), using the appropriate alcohol. Example 68a: (S)-isopropyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-isopropoxy-3-(3-methyl-1H-pyrazol-1 -yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

[00624] The title compound was prepared as described for (S)-isopropyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl- 1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]de-cane- 3-carboxylate (Example 67a) starting with (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-isopropoxy-3-(3-methyl) acid -1H-pyrazol-1-yl)- [1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 1l ).

[00625] Applying the generic scheme below, the following examples from Table 23 were prepared as described above for (S)-isopropyl 8-(2-amino-6-((R)-2,2,2-trifluoro- 1-(4'-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2, 8-diazaspiro[4.5]decane-3-carboxylate (Example 68a), using the appropriate alcohol. Example 69a: (S)-isopropyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]de-cane-3-carboxylate

[00626] The title compound was prepared as described for (S)-isopropyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl- 1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]de-cane- 3-carboxylate (Example 67a) starting with (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2 acid ,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 34c).

[00627] Applying the generic scheme below, the following examples from Table 24 were prepared as described above for (S)-isopropyl 8-(2-amino-6-((R)-2,2,2-trifluoro- 1-(4'-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2, 8-diazaspiro[4.5]decane-3-carboxylate (Example 68a), using the appropriate alcohol. Example 70: (S)-methyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(methylsulfonyl)- [1,1'-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

[00628] The title compound was prepared as described for (S)-isopropyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl- 1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]de-cane- 3-carboxylate (Example 67a) starting with (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(methylsulfonyl)-[1,1'-biphenyl] acid -2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 34w). 1H NMR (400 MHz, MeOH-d4): δ ppm 1.51 (q, J = 7.1, 6.7 Hz, 6H), 1.72 (dd, J = 13.0, 7.3 Hz, 1H), 2.07 (dd, J = 13.2, 8.7 Hz, 1H), 2.75 (d, J = 11.0 Hz, 1H), 2.87 (d, J = 11.0 Hz, 1H), 3.21 (s, 4H), 3.50 (tdt, J = 20.3, 13.5, 7.0 Hz, 4H), 3.71 (s, 2H), 3.84 (t, J = 8.0 Hz, 1H), 4.87 (m, 1H), 5.57 (s, 1H), 6.57 (q, J = 6.6 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.41 (s, 2H), 7.48 (dd, J = 8.5, 2.2 Hz, 1H), 7.75 (m, 3H) , 8.07 (d, J = 7.8 Hz, 1H), 8.43 (s, 1H). LCMS (MH+): 655. Example 71: (S)-methyl 8-(2-amino-6-((R)-1-(5-chloro-3'-sulfamoyl-[1,1'-biphenyl]- 2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4.5]decane-3-carboxylate

[00629] The title compound was prepared as described for (S)-isopropyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H- pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaes- piro[4.5]decane-3- carboxylate (Example 67a) starting with (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-sulfamoyl-[1,1'-biphenyl]-2-yl acid )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 34u). 1H NMR (400 MHz, MeOH-d4): δ ppm 1.54 (dt, J = 8.9, 6.0 Hz, 5H), 1.75 (dd, J = 13.1, 7.4 Hz, 1H), 2.10 (dd, J = 13.1, 8.7 Hz, 1H), 2.77 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.53 (qt, J = 14.0, 7.8 Hz, 4H), 3.72 (s, 3H), 3.86 (dd, J = 8.7, 7.3 Hz , 1H), 4.91 (s, 13H), 5.57 (s, 1H), 6.60 (q, J = 6.5 Hz, 1H), 7.31 (d, J = 2.2 Hz , 1H), 7.49 (dd, J = 8.5, 2.3 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.71 (m, 2H), 8 .02 (ddd, J = 7.9, 1.9, 1.1 Hz, 1H), 8.33 (s, 1H). LCMS (MH+): 656. LCMS (MH+): 656. Example A: In vitro Inhibition Assays TPH1 and TPH2 Assays

[00630] Recombinant human TPH1 (rTPH1 GenBank TM accession no. NP_004179) was expressed by cloning the full-length human TPH1 cDNA into a bacterial pMAL-c5E expression vector to produce the binding protein TPH1 fusion proteins of maltose (MBP). E.coli BL21 (DE3) containing pMAL-c5E-TPH1 was used for protein generation and the recombinant protein was purified using standard column chromatography techniques. MBP-targeted TPH1 (MBP-TPH1) was used directly to evaluate compounds as described below. Recombinant human TPH2 (rTPH2 GenBank TM accession no. 173353), PheOH (rPheOH GenBank TM accession no. K03020) and TH (rTH GenBank TM accession no. L20679) with an MBP tag were produced similarly.

[00631] TPH1 activities were measured in an assay containing 200 mM ammonium sulfate, 7 mM DTT, 50 μg/mL catalase, 25 μM ammonium iron sulfate, 50 mM MES, pH 7.1 . Test compounds were diluted in 100% DMSO and added to the assay plate in 1 μL aliquots at 100x final concentration. Fifty microliters of assay buffer containing 30 nM TPH1 enzyme (labeled by MBP) was added to the wells of the plate containing the test compound by use of an Eppendorf repeating pipette. The reaction was initiated by adding 50 μL of assay buffer containing 60 μM tryptophan and 72 μM 6-6-methylatetrahydropterin (2x final concentration) using a Multidrop (LabSystems). Final reaction conditions were 15 nM TPH1 enzyme, 30 μM tryptophan, 36 μM 6-methylatetrahydropterin, 200 mM ammonium sulfate, 7 mM DTT, 25 μg/mL catalase, 25 μM ferrous ammonium sulfate, 50 mM MES, pH 7.1, with atmospheric oxygen at room temperature. The plate was immediately placed on an M5 plate reader (Molecular Devices) for kinetic fluorescence measurement using an excitation setting of 300 nm and an emission setting of 335 nm. Fluorescence readings are recorded in kinetic mode for 300 seconds (5 minutes).

[00632] Kinetic assay data for compounds at specific concentrations were translated into slopes using Softmax Pro software on a Spectramax reader, and compound inhibition slopes were compared to wells containing enzyme, substrate, and cofactor in the absence of inhibitor ( 100%), and the cavities containing substrate and cofactor in the absence of enzyme (0%). The concentration of DMSO in the assay was 1%. Typically, in the absence of enzyme, reaction slopes were ~0. IC50’s were determined using Graphpad Prism.

[00633] Compounds having an IC50 of 10,000 nM or less were considered active.

[00634] The inhibition of TPH2 activity by the compounds of the invention was measured similarly. In some examples, compounds of the invention have shown dual inhibition of both TPH1 and TPH2.

[00635] Data reported for the TPH1 inhibition activity of the compounds of the invention are provided below in Table 25. Compounds that inhibit TPH1 with an IC50 of 3,000 nM to 10,000 nM are indicated by +. Compounds that inhibit TPH1 with an IC50 of less than 3,000 nM but more than 300 nM are indicated by ++. Compounds that inhibit TPH1 from 50 nM to 300 nM are indicated by +++. Compounds that inhibit TPH1 with an IC50 less than 50 nM are indicated by ++++. Ester prodrugs listed, for example, in Tables 18a, 19a, 20a, and 21a-24a, as well as in Examples 70 and 71, are not expected to be active in this in vitro assay. Table 25. TPH1 Inhibition Data PheOH and TH inhibition counterassays

[00636] Certain compounds of the Examples were found to selectively inhibit tryptophan hydroxylase (TPH) in phenylalanine hydroxylase (PheOH). The inhibitory activity with PheOH can be evaluated according to the methods described for example in J. Med. Chem.10, 64–66 (1967), or J. Antibiot.35, 458–462 (1982), or WO 2007 /089335.

[00637] Certain compounds of the invention have been found to selectively inhibit tryptophan hydroxylase (TPH) in tyrosine hydroxylase (TH). The inhibitory activity towards TH can be evaluated according to the methods described for example in Life Sci.39, 2185–2189 (1986), or Mol. Pharmacol. 41, 339–344 (1992), or J. Antibiot.35, 458–462 (1982), or WO 2007/089335. Example B: Intestinal 5-HT depletion assay

[00638] The effectiveness of the TPH1 inhibitors of the invention was evaluated in terms of their ability to decrease the concentration of intestinal serotonin in mice. Mice (C57 BL6) were administered a single dose of 150 mg/kg of the test article by oral gavage. Each animal was euthanized by exsanguination under isoflurane anesthesia. Jejunal intestinal mucosa was isolated and homogenized in 300 μL of a buffer containing 0.3 M trichloroacetic acid, 0.1 M sodium acetate, 10 mM EDTA, 20 mM sodium bisulfate, and 50 mM ascorbic acid. Following centrifugation, 5-HT levels in the supernatants were measured by HPLC. The remaining mucosal pellet was solubilized overnight at 37°C in a buffer of 0.1% sodium dodecyl sulfate in 0.1N NaOH followed by determination of protein concentrations using a BCA protein assay (Pierce, Rockford , Il. 5-HT levels were normalized to protein and data were expressed as percentage of mean reduction in mucosal 5-HT levels in relation to vehicle control ± SEM (percentage of 5-HT reduction). All studies with Animals were performed with protocols approved by the Institutional Animal Care and Use Committee.

[00639] The Examples listed in Table 26 below were tested and found to elicit a reduction in mean mucosal 5-HT concentrations relative to vehicle-treated animals according to the in vivo assay described above. P values, indicating statistical significance of the data (ANOVA) are provided in the table: * refers to P<0.05, ** refers to P<0.01, *** refers to P< 0.005, and **** refers to P<0.0005. Table 26. In Vivo Efficacy of TPH1 Inhibitors in Mice (reduction in mucosal 5-HT concentrations one day after oral administration of a single dose of 150 mg/kg) Example C: Reduction of mucosal 5-HT concentrations

[00640] The Examples listed in Table 27 below were tested and found to elicit a reduction in mean mucosal 5-HT concentrations relative to vehicle-treated animals according to the following in vivo assay.

[00641] The effectiveness of the TPH1 inhibitors of the invention was evaluated regarding the ability to decrease the concentration of intestinal serotonin in mice. Mice (C57 BL6) were administered an oral dose of 10 or 50 mg/kg of the test article in the evening. Approximately 16 h after the first dose, mice were administered a second oral dose of 50 mg/kg of the appropriate compound. A third oral dose of 50 mg/kg of the appropriate test article was administered 12 h after dose 2. After an overnight fast, each animal was euthanized by exsanguination under isoflurane anesthesia. The jejunal intestinal mucosa was isolated and homogenized in 300 mL of a buffer containing 0.3 M trichloroacetic acid, 0.1 M sodium acetate, 10 mM EDTA, 20 mM sodium bisulfate and 50 mM ascorbic acid. After centrifugation, 5-HT levels in the supernatants were measured by HPLC. The remaining mucosal pellet was solubilized overnight at 37°C in a buffer of 0.1% sodium dodecyl sulfate in 0.1N NaOH followed by determination of protein concentrations using a BCA protein assay (Pierce, Rockford , IL). 5-HT levels were normalized to protein and data were expressed as mean percent reduction in mucosal 5-HT levels relative to vehicle control ± SEM (percent 5-HT reduction). All animal studies were performed with protocols approved by the Institutional Animal Care and Use Committee. P values, indicating statistical significance of the data (ANOVA) are provided in the table: * refers to P<0.05, ** refers to P<0.01, *** refers to P<0.005 , and **** refers to P<0.0005. Table 27. In Vivo Efficacy of TPH1 Inhibitors in Mice (reduction in mucosal 5-HT concentrations two days after oral administration of a single dose of 50 mg/kg) Example D: In vivo Assay for Inflammatory Bowel Diseases

[00642] The usefulness of the compounds of the invention for the treatment of inflammatory bowel diseases can be measured, for example, using experimental models of colitis induced by trinitrobenzene sulfonic acid (TNBS), dinitrobenzene sulfonic acid (DNBS), and sodium sulfate of dextran (DSS), as described by Ghia, J.-E. et al. in Gastroenterol. 137, 1649-60 (2009). Example E: In vivo assay for low bone mass diseases

[00643] The usefulness of the compounds of the invention for the treatment of low bone mass diseases, such as osteoporosis, can be measured, for example, using the rat model of ovariectomy-induced osteopenia, as described by Yadav, V. K. et al. in Nature Med.16, 308-12 (2010). Example F: In vivo assay for PAH

[00644] The usefulness of the compounds of the invention for the treatment of pulmonary arterial hypertension (PAH) can be measured, for example, using the hypoxic mouse model, as described by Abid, S. et al. in Am. J. Physiol., Lung Cellular and Molecular Physiology 303, L500-8 (2012), or using the rat monocrotaline-induced PAH or rat chronic hypoxia model, as described by Kay, J. M. et al. Respiration 47, 48-56 (1985). Example G: In vivo assay for allergic airway inflammation

[00645] The usefulness of the compounds of the invention for the treatment of allergic airway inflammation can be measured, for example, using the mouse model of allergic asthma, as described by Dürk, T. et al. in Am. J. Respir. Crit. Care Med.187, 476-485 (2013). Example H: In vivo assay for gastrointestinal disorders

[00646] The utility of the compounds of the invention for treating gastrointestinal disorders associated with dysregulation of the GI serotonergic system, such as chemotherapy-induced emesis and irritable bowel syndrome, can be measured, for example, using a ferret model of emesis induced by chemotherapy, as described by Liu, Q. et al. in J. Pharmacol. Exp. Ther. 325, 47-55 (2008). Example I: In vivo assay for tumor growth

[00647] The usefulness of the compounds of the invention for the treatment of tumor growth can be measured, for example, using the xenograft model of cholangiocarcinoma tumor growth, as described by Alpini, G. et al. in Cancer Res.68, 9184-93 (2008). Example J: In vivo assay for leukemia

[00648] The usefulness of the compounds of the invention for the treatment and prevention of leukemia and other blood cancers, can be measured, for example, using the mouse leukemia model, the osteoblast-deficient mouse model, or the murine model of acute myeloid leukemia, as described in WO 2013/074889. Example K: In vivo assay for atherosclerosis

[00649] The usefulness of the compounds of the invention for the treatment of atherosclerosis, and the reduction of plasma cholesterol and triglyceride levels, can be measured, for example, using the Apo E -/- or LDLR - mouse models /- of the development of atherosclerotic plaque, as described in WO 2012/058598.

[00650] Various modifications of the invention, in addition to those described here, will be apparent to those skilled in the art of the previous description. It is intended that such modifications are likewise included within the scope of the attached claims. Each reference, including all patents, patent applications, and publications, cited in this application is incorporated herein by reference in its entirety.

Claims (21)

1. Compound, characterized by the fact that it has Formula I: or a pharmaceutically acceptable salt thereof, in which: Ring A is C3-10 cycloalkyl, C6-10 aryl, 4- to 10-membered heterocycloalkyl, or 5 to 10-membered heteroaryl; L is O or NR4; W is N or CR5; X is N or CR6; Y is N or CR7; where only one of X and Y is N; R1 is H, C1-10 alkyl, C3-10 cycloalkyl, phenyl, - (CR8R9)pOC(O)R10, -(CR8R9)p NR11R12, or -(CR8R9)pC(O)NR11R12, wherein said C1- 10 alkyl, C3-10 cycloalkyl, and phenyl are each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from F, Cl, Br, CN, C1-4 alkyl, and C1- 4 haloalkyl; R2 and R3 are each independently selected from H, C1-4 alkyl, and C1-4 haloalkyl; R4 is H or C1-4 alkyl; R5 and R6 are each independently selected from H, halo, and C1-4 alkyl; R7 is H, C1-4 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 4- heterocycloalkyl 10 membered, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-C1-4 alkyl, NR13R14, OR15, C(O)R16, S(O)qR17, wherein said C1-4 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-C1-4 alkyl are each optionally substituted. titrated by 1, 2, or 3 substituents selected from halo, C1-4 alkyl, C2-6 alkenyl, amino, C1-4 alkylamino, C2-8 dialkylamino, hydroxy, and C1-4 alkoxy; R8 and R9 are each independently selected from H and C1-4 alkyl; R10 is C1-6 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from C1-6 haloalkyl, C3-10 cycloalkyl, ORa, and NRcRd; R11 and R12 are each independently selected from H and C1-6 alkyl; R13 is H or C1-4 alkyl; R14 is H, C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 510 membered heteroaryl, or (5-10 membered heteroaryl)-C1-4 alkyl, C(O)Rb1, C(O)ORa1, C(O) NRc1Rd1, S(O)Rb1, S(O)2Rb1, or S(O)2NRc1Rd1, wherein said C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C610 aryl, C6- 10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)- C1-4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; or R13 and R14 together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl , C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, halo, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O )ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O )2Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C37 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-membered heteroaryl -6 members are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O )Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S(O )2Rb1, NRc1S(O)2NRc1Rd1, and S(O)2NRc1Rd1; R15 is H, C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 510-membered heteroaryl, or (5-10 membered heteroaryl)-C1-4 alkyl, wherein said C1-4 alkyl, C3-7 cycloalkyl, C3- 7 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 5- heteroaryl 10 member, and (5-10 member heteroaryl)-C1-4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 member heterocycloalkyl, C6 -10 aryl, 5-6 membered heteroaryl, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C (O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, and S( O)2NRc1Rd1; R16 is C1-4 alkyl or NR18aR18b wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl , 5-6 membered heteroaryl, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O) Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, and S(O)2NRc1Rd1 ; R17 is C1-4 alkyl, NR18aR18b, or OR18c, wherein said C14 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 heterocycloalkyl members, C6-10 aryl, 5-6 member heteroaryl, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, and S(O)2NRc1Rd1; R18a and R18b are each independently selected from H and C1-4 alkyl wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, heterocycloalkyl. 4-7 membered, C610 aryl, 5-6 membered heteroaryl, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1 , NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc4C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1 , and S(O)2NRc1Rd1; or R18a and R18b together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1- 6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, halo, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O )ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O )2Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O )ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(O )2Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, and S(O)2NRc1Rd1; R18c is H, C1-6 alkyl, C3-10 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 510 membered heteroaryl, or (5-10 membered heteroaryl)-C1-4 alkyl, wherein said C1-6 alkyl, C3-7 cycloalkyl, C3- 10 cycloalkyl-C1-4 alkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, 5- heteroaryl 10 member, and (5-10 member heteroaryl)-C1-4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, NO2 , ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C (O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; RA is H, Cy1, halo, C1-6 alkyl, C2-6 alkenyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, or S(O)2NRc2Rd2, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy1, halo, C16 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC (O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S (O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; RB is H, Cy2, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC (O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S (O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, or S(O)2NRc3Rd3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4 , or 5 substituents independently selected from Cy2, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C( O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc1S(O)2Rb3, NRc3S( O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3; RC and RD are independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C( O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S( O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C6-10 aryl, C3-10 cycloalkyl, heteroaryl 5-10 membered, 4-10 membered heterocycloalkyl, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; Cy1 and Cy2 are each independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy; each RCy is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN , NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5 , NRc5C(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5, wherein said C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, 510-membered heteroaryl, and 4-10-membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 , or 5 substituents independently selected from halo, C1-6 alkyl, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5; each Ra, Ra1, Ra2, Ra3, Ra4, and Ra5 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C610 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, or (410 membered heterocycloalkyl )-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, and (4-10 membered heterocycloalkyl)-C1-4 alkyl are each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, halo, CN, ORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O) Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, NRc6S(O) 2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6; each Rb1, Rb2, Rb3, Rb4, and Rb5 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, 5-heteroaryl 10 membered, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, or (5-10 membered heterocycloalkyl) 4-10 members)-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 member heteroaryl, 4-10 member heterocycloalkyl , C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, and (4-10 membered heterocycloalkyl)-C1-4 alkyl are each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, halo, CN, ORa6, C(O)Rb6, C(O)NRc6Rd6, C(O) ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(O) 2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6; each Rc, Rd, Rc1, Rd1, Rc2, Rd2, Rc3, Rd3, Rc4, Rd4, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C310 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl) -C1-4 alkyl, or (4-10-membered heterocycloalkyl)-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C3-10 cycloalkyl, 510-membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, and (4-10 membered heterocycloalkyl) -C1-4 alkyl are each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6; or any Rc and Rd together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C( O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S( O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6, wherein said C1-6 alkyl, C37 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 4-7 membered heteroaryl 5-6 members are optionally replaced by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC( O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, NRc6S( O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6; or any Rc1 and Rd1 together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C( O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S( O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6, wherein said C1-6 alkyl, C37 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 4-7 membered heteroaryl 5-6 members are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC( O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, NRc6S( O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6; or any Rc2 and Rd2 together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa6, SRa6, C(O)Rb6, C( O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S( O)NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O) NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O) NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6; or any Rc3 and Rd3 together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa6, SRa6, C(O)Rb6, C(O )NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O )NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6 -10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6 , C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6 , S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6; or any Rc4 and Rd4 together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa6, SRa6, C(O)Rb6, C(O )NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O )NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6 -10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C (O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S (O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6; or any Rc5 and Rd5 together with the N atom to which they are attached form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa6, SRa6, C(O)Rb6, C(O )NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O )NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6 -10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6 , C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6 , S(O)2Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, and S(O)2NRc6Rd6; each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl , wherein said C1-4 alkyl, C2-4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, or 3 independent substituents -mente selected from OH, CN, amino, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, and di(C1-4 alkyl)amino; n is 1 or 2; p is 1, 2, or 3; eq is 1 or 2; wherein any aforementioned 4-10 or 4-7 membered heterocycloalkyl group optionally comprises 1, 2, or 3 oxo substituents, wherein each oxo substituent that is present is substituted on a carbon atom, nitrogen , or ring-forming sulfur of the 4-10 or 4-7 membered heterocycloalkyl group. 2. Compound, according to claim 1, or a pharmaceutically acceptable salt thereof, characterized by the fact that: L is O; or L is NR4; and/or wherein a) W is CR5; X is N; and Y is CR7; or b) W is N; X is N; and Y is CR7; or c) W is CR5; X is CR6; and Y is N; or d) W is CR5; X is CR6; and Y is CR7; or e) W is N; X is CR6; and Y is CR7; and/or where: a) R2 is H and R3 is H; or b) R2 is H and R3 is C1-4 alkyl; or c) R2 is H and R3 is methyl; or d) R2 is H and R3 is C1-4 haloalkyl; or e) R2 is H and R3 is trifluoromethyl; and/or where: a) n is 1; or b) n is 2; and/or where: a) R1 is H; or b) R1 is C1-10 alkyl, C3-10 cycloalkyl, phenyl, - (CR8R9)pOC(O)R10, -(CR8R9)pNR11R12, or -(CR8R9)pC(O)NR11R12, wherein said C1- 10 alkyl, C3-10 cycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from F, Cl, Br, CN, C1-4 alkyl, and C1- 4 haloalkyl; or c) R1 is C1-10 alkyl; and/or wherein R4 is H; and/or wherein R5 is H; and/or wherein R6 is H; and/or where: a) R7 is different from H; or b) R7 is C1-4 alkyl, NR13R14, or OR15; or c) R7 is NR13R14; or d) R7 is NH2; or e) R7 is C1-4 alkyl; or f) R7 is OR15; and/or wherein: a) Ring A is C3-10 cycloalkyl; or b) Ring A is C6-10 aryl; or c) Ring A is phenyl; or d) Ring A is 4 to 10 membered heterocycloalkyl; or e) Ring A is phenyl, adamantanyl, naphthyl, 1,2,3,4-tetrahydroquinazolinyl, 3,4-dihydroquinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, or pyridyl; or f) Ring A is 5 to 10 membered heteroaryl; and/or wherein: a) at least one of RA, RB, RC, and RD is other than hydrogen; or b) at least two of RA, RB, RC, and RD are other than hydrogen; and/or where: a) RA is Cy1; or b) RA is C6-10 aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy; or c) RA is 5-10 membered heteroaryl that is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy; or d) RA is pyrazolyl which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy; or e) RA is 3-methyl-1H-pyrazol-1-yl; or f) RA is C6-10 aryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy; or g) RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy; and/or where: a) RB is H; or b) RB is Cy2, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, or S(O)2NRc3Rd3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from Cy2, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C (O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc1S(O)2Rb3, NRc3S (O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3. c) RB is Cy2; or d) RB is C6-10 aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy; or e) RB is halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC( O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S( O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, or S(O)2NRc3Rd3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from Cy2, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O )ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc1S(O)2Rb3, NRc3S(O )2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3; or f) RB is halo; and/or where: a) RC is H; or b) RC is halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC( O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S( O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, or S(O)2NRc4Rd4; wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 heteroaryl members, 4-10 membered heterocycloalkyl, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C( O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S( O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; and where: a) RD is H; or b) RD is halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC( O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S( O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, or S(O)2NRc4Rd4; wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 heteroaryl members, 4-10 membered heterocycloalkyl, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C( O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S( O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4. 3. Compound, according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized by the fact that: a) it has Formula IIa: b) presents Formula IIb: c) presents Formula IIc: d) presents Formula IId: e) presents Formula IIe: 4. Compound, according to claim 3, or a pharmaceutically acceptable salt thereof, characterized by the fact that: a) L is O; or b) L is NR4; and/or where: a) R3 is H; or b) R2 is CF3 and R3 is H; and/or wherein R1 is H or C1-10 alkyl; and/or wherein: a) RA is a 5- to 10-membered heteroaryl that is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy; or b) RA is a 5- to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy; or c) RA is C6-10 aryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy; or d) RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy; and/or where: a) RB is Cy2; or b) RB is H, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, ORa3, C(O)NRc3Rd3, or C(O)ORa3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C (O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc1S(O)2Rb3, NRc3S (O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3; and/or where: a) RC is H; and/or b) RD is H; and/or c) R5 is H; and/or d) R is H. 5. Compound, according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized by the fact that it has Formula IIIa or IIIb: 6. Compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that it has Formula IV or Va: 7. Compound, according to claim 5 or 6, or a pharmaceutically acceptable salt thereof, characterized by the fact that: a) RA is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy; or b) RA is a 5- to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy; or c) RA is C6-10 aryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy; or d) RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy. 8. Compound, according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized by the fact that it has Formula VI: 9. Compound, according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized by the fact that it has Formula VII: where a is 0, 1, 2, or 3. 10. Compound according to claim 9, or a pharmaceutically acceptable salt thereof, characterized in that RCy is halo, C1-6 alkyl, C1-6 haloalkyl, 4-10 member heterocycloalkyl, CN, NO2 , ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5, wherein said C1-6 alkyl and heterocycloalkyl of 4-10 members are each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, CN, NO2, ORa5, SRa5, C(O)Rb5, C( O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S( O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5. 11. Compound, according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, characterized by the fact that: a) RC is H; and/or b) RD is H; and/or where: c) R2 is CF3; and/or d) R1 is H or C1-10 alkyl; and/or where: e) RB is Cy2; or f) RB is H, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, ORa3, C(O)NRc3Rd3, or C(O)ORa3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C (O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc1S(O)2Rb3, NRc3S (O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3. 12. Compound according to claim 1, characterized by the fact that it is: a) selected from: (3S)-8-(2-amino-6-((1R)-2,2,2-trifluoro- acid 1-(3-(3-methyl-1H-pyrazol-1-yl)-4'-(methylsulfinyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2, 8-diazaes- piro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)- 4'-( methylthio)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3'-carboxy-3-(3-methyl-1H-pyrazol-1-yl)- [1,1'-biphenyl) acid ]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3'-carboxy-3-(3-methyl-1H-pyrazol-1-yl)- [1,1'-biphenyl) acid ]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-carboxy-3-(3-methyl-1H-pyrazol-1-yl)- [1,1'-biphenyl) acid ]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)- 4-(1 ,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(pyridin) acid -4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)- 4-(1 -methyl-1H-pyrazol-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(isoxazol-4-yl)-2-(3-methyl-1H-pyrazole) acid -1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-(3,6-dihydro-2H-pyran-4-yl)-2-(3-methyl-1H) acid -pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(6-((R)-1-(4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3-methyl-1H-pyrazole -1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl) acid -[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)- [1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-methoxypyridin-4-yl)-2-(3-methyl-1H) acid -pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-methyl-1H-indazol-6-yl)- 2-(3 -methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4'-(tert-butyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1, 1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-ethoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl acid) ]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-methoxypyrimidin-5-yl)-2-(3-methyl-1H) acid -pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(6-methoxypyridin-3-yl)-2-(3-methyl-1H) acid -pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-2',3 acid ',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaes-pyro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3'-cyano-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl acid) ]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(6-((R)-1-(4'-(acetamidomethyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]- 4-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(6-((R)-1-(4'-(2-acetamidoethyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl) acid ]-4-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(quinolin) acid -7-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(6-((R)-1-(4-(1H-indol-6-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2, 2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane- 3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4'-(aminomethyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1' -biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-3-(3-methyl-1H-pyrazol-1- il)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(quinolin) acid -6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-methyl-3-(3-methyl-1H-pyrazol-1-yl) acid -[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3',4'-dichloro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3',4'-difluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-chloro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl) acid ]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(pyrimidin) acid -5-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(piperidin) acid -4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)- 4-(1 -(methylsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(6-((R)-1-(4-(1-acetylpiperidin-4-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2, 2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)- 4-(tetrahydro) acid -2H-pyran-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methoxy-4'-(methoxycarbonyl)-3-(3-methyl) acid -1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1' -biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4'-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1' -biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-(3-carboxypropyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2 acid, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane- 3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4-(2-carboxyethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-(3-ethoxy-3-oxopropyl)-2-(3-methyl-1H-pyrazol-1-yl acid) )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4 acid -il)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (R)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin acid -4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(trifluoromethyl) acid )phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-methyl-2-(3-methyl-1H- pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-fluoro-2-(3-methyl-1H-pyrazol- 1-yl)phenyl)ethoxy)pyrimidin acid -4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-methoxy-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; 8-(2-amino-6-((R)-1-(5-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-methoxy-2-(3-methyl-1H-pyrazol-1-yl) acid )phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl) acid )pyridin-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-propylphenyl) acid ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4-butyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (3S)-8-(2-amino-6-((1R)-1-(4-(1,2-dihydroxyethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl acid )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4-cyano-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-carbamoyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2 acid, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-carboxy-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2 acid, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2 acid, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(((1,1,1,3,3,3-hexafluoro- acid) -2-methylapropan-2-yl)oxy)carbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)- 4-(propoxycarbonyl) acid )phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane- 3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-(butoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2 acid, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane- 3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-(tert-butoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- acid 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(isobutoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl acid) )phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4-((cyclopentyloxy)carbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2 ,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl) acid ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)- 5-(( E)-prop-1-en-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-((E)-but-1-en-1-yl)-2-(3-methyl-1H-pyre acid) - zol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-((E)-2-carboxyvinyl)-2-(3-methyl-1H-pyrazol-1-yl acid )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-4-(3-methyl-1H-pyrazol-1-yl)- [1,1 '-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3'-carboxy-4-(3-methyl-1H-pyrazol-1-yl)- [1,1'-biphenyl) acid ]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-carboxy-4-(3-methyl-1H-pyrazol-1-yl)- [1,1'-biphenyl) acid ]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-((E)-2-carboxyvinyl)-4-(3-methyl-1H-pyrazol-1- il)-[1,1'-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4'-((E)-2-carboxyvinyl)-4-(3-methyl-1H-pyrazol-1- il)-[1,1'-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-(2-carboxyethyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1, 1'-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4'-(2-carboxyethyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1, 1'-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-(hydroxymethyl)-3'-methyl-4-(3-methyl-1H) acid -pyrazol-1-yl)-[1,1'-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(hydroxymethyl)-4'-methyl-4-(3-methyl-1H) acid -pyrazol-1-yl)-[1,1'-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3',4'-difluoro-4-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3',4'-dichloro-4-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-chloro-4-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl) acid ]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(2'-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1' -biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4'-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1' -biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-propylphenyl) acid ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-butyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2 acid, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-carboxy-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2 acid, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(hydroxymethyl)-2-(3-methyl-1H-pyrazol-1-yl acid) )phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-((dimethylamino)methyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl) acid) -2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy acid) -2-methylpyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy acid) -2-methylpyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(4-(2-methoxypyridin-4-yl)-2-(3-methyl-1H -pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)- 4'-( methylsulfonyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(6-((R)-1-(3',4'-difluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphe- nyl]-4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphe- nyl]-4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(6-((R)-1-(3'-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]- 4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(4-(6-methoxypyridin-3-yl)-2-(3-methyl-1H -pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(4-(2-methoxypyrimidin-5-yl)-2-(3-methyl-1H -pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(6-((R)-1-(2',4'-dimethoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphe- nyl]-4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(6-((R)-1-(4'-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]- 4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(6-((R)-1-(4'-(dimethylacarbamoyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]- 4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(4-(2-methoxypyridin-3-yl)-2-(3-methyl-1H) acid -pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-4'-methoxy-3-(3-methyl-1H -pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(6-((R)-1-(3'-(dimethylacarbamoyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]- 4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(2',4',6'-trimethyl-3-(3-methyl- 1H- pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(4'-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl) acid -[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(2'-methoxy-3-(3-methyl-1H-pyrazol-1- il)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3'-methoxy-4'-(methoxycarbonyl)-3-(3-methyl) acid -1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(6-((R)-1-(4'-(tert-butyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-steak -nyl]-4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(6-((R)-1-(4'-ethoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane- 3-carboxylic acid; acid (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)- 4'-( trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3'-(methoxycarbonyl)-3-(3-methyl-1H-pyrazol- 1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(pyrimidin) acid -5-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3'-methoxy-3-(3-methyl-1H-pyrazol-1- il)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3'-isopropyl-3-(3-methyl-1H-pyrazol-1-yl) acid) -[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-3-(3-methyl-1H-pyrazol-1- il)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane- 3-carboxylic acid; (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(pyridine) acid -3-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3'-methoxy-3-(3-methyl-1H-pyrazol-1- il)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(pyridine) acid -4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; 8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-phenoxypyrimidin acid -4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; 8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-( cyclohexyloxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; 8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(cyclohexylamino) acid pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy acid) -2-(cyclobutanecarboxamido)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(2-oxopyrrolidin-1-yl)phenyl)-2,2,2-trifluoroethoxy) pyrimidin acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3',5-dichloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluo acid - roethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-methyl-[1,1'-biphenyl]-2-yl)-2,2,2 acid - trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- acid il)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; 8-(2-amino-6-((R)-1-(2'-amino-5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; 8-(2-amino-6-((R)-1-(5-chloro-3'-nitro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; 8-(2-amino-6-((R)-1-(3'-amino-5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; 8-(2-amino-6-((R)-1-(5-chloro-4'-nitro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; 8-(2-amino-6-((R)-1-(4'-amino-5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(6-methylpyridin-2-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(ethylsulfonyl)-[1,1'-biphenyl]-2-yl)- 2.2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(propylsulfonyl)-[1,1'-biphenyl]-2-yl)-2,2 acid ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-(butylsulfonyl)-5-chloro-[1,1'-biphenyl]-2-yl)- 2.2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(hydroxymethyl)-[1,1'-biphenyl]-2-yl)- 2.2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(methylsulfonamido)-[1,1'-biphenyl]-2-yl)-2 ,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(2-oxopyrrolidin-1-yl)-[1,1'-biphenyl]- 2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(3-methyl-2-oxoimidazolidin-1-yl)-[1,1'-biphenyl) acid ]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)-2,2 acid ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(5-chlorothiophen-2-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(1-methyl-1H-pyrazol-3-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-sulfamoyl-[1,1'-biphenyl]-2-yl)- 2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-hydroxy-[1,1'-biphenyl]-2-yl)-2,2,2 acid - trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)-2,2 acid ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-cyano-[1,1'-biphenyl]-2-yl)-2,2,2 acid - trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-methoxy-[1,1'-biphenyl]-2-yl)-2,2,2 acid - trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-(aminomethyl)-5-chloro-[1,1'-biphenyl]-2-yl)- 2.2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(6-((R)-1-(3'-(acrylamidomethyl)-5-chloro-[1,1'-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy acid )-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane- 3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-carboxy-5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2 - trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-carbamoyl-5-chloro-[1,1'-biphenyl]-2-yl)- 2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)-2,2 acid ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-4'-sulfamoyl-[1,1'-biphenyl]-2-yl)- 2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4',5-dichloro-3'-fluoro-[1,1'-biphenyl]-2-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-isopropoxy-[1,1'-biphenyl]-2-yl)- 2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-ethoxy-[1,1'-biphenyl]-2-yl)-2,2,2 acid - trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3',5-dichloro-4'-ethoxy-[1,1'-biphenyl]-2-yl)- 2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3',5-dichloro-4'-methyl-[1,1'-biphenyl]-2-yl)- 2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3',5-dichloro-4'-isopropoxy-[1,1'-biphenyl]-2-yl)-2 acid, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-fluoro-4'-isopropoxy-[1,1'-biphenyl]-2-yl acid )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4',5-dichloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl acid )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3',5-dichloro-5'-fluoro-[1,1'-biphenyl]-2-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-(tert-butyl)-5-chloro-[1,1'-biphenyl]-2-yl)- 2 ,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3',5-dichloro-5'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl acid )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-fluoro-5'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl acid )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-methoxy-[1,1'-biphenyl]-2-yl)-2,2,2 acid - trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-fluoro-[1,1'-biphenyl]-2-yl)-2,2,2 acid - trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4',5-dichloro-3'-methyl-[1,1'-biphenyl]-2-yl)- 2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3',5'-difluoro-[1,1'-biphenyl]-2-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3',5-dichloro-4'-fluoro-[1,1'-biphenyl]-2-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3',4'-difluoro-[1,1'-biphenyl]-2-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3',5-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl acid )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(ethoxycarbonyl)-[1,1'-biphenyl]-2-yl)-2,2 acid ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(2-methoxyethoxy)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- acid il)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (3S)-8-(6-(1-((1r,3r,5S,7S)-adamantan-2-yl)ethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[ 4. 5]decane-3-carboxylic acid; (S)-8-(6-((1r,3r,5S,7S)-adamantan-2-ylmethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; 8-(4-amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4 acid. 5]decane-3-carboxylic acid; 8-(4-(([1,1'-biphenyl]-4-ylmethyl)amino)-6-amino-1,3,5-triazin-2-yl)-2,8-diazaspiro[4 acid. 5]decane-3-carboxylic acid; 8-(4-amino-6-((2-(piperidin-1-yl)benzyl)amino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4 acid. 5]decane-3-carboxylic acid; 8-(4-(([1,1'-biphenyl]-3-ylmethyl)amino)-6-amino-1,3,5-triazin-2-yl)-2,8-diazaspiro[4 acid. 5]decane-3-carboxylic acid; 8-(4-amino-6-(((R)-1-(naphthalen-2-yl)ethyl)amino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4] . 5]decane-3-carboxylic acid; 8-(4-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy acid)-1 ,3,5-triazin-2-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((2-(piperidin-1-yl)benzyl)amino)pyrimidin-4-yl)-2,8-diazaspiro[4 acid. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((2-phenoxy-6-(piperidin-1-yl)benzyl)amino)pyrimidin-4-yl)-2,8-diazaspiro[4 acid. 5]decane-3-carboxylic acid; (3S)-8-(6-(((3S,5S)-adamantan-1-ylmethyl)amino)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4 acid. 5]decane-3-carboxylic acid; (3S)-8-(6-((1-((1R,3S,5S)-adamantan-1-yl)ethyl)amino)-2-aminopyrimidin-4-yl)-2,8-diazaspiro acid [4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3'-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-[1,1'-biphenyl]-2-yl)ethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(5-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy acid) pyridazin-3-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(4-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyridin-2 acid -il)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy acid) pyridin-2-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6 -phenoxypyrimidin-2-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (3S)-8-(2-amino-6-(1-(2,6-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4 acid. 5]decane-3-carboxylic acid; (S)-8-(2-Amino-6-((R)-1-(2,5-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- acid diazaespiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-1-(3'-(methylsulfonyl)-4-propyl- [1,1'-biphenyl]- acid 2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(methylsulfonyl)-4-((E)-prop-1-en- 1-yl)-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(6-((R)-1-([1,1':4',1''-terphenyl]-2'-yl)-2,2,2-trifluoroethoxy)-2 -aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(6-((R)-1-([1,1':3',1''-terphenyl]-2'-yl)-2,2,2-trifluoroethoxy)-2 -aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3,4-dimethyl-3''-(methylsulfonyl)-[1,1':3',1''- terphenyl acid) ]-4'-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(methylsulfonyl)-5-(quinolin-6-yl)-[ acid 1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(methylsulfonyl)-5-((E)-prop-1-en- 1-yl)-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(methylsulfonyl)-5-propyl- [1,1'-biphenyl]- acid 2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(6-((R)-1-([1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl acid )-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-methyl-1H-indazol-5-yl)phenyl)ethoxy)pyrimidin acid -4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-methyl-1H-benzo[d]imidazol-5-yl acid )phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(6-((R)-1-(4-(1H-benzo[d]imidazol-5-yl)phenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin acid -4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-4'-methoxy-[1,1'-biphenyl] acid -4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-(benzo[d]isothiazol-6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-(benzo[d]isoxazol-6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(6-((R)-1-(4-(1H-indazol-6-yl)phenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)- acid 2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-methyl-1H-indazol-6-yl)phenyl)ethoxy)pyrimidin acid -4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-(benzo[d]isothiazol-5-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-(benzo[d]thiazol-6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(6-((R)-1-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)-2,2,2 -trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(naphthalen-2-yl)phenyl)ethoxy)pyrimidin-4-yl acid )-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methoxy-4'-methyl-[1,1'-biphenyl] acid -4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methoxy-5'-methyl-[1,1'-biphenyl] acid -4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(5'-methoxy-2'-methyl-[1,1'-biphenyl] acid) -4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3',4'-dimethoxy-[1,1'-biphenyl]-4-yl)-2,2,2- acid trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methoxy-4'-(pyrrolidine-1-carbonyl)-[1,1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-oxo-1,3-dihydroiso-benzofuran-5-yl) acid )phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-oxo-1,2-dihydroquinolin-6-yl) acid )phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-methyl-2-oxo-1,2-dihydroquinolin-6) acid -yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-oxo-1,2,3,4-tetrahydro-quinolin-6) acid -yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(6-((R)-1-(4-(1H-indazol-5-yl)phenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)- acid 2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-(1,3-dimethyl-1H-indazol-5-yl)phenyl)-2,2,2-trifluoroethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-(1,3-dimethyl-1H-indol-5-yl)phenyl)-2,2,2-trifluoroethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methoxy-5'-(trifluoromethyl)-[1,1'- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-cyano-5'-methoxy-[1,1'-biphenyl]-4-yl)- 2.2, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-oxo-2,3-dihydrobenzo[d]oxazole acid) -6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-methyl-1H-indol-5-yl)phenyl)ethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(6-((R)-1-(3'-acetoxy-4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)- 2,2,2- trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane- 3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-oxo-2H-chromen-7-yl)phenyl)ethoxy)pyrimidin acid -4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3) acid -yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4'-carboxy-3'-hydroxy-[1,1'-biphenyl]-4-yl)- 2.2, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-methoxyquinolin-6-yl)phenyl)ethoxy)pyrimidin-4 acid -il)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-(methylthio)quinolin-6-yl)phenyl)ethoxy)pyrimidin-acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin) acid -6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (3S)-8-(2-amino-6-(2,2,2-trifluoro-1-(3'-fluoro-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4- acid il)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (3S)-8-(2-amino-6-(2,2,2-trifluoro-1-(3'-methoxy-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4- acid il)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-[1,1'-biphenyl]-4-yl)ethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methoxy-[1,1'-biphenyl]-4-yl)ethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-5'-methoxy-[1,1'-biphenyl] acid -4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3',5'-difluoro-[1,1'-biphenyl]-4-yl)-2,2,2- acid trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-methoxy-[1,1'-biphenyl]-4-yl)ethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2'-methoxy-[1,1'-biphenyl]-4-yl)ethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4- acid yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(trifluoromethoxy)-[1,1'-biphenyl]-4- acid yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3'-ethoxy-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-isopropoxy-[1,1'-biphenyl]-4-yl)ethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(pyridin-3-yl)phenyl)ethoxy)pyrimidin-4-yl acid )-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(pyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl acid )-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(pyrimidin-5-yl)phenyl)ethoxy)pyrimidin-4-yl acid )-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-methyl-1H-indazol-6-yl)phenyl)ethoxy)pyrimidin acid -4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-(1,3-dimethyl-1H-indazol-6-yl)phenyl)-2,2,2-trifluoroethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-(2,3-dimethyl-2H-indazol-6-yl)phenyl)-2,2,2-trifluoroethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6) acid -yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane- 3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(isoquinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl acid )-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(isoquinolin-7-yl)phenyl)ethoxy)pyrimidin-4-yl acid )-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4'-((dimethylamino)methyl)-[1,1'-biphenyl]-4-yl)- 2.2, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(quinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl acid )-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(quinolin-7-yl)phenyl)ethoxy)pyrimidin-4-yl acid )-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(quinoxalin-6-yl)phenyl)ethoxy)pyrimidin-4-yl acid )-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin) acid -6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(quinazolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl acid )-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-fluoro-2'-methoxy-[1,1'-biphenyl] acid) -4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2'-fluoro-3'-methoxy-[1,1'-biphenyl] acid) -4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2'-fluoro-5'-methoxy-[1,1'-biphenyl] acid) -4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(6-methylpyridin-3-yl)phenyl)ethoxy)pyrimidin-4 acid -il)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-(pyrrolidine-1-carbonyl)- [1,1'-biphenyl]- acid 4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3'-carboxy-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-carboxy-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-propyl-[1,1'-biphenyl]-4-yl)ethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(hydroxymethyl)-[1,1'-biphenyl]-4- acid yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2'-(hydroxymethyl)-[1,1'-biphenyl]-4- acid yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-isopropoxy-[1,1'-biphenyl]-4-yl)ethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-(dimethylacarbamoyl)-[1,1'-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(piperidine-1-carbonyl)- [1,1'-biphenyl]- acid 4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(2'-((dimethylamino)methyl)-[1,1'-biphenyl]-4-yl)- 2.2, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-ethyl-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-hydroxy-[1,1'-biphenyl]-4-yl)ethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)ethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(2',4'-dimethoxy-[1,1'-biphenyl]-4-yl)-2,2,2- acid trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4- acid yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4- acid yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(2',6'-difluoro-[1,1'-biphenyl]-4-yl)-2,2,2- acid trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(2',6'-dimethyl-[1,1'-biphenyl]-4-yl)-2,2,2- acid trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-[1,1'-biphenyl]-4-yl)-2,2,2- acid trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-isopropyl-[1,1'-biphenyl]-4-yl)ethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-isopropyl-[1,1'-biphenyl]-4-yl)ethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)-2,2,2- acid trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4- acid yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(2',3'-dimethyl-[1,1'-biphenyl]-4-yl)-2,2,2- acid trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3',4',5'-trifluoro-[1,1'-biphenyl) acid ]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-chloro-2'-methyl-[1,1'-biphenyl]-4-yl)-2,2 acid, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3',5'-dimethyl-[1,1'-biphenyl]-4-yl)-2,2,2- acid trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3',4'-difluoro-[1,1'-biphenyl]-4-yl)-2,2,2- acid trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(2',5'-dimethyl-[1,1'-biphenyl]-4-yl)-2,2,2- acid trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-butyl-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-4'-methyl-[1,1'-biphenyl] acid) -4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-(methylsulfonyl)-[1,1'-biphenyl]-4- acid yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-methyl-[1,1'-biphenyl]-4-yl)ethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methyl-[1,1'-biphenyl]-4-yl)ethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-chloro-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-(benzofuran-3-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl acid) -2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(5'-fluoro-2'-methoxy-[1,1'-biphenyl] acid) -4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-oxochroman-7-yl)phenyl)ethoxy)pyrimidin-4 acid -il)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)ethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3,4-dihydroquinazolin-6-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- acid 2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(1,2,3,4-tetrahydroquinazolin-6-yl)ethoxy) pyrimidin-acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4 acid. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(naphthalen-2-yl)ethoxy)pyrimidin-4-yl)-2,8 acid -diazaespiro[4. 5]decane-3-carboxylic acid; 9-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin acid 4-yl)-3,9-diazaspiro[5. 5]undecane-2-carboxylic acid; (S)-8-(2-amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[ acid 4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((5-chloro-3'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)methoxy)pyrimidin-4-yl acid) -2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-ethyl 8-(2-amino-6-((R)-1-(4-(benzo[d]thiazol-6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(6-((R)-1-(4-(1H-indazol-5-yl)phenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl )-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methoxy-4'-(pyrrolidine-1-carbonyl)-[1,1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-4'-nitro-[1,1'-biphenyl]-2-yl)-2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-(benzo[d]isothiazol-5-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-(benzo[d]isothiazol-6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',4'-dimethoxy-[1,1'-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-methyl-2-oxo-1,2-dihydroquinolin -6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-amino-5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2 - trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(methylsulfonyl)-5-propyl-[1,1'-biphenyl]- 2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-(1,3-dimethyl-1H-indol-5-yl)phenyl)-2,2,2-tri- fluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(6-((R)-1-(3'-acrylamido-5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy )-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-4'-methoxy-[1,1'-biphenyl] -4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-methyl-6-oxo-1,6-dihydro-pyridine -3-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-6 -yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-oxo-1,2-dihydroquinolin-6-yl)phenyl )ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(methylsulfonyl)-5-((E)-prop-1-en- 1-yl)-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-methyl-1H-pyrazol-1-yl)- [1,1 '-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-chloro-4-(3-methyl-1H-pyrazol-1-yl)-[1,1'-bi - phenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(methylsulfonyl)-4-propyl-[1,1'-biphenyl]- 2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(methylsulfonyl)-4-((E)-prop-1-en- 1-yl)-[1,1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(ethylsulfonyl)-[1,1'-biphenyl]-2-yl)- 2.2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(propylsulfonyl)-[1,1'-biphenyl]-2-yl)- 2.2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(butylsulfonyl)-[1,1'-biphenyl]-2-yl)- 2.2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-oxo-1,3-dihydroisobenzofuran-5-yl )phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-methoxyquinolin-6-yl)phenyl)ethoxy)pyrimidin-4 -il)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(hydroxymethyl)-[1,1'-biphenyl]-2-yl)- 2.2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(2-oxopyrrolidin-1-yl)-[1,1'-biphenyl]- 2- il)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(3-methyl-2-oxoimidazolidin-1-yl)-[1,1'-biphenyl ]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-3'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)- 2.2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(methylsulfonamido)-[1,1'-biphenyl]-2-yl)-2,2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(2-bromo-5-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-methyl-2-oxo-1,2,3,4-te - trahydroquinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-(methylthio)quinolin-6-yl)phenyl)ethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(2,5-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaespiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(6-((R)-1-([1,1':4',1''-terphenyl]-2'-yl)-2,2,2-trifluoroethoxy)-2 -aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(2'-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1' -biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1' -biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1' -biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(2,6-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaespiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',5-dichloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoro - ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-methyl-[1,1'-biphenyl]-2-yl)-2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)- 2.2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4'- ( methylthio)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-methyl-3-(3-methyl-1H-pyrazol-1- il)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methyl-3-(3-methyl-1H-pyrazol-1- il)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',4'-dichloro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(2-oxopyrrolidin-1-yl)phenyl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methoxy-[1,1'-biphenyl]-4-yl)ethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-methoxy-2-(3-methyl-1H-pyrazol-1-yl )phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-[1,1'-biphenyl]-4-yl)ethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-propylphenyl) ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-butyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-2-(3 - methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-(3-ethoxy-3-oxopropyl)-2-(3-methyl-1H-pyrazol-1-yl )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin -3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-(( E)-prop-1-en-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-4-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-propylphenyl) ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-butyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl) ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-((E)-but-1-en-1-yl)-2-(3-methyl-1H-pyrazole - 1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(1-methyl-1H-pyrazol-3-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(1-methyl-1H-pyrazol-3-yl)phenyl)ethoxy )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-(1,3-dimethyl-1H-indazol-6-yl)phenyl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-(2,3-dimethyl-2H-indazol-6-yl)phenyl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-oxo-1,2,3,4-tetrahydroiso-quinolin-6 -yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(isoquinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl )-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-(3-ethoxy-3-oxopropyl)-2-(3-methyl-1H-pyrazol-1-yl )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(isoquinolin-7-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-(4-ethoxy-4-oxobutyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-(4-ethoxy-4-oxobutyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- il)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-(4-ethoxy-4-oxobutyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-cyano-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-bi -phenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-cyano-[1,1'-biphenyl]-2-yl)-2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-methoxy-[1,1'-biphenyl]-2-yl)-2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-sulfamoyl-[1,1'-biphenyl]-2-yl)-2,2,2 - trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-hydroxy-[1,1'-biphenyl]-2-yl)-2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)- 2.2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-(aminomethyl)-5-chloro-[1,1'-biphenyl]-2-yl)- 2.2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(quinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl )-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(quinolin-7-yl)phenyl)ethoxy)pyrimidin-4-yl )-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl) -[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(quinoxalin-6-yl)phenyl)ethoxy)pyrimidin-4-yl )-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(6-((R)-1-(4'-(acetamidomethyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]- 4-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(6-((R)-1-(4'-(2-acetamidoethyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl ]-4-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(quinolin -7-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-methoxypyridin-4-yl)-2-(3-methyl-1H -pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylate; (S)-ethyl 8-(6-((R)-1-(4-(1H-indol-6-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2, 2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(ethoxycarbonyl)-[1,1'-biphenyl]-2-yl)- 2.2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; 2'-((R)-1-((2-amino-6-((S)-3-(ethoxycarbonyl)-2,8-diazaspiro[4. 5]decan-8-yl)pyrimidin-4-yl)oxy)-2,2,2-trifluoroethyl)-5'-chloro-[1,1'-biphenyl]-3-carboxylic acid; (S)-ethyl 8-(6-((R)-1-(3'-(acrylamidomethyl)-5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy )-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-carbamoyl-5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2 - trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)- 2.2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-4'-sulfamoyl-[1,1'-biphenyl]-2-yl)-2,2,2 - trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate (S)-ethyl 8-(2-amino-6-((R)-1-(2'-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-1-yl )-[1,1'-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1' -biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1' -biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (3S)-ethyl 8-(2-amino-6-((1R)-1-(4-(1,2-dihydroxyethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-(aminomethyl)-3-(3-methyl-1H-pyrazol-1-yl)- [1,1' -biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-4-( 3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-4-( 3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-(3-ethoxy-3-oxopropyl)-4-(3-methyl-1H-pyrazol-1- il)-[1,1'-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-(3-ethoxy-3-oxopropyl)-4-(3-methyl-1H-pyrazol-1- il)-[1,1'-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-3-(3-methyl-1H-pyrazol-1- il)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(quinolin -6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (3S)-ethyl 8-(2-amino-6-((1R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)- 4-(2 -oxo-1,3-dioxolan-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaes-pyro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-methyl-1-oxo-1,2,3,4-te - trahydroisoquinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylate; (S)-ethyl 8-(6-((R)-1-(4-(acetamidomethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethoxy) -2-aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (3S)-ethyl 8-(2-amino-6-((1R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)- 4'-( (2-((2-oxotetrahydrofuran-3-yl)thio)ethyl)carbamoyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3,4-dimethyl-3''-(methylsulfonyl)-[1,1':3',1''-ter - phenyl]-4'-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(methylsulfonyl)-5-(quinolin-6-yl)-[1, 1'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-(hydroxymethyl)-3'-methyl-4-(3-methyl-1H -pyrazol-1-yl)-[1,1'-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(hydroxymethyl)-4'-methyl-4-(3-methyl-1H -pyrazol-1-yl)-[1,1'-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-(methoxycarbonyl)-4-(3-methyl-1H-pyrazol- 1-yl)-[1,1'-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; 3'-((S)-1-((2-amino-6-((R)-3-(ethoxycarbonyl)-2,8-diazaspiro[4. 5]decan-8-yl)pyrimidin-4-yl)oxy)-2,2,2-trifluoroethyl)-4'-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl ]-4-carboxylic acid; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4- (1 -oxo-1,3-dihydroisobenzofuran-5-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(quinazolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl )-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(pyrimidin -5-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',4'-difluoro-3-(3-methyl-1H-pyrazol-1-yl)- [1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate (S)-ethyl 8-(2-amino-6-((R)-1-(4'-chloro-3-(3-methyl-1H-pyrazol-1-yl)- [1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-chloro-4-(3-methyl-1H-pyrazol-1-yl)-[1,1'-bi - phenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',4'-difluoro-4-(3-methyl-1H-pyrazol-1-yl)- [1,1 '-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-methyl-1H-pyrazol-1-yl)- [1,1 '-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',4'-dichloro-4-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-[1,1'-biphenyl]-2-yl)ethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-(pyrimidin -5-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4',5-dichloro-3'-fluoro-[1,1'-biphenyl]-2-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-ethoxy-[1,1'-biphenyl]-2-yl)-2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',5-dichloro-4'-ethoxy-[1,1'-biphenyl]-2-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',5-dichloro-5'-fluoro-[1,1'-biphenyl]-2-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-(tert-butyl)-5-chloro-[1,1'-biphenyl]-2-yl)- 2 ,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',5-dichloro-5'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-fluoro-5'-(trifluoromethyl)-[1,1'-biphenyl]-2 -yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin -4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-methoxy-[1,1'-biphenyl]-2-yl)-2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-isopropoxy-[1,1'-biphenyl]-2-yl)- 2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',5-dichloro-4'-methyl-[1,1'-biphenyl]-2-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',5-dichloro-4'-isopropoxy-[1,1'-biphenyl]-2-yl)- 2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-fluoro-4'-isopropoxy-[1,1'-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4',5-dichloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-fluoro-[1,1'-biphenyl]-2-yl)-2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4',5-dichloro-3'-methyl-[1,1'-biphenyl]-2-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',5-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3',5'-difluoro-[1,1'-biphenyl]-2-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',5-dichloro-4'-fluoro-[1,1'-biphenyl]-2-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3',4'-difluoro-[1,1'-biphenyl]-2-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-octyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-cyclopentyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-pentyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-cyclohexyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-propyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-neopentyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-butyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-isopropyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-tert-butyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-tert-butyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4- propylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-2-(dimethylamino)ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl) -2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylate; (S)-2-(dimethylamino)-2-oxoethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-2-(((R)-2-amino-3-methylabutanoyl)oxy)ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl -1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; and (3S)-1-(pivaloyloxy)ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylate; or a pharmaceutically acceptable salt of any of the aforementioned; or b) selected from: (S)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1) acid -yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaes-piro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3'-chloro-3-(3-methyl-1H-pyrazol-1-yl)-5'-(trifluoromethyl) acid )-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-chloro-4'-ethoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)- 3'-( trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-chloro-5'-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4'-chloro-3'-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3'-ethoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl acid) ]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-4'-methyl-3-(3-methyl-1H -pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-chloro-4'-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)- 3'-( trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3',5'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)- [1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3',4'-difluoro-3-(3-methyl-1H-pyrazol-1-yl)- [1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3',5'-difluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-fluoro-3-(3-methyl-1H-pyrazol-1- yl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-4'-isopropoxy-3-(3-methyl-1H-pyrazole) acid -1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-ethoxy-5'-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-(tert-butyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1, 1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-fluoro-3'-methyl-3-(3-methyl-1H) acid -pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-isopropyl-3-(3-methyl-1H-pyrazol-1-yl) acid -[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl) acid -[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4'-chloro-3'-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3'-carbamoyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl) acid ]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-3',5 acid '-bis(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-ethoxy-4'-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4'-chloro-3',5'-dimethyl-3-(3-methyl-1H-pyrazol-1- il)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3',5'-dichloro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-(tert-butyl)-5'-methyl-3-(3-methyl-1H-pyrazole-1 -yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3'-chloro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl acid) ]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3'-chloro-3-(3-methyl-1H-pyrazol-1-yl)-4'-(trifluoromethyl) acid )-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-methoxy-3-(3-methyl-1H-pyrazol-1- il)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3',4'-dimethyl-[1,1'-biphenyl]-2-yl)- 2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-4'-ethoxy-3'-fluoro-[1,1'-biphenyl]-2-yl)- acid 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3',5'-dimethyl-[1,1'-biphenyl]-2-yl)- 2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl acid )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4',5-dichloro-3',5'-dimethyl-[1,1'-biphenyl]-2-yl) acid - 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-4'-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl)- acid 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3',5-dichloro-5'-methyl-[1,1'-biphenyl]-2-yl)-2 acid, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl) acid - 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)-2,2 acid ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3',5'-bis(trifluoromethyl)-[1,1'-biphenyl]-2- il)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-isopropyl-[1,1'-biphenyl]-2-yl)- 2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3',5,5'-trichloro-[1,1'-biphenyl]-2 -yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-4'-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl acid )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-fluoro-5'-isopropoxy-[1,1'-biphenyl]-2-yl acid )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3'-(tert-butyl)-5-chloro-5'-methyl-[1,1'-biphenyl] acid -2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-fluoro-4'-methyl-[1,1'-biphenyl]-2-yl)- acid 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(pyridin-3-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-ethoxy-4'-fluoro-[1,1'-biphenyl]-2-yl)- acid 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3',4'-dimethyl-[1,1'-biphenyl]-2-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4',5-dichloro-3',5'-dimethyl-[1,1'-biphenyl]-2-yl) - 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-4'-ethoxy-3'-fluoro-[1,1'-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3',5'-dimethyl-[1,1'-biphenyl]-2-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',5-dichloro-5'-methyl-[1,1'-biphenyl]-2-yl)-2, 2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-4'-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-2 -yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)-2,2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-isopropyl-[1,1'-biphenyl]-2-yl)-2,2,2 - trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3',5'-bis(trifluoromethyl)-[1,1'-biphenyl]-2-yl) -2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-fluoro-4'-methyl-[1,1'-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3',5,5'-trichloro-[1,1'-biphenyl]-2 - yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-4'-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-2 -yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(pyridin-3-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-fluoro-5'-isopropoxy-[1,1'-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-ethoxy-5'-fluoro-[1,1'-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-(tert-butyl)-5-chloro-5'-methyl-[1,1'-biphenyl]-2 - il)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-cyano-[1,1'-biphenyl]-2-yl)-2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-ethoxy-5'-fluoro-3-(3-methyl-1H-pyrazol-1-yl)- [1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-chloro-3'-fluoro-3-(3-methyl-1H-pyrazol-1-yl)- [1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-chloro-4'-ethoxy-3-(3-methyl-1H-pyrazol-1-yl)- [1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-ethoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-steak - nyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',5'-difluoro-3-(3-methyl-1H-pyrazol-1-yl)- [1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-3'- ( trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-ethoxy-4'-fluoro-[1,1'-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-4'-isopropoxy-3-(3-methyl-1H-pyrazole -1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaes-piro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',5'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-chloro-5'-methyl-3-(3-methyl-1H-pyrazol-1-yl)- [1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-4'-methyl-3-(3-methyl-1H-pyrazole -1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaes-piro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-(tert-butyl)-3-(3-methyl-1H-pyrazol-1-yl)- [1, 1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-chloro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-bi -phenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-chloro-4'-fluoro-3-(3-methyl-1H-pyrazol-1-yl)- [1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',4'-difluoro-3-(3-methyl-1H-pyrazol-1-yl)- [1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-fluoro-3-(3-methyl-1H-pyrazol-1- yl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-chloro-3-(3-methyl-1H-pyrazol-1-yl)-5'-(trifluoromethyl )-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-3'- ( trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-(tert-butyl)-5'-methyl-3-(3-methyl-1H-pyrazol-1-yl )-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-chloro-3'-methyl-3-(3-methyl-1H-pyrazol-1-yl)- [1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-chloro-3',5'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl) -[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-fluoro-3'-methyl-3-(3-methyl-1H-pyrazole -1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaes-piro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-ethoxy-3'-fluoro-3-(3-methyl-1H-pyrazol-1-yl)- [1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',5'-dichloro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-isopropyl-3-(3-methyl-1H-pyrazol-1- il)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-chloro-3-(3-methyl-1H-pyrazol-1-yl)-3'-(trifluoromethyl )-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-chloro-3-(3-methyl-1H-pyrazol-1-yl)-4'-(trifluoromethyl )-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-carbamoyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl ]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)- 3',5 '-bis(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl) -[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-ethoxy-4'-fluoro-3-(3-methyl-1H-pyrazol-1-yl)- [1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-5'-isopropoxy-3-(3-methyl-1H-pyrazole -1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaes-piro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-methoxy-3-(3-methyl-1H-pyrazol-1- il)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; and (S)-ethyl 8-(2-amino-6-((R)-1-(4'-ethoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; or a pharmaceutically acceptable salt of any of the aforementioned; or c) selected from: (S)-8-(2-amino-6-((R)-1-(4'-ethoxy-3'-fluoro-3-(3-methyl-1H-pyrazole) acid -1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3',4',5'-trifluoro-3-(3-methyl-1H- pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-chloro-4'-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methyl-3-(3-methyl-1H-pyrazole-1- il)-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-5'-isopropoxy-3-(3-methyl-1H-pyrazole) acid -1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-chloro-5'-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-chloro-3-(3-methyl-1H-pyrazol-1-yl)-3'-(trifluoromethyl) acid )-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-3-(3-methyl-1H-pyrazol-1- yl)-5'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-chloro-4'-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)- [1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(naphthalen) acid -2-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-(benzyloxy)-3'-fluoro-3-(3-methyl-1H-pyrazol-1-yl acid) )-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-isopropoxy-3'-methyl-3-(3-methyl-1H-pyrazole) acid -1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaes-piro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-3-(3-methyl-1H-pyrazol-1- il)-4'-propoxy-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4'-butoxy-3'-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-4'-(5-methyl-1,3,4-oxadiazole) acid -2-yl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[ 4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)- 4'-( methylsulfonyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4'-propoxy acid -[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)- 4'-( (2-morpholinoethyl)carbamoyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4'-sulfamoyl acid -[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-carbamoyl-3-(3-methyl-1H-pyrazol-1-yl)- [1,1'-biphenyl) acid ]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)- 4'-( methylcarbamoyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-4'-methoxy-3-(3-methyl-1H-pyrazole) acid -1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaes-piro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)- 4'-( piperazine-1-carbonyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4'-(dimethylacarbamoyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1, 1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-isobutoxy-3-(3-methyl-1H-pyrazol-1-yl) acid) -[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4'-(diethylacarbamoyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1, 1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)- 4'-( neopentyloxy)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-(chroman-6-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- acid 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4-(cinnolin-6-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(hydroxymethyl)-4'-methyl-3-(3-methyl-1H) acid -pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-(hydroxymethyl)-3'-methyl-3-(3-methyl-1H) acid -pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-(6-ethoxypyridin-3-yl)-2-(3-methyl-1H-pyrazol-1-yl) acid )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((S)-1-(3',4'-bis(hydroxymethyl)-3-(3-methyl-1H-pyrazol-1-yl) acid -[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)- [1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2,2 acid, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(2-(3-(tert-butyl)-1H-pyrazol-1-yl)-4-chlorophenyl)-2 acid ,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-isopropyl-1H-pyrazol-1-yl)phenyl)-2,2 acid, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-cyclopropyl-1H-pyrazol-1-yl)phenyl)-2,2 acid, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-(hydroxymethyl)-4-(3-methyl- 1H-pyrazol-1- il)-[1,1'-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(3'-(tert-butyl)-5-chloro-[1,1'-biphenyl]-2-yl)- 2 ,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(prop-1-en-2-yl)-[1,1'-biphenyl]- 2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(2-(dimethylamino)pyridin-4-yl)phenyl)-2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(naphthalen-2-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(2-isopropylpyridin-4-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)-2,2,2 acid - trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4',5-dichloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluo acid - roethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-4'-methyl-[1,1'-biphenyl]-2-yl)-2,2,2 acid - trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2 - il)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-isobutoxy-[1,1'-biphenyl]-2-yl)- 2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(pyrrolidine-1-carbonyl)-[1,1'-biphenyl]-2- il)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane- 3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(cyclopentyloxy)-[1,1'-biphenyl]-2-yl)-2,2 acid ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(((1R,4R)-4-hydroxycyclohexyl) carbamoyl acid)-[1,1'- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-ethyl-[1,1'-biphenyl]-2-yl)-2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-isopropyl-[1,1'-biphenyl]-2-yl)- 2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)-[1, 1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(morpholine-4-carbonyl)-[1,1'-biphenyl]-2-yl) acid -2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(4-methylapiperazine-1-carbonyl)-[1,1'-biphenyl]- acid 2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(2-methylthiazol-5-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl) acid )phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(N-methylasulfamoyl)-[1,1'-biphenyl]-2-yl) acid -2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(N,N-dimethylasulfamoyl)-[1,1'-biphenyl]-2-yl) acid -2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(methylacarbamoyl)-[1,1'-biphenyl]-2-yl)-2,2 acid ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(dimethylacarbamoyl)-[1,1'-biphenyl]-2-yl)-2 ,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(diethylacarbamoyl)-[1,1'-biphenyl]-2-yl)-2,2 acid ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(6-((R)-1-(2-(1H-benzo[d]imidazol-4-yl)-4-chlorophenyl)-2,2,2-trifluoroethoxy)- acid 2-aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(piperazine-1-carbonyl)-[1,1'-biphenyl]-2-yl) acid -2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]de-cane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(4-cyclopropylpiperazine-1-carbonyl)-[1,1'-biphenyl]- acid 2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(pyridin-2-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(pyrimidin-2-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- acid il)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(pyrazin-2-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(5-chloro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-2-yl)-2 acid ,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(6-((R)-1-(2-(1H-benzo[d]imidazol-1-yl)-4-chlorophenyl)-2,2,2-trifluoroethoxy)- acid 2-aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(1H-indazol-1-yl)phenyl)-2,2,2-trifluoroethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-bromo-2-(piperazin-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-isopropoxy-3-(piperazin-1-yl)-[1,1' acid) -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-isopropoxy-3-morpholino-[1,1'-biphenyl]- acid 4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(6-((R)-1-([1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)-2-amino pyrimidin-4- acid il)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1':3',1''-ter-phenyl acid) ]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-propoxy-[1,1':3',1''-terphenyl) acid ]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1'-biphenyl]-2-yl acid )ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-fluoro-4-propoxy-[1,1':3',1'' acid) -terphenyl]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane- 3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(3,4-dimethyl-[1,1':3',1''-terphenyl]-4'-yl)- acid 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(6-((R)-1-([1,1':3',1''-terphenyl]-4'-yl)-2,2,2-trifluoroethoxy)-2 -aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (R)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (R)-8-(2-amino-6-((S)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((S)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((S)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (R)-8-(2-amino-6-((S)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; acid (R)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-fluoroquinolin-6-yl)phenyl)ethoxy)pyrimidin-4 acid -il)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-propoxy-[1,1'-biphenyl]-4-yl)ethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-(diethylacarbamoyl)-[1,1'-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy acid ) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-(methylacarbamoyl)-[1,1'-biphenyl]-4-yl) acid ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-((2-morpholinoethyl)carbamoyl)-[1,1'- acid) biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane- 3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-(methylsulfonyl)-[1,1'-biphenyl]-4- acid yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-sulfamoyl-[1,1'-biphenyl]-4-yl)ethoxy acid) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-(dimethylacarbamoyl)-[1,1'-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-(piperazine-1-carbonyl)- [1,1'-biphenyl]- acid 4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-4'-propoxy-[1,1'-biphenyl]-4 acid -yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-ethoxy-3'-fluoro-[1,1'-biphenyl]-4-yl)-2,2 acid, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy acid )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; acid (S)-8-(2-amino-6-((R)-1-(4-(cinnolin-6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2 ,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(4-(chroman-6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl acid) -2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-fluoroquinolin-6-yl)-2-methylphenyl)ethoxy)pyrimidin-acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-1-(2-ethyl-4-(3-fluoroquinolin-6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin acid 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylic acid; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3',4',5'-trifluoro-3-(3-methyl- 1H- pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methyl-3-(3-methyl-1H-pyrazol-1- il)-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-chloro-4'-methyl-3-(3-methyl-1H-pyrazol-1-yl)- [1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-3-(3-methyl-1H-pyrazol-1- yl)-5'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diaza-spiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-chloro-5'-fluoro-3-(3-methyl-1H-pyrazol-1-yl)- [1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-cyclopropyl-[1,1'-biphenyl]-2-yl)- 2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-chloro-4'-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(2-(benzo[d]thiazol-5-yl)-4-chlorophenyl)-2,2,2-trifluoroethoxy )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(2-(dimethylamino)pyridin-4-yl)phenyl)- 2,2,2-trifluoroethoxy )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(naphthalen-2-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- il)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3'-(tert-butyl)-5-chloro-[1,1'-biphenyl]-2-yl)- 2 ,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(6-((R)-1-(2-(1H-benzo[d]imidazol-1-yl)-4-chlorophenyl)-2,2,2-trifluoroethoxy)- 2-aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(1H-indazol-1-yl)phenyl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(2-isopropylpyridin-4-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)-2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4',5-dichloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoro - ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-4'-methyl-[1,1'-biphenyl]-2-yl)-2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(naphthalen -2-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2 -yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-(benzyloxy)-3'-fluoro-3-(3-methyl-1H-pyrazol-1-yl )-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-isopropoxy-3'-methyl-3-(3-methyl-1H-pyrazole -1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaes-piro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-isobutoxy-[1,1'-biphenyl]-2-yl)-2,2,2 - trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1':3',1''-terphenyl ]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-fluoroquinolin-6-yl)phenyl)ethoxy)pyrimidin-4 -il)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-3-(3-methyl-1H-pyrazol-1- il)-4'-propoxy-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-butoxy-3'-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-4'-(5-methyl-1,3,4-oxadiazole -2-yl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[ 4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(pyrrolidine-1-carbonyl)-[1,1'-biphenyl]-2- il)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(cyclopentyloxy)-[1,1'-biphenyl]-2-yl)- 2.2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(morpholine-4-carbonyl)-[1,1'-bi-phenyl]-2- il)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(((1R,4R)-4-hydroxycyclohexyl) carbamoyl)-[1,1 '-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-ethyl-[1,1'-biphenyl]-2-yl)-2,2,2 -trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-isopropyl-[1,1'-biphenyl]-2-yl)-2,2,2 - trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-propoxy-[1,1'-biphenyl]-4-yl)ethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(2-ethyl-4-(3-fluoroquinolin-6-yl)phenyl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(4-methylapiperazine-1-carbonyl)-[1,1'-biphenyl]-2- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-fluoroquinolin-6-yl)-2-methylphenyl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-(diethylacarbamoyl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(2-methylthiazol-5-yl)phenyl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-propoxy-[1,1':3',1''-terphenyl]- 4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(5-chlorothiophen-2-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-(methylsulfonyl)-[1,1'-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4'- ( methylsulfonyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4'-propoxy -[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-(diethylacarbamoyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1' -biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-(methylacarbamoyl)-[1,1'-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4'-sulfamoyl -[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decano-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-sulfamoyl-[1,1'-biphenyl]-4-yl)ethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-((2-morpholinoethyl)carbamoyl)-[1,1'- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4'- ( (2-morpholinoethyl)carbamoyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-(dimethylacarbamoyl)-[1,1'-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-(piperazine-1-carbonyl)- [1,1'-biphenyl]- 4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4'- ( piperazine-1-carbonyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-(dimethylacarbamoyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1' -biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-4'-methoxy-3-(3-methyl-1H-pyrazole -1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaes-piro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-4'-propoxy-[1,1'-biphenyl] -4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4'- ( methylcarbamoyl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(N-methylasulfamoyl)-[1,1'-biphenyl]-2-yl)-2 ,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(N,N-dimethylasulfamoyl)-[1,1'-biphenyl]-2- il)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-isopropoxy-3-morpholino-[1,1'-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(methylacarbamoyl)-[1,1'-biphenyl]-2-yl)-2,2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(dimethylacarbamoyl)-[1,1'-biphenyl]-2-yl)-2,2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-ethoxy-3'-fluoro-[1,1'-biphenyl]-4-yl)-2,2, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)ethoxy )pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(diethylacarbamoyl)-[1,1'-biphenyl]-2-yl)-2,2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-isobutoxy-3-(3-methyl-1H-pyrazol-1- il)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5] decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4'- ( neopentyloxy)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(6-((R)-1-(2-(1H-benzo[d]imidazol-4-yl)-4-chlorophenyl)-2,2,2-trifluoroethoxy)- 2-aminopyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-(chroman-6-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(piperazine-1-carbonyl)-[1,1'-biphenyl]-2- il)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5] decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(4-cyclopropylpiperazine-1-carbonyl)-[1,1'-biphenyl]- 2-yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-(cinnolin-6-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2,2, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(2-(3-(tert-butyl)-1H-pyrazol-1-yl)-4-chlorophenyl)-2 ,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-isopropyl-1H-pyrazol-1-yl)phenyl)- 2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-cyclopropyl-1H-pyrazol-1-yl)phenyl)-2,2, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(3,4-dimethyl-[1,1':3',1''-terphenyl]-4'-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-fluoro-4-propoxy-[1,1':3',1'' - terphenyl]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(6-((R)-1-([1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl )-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(6-((R)-1-([1,1':3',1''-terphenyl]-4'-yl)-2,2,2-trifluoroethoxy)-2 -amino-pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-(hydroxymethyl)-4-(3-methyl- 1H-pyrazol-1- il)-[1,1'-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-(chroman-6-yl)phenyl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2 ,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(pyridin-2-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(pyrimidin-2-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-(hydroxymethyl)-4'-methyl-3-(3-methyl-1H -pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-(hydroxymethyl)-3'-methyl-3-(3-methyl-1H -pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-(6-ethoxypyridin-3-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl )-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(6-methoxypyridin-3-yl)-2-(3-methyl-1H -pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5] decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]-2-yl)- 2 ,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(pyrazin-2-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((S)-1-(3',4'-bis(hydroxymethyl)-3-(3-methyl-1H-pyrazol-1-yl)-[ 1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4. 5]decane-3-carboxylate; (S)-tert-butyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1 ,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4. 5]decane-3-carboxylate; (S)-tert-butyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-isopropoxy-3-(3-methyl-1H-pyrazol- 1-yl)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-isopropyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (S)-cyclopentyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4. 5] decane-3-carboxylate; (S)-methyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)- [1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5] decane-3-carboxylate; (S)-propyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)- [1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5] decane-3-carboxylate; (S)-isopropyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-isopropoxy-3-(3-methyl-1H-pyrazol-1- il)-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaespiro[4. 5]decane-3-carboxylate; (S)-cyclopentyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl) -[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4. 5]decane-3-carboxylate; (S)-propyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl) -[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4. 5]decane-3-carboxylate; (S)-isopropyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-cyclopentyl 8-(2-amino-6-((R)-1-(4'-chloro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl ]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5] decane-3-carboxylate; (S)-propyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; (S)-methyl 8-(2-amino-6-((R)-1-(5-chloro-3'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)-2,2 ,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; and (S)-methyl 8-(2-amino-6-((R)-1-(5-chloro-3'-sulfamoyl-[1,1'-biphenyl]-2-yl)- 2,2, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4. 5]decane-3-carboxylate; or a pharmaceutically acceptable salt of any of the aforementioned. 13. Compound, according to claim 1, characterized by the fact that it is (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1' -biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof. 14. Compound, according to claim 1, characterized by the fact that it is acid (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1' -bi-phenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid, or a pharmaceutically acceptable salt thereof. 15. Compound, according to claim 1, characterized by the fact that it is: (S)-ethyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl- 3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazas - pyro[4.5]decane-3-carboxylate; acid (S)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1 '-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazas-pyro[4.5]decane-3-carboxylic acid; (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2, 2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate; acid (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-3-(3-methyl-1H-pyrazol-1-yl) -4'-propoxy-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazas-pyro[4.5]decane-3-carboxylate; or (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-fluoro-3-(3-methyl-1H-pyrazol-1-yl) acid )-4'-propoxy-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid; or a pharmaceutically acceptable salt thereof. 16. Pharmaceutical composition, characterized in that it comprises a compound, as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. 17. Use of a compound, as defined in any one of claims 1 to 15, characterized by the fact that it is for the preparation of a pharmaceutical composition, as defined in claim 16, or a medicament for treating or preventing a disease in a patient, wherein said disease is selected from bone disease, cardiovascular disease, metabolic disease, lung disease, gastrointestinal disease, liver disease, cancer, and inflammatory disease. 18. Use of a compound, as defined in any one of claims 1 to 15, characterized by the fact that it is for the preparation of a pharmaceutical composition, as defined in claim 16, or a medicament for treating a disease in a patient , in which said disease is osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fractures, bone metastasis, pulmonary arterial hypertension (PAH), diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), pulmonary embolism, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia , constipation, lactose intolerance, MEN types I and II, Ogilvie syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, chronic liver disease, liver cancer, breast cancer , cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, or blood cancer, allergic airway inflammation. 19. Use according to claim 17, characterized by the fact that it is to treat or prevent a lung disease in a patient. 20. Use according to claim 18, characterized by the fact that it is to treat pulmonary arterial hypertension (PAH) in a patient. 21. Use according to claim 20, characterized by the fact that pulmonary arterial hypertension (PAH) is associated pulmonary arterial hypertension (APAH).