NZ717556B2 - Spirocyclic compounds as tryptophan hydroxylase inhibitors - Google Patents

Spirocyclic compounds as tryptophan hydroxylase inhibitors Download PDF

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NZ717556B2
NZ717556B2 NZ717556A NZ71755614A NZ717556B2 NZ 717556 B2 NZ717556 B2 NZ 717556B2 NZ 717556 A NZ717556 A NZ 717556A NZ 71755614 A NZ71755614 A NZ 71755614A NZ 717556 B2 NZ717556 B2 NZ 717556B2
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diazaspiro
pyrimidinyl
amino
biphenyl
trifluoroethoxy
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NZ717556A
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NZ717556A (en
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Kenneth Brameld
Lombaert Stephane De
Daniel R Goldberg
Andrew Scribner
Eric Brian Sjogren
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Roviant Sciences GmbH
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Priority claimed from PCT/US2014/054202 external-priority patent/WO2015035113A1/en
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Publication of NZ717556B2 publication Critical patent/NZ717556B2/en

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Abstract

The present invention is directed to spirocyclic compounds of formula IIa which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPH1), that are useful in the treatment of diseases or disorders associated with peripheral serotonin including, for example, gastrointestinal and cardiovasculardiseases. ardiovasculardiseases.

Description

SPIROCYCLIC NDS AS TRYPTOPHAN HYDROXYLASE INHIBITORS FIELD OF THE INVENTION The present invention is directed to spirocyclic compounds which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPHl ), that are useful in the treatment of diseases or disorders associated with peripheral serotonin including, for example, gastrointestinal, cardiovascular, ary, inflammatory, metabolic, and low bone mass diseases, as well as serotonin syndrome, and cancer.
BACKGROUND OF THE INVENTION Serotonin (S�hydroxytryptamine, 5-HT) is a neurotransmitter that modulates central and peripheral functions byacting on neuro ns, smooth muscle, an d other cell types. 5-HT is involved in the control and modulati on ofmultiple physiological and psychological processes. In the centra l nervous system (CNS), 5-HT regulates mood, te, and other ora l ons. In theGI system, 5-HT plays a general prokinetic role and is an important mediator of sensation (e.g., nausea and satiety) between the GI tra ct and the bra in. Dysregulation of the peripheral5-HT signaling system has been reported to be involved in the etiology of severa l conditions (see for example: Mawe, G. M. & Hoffman, J. M. Serotonin Signa1ling In The Gutfunctions , Dysfunctions And Therapeutic Targets. Nature Reviews. Gastroenterology & Hepatology 10, 473-486 (2013); Gershon, M. D. 5-hydmxytryptamine (serotoni n) In The Gastrointestinal Tra ct. Current Opinion in Endocrinology, Diabetes, and Obesity 20, 14-21 (2013); el, M., Soll, C., Graf, R. & Clavien, P.-A. Role of Serotonin In The Hepatogastrointestinal Tract: An Old Molecule For New ctives. Cellular And Molecular Life Sciences: C1\1LS 65, 940-52 (2008)). These include osteoporosis (e.g. Kode, A. et al. FOXOl Orchestrates The uppressing Function Of Gut-derived Serotonin. The Journal of Clinical Investigation 122, 3490-503 ; Yadav, V. K. et al. Pharmacological tion Of Gut- derived nin sis 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 sis 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 FOX03a. Molecular Cancer 12, 14 (2013); Soll, C. et al. Serotonin Promotes Tumor Growth In Human Hepatocellular . Hepatology 51, 1244-1254 (2010); Pai, V. Pet al. Altered Serotonin Physiology In Human Breast Cancers Favors Paradoxical Growth And Cell Survival. Breast Cancer ch: BCR 11, R81 (2009); Engelman, K., erg, W. & Sjoerdsma, A. Inhibition Of Serotonin Synthesis By Para-chlorophenylalanine In Patients With The Carci noid me. The New England Journal of Mediclne 277, 1103-8 (1967)), cardiovascular (e.g. Robiolio, P. A. et al. Carcinoid Heart Disease : Correlation of High nin Levels With Valvular Abnormalities Detected by Cardiac Catheterization and Echocardiography. Circulation 92, 790-795 (1995).), diabetes (e.g. Sumara, G., Sumara, 0., Kim, J. K. & ty, G. Gut-derived Serotonin Is A Multifunctional Determinant To Fasting Adaptation. Cell Metabolism 16, 588-600 (2012)), atherosclero sis (e.g. Ban, Y. et al. Impact Of Increased Plasma Serotonin Levels And Carotid sclero sis On Vascular Dementia.
Atherosclerosis 195, 153-9 (2007)), as well as gastrointestinal (e.g. Manocha, M. & Kh an, 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 Experi mental Colitis. enterology 137, 0 (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 Serotoni n In Gastrointestinal Motility In Functional Bowel Disorders: Alterations In 5-HT Signalling And Metabolism In Human Disease. Neurogastroenterology and Motility: The Official Journal of The an Gastrointestinal Motility Society 19 Suppl 2, 25-31 (2007); Costedio, M. M., Hyman, N. & Mawe, G. M. Serotonin An d Its Role In Colonic Function And In Gastrointestinal Disorders. es of the Colon and Rectum 50, 376-88 (2007); Gershon, M. D. & Tack, J. The Serotonin Signaling System: Fro m Basic Understanding To Drug Development For Functional GI Disorders. enterology 132, 397-4 14 (2007); Mawe, G. M., Coates, M. D. &Moses, P. L.
Review Article: Intestinal Serotonin ling In Irritable Bowel Syndrome. Alimentary Pharmacology & Therapeutics 23, 1067-76 ; Crowell, M. D. Role Of Seroto nin In The hysiology 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 ctive Pulmonary Disease. PloS One 7, e31617 (2012); Egerrnayer, 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.l 136/gutjnl304901 ; Duerschmied, D. et al. Platelet Serotonin Promotes The Recruitment OfNeutrophils To Sites Of Acute Infl ammation In Mice. Blood 121, 1008-15 (2013); Li, N. et al. Serotonin Activates Dendritic Cell Function In The Context Of Gut Infl ammation. The American Journal of Pathology 178, 662-71 (2011)), or liver diseases or disorders (e.g. Ebra himkh ani, M. R. et al.
Stimulating Healthy Tissue Regeneration By Targeting The 5-HT2B or In Chronic Liver Disease. Nature Medicine 17, 1668-73 (2011)). The large number of pharmaceutical agents that block or stimulate the various 5-HT ors is also tive of the wide range of medical ers that have been associated with 5-HT dysregulation (see for example: Wacker, D. et al.
Structural es For Functional ivity At Serotonin Receptors. Science (New York, N. Y) 340, 615-9 (2013)).
The rate-limiting step in 5-HT thesis is the hydroxy lation oftryptophan 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 alanine hydroxylase ) and tyrosine hydrox ylase (TH), TPH belongs to the pterin-depe ndent ic amino acid hydroxylase family.
Two vertebrate isoforms of TPH, namely TPHl and TPH2, have been identifi ed. TPHl is primarily expressed in the pineal gland and non-neuronal tissues, such as enterochromaffin (EC) cells located in the gastrointestinal (GI) tract. TPH2 (the dominant form in the brain) is expressed exclusively in al cells, such as dorsal ra phe or myenteric plexus cells. The peripheral and centra l systems ed in 5-HT biosynthesis are isolated, with 5-HT being unable to cross the blood-brain barr ier. Therefore, the pharmacological effects of 5-HT can be modulated by agents aff ecting TPH in the peri phery, mainly TPHl in the gut.
A small number of phenylalanine-derived TPHl inhibitors are known. One example, pchlorophenylalanine (pCPA), a very weak and unselective irreversible inhibitor of TPH, has proven effective in treating chemotherapy-induced emesis, as well as diarrhea, in carcinoid tumor patients. However, pCP A is distibuted centrally and, as a result, its administration has been linked to the onset of depression and other tions of CNS functions in patients and animals. p-Ethynyl phenylalanine is a more selective and more potent TPH inhibitor than pCP A (Stokes, A.H. et al. p-Ethynylphenylalanine: A Potent Inhibitor OfTryptophan Hydroxylase.
Journal of Neurochemistry 74, 3 (2000), but also s central 5-HT production and, like pCPA, is believed to irreversibly ere with the synthesis ofTPH (and possibly other prote ins).
More recently, bulkier phenylalanine-derived TPH tors have been ed to reduce intestinal 5-HT concentration without affecting brai n 5-HT levels (Zhong, H. et al.
Molecular dynamics simulation oftryptophan hydroxylase-I: binding modes and free energy analysis to phenylalanine tive inhi bitors. International Journal of Molecular Sciences 14, 9947-62 (2013); Ouyang, L. et al. Combined Structure-Based Pharmacophore and 3D-QSAR s on Phenylalanine Seri es Compounds as TPHl Inh ibitors. International Journal of Molecular es 13, 5348-63 (2012); eri, M. LX-1031, A Tryptophan S"hydroxylase Inh ibitor, And Its Potential In Chronic Diarrhea Associated With Increased Sero tonin.
Neurogastroenterology and Motility: The Official Journal of The European Gastrointestinal Motility Society 23, 193-200 (2011); Cianchetta, G. et al. Mechanism ofinh ibition ofNovel Tryptophan Hydroxylase Inh ibitors 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-triazinyl)" phenylj-z-aminopropanoic Acids As Novel Tryptophan Hydroxylase Inh ibitors. anic & Medicinal Chemistry Letters 19, 5229-32 (2009); Shi, Z.-C. et al. tion Of Peripheral Sero tonin Levels By Novel Tryptophan Hydroxylase InhibitorsFor The Potential Treatment Of Functional Gastrointestinal Disorders. l of medicinal chemistry 51, 3684- 7 (2008); Liu, Q. et al. Discovery And Characterization ofNovel Tryptophan Hydroxylase Inhibitors That ively Inhibit Sero tonin Synthesis In The Gastrointestinal Tra ct. The l of Pharmacology and Experimental Therapeutics 325, 47-55 (2008)).
There is a current need to selectively reduce intestinal 5-HT levels as a means for ng and preventing 5-HT-associated diseases. The TPHl inhibitors described herein are intended to s this need.
SUMMARY OF THE INVENTION The t invention relates to a TPH-inhibiting compound of Formula I: L�W�N X,II �NI or a pharmaceutically acceptable salt thereof, wherein constituent variables are defined herein.
The present invention further s to a pharmaceutical composition comprising a TPH­ inhibiting compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically able carrier.
The present invention further relates to a method of inhibiting TPH, such as TPHl, by contacting the TPH enzyme with a compound of Formula I, or a pharmaceutically able salt thereof.
The present invention further s to a method of lowering peripheral serotonin in a patient comprising administering to the patient an effective amount of a nd of Formula I, or a pharmaceutically acceptable salt thereof.
The present invention further relates to a method of treating or preventing a disease in a patient comprising administering to the patient a therapeutically effective amount of a nd of Formula I, or a pharmaceutically acceptable salt thereof.
The present invention further relates to a compound ofFonnula I, or a ceutically acceptable salt thereof, for use in the treatment or prevention of disease in a patient.
The present invention further s to use of a compound of Formula I or a ceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of disease in a patient.
DETAILED DESCRIPTION Compounds The present invention relates to a TPH-inhibiting compound of Formula I: L�W�N X'-II -rNI or a ceutically acceptable salt thereof, wherein: Ring A is CJ-10 cycloalkyl, Cs.io aryl, 4 to 10-membered heterocycloalkyl, or 5 to 10- membered heteroaryI; Lis OorNR4• WisN or CR5· XisNor CR6; YisNorCR7• wherein only one of X and Y is N; R1 is H, C1-10 alkyl, Ci.rocycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, -(CR8R9)pOC(O)R10, 9)p NR11R12, or -(CR8R9)pC(O)NR11R12, wherein said C1-10 alkyl, CJ-10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl are each optionally tuted with 1, 2, 3, 4, or 5 substituents independently ed from F, Cl, Br, CN, Ci-4 alkyl, and C1.4 haloalkyl; R2 and R3 are each independently selected from H, C1-4 alkyl, and Ci-4 haloalky l; R4 is Hor C1.4 alkyl; R5 and R6 are each independently ed from H, halo, and Ci-4 alkyl; R7 is H, Ct-4 alkyl, C2-6 alkenyl, CJ.JO cycloalkyl, C3.10 cycloalkyl-Cr.a alkyl, C6-IO aryl, C6- aryl-Cr.a alkyl, 4-10 membered heterocycloalkyl, (4-10 membered cycloalkylj-Ci., alkyl, -10 red heteroaryl, (5-10 membered heteroarylj-Ci., alkyl, NR13R14, OR15, C(O)R16, S(O)qR17, wherein said C1.4 alkyl, C2-6 alkenyl, C3.10 cycloalkyl, C3.10 cycloalkyl-Ci.a alkyl, C6-to aryl, C6-tO i.a alkyl, 4-10 membered cycloalkyl, (4- 10 membered heterocycloalkyl)­ C t-4 alkyl, 5- 10 membered heteroaryl, and (5-10 ed heteroarylj-Cr., alkyl are each optionally substituted by 1, 2, or 3 substituents selected from halo, Ct-4 alkyl, C2-6 alkenyl, amino, Ci-4 alkylamino, C2.s dialkylamino, hydroxy, and C1.4 alkoxy; R8 and R9 are each independently selected from Hand C1.4 alky l; R10 is Ci.s alkyl optionally substituted by 1, 2 or 3 tuents independently selected from C1-6 kyl, CJ.10 cycloalkyl, OR\ and NRcRd; R11 and R12 are each independently selected from Hand C1-6 alkyl; R13 is H or C1.4 alk yl; R14 is H, C1.4 alkyl, C3.7 cycloalkyl, C3.7 cycloalkyl-Ci.a alkyl, C6-10 aryl, Cs.io i., alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkylj-Ci., alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl j-Ci,a alky l, C(O)Rb1, C(O)ORa1, C(O)NRc1Rd1, S(O)Rb1, S(0)2Rb1, or Rc1Rd1, wherein said Ci-4 alkyl, C3.7 cycloalkyl, C3.7 cycloalkyl-C 1.4 alkyl, C6.JO aryl, C6-JO aryl-C 1-4 alkyl, 4-10 membered hetero cycloalkyl, (4-10 membered heterocycloalkyl)-C t-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroarylj-Ci., alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1.4 alkyl, C1.4 haloalkyl, CN, N02, 0Ra1, SR81, C(O)Rb1, C(O)NRc1Rd1, C(O)OR81, OC(O)Rb1, OC(O)NRc1R<l1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rct 1, NRc1S(O)Rb1, NRc1S(0)2Rb1, NRc1S(0)2NRc1Rct 1, S(O)Rb1, S(O)NRctRd1, S(0)2Rb1, and S(0)2NRc1Rd1; or R13 and R14 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7- membered hetero cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently ed from Cr-6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-IO aryl, 5-6 membered heteroaryl, halo, CN, OR81, SR111, C(O)Rb1, C(O)NRc1Rd1, C(O)OR111, OC(O)Rb1, OC(O)NRc1Rd1, NRc!Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rct 1, S(0)2Rb1, NRc1S(0)2Rb1, NRc1S(0)2NRctRct 1, and S(0)2NRc1Rd1, wherein said C1-6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-JO aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, 0Ra1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, 1, NRc1C(O)Rb1, NRc1C(O)NRc1Rct1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rd1, S(0)2Rb1, NRc1S(0)2Rb1, 0)2NRc1Rd1, and S(0)2NRc1Rd1; R15 is H, C 1.4 alkyl, C3.7 cycloalkyl, C3-7 cycloalkyl-Ci.a alky l, CG-to aryl, C6.JO i.a alkyl, 4-10membered heterocyc l, (4-10 membered heterocycloalkylj-Ci., alky l, 5-10 membered hetero aryl, or (5-10 membered heteroarylj-Ci., alkyl, wherein said C1-4 alkyl, C3.7 cycloalkyl, C3.7 cycloalkyl-Ci.a alkyl, C6-10 aryl, C6-JO aryl-Ci., alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkylj-Ci.a alkyl, 5-10 membered heteroaryl, and (5-10 membered arylj-C 1-4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently ed from halo, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-IO aryl, 5-6 membered heteroaryl, CN, ORat, SRa1, C(O)Rb1, c1Rct 1, C(0)0Ra1, OC(O)Rb1, OC(O)NRclRdl' NRc!Rdl' NRC1C(O)Rbl, NRC1C(O)NRC1Rdl' NRC1C(O)ORa1, S(O)Rbl' ctRd1, S(0)2Rb1, NRc1 S(0)2Rbl, NRc1 S(0)2NRc 1Rdi, and S(0)2NRc1Rd1; R16 is C1.4 alkyl or NR18aR18b wherein said C1-4 alky l is ally substituted by 1, 2, or 3 substituents ndently selected from halo, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-1oaryl, 5-6 membered heteroaryl, CN, 0Ra1, SRal, C(O)Rb1, C(O)NRc1Rd1, C(O)ORat, OC(O)Rb1, OC(O)NRc1Rd1, NRc 1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)OR81, S(O)Rb1, S(O)NRc1Rd1, S(0)2Rb1, NRc1S(0)2Rb1, NRc1S(0)2NRc1Rd1, and S(0)2NRc1Rd1; R17 is C1.4 alkyl, NR188R18h, or OR18C, 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-tO aryl, 5-6 membered heteroaryl, CN, 0Ra1, SR01, C(O)Rb1, C(O)NRc1Rd1, C(O)ORat, OC(O)Rb1, OC(O)NRc1Rct1 , NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, c1Rd1, b1, NRc1S(0)2Rb1, NRc1S(0)2NRc1Rd1, and S(0)2NRc1Rd1; R18a and R18b are each independently selected from Hand C1.4 alkyl wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 substitu ents independently selected from halo, C3.7 cycloalky1,4- 7 membered heterocycloalkyI, C6- IO ary1, 5-6 membered heteroary1, CN, 0Ra 1, SR31, C(O)Rb1, C(O)NRc1Rct 1, C(O)OR31, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, O)NRc1Rd1, NRc4C(O)ORa 1, S(O)Rb1, S(O)NRc1Rct 1, S(O)iR_bl, NRc1S(0)2Rb1, 0)2NRc1Rd1, and Rc1Rd1; or R18a and R18b er with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally tuted with 1, 2, or 3 substituents independently selected from Cr-6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-IO aryl, 5-6 membered heteroaryl, halo, CN, 0Ra1, SRa1, C(O)Rb1, 01Rd1, C(O)ORa1, b1, OC(O)NR01Rd1, t1, O)Rb1, NRc1C(O)NRc1Rct 1, NRc1C(O)ORa1, 1, S(O)NRcIRd1, S(0)2Rb1, NRc1S(0)2Rb1, NRc1S(0)2NRc1Rd1, and S(0)2NRc1Rct 1, wherein said C1-6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, Cs.io aryl, and 5-6 membered heteroar yl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, 0Ra1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Ra1, NRc1C(O)Rb1, NRc 1C(O)NRc1R<l 1, NR01C(O)ORa1, 1, S(O)NRc1Rct 1, S(0)2Rb1, NRc1S(0)2Rb1, NRc1S(0)2l\lR.c 1Ra1, an d S(0)2NRc1Rd1; R18c is H, C1-6 alkyl, CJ-10 cycloalkyl, C3.7 cycloalkyl-Ci., alkyl, C6-JO aryl, CG-IO aryl-Ci., alkyl, 4-10 membered hetero cycloalkyl, (4-10 memberedheterocycloalkyl)-C1.4alkyl, 5-10 membered aryl, or (5-10 membered heteroarylj-Ci.a alkyl, wherein said C1-6 alkyl, C3.7 cycloalkyl, C3.10 cycloalkyl-Ci.a alkyl, C6-IO aryl, C6-IO aryl-Ci., alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkylj-Ci., alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroarylj-Ci., alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1.4 alkyl, C1.4 haloalkyl, CN, N02, OR11, SR31, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc!Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)OR01, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, 0)2Rb1, 0)2NR01Rd1, S(O)Rb1, S(O)NRc1Rd1, S(0)2Rb1, and S(0)2NRc1Rct1; RA is H, Cy1, halo, Ct-6 alkyl, C2-6 alkenyl, CN, N02, OR112, 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(0)2Rb2, NRc2S(0)2NRc2Rct2, S(O)Rb2, S(O)NRc2Rd2, S(0)2Rb2, or S(0)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, Ct-6 alkyl, C2. 6 alkenyl, Ct-6 haloalkyl, CN, N02, OR12, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)OR32, OC(O)Rb2, OC(O)NRc2Rct 2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NR02S(0)2Rb2, NR02S(0)2NRc2Rd2, S(O)Rb2, S(O)NRc2R<l2, S(0)2Rb2, and S(0)2NR02Rd2; R8 is H, Cy2, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, N02, 0Ra3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)OR03, OC(O)Rb3, OC(O)NRc3Rd3, 3, NRc3C(O)Rb3, NRc3C(O)OR83, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(0)2Rb3, NRc3S(0)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, b3, or S(0)2NRc3Rd3, wherein said Cr-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 alky l, C2. 6 alkenyl, C1-6 haloalkyl, CN, N02, 0Ra3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, O)ORa3, NW3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc1S(0)2Rb3, NRc3S(0)2NRc3Rd3, S(O)Rb3, S(O)NRc3R<l 3, S(0)2Rb3, and S(0)2NRc3Rd3; Re and R0 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, Cr-6 haloalkyl, CN, N02, 0Ra4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)OR84, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb 4, NW4C(O)ORa4, NRc4C(O)NRc4Rd 4, NRc4S(O)Rb4, NRc4S(0)2Rb>l, NRc4S(0)2NRc4Rd 4, 4, S(O)NRc4Rd4, S(0)2Rb4, and Rc4Rd 4; n said C1.6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cs.m aryl, C3.rocycloalkyl, 5N10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, N02, 0Rn4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd", NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb 4, NRc4S(0)2Rb4, NRc4S(0)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(0)2Rb4, and Rc4Rd4; Cyl and Cy2 are each independently selected from C6-IO aryl, CJ.JO cycloalkyl, SN10 membered heteroaryl, and 4-10membered cycloalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCY; each Rey is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 l, C6-IO aryl, CJ-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, N02, OR85, SR85, 5, C(O)NRc 5Rd5, 35, OC(O)Rb5, OC(O)NRc5Rd5, NRc 5Rd5, O)Rb5, O)OR85, NRc5C(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(0)2Rb5, NRc5S(0)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(0)2Rb5, and S(0)2NRc5Rd5, wherein said C1-6 alkyl, C2-6 l C6-IO aryl, C3.10 cycloalkyl, 5-10membered heteroaryl, and 4-10 membered heterocycloal kyl are each optionally substituted with 1, 2, 3, 4, or 5 tu ents independently selected from halo, C1-6 alkyl, CN, N02, 0Ra5, SR35, C(O)Rb5, C(O)NRc5Rd5, C(O)OR85, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NW5C(O)OR65, NRc5C(O)NRc 5Rd5, NRc5S(O)Rb5, NRc5S(0)2Rb5, NRc5S(0)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, b5, and S(0)2NRc5Rd5; each Ra, Ra1, Ra2, Ra3, Ra\ and Ras is independently selected from H, C1-6 alkyl, C1.4 haloalkyl, C2-6 alkenyl, Cs.in aryl, Cr.ro cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-IO aryl-Ci., alkyl, C3.10 cycloalkyl-Ci., alkyl, (5-10 membered heteroarylj-Ci. 4 alkyl, or (4-10 membered heterocycloalkylj-Ci., alkyl, n said C1-6 alkyl, C2-6 alkenyl, C6- aryl, CJ.JO cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CG-10 aryl­ C1.4 alkyl, C3.10 lkyl-Ci.a alkyl, (5-10 membered heteroarylj-Ci., alkyl, and (4-10 membered heterocycloalkylj-Cr., alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1.4 alkyl, halo, CN, OR86, C(O)Rb6, C(O)NRc6Rd6, a6, OC(O)Rb6, OC(O)NRC6Rd6, NRC6Rd6, NRC6C(O)Rb6, NRC6C(O)NRC6Rd6, O)ORa6, S(O)Rb6, S(O)NRc6Ru6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6R<l6; each Rb1, Rb2, Rb3, Rb4, and Rbs is independently selected from H, C1-6 alkyl, C1.4 haloalkyl, C2-6 alkenyl, C6-JO aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetero lkyl, C6-10 aryl-Ci., alkyl, C3.10 lkyl-Cr., alk yl, (5-10 membered heteroarylj-Ci. a alkyl, or (4-10 membered heterocycloalkyl)-C t-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C6- aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl­ C1.4 alkyl, Cr.m cycloalkyl-Cr.a alkyl, embered heteroarylj-Ci.a alkyl, and (4-10 membered heterocycloalkylj-Cr., alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1.4 alkyl, halo, CN, OR86, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rct 6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(0)2Rb6, 0)2Rb6, NRc6S(0)2NRc6R<l6, and S(0)2NRc6Rd6; each Re, Rd, Rel, Rd1, Rc2, Rd2, Rc3, Rd3, Rc·t, Rd4, Rc5, and Rds is independently ed from H, Ct-6 alkyl, C1.4 haloalkyl, C2-6 alkenyl, C6-IO aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C6-IO aryl-Ci., alkyl, C3.10 cycloalkyl-Ci.a alkyl, (5- memberedheteroarylj-Ci.a alkyl, or (4-10 membered heterocycloalkylj-Ci., alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C6-to aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CG-10 aryl-Ci.a alkyl, C3.10 cycloalkyl-Ci.a alkyl, (5-10 membered arylj-Ci.a alkyl, and (4-10 membered heterocycloalkylj-Ci,a alkyl are each optionally tuted with 1, 2, 3, 4, or 5 substituents independently selected from C1.4 alkyl, halo, CN, 0Ra6, SRa6, C(O)Rb6, C6Rd6, C(0)0Ra6, OC(O)Rb6, OC(O)NRC6Rd6, NRC6Rd6, NRc6C(O)Rb6, O)NRc6Rd6, O)ORa6, S(O)Rb6, S(O)NRc6R06, S(0)2Rb6, NRc6S(0)2Rb6, NR'6S(0)2NRc6Rct 6, and S(0)2NRc6Rct 6; or any R' and Rd together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group ally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3.7 cycloalkyl, 4-7 ed heterocycloalkyl, C6.JO aryl, 5-6 membered heteroaryl, halo, CN, 0Ra6, SR116, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rct6, NRc6R<l 6, NRc6C(O)Rb6, NRc6C(O)NRc6R<l 6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rct 6, wherein said C1-6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, CG.JO aryl, and 5-6 membered heteroaryl are ally substituted by l, 2, or 3 substituents independently selected from halo, CN, OR116, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rct 6, O)Rb6, NRc6C(O)NRc6Rct 6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rct 6, b6, NRc6S(0)2Rb6, NRc6S(0)21\TRc6Rct 6, and S(0)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 substitu ted with 1, 2, or 3 tuents independently selected from C1- 6 alkyl, Ci.rcycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, halo, CN, 0Ra6, SRa6, 6, c6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rct 6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc 6Rct 6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said C1-6 alkyl, C3.7 cycloa1kyl, 4-7 membered heterocycloalkyl, C6-JO aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, 0Ra6, SRa6, C(O)Rb6, C(O)NRc6Rct 6, C(O)OR116, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rct 6; or any Rc2 and Rd2 er with the N atom to which they are attached form a 4-, 5-, 6-, or ered hetero cycloalkyl group optionally substituted with I , 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, CG-JO aryl, and 5-6 membered heteroaryl, Ci.s haloalkyl, halo, CN, 0Ra6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(0)0Ra6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)OR86, S(O)Rb6, S(O)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, 0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Cr-6 alkyl, CJ-7 cycloalkyl, 4-7 membered heterocycloalkyl, CG-to aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents ndently ed from halo, CN, OR86, SR86, C(O)Rb6, c6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, 6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6; or any Rc3 and Rd3 er with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with I, 2, or 3 substituents independently selected from Ct-6 alkyl, CJ-7 cycloalkyl, 4-7 membered heterocycloalkyl, CG-10 aryl, 5-6 membered heteroaryl, Ci.s haloalkyl, halo, CN, OR86, SR86, C(O)Rb6, c6Rd6, C(O)OR86, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said C1-6 alkyl, C3_7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-lO aryl, and 5-6 membered heteroaryl are each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, CN, 0Ra6, SR06, C(O)Rb6, C(O)NRc6Rd6, C(O)OR86, b6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and Rc6Rd6; or anyRc4 and Rd4 together with the N atom to which they are ed form a 4-, 5-, 6-, or 7-membered heterocycloalky] group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alky l, CJ-7 cycloalkyl, 4-7 membered heterocycloalkyl, Cs.ro aryl, 5-6 membered heteroaryl, Ci.s haloalkyl, halo, CN, OR16, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, O)NRc6Rd6, NRc6C(O)OR86, S(O)Rb6, S(O)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rct 6, and S(0)2NRc6Rd6, n said Cr-6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloa1kyl, C6-JO aryl , and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substitu ents independently selected from halo, CN,OR86, SRa6, \ C(O)NRc6Rd6, C(O)OR86, OC(O)Rb6, OC(O)NRc 6Rd6, NRc6R<l 6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)OR86, S(O)Rb6, S(O)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6; or any Res 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, CJ-7 lkyl, 4-7 membered heterocycloalkyl, C5.10 aryl, 5-6 membered heteroaryl, Cr.s haloalkyl, halo, CN, 0Ra6, SRa6, C(O)Rb6, C(O)NRc 6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRC6Rd6, NRC6Rd6, NRC6C(O)Rb6, NRC6C(O)NRC6Rd6, O)ORa6, S(O)Rb6, S(O)NRc6R<l 6, b6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said C1-6 alkyl, C3.7cycloalkyl, 4-7 ed heterocycloalkyl, C6-IO aryl, and 5-6 ed heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, 0Ra6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)OR86, OC(O)Rb6, Rc6Rd\ NRc6R<l6, NRc 6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6; each R86, Rb6, Rc6, and Rd6 is independently selected from H, C1.4 alkyl, C2.4 l, C3.7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycl oalkyl, wherein said C1.4 alkyl, C2.4 alkenyl, C3.7 cycloalkyl, , 5-6 membered heteroaryl, and 4-7 membered 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; pi s 1, 2, or 3; and q is 1 or 2; wherein any aforementioned 4-10 or 4-7 membered cycloalkyl group optionally ses 1, 2, or 3 oxo substituents, wherein each oxo substituent that is present is substituted on a ring- forming carbon, nitrogen, or sulfur atom of the 4-10 or 4-7 membered heterocycloalkyl group.
In some embodiments, the present invention relates to a TPH-inhi biting compound of Formula I: or a pharmaceutically acceptable salt f, wherein: Ring A is C3.10 cycloalkyl, C6.JO aryl, 4 to I 0-membered cycloalkyl, or 5 to 10- membered heteroaryl; Lis O or NR4•, W is N or CR5; X isNorCR6• Y is Nor CR7·, wherein only one ofX and Y is N; R1 is H, C1.10 alkyl, C3.10 cycloalkyl, phenyl, -(CR8R9)pOC(O)R10, -(CR8R9)p NR11R12, or 9)pC(O)NR 11R12, 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, Ci.a alkyl, and Ci.a haloalkyl; R2 and R3 are each independently selected from H, C1.4 alkyl, and C1.4 haloalkyl; R4 is Hor 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.J0 cycloalkyl, CJ.10 cycloalkyl-Ci., alkyl, C6-JO aryl, C6- aryl-Ci., alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkylj-Ci.a alkyl, -10 membered heteroaryl, (5-10 membered heteroarylj-Cr.a alkyl, NR13R14, OR15, C(O)R16, S(O)qR17, wherein said C1-4 alkyl, C2-6 alkenyl, C3.1ocycloalkyl, C3.10 cycloalkyl-Ci.a alkyl, C6.10 aryl, C6.JO aryl-C 1-4 alkyl, 4-10 membered hetero cycloalkyl, (4-10 membered heterocycloalkyl)­ C1.4 alkyl, 5-10 memberedheteroaryl, and (5-10 membered heteroarylj-Cr.a 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.s dialkylamino, hydrox y, and C1.4 alkoxy; R8 and R9 are each independently selected from Hand Ct-4 alkyl; R10 is C1-6 alkyl optionally tuted by 1, 2 or 3 substituents independently ed from Ci-6 kyl, C3.10 cycloalkyl, OR\ and NRcRd; R11 and R12 are each independently selected from Hand C1-6 alkyl; R13 is Hor Ci.a alkyl; R14 is H, C1.4 alkyl, C3.7 lkyl, C3.7 cycloalkyl-Ci.a alkyl, C6.10 aryl, C6-IO aryl-Ci., alkyl, 4-10 ed heterocycloalkyl, (4-10 membered heterocycloalkylj-Cr., alk yl, 5-10 membered heteroaryl, or (5-10 membered heteroarylj-Ci., alkyl, C(O)Rb1, C(O)ORa1, C(O)NRc1Rd1, S(O)Rb1, S(0)2Rb1, or S(0)2NRc1Rd1, wherein said Cr.a alkyl, Cr.r cycloalkyl, C3.7 cycloalkyl-Ci.a alkyl, Cs.ro aryl, C6-10 aryl-Ci.a alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkylj-Ci .4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroarylj-Ci.a alkyl are each optionally substituted by 1, 2, or 3 substituents independently ed from halo, C1.4 alkyl, C1.4 haloalkyl, CN, N02, OR111, SR111, C(O)Rb1, C(O)NRc1Rct 1, C(O)ORa1, OC(O)Rb1, OC(O)NRclR<l 1, t1, NRc1C(O)Rb1, NRc1C(O)OR111, NRc1C(O)NRc1Rd1, O)Rb1, 0)2Rb1, NRc1S(0)2NRc1Rctt, S(O)Rbt, S(O)NRc1Rct 1, S(0)2R b1, and S(0)2NRclRdi; or R13 and R14 together with the N atom to which they are ed form a 4-, 5-, 6-, or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, Ci.v cycloalkyl, 4-7 membered heterocycloalkyl, C6-to aryl, 5-6 membered heteroaryl, halo, CN, ORat, SR111, C(O)Rh1, C(O)NRc1Rd1, a1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rdt, NRc1C(O)ORa1, S(O)Rb1, c1R01, S(0)2Rb1, NRc1S(0)2Rb1, NRc1S(0)2NRc1Rct1 , and S(0)2NRc1Rctt, n said C1-6 alkyl, Cs.rcycloelkyl, 4-7 membered heterocycloalkyl, Cs.io aryl, and 5-6 membered hetero aryl are each optionally tuted by 1, 2, or 3 substituents independently selected from halo, CN, 0Ra1, SRa1, C(O)Rb1, c1Rct 1, C(O)OR111, OC(O)Rb1, OC(O)NRc1Rct 1, NRc1Rct 1, NRc1C(O)Rb1, NRc1C(O)NRc1Rct 1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRc1Rct 1, S(0)2Rb1, NRc1S(0)2Rb1, NRc1S(0)2NRc1Rct 1, and S(0)2NRc1Rd1; R15 is H, C1.4 alkyl, C3.7 cycloalkyl, C3.7 cycloalkyl-Cr., alkyl, C6-IO aryl, C6-IO aryl-Ci., alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkylj-Ci., alkyl, 5-10 mernbe redheteroaryl, or (5-10 membered heteroarylj-Ci.s alkyl, wherein said C1.,i alkyl, C3.7 cycloalkyl, C3.7 cycloalkyl-Ci., alkyl, C6-10 aryl, CG-to aryl-Ci., alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkylj-Cr.a alkyl, 5-10 membered heteroaryl, and (S-10 membered arylj-Ci.a alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-IO aryl, 5-6 membered heteroaryl, CN, 0Ra1, SRa1, C(O)Rb1, C(O)NRc1Ra1, C(O)OR81, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, S(O)Rb1, S(O)NRctR<l 1, S(0)2Rll 1, NRc1S(0)2Rb1, NRc1S(0)2NRc1Rct 1, and S(0)2NRc1Rct 1; R16 is C1.4 alkyl or 18b wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, Cs.r lkyl, 4-7 membered heterocycloalkyl, Cs.m aryl, 5-6 membered heteroaryl, CN, 0Ra1, SR111, C(O)Rb1, C(O)NRc1Rct\ C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rct 1, NRc1Rct 1, NRc1C(O)Rb1, NRc1C(O)NRc1Rct 1, NRc1C(O)OR111, S(O)Rb1, S(O)NRc1Rct 1, S(0)2Rb1, NRc1S(0)2Rb1, NRc1S(0)2NRc1Rct 1, and S(0)2NRc1Rct 1; R17 is 18aR18b, or OR18 C1.4 alkyl, NR C, wherein said Ci.a alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, CJ-7 cycloalkyl, 4-7 membered heterocycloalky l, C6-IO aryl, 5-6 membered heteroaryl, CN, 0Ra1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rct 1, NRc1C(O)OR111, S(O)Rb1, S(O)NRc1Rct 1, S(0)2Rb1, NRc1S(0)2Rb1, NRc1S(0)2NRc1Rct 1, and S(0)2NRc1Rct 1; R188 and R18b are each independently ed fromH and Ci.a alkyl wherein said Ct-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, CJ-7 cycloalkyl, 4-7 membered cycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, CN, OR81, SR81, C(O)Rb1, C(O)NRc1Rct 1, C(O)ORa1, OC(O)Rb1, Rc1Rct 1, NRc1Rct1, O)Rb1, NRc1C(O)NRc1Rct1, NRc4C(O)OR01, S(O)Rb1, S(O)NRc1Rct 1, S(0)2Rb1, NRc1S(0)2Rb1, NRc1S(0)2NRc1Rct1, and S(0)2NRc1Rct 1; or R1811 and R18b together with the N atom to which they ar e 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-IO aryl, 5-6 membered heteroaryl, halo, CN, OR81, SR81, C(O)Rb1, c1Rd1, C(O)OR81, b1, OC(O)NRc1Rct 1, NRc1R". NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, 1, S(O)NRc1Rct 1, S(0)2Rb1, NRc1S(0)2Rb1, NRc1S(0)2NRc1Rd1, and S(0)2NRc1Rd1, n saidC1-6 alkyl, CJ-7 cycloalkyl, 4-7 membered cycloalkyl, C6-IO aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, 0Ra1, SR111, C(O)Rb1, c1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc!Rd1, NRc1Rct 1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NR01C(O)OR11 1, 1, S(O)NR01Rd1, S(0)2Rb1, NRc1S(0)2Rb1, 0)2NRc1Rct 1, and S(0)2NRc1Rd1; R18c is H, C1.6 alkyl, Cr.m cycloalkyl, C3.7 cycloalkyl-Ci.a alkyl, CG-10 aryl, C6-IO i.a alkyl, 4-10 membered hetero cycloalkyl, (4-10 membered heterocycloalkylj-Ci.a alkyl, 5-10 ed heteroaryl, or (5-10 membered heteroarylj-Ci., alkyl, wherein said C1-6 alkyl, C3.7 cycloalkyl, CJ-10 cycloalkyl-Ci.a alkyl, C6-t0 aryl, CG.JO aryl-Ci.a alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkylj-Ci., alkyl, 5-10 membered heteroary l, and (5-10 membered heteroarylj-Ci., alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1.4 alkyl, C1.4 kyl, CN, N02, 0Ra1, SRal, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, O)ORa1, NRC1C(O)NRC1Rdl, NRC1S(O)Rbl' 0)2Rb1, NRC1S(0)2NRclRdl' S(O)Rb1, S(O)NRc!Rdl' S(0)2Rb1, and Rc1Rd1; RA is H, Cy1, halo, C1.6 alkyl, C2.5 alkenyl, CN, N02, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)OR02, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NR02S(O)Rb2, NRc2S(0)2Rb2, NRc2S(0)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(0)2Rb2, or S(0)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 Cy', halo, C1-6 alkyl, C2. 6 alkenyl, Ct-6 haloalkyl, CN, N02, 0Ra2, SR02, C(O)Rb2, c2Rd2, C(O)OR02, OC(O)Rb2, Rc2Rd2, 2, O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rc12, NRc2S(O)Rb2, NRc2S(0)2Rb2, NRc2S(0)2NRc2Rd2, S(O)Rb2, c2Rd2, S(0)2Rb2, and S(0)2NRc2Rd2; R13 is H, Cy2, halo, C1.6 alkyl, C2-6 alkenyl, Ct-6 haloalkyl, CN, N02, OR"3, SR03, C(O)Rb3, C(O)NRc3Rd3, C(O)ORo3, OC(O)Rb3, OC(O)NRc3R<l 3, NRc3R<l 3, NRc3C(O)Rb3, NR03C(O)ORo3, O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(0)2Rb3, NRc3S(0)2NR03Rd3, 3, S(O)NRc3Rd3, S(0)2Rb3, or S(0)2NRc3Rd3, wherein said C1-6 alky l 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, N02, OR13, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NR03Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, 0)2Rb3, NRc3S(0)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)iRb 3, and S(0)2NRc3Rd3; Re and R0 are each independently selected fr om H, halo, Ct-6 alkyl, C2-6 alkenyl, Ct-6 haloalkyl, CN, N02, 0Ra4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(0)0Ra4, OC(O)Rb4, OC(O)NRc4Rd 4, NRc4RM, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(0)2Rh4, NRc4S(0)2NRc4Rd4, S(O)Rb4, c4Rd", S(0)2Rb4, and S(0)2NRc4Rd 4; wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from CG.JO aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyc loalkyl, halo, Ct-6 alkyl, C2-6 alkenyl, Ct-6 haloalkyl, CN, N02, OR04, SR114, C(O)Rb4, C(O)NRc4Rd 4, C(O)OR11 4, OC(O)Rb", OC(O)NRc4Rct4 , NRc4Rct 4, NRc4C(O)Rb 4, NRc4C(O)OR"4, O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(0)2Rb4, NRc4S(0)2NRc 4Rd4, , S(O)NRc4 Rd4, S(0)2Rb4, and S(0)2NRc4Rd4; Cy1 and Cy2 are each independently ed from C6-l O aryl, C3-10 cycloalkyl, 5-10 ed heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally tuted by 1, 2, 3, 4, or 5 substituents independently selected from RCy; each Rey is ndently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 l, C6-10 aryl, Cs.m cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, N02, OR85, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORu5, NRc5C(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(0)2Rb5, NRc5S(0)2NRc5Rd5, S(O)Rb\ S(O)NRc5Rd5, S(0)2Rb5, and S(0)2NRc5Rd5, wherein said C1-6 alkyl, C2-6 alkenyl C6-IO aryl, CJ-to cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered cycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, CN, N02, OR85, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, O)Rb5, NRc5C(O)OR85, NRc5C(O)NRc5R<l 5, NRc5S(O)Rb5, NRc5S(0)2Rb5, NRc5S(0)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(0)2Rb5, and S(0)2NRc5R": each Ra, Ra1, R32, Ra3, Ra4, and R35 is independently selected from H, C1-6 alkyl, C1.4 haloalkyl, C2-6 alkenyl, C6-1oaryl, ycloa]kyl, 5-10 membered hetero aryl, 4-10membered heterocycloalkyl, C6-IO aryl-Cr., alkyl, CJ-10 cycloalkyl-Ci., alkyl, (5-10 membered heteroarylj-Ci. 4 alkyl, or (4-10 membered heterocycloalkylj-Ci .4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C6. aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CG-to aryl- Ci.a alkyl, Cr.mcycloalkyl-Ci.a alkyl, (5-10 membered heteroarylj-Ci.a alkyl, and (4-10 membered heterocycloalkylj-Ci., alkyl are each optionally tu ted with 1 , 2, 3, 4, or S substituents independently ed from C1.4 alkyl, halo, CN, ORR6, C(O)Rb6, C(O)NRc6R<l 6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6R<l6, NRc6C(O)Rb6, O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rh6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6; each Rb1, Rb2, Rb3, Rb4, and Rb5 is independently selected from H, C1-6 alkyl, C1.4 haloalkyJ, C2-6 alkenyl, C6-10 aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Cs.io aryl-Ci.a alkyl, C3.10 cycloalkyl-Ci., alkyl, (5-10 membered heteroarylj-Ci. 4 alkyl, or (4-10 membered cycloalkylj-Cr., alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C6- 10 aryl, C3.10 cycloalkyl, 5-10 membered aryl, 4-10 membered hetero cycloalkyl, Cs.ro aryl­ Ct-4 alkyl, C3.10 cycloalkyl-Ci.a alkyl, (5-10 membered heteroarylj-Ci.s alkyl, and (4-10 membered heterocycloalkylj-Cr.a alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cr.4 alkyl, halo, CN, OR86, C(O)Rh6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, Rc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, O)OR86, S(O)Rb6, S(O)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and Rc6Rd6; each Re Rd Rel Rd! Rc2 Rd2 RcJ Rd3 Rc4 Rd4 Res and Rd5 is independently selected ' ' ' ' ' ' ' ' ' ' ' from H, C1-G alkyl, C1-4 haloalkyl, C2-6 alkenyl, C6-IO aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-IO aryl-Ci., alkyl, CJ.Jo cycloalkyl-Ci.a alkyl, (5- membered heteroarylj-Ci., alkyl, or (4-10 membered heterocycloalkylj-Ci., alkyl, wherein said C1.G alkyl, C2-6 alkenyl, Cs.m aryl, Ca.ro cycloalkyl, 5-10 membered heteroaryl, 4-10 membered cycloalkyl, C6-10 aryl-Cr., alkyl, C3.10 cycloalkyl-Ci., alk yl, (5-10 membered heteroarylj-Cr., alkyl, and (4-10 membered heterocycloalkylj-Ci., alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1.4 alkyl, halo, CN, 0Ra6, SR86, C(O)Rb6, C(O)NRc6R<l 6, C(O)OR86, b6, OC(O)NRc6R<l 6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)OR86, S(O)Rh6, S(O)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6; or any Re and Rd together with the N atom to which they are ed form a 4-, 5-, 6-, or 7-membered cycloalkyl 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, 0Ra6, SR86, C(O)Rb6, C(O)NRc6Rd6, C(0)0Ra6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rh6, NRc6C(O)NRc6Rd6, NRc 6C(O)OR86, 6, S(O)NRc6Ra6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Ra6, and S(0)2NRc6Rd6, wherein said C1.6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, Cs.io aryl, and 5-6 membered heteroa ryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR86, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)OR86, OC(O)Rh6, OC(O)NRc6R<l 6, NRc6Rd6, O)Rh6, NRc6C(O)NRc6Rd6, NRc6C(O)OR86, S(O)Rb6, S(O)NRc6Rd6, b6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6; 1 and Rd1 together with the N atom to which they are att 01· any Rc ached form a 4-, 5-, 6-, or ?-membered cycloalkyl gro up optionally substituted with 1 , 2, or 3 substituents independently selected from C1-6 alkyl, C3.7 cycloalkyl, 4-7 ed hetero cycloalky1, CG.JO aryl, 5-6 ed aryl, halo, CN, 0Ra6, SR36, C(O)Rh6, C(O)NRc6Rd6, C(O)OR86, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc 6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)OR06, S(O)Rb6, c6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said C1-6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-JO aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, 0Ra6, 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)OR06, S(O)Rb6, S(O)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)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 with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3.7 cycloalkyl, 4- 7 ed heterocycloalkyl, C6-JO aryl, and 5-6 membered heteroaryl, Ci.s haloalkyl, halo, CN, OR86, SR86, C(O)Rb6, c6Rd6, 86, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, S(O)NRc6Rd6, S(0)2Rb6, 1\TR.c 6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Cr-6 alkyl, C3.7 cycloalkyl, 4-7 ed heterocycloalkyl, C6-IO aryl, and 5-6 membered heteroaryl are each ally substituted by 1, 2, or 3 substituents independently selected from halo, CN, 0Ra6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)OR86, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)OR"6, S(O)Rb6, S(O)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)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, CG-10 aryl, 5-6 ed heteroaryl, Ci.s haloalkyl, halo, CN, OR116, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, b6, OC(O)NRc6R<l 6, NRc6Rd6, O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, S(O)Rb6, c6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NR'6Rd6, and Rc6Rd6, wherein said Ct-6 alkyl, C3.7 cycloalky l, 4-7 membered heterocycloalkyl, CG.JO aryl, and 5-6 membered heteroaryl are each ally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR116, SRa6, C(O)Rb6, c6Rd6, C(O)OR"6, OC(O)Rb6, OC(O)NRc6Rd6, 6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORn6, S(O)Rb6, S(O)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6; or any Rc4 and Rd4 together with the N atom to which they are att ached form a 4-, 5-, 6-, or 7-membered heteroc kyl group optionally substituted with 1, 2, or 3 substituents ndently selected from C1-6 alkyl, C3_7 cycloalky1, 4" 7 membered cycloalkyl, C6-IO aryl, 5"6 membered heteroaryl, C1-6 haloalkyl, halo, CN, OR116, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NW6C(O)Rb6, NRc6C(O)NRc6Rd6, O)OR116, S(O)Rb6, S(O)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6R<l 6, wherein said C1-6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-IO aryl, and 5"6 ed aryl are each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, CN, OR116, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)OR11 6, OC(O)Rb6, OC(O)NRc6R<l6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)OR116, S(O)Rb6, S(O)NRc6Rct 6, S(0)2Rb6, NRc6S(0)2Rb 6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6; or any Res and Rd5 together with the N atom to which they are attached form a 4-, 5", 6-, or ered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3.7 cycloalkyl, 4"7 membered heterocycloalkyl, CG-10 aryl, 5"6 membered hetero aryl, Ci.s haloalkyl, halo, CN, 0Ra6, SR116, C(O)Rb6, C(O)NRc6Rd6, C(O)OR11 6, OC(O)Rb6, OC(O)NRc6Rct 6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)OR116, S(O)Rb6, c6Rd6, S(0)2Rb6, 0)2Rb6, 0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said C1-6 alkyl, Cs.r cycloalkyl, 4-7 membered heterocycloalkyl, C6-IO aryl, and 5-6 ed heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, 0Ra6, SR11 6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rct6, NRc6C(O)ORa6, S(O)Rb6, c6R<l 6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6; each R11 6, Rb6, Rc6, and Rd6 is independently selected from H, C1.4 alkyl, C2-4 alkenyl, C3.7 cycloalkyl, , 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said Ci-4 alkyl, C2.4 alkeny1, C3.7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered hetero cycloalkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci.a alkyl, C1.4 alkoxy, C1.4 alkylthio, C1.4 alkylamino, and di(C1.4 alkyl)amino; n is 1 or 2; pis l , 2 , o r 3 ;a n d qis 1 or 2; wherein any aforementioned 4- lO or 4- 7 membered heterocycloalky I gro up optionally comprises 1, 2, or 3 oxo substituents, n each oxo substituent that is present is substituted on a ring-forming carbon, nitrogen, or sulfur atom of the 4-10 or 4-7 membered heterocycloalkyl group.
In some embodiments, Lis 0.
In some embodiments, Lis NR4.
In some embodiments, Wis CR5; Xis N; and Y is CR7.
In some embodiments, WisN; XisN; and Y is CR7.
In some embodiments, Wis CR5; XisCR6; and Y is N.
In some embodiments, Wis CR5; Xis CR6; and Y is CR7• In some embodiments, Wis N; Xis CR6; and Y is CR7• In some embodiments, R2 is H and R3 is H.
In some embodiments, R2 is Hand R3 is C1-4 alkyl.
In some embodiments, R2 is H and R3 is methyl.
In some embodiments, R2 is Hand R3 is C1-4 haloalkyl.
In some embodiments, R2 is Hand R3 is oromethyl.
In some embodiments, n is 1.
In some embodiments, n is 2.
In some embodiments, RI is H.
In some embodiments, R1 is C1-10 alkyl, Cs.mcycioalkyl, 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 ally substituted with 1, 2, 3, 4, or 5 tuents independently selected from F, Cl, Br, CN, C1.4 alkyl, and C1.4 haloalkyl.
In some embodiments, R1 is C1-10 alkyl.
In some embodiments, R1 is ethyl.
In some ments, R4 is H.
In some embodiments, R5 is H.
In some embodiments, R6 is H.
In some embodiments , R7 is other than H.
In some embodiments, R7 is C1-4 alkyl, NR13R14, or OR15.
In some embodiments, R7 is 4.
In some embodiments, R7 is NH2.
In some embodiments, R7 is C1.4 alkyl.
In some embodiments, R7 is OR15• In some embodiments, Ring A is Ci.io cycloalkyl.
In some embodiments, Ring A is C6.JO aryl.
In some embodiments, Ring A is phenyl.
In some embodiments, Ring A is 4 to 10-membered heterocycloalkyl.
In some embodiments, Ring A is phenyl, adarnantanyl, naphthyl, 1,2,3,4- ydroquinoxalinyl, 3,4-dihydroqinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, or pyridyl.
In some embodiments, Ring A is 5 to 10-membered heteroaryl, In some embodiments, at least one of RA, R13, Re, and R0 is other than hydrogen.
In some ments, at least two of RA, RB, Re, an d R0 are other than hydrogen.
In some embodiments, RA is Cy1.
In some embodiments, RA is C6.10 aryl or 5-10 membered aryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from Re>'.
In some embodiments, RA is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently ed from ReY.
In some embodiments, RA is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from Re>'.
In some embodiments, RA is pyra zolyl which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RcY.
In some embodiments, RA is 3-methyl-lH-pyrazolyl.
In some embodiments, RA is C6.10aryl optionally substituted by 1, 2, or 3 substituents independently selected from RcY.
In some embodiments, RA is phenyl optionally tuted by 1, 2, or 3 substituents independently selected from Re>'.
In some embodiments, RB is H.
In some embodiments, RB is Cy2, halo, C1-6 alkyl, C2-6 alkenyl, C1.6 ky 1, CN, N02, OR83, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)OR33, OC(O)Rb3, OC(O)NR03Rd3, 3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NR03Ra3, NRc3S(O)Rb3, 0)2Rb3, NRc3S(0)2NRc3Rct 3, S(O)Rh3, S(O)NRc3Rd3, h3, and S(0)2NRc3Rct 3, 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, Ct-6 alkyl, C2.6 alkenyl, Ct-6 haloalkyl, CN, N02, OR33, SR11\ C(O)Rh3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, O)Rb3, NRc3C(O)ORa3, O)NRc3Rd3, NRc3S(O)Rb3, 0)2Rb3, NRc3S(0)2NRc3Rd3, S(O)Rb3, c3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3.
In some embodiments, R8 is Cy2.
In some embodiments, R13 is C6-IO aryl or 5-10 membered heteroaryl, each of which is ally substituted by 1, 2, 3, 4, or 5 tuents independently selected from RcY.
In some embodiments, R8 is halo, C1-6 alkyl, C2-6 alkenyl, Cr-6 haloalkyl, CN, N02, 0Ra3, 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, 0)2Rb3, NRc3S(0)2NRc3Rd3, S(O)Rb3, c3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3, wherein said C1-6 alkyl and C2.6 alkenyl are each ally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy2, halo, C,. 3Rd3, C(O)ORa3, 6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, N02, 0Ra3, SRa3, C(O)Rb3, C(O)NRc OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc 3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc1S(0)2Rb3, NRc3S(0)2NRc3R<l 3, S(O)Rb3, S(O)NRc3Rd3, b3, and S(0)2NRc3R<l 3• In some embodiments, R8 is halo.
In some embodiments, Rc is H.
In some embodiments, Rc is halo, Cr.6 alkyl, C2-6 alkenyl, Ct-6 kyl, CN, N02, 0Ra4, SR"\ C(O)Rb4, C(O)NRc4Rd", C(O)OR84, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc 4Rd4, NRc4S(O)Rb4, NRc4S(0)2Rb4, NRc4S(0)2NRc 4Rd4, S(O)Rb4, c4Rd4, S(0)2Rb4, and S(0)2NRc4Rd4; wherein said C1-6 alkyl and C2-6 alkenyl are each ally substituted with 1, 2, 3, 4, or 5 substituents ndently selected from C6-tO aryl, C3. io cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, halo, C1-6 alkyl, C2-6 alkenyl, Ct-6 haloalkyl, CN, N02, 0Ra4, SRa4, C(O)RM, C(O)NRc4Rd4, C(O)ORn4, OC(O)R04, OC(O)NRC4Rd4, NRc4Rd 4, NRC4C(O)Rb4, NRC4C(O)OR84, NRC4C(O)NRC4Rd4, NRC4S(O)Rb4, NRc4S(0)2Rb4, NRc4S(0)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(0)2R04, and S(0)2NRc4Rd4.
In some embodiments, RO is H.
In some embodiments, R0 is halo, Ct-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, N02, 0Rn4, SR04, C(O)RM, C(O)NRc4Rd4, C(O)OR"4, OC(O)Rb4, OC(O)NRc4Rd 4, NRc4Rd4, NRc4C(O)R 04, NRC4C(O)OR84, NRc4C(O)NRc4Rd 4, NRc4S(O)Rb4, NRC4S(0)2Rb4, NRc4S(0)2NRc4Rd 4, S(O)Rb4, S(O)NRc4Rd4, S(0)2Rb4, and S(0)2NRc4Rd4; wherein said Ct-6 alkyl and C2-6 alkenyl are each ally substituted with 1, 2, 3, 4, or 5 substituents independently ed from CG-!O aryl, C3. to cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, N02, 0Ra4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)OR11 4, OC(O)Rb4, OC(O)NRC4Rd4, 4, NRC4C(O)Rb4, NRC4C(O)ORa4, NRC4C(O)NRC4Rd4, NRC4S(O)Rb4, NRc4S(0)2Rb 4, NRc4S(0)2NRc4Rd 4, S(O)Rb4, c4Rd4, S(0)2Rb4, and S(0)2NRc4Rd4.
In some embodiments, the compounds of the invention have Formula Ila: LylyN NH R2 R3 NyN Ila.
In some embodiments, the compounds of the invention have Formula Ilb: In some embodiments, the compounds of the invention have Formula Ile: L�NYN R2 R3 I N R6 # Ile.
In some embodiments, the compounds of the ion have Formula Ud: R7 lid.
In some embodiments, the compounds of the invention have Formula Ile: Ile.
In some embodiments, where the compounds of the invention have Formula Ha, lib, Ile, Ild, or Ile, Lis 0.
In some ments, where the compounds of the ion have Formula Ila, Ilb, IIc, lid, or Ile, L is NR,i.
In some embodiments, where the compounds of the invention have Formula Ila, lib, Ile, lid, or Ile, R3 is H.
In some embodiments, where the compounds of the invention have Formula Ila, Ilb, Ile, lid, or Ile, R2 is CF3 and R3 is H.
In some embodiments, where the compounds of the ion have Formula Ila, lib, Jic, lid, or Ile, R1 is I-I or C1.10 alkyl.
In some embodiments, where the compounds of the invention have Formula Ila, Ilb, Ile, IId, or Ile, RA is Cy1• In some embodiments, where the nds of the invention have Formula Ila, Ilb, lie, IId, or lie, 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 Rey.
In some ments, where the compounds of the invention have Formula Ila, IIb, Ile, lid, or Ile, RA is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from ReY.
In some embodiments, where the compounds of the in vention have Formula Ila, lib, Ile, Jid, or Ile, RA is 5 to 6-membered aryl optionally substituted by 1, 2, or 3 substituents independently selected from RC)'.
In some embodiments, where the compounds of the invention have Formula Ila, Ilb, Ile, Ild, or Ile, RA is C6-l0 aryl optionally substituted by 1, 2, or 3 substituents independently selected from Re�,.
In some embodiments, where the compounds of the invention have Formula Ila, lib, Ile, Ild, or Ile, RA is phenyl optionally substituted by 1, 2, or 3 tuents independently selected from ReY.
In some embodiments, where the compounds of the invention have Formula Ila, Ilb, Ile, IId, or Ile, R8 is Cy2.
In some embodiments, where the compounds of the invention have Formula Ila, Ilb, He, Ild, or Ile, R8 is H, halo, C1-6 alkyl, C2.6 alkenyl, C1-6 haloalkyl, CN, 0Ra3, C(O)NRc3Rd3, or a3, 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, N02, 0Ra3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)OR83, OC(O)Rb3, OC(O)NRc3R<l 3, NRc3Rd3, O)Rb3, NRc 3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc1S(0)2Rb3, NRc3S(0)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3• In some embodiments, where the compounds of the invention have Formula Ila, lib, Ile, IId, or Ile, Re is H.
In some embodiments, where the compounds of the invention have Formula Ila, Ilb, lie, Ild, or He, R0 is H.
In some embodiments, where the nds of the invention have Formula Ila, Ilb, Ile, Ild, or Ile, R5 is H.
In some embodiments, where the compounds of the ion have Formula Ila, Ilb, Ile, Ild, or lie, R6 is H.
In some embodiments, the nds of the invention have Formula Illa or Illb: O'YYN R �YN Illa In some embodiments, where the compounds of the invention have Formula Illa or Illb, R2 is CF3.
In some embodiments, where the compounds of the invention have Formula Illa or IIIb, R1 is Hor C1-10 alkyl.
In some embodiments, where the compounds of the invention have Formula Ula or IIIb, RA is cyl.
In some embodiments, where the compounds of the invention have Formula Illa or Illb, RA is Cs.m aryl or 5-10 membered heteroaryl, each of which is optionally substituted by I, 2, 3, 4, or 5 substituents ndently selected from RcY.
In some embodiments, where the compounds of the invention have a Illa or Illb, RA is 5�10 ed heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RcY.
In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, RA is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the nds of the invention have Formula Ula or lllb, RA is C6.10 aryl optionally substituted by 1 , 2, or 3 substituents independently selected from RcY.
In some embodiments, where the compounds of the invention have Formula IIIa or Illb, RA is phenyl ally substituted by 1, 2, or 3 substituents independently selected from RcY.
In some embodiments, where the compounds of the invention have Formula Illa or Illb, RB is Cy2.
In some ments, where the compounds of the invention have Formula Illa or IIIb, R8 is H, halo, C1.6 alkyl, C2.6 alkenyl, C1.6 kyl, CN, OR83, C(O)NRc3Rd3, or C(O)OR83, n said C1.6 alkyl and C2-6 l are each optionally substituted with 1, 2, or 3 tuents independently selected from halo, Ct-6 haloalkyl, CN, N02, OR83, SRa3, C(O)Rb3, C(O)NRc3R<l 3, C(O)OR83, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc1S(0)2Rb3, NRc3S(0)2NRc3Rd3, S(O)Rb3, S(O)NRc3R<l3, S(0)2Rb3, and S(0)2NRc3R<l3• In some embodiments, where the compounds of the invention have Formula Illa or Illb, Re is H.
In some embodiments, where the compounds of the invention have Formula Illa or IIIb, R0isH.
In some embodiments, the compounds of the invention have Formula IV: 0 I In some ments, where the compounds of the invention have Formula IV, R2 is In some embodiments, where the compounds of the invention have Formula IV, R1 is H or C1.10 alkyl.
In some embodiments, where the compounds of the invention have Formula IV, RA is Cy1• In some embodiments, where the compounds of the invention have Formula IV, RA is C6.
Io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RcY, In some embodiments, where the compounds of the invention have Formula IV, RA is 5- membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RcY.
In some embodiments, where the compounds of the ion have Formula IV, RA is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RcY.
In some embodiments, where the compounds of the invention have Formula IV, RA is CG- aryl optionally tuted by 1, 2, or 3 substituents independently selected from RcY.
In some ments, where the compounds of the invention have Formula IV, RA is phenyl ally substituted by 1, 2, qr 3 substituents independently selected from Rey.
In some embodiments, where the compounds of the invention have Formula IV, R8 is cy2.
In some embodiments, where the compounds of the invention have Formula IV, RB is H, halo, Ct-6 alkyl, C2-6 alkenyl, C1.6 haloalkyl, CN, 0Ra3, C(O)NRc3Rd3, or C(O)OR33, wherein said Ct-6 alkyl and C2-6 alkenyl are each optionally substitu ted with 1 , 2, or 3 substituents independently selected fr om halo, Ct-6 haloalkyl, CN, N02, OR83, SRa3, 3, C(O)NRc3Rd3, C(O)OR33, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRctS(0)2Rb3, 0)2NRc3Rd3, 3, S(O)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3• In some embodiments, where the compounds of the invention have Formula IV , Re is H.
In some embodiments, where the compounds of the invention have Formula IV; R0 is H.
In some embodiments; the compounds of the invention have Formula Va: In some embodiments, where the compounds of the invention have Formula Va, R2 is In some embodiments, where the compounds of the invention have a Va, R1 is H or C1-10 alkyl.
In some embodiments, where the compounds of the invention have Formula Va, RA is In some embodiments, where the nds of the invention have Formula Va, RA is C6. ro aryl or 5-10 membered aryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RcY.
In some embodiments, where the nds of the invention have Formula Va, RA is 5- membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RcY.
In some embodiments, where the compounds of the invention have Formula Va, RA is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RcY.
In some embodiments, where the compounds of the invention have Formula Va, RA is C6. aryl optionally substituted by 1 , 2, or 3 substituents independently selected from Rcy.
In some embodiments, where the nds of the invention have Formula Va, RA is phenyl optionally tuted by 1, 2, or 3 tuents independently selected from RcY.
In some ments, where the compounds of the invention have Formula Va, R8 is Cy', In some ments, where the compounds of the invention have Formula Va, R8 is H, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, OR03, C(O)NRc3Rd3, or C(O)OR33, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substitu ents independently selected from halo, C1-6 haloalkyl, CN, N02, OR03, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)OR13, NRc3C(O)NRc3Rct 3, NRc3S(O)Rb3, NRc1S(0)2Rb3, NRc3S(0)2NRc3Rd3, 3, S(O)NRc3R<l3, S(0)2Rb3, and S(0)2NRc3Rd3.
In some embodiments, the compounds of the invention have Formula Vb: In some embodiments, where the compounds of the invention have Formula Vb, R2 is CF3.
In some embodiments, where the compounds of the invention have Formula Vb, R1 is H or C1-10 alkyl.
In some embodiments, where the compounds of the invention have Formula Vb, RA is In some embodiments, where the compounds of the invention have Formula Vb, R'\ is C6- 10 aryl or 5-10 ed heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from Re>'.
In some ments, where the compounds of the invention have Formula Vb, RA is 5- membered heteroaryl ally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RC}'.
In some embodiments, where the compounds of the invention have a Vb, RA is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from Rey.
In some embodiments, where the compounds of the invention have Formula Vb, RA is C6- aryl optionally substituted by 1, 2, or 3 substituents independently selected from Rey.
In some embodiments, where the compounds of the invention have Formula Vb, RA is phenyl optionally substituted by 1, 2, or 3 substituents ndently selected from RC}·.
In some embodiments, where the compounds of the ion have Formula Vb, R8 is cy2.
In some embodiments, where the compounds of the invention have Formula Vb, R8 is H, halo, Ct-6 alkyl, C2-6 alkenyl, Cr-6 haloalkyl, CN, 0Ra3, C(O)NRc3Rd3, or C(O)ORaJ, wherein said Ct-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 tuents independently selected from halo, C1-6 haloalkyl, CN, N02, OR83, SR83, C(O)Rb3, C(O)NRc3Rd3, C(0)0Ra3, OC(O)Rb3, OC(O)NRC3Rd3, NRC3Rd3, NRC3C(O)Rb3, NRC3C(O)ORa3, NRc3C(O)NRc3Rrl 3, NRc3S(O)Rb3, NRc1S(0)2Rb3, NRc3S(0)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rrl 3, S(0)2Rb3, and S(0)2NRc 3Rd3.
In some embodiments, the compounds of the invention have Formula VI: Re lB � NH RD ( I � OYYN µ R2 NYN 8 NR13R14 VI.
In some embodiments, where the compounds of the ion have Formula VI, R2 is In some embodiments, where the nds of the invention have Formula VI, RI is I-I or Ci.ro alkyl.
In some embodiments, where the compounds of the invention have Formula VI, R8 is In some embodiments, where the compounds of the invention have Formula VI, Cy2 is phenyl optionally substituted by 1, 2, or 3 substituents ndently selected from RcY.
In some ments, where the compounds of the invention have Formula VI, R8 is H, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 kyl, CN, OR83, C(O)NRc3Rd3, or C(O)ORa3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with l, 2, or 3 substituents independently selected from halo, C1-6 haloalkyl, CN, N02, 0Ra3, SR03, C(O)Rb3, C(O)NRc3Rd3, C(O)OR03, b3, OC(O)NRc3Ra3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)OR33, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc1S(0)2Rb3, NRc3S(0)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3• In some embodiments, where the compounds of the invention have a VI, Re is H.
In some embodiments, where the nds of the invention have Formula VI, R0 is H.
In some embodiments, the compounds of the invention have Formula VIA: VIA.
In some embodiments, where the compounds of the invention have Formula VIA, R2 is In some embodiments, where the compounds of the invention have Formula VIA, R1 is H or C1.10 alkyl.
In some embodiments, where the compounds of the ion have Formula VIA, RB is Cy2.
In some ments, where the compounds of the invention have Formula VIA, Cy2 is phenyl optionally substituted by 1, 2, or 3 substituents ndently selected from Rey.
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, OR83, 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 ndently selected from halo, C1-6 haloalkyl, CN, N02, OR03, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, O)ORa3, O)NRc3Rd3, NRc3S(O)Rb3, NRc1S(0)2Rb3, 0)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3• In some embodiments, the compounds of the invention have a VII: wherein a is 0, 1, 2, or 3.
In some embodiments, where the compounds of the invention have Formula VII, R2 is CF3.
In some embodiments, where the compounds of the invention have Formula VII, R1 is H or C1-10 alkyl.
In some embodiments, where the compounds of the invention have Formula VII, R13 is Cy2.
In some embodiments, where the compounds of the invention have Formula VII, R8 is H, halo, C1-6 alkyl, C2-6 l, C1-6 haloalkyl, CN, 0Ra3, C(O)NRc3R<l 3, or C(O)ORa3, wherein said Ct-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ct-6 haloalkyl, CN, N02, ORaJ, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc 3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)OR33, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc1S(0)2Rb3, NRc3S(0)2NRc3Rd3, S(O)Rb3, c3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3.
In some embodiments, where the compounds of the invention have Formula VII, R13 is H or halo.
In some embodiments, where the compounds of the invention have Formula VII, R8 is halo.
In some embodiments, where the compounds of the invention have Formula VII, Re is H.
In some ments, where the compounds of the invention have Formula VII, R0 is H.
In some embodiments, where the compounds of the invention have Formula VII, Rey is halo, Ct-6 alkyl, C1-6 kyl, 4-10 membered heterocycloalkyl, CN, N02, 0Ra5, SRas, C(O)Rb5, C(O)NRc5Rd5, a5, 5, S(0)2Rb5, and S(0)2NRc5Rd5, wherein said C1-6 alkyl and 4- membered cycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, CN, N02, 0Ra5, SRa5, C(O)Rh5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRcsc(O)NRcsRds, NRcss(O)Rbs, NRcss(0)2Rbs, NRcsS(0)21\TRcsRds, S(O)Rbs, S(O)NRcsRds, S(0)2Rb5, and S(0)2NRc5Rd5.
In some embodiments, the compounds of the invention have Formula VIII: VIII wherein a is 0, 1, 2, or 3.
In some embodiments, where the compounds of the invention have Formula VIII, R2 is In some embodiments, where the compounds of the invention have Formula VIII, R1 is H or C1-10 alkyl.
In some embodiments, where the nds of the invention have Formula VIII, R8 is In some embodiments, where the compounds of the invention have Formula VIII, R8 is H, halo, C1-6 alkyl, C2-6 alkenyl, Ct-6 haloalkyl, CN, 0Ra3, C(O)NRc3Rd3, or C(0)0Ra3, 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, N02, 0Ra3, SRll3, C(O)Rb3, c3Rd3, C(O)OR83, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)OR33, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc1S(0)2Rb3, NRc3S(0)2NRc3Rd3, S(O)Rb3, S(O)NRc 3Rd3, b3, and \TRc 3Rd3.
In some embodiments, where the compounds of the invention have a VIII, R8 is H or halo.
In some embodiments, where the nds of the invention have Formula VIII, R8 is halo.
In some embodiments, where the nds of the invention have Formula VIII, Re is In some embodiments, where the compounds of the invention have Formula VIII, RO is H.
In some ments, where the compounds of the invention some embodiments have Formula VIII, Rey is halo, C1-6 alkyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, CN, N02, 0Ra5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, NRc5Rd5, S(0)2Rb5, and Rc5Rd5, wherein said C1-6 alkyl and 4-10 membered heterocycloalkyl are each ally substitu ted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, CN, N02, OR115, SR05, C(O)Rb5, C(O)NRcsRc15, C(O)OR35, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)OR35, O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(0)2R05, NRc5S(0)2NRc5Rc15, S(O)Rb5, S(O)NRc5Rct 5, S(0)2Rh5, and S(0)2NRc5Rd5• In some embodiments, where the compounds of the invention have Formula VIII, a is 0.
In some embodiments, the chiral carbon to which -C(O)OR1 is att ached has an S config uration.
In some embodiments, the carbon to which -R2 is attached is chiral and has an R config uration.
It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be ed in combination in a single embodiment. Conversely, various features of the invention which are, for brevity , described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.
The term ituted" 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 by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. The term "optionally substituted" means tituted or substituted. The substituents are ndently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. Throughout the definitions, the term "Ci/ indicates a range which includes the endpoints, wherein i and j are integers and indicate the number of carbons. es include C1.4, C1-6, and the like.
The term bered" where n is an integer typically describes the number of ringforming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an e of a 5- membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, an d 1, 2, 3, 4- tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
At various places in the present specifi cation vari ous aryl, hetercaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specifi ed, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term "a ne ring" or "pyridinyl" may refer to a pyridinyl, pyridinyl, or pyridinyl ring.
For compounds of the invention in which a variable appears more than once, each vari able can be a different moiety independently selected from the gro up defi ning the variable.
For example, where a structure is bed having two R grou ps that are simultaneously present on the same nd, the two R groups can represent different moieties ndently selected from the group defi ned for R.
As used herein, the term "Ci.] alkyl," employed alone or in combination with other terms, refers to a saturated hydroc arbon group that may be straight-chain or bran ched, having i to j carbon atoms. In some embodiments, the alkyl group contains from 1 to 10, 1 to 6, 1 to 4, or from 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not d to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl.
As used herein, the term "Ci-j alkoxy," employed alone or in combination with other terms, refers to a group of formula alky l, wherein the alkyl group has i to j carbon atoms. e 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.
As used herein, 11Ci-j alkenyl" refers to an alkyl group having one or more double carboncarbon bonds and having i to j carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6 or to 2 to 4 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, nyl, sec-butenyl, and the like.
As used herein, the term "Ci-j alkylamino" refers to a group of a -NH(alkyl), wherein the alkyl group has i to j carbon atoms. In some ments, the alkyl group has 1 to 6 or l to 4 carbon atoms.
As used herein, the term "di-Crj-alkylamino" refers to a gro up of formula -Ntalkylji, wherein the two alkyl groups each has, independently, i to j carbon atoms. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "thio" refers to a group of formula -SH.
As used herein, the term "Ci-j alkylthio" refers to a group of formula -S-alkyl, wherein the alkyl gro up has i to j carbon atoms. In some embodiments, the alkyl grou p has 1 to 6 or 1 to 4 carbon atoms.
As used , the term "amino" refers to a group of formula -NH2.
As used herein, the term II Ci-j aryl," employed alone or in combination with other terms, refers to a clic or polycyclic (e.g., having 2, 3 or 4 fused rin gs) aromatic hydrocarbon having i to j ring-forming carbon atoms, such as, but not limited to, phenyl, l-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.
As used herein, the term lkyl II refers to a group of formula -Ci-j alkyl-(Ci-j aryl). In some embodiments, arylalkyl is C6-IO aryl -Ci.i alkyl. In some embodiments, arylalkyl is C6-10 aryl-Ci.a alky l. In some embodiments, arylalkyl is benzyl.
As used herein, the term "carbonyl," employed alone or in combination with other terms, refers to a -C(:=0)- group.
As used herein, the term xy'' refers to a group of formula -C(=O)OH.
As used , the term 11C.i cycloalkyl," employed alone or in combination with other terms, refers to a non-aro matic cyclic hydro carbon moiety having i to j ring-forming carbon atoms, which may optionally contain one or more alkenylene groups as part of the ring structure.
Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems. Also included in the definition of lkyl 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 lkyl group includes a fused aromatic ring, the cycloalkyl group can be attached at either 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 linkages. In some embodiments, cycloalkyl is C3.10 or C3.7 cycloalkyl, which can be monocyclic or clic. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, exyl, cycloheptyl, cyclopentenyl, cyclohexenyl, exadienyl, eptatrienyl, norbornyl, norpinyl, norcarnyl, adamantany l and the like. In some embodiments, the cycloalkyl group is cyclopro pyl, cyclobuty l, cyclopenty l, or cyclohexyl.
As used herein, the term a1kylalk y1" refers to a group of formula -Ci-j alkyl-(Ci-j cycloalkyl). In some ments, cycloalkylalkyl is C3.7 cycloalkyl-Cr.i alkyl, wherein the cycloalkyl portion is monocyclic. In some embodiments, cycloalkylalkyl is C3.7 cycloalkyl-Ci.s alkyl.
As used herein, "Ci-j haloalkoxy" refers to a group of formula haloalkyl having i to j carbon atoms. An example haloalkoxy group is OCF3. An additional example haloa1koxy gro up is OCHF2. In some embodiments, the alkyl group has 1 to 6 or l to 4 carbon atoms.
As 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 ments, the halo gro up is F.
As used herein, the term "C-j haloalkyl," employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+ 1 halogen atoms which may be the same or different, where "s" is the number of carbon atoms in the alkyl gro up, wherein the alkyl group has i to j carbon atoms. In some ments, the haloalkyl group is fl thyl, difl uoromethyl, or oromethyl, In some embodiments, the haloalky l group is trifl uoro methyl.
In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "heteroaryl," employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fu sed rings) aromatic moiety, having one or more hetero atom ring members selected from nitrogen, sulfur an d 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 s independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl ring, which is clic and which has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. When the heteroaryl group contains more than one 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. e heteroaryl groups e, but are not limited to, pyridine, pyrimidine, pyrazine, pyrid azine, pyrrole, pyrazole, azolyl, oxazole, thiazole, imidazole, furan, thiophene, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole, imidazo[l ,2-b]thiazole, puri ne, and the like.
A 5-membered heteroaryl is a hetero aryl group having fiv e ring-forming atoms comprising carbon and one or more (e.g., 1, 2, or 3) ring atoms independently selected from N, 0, and S. Example fiv e-membered heteroaryls include thienyl, furyl, yl, imidazolyl, thiazolyl, oxazolyl, lyl, 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.
A six-membered heteroaryl is a heteroaryl group having six rin ing atoms n one or more (e.g., 1 , 2, or 3) ring atoms are independently selected from N, 0, and S. Example six-membered heteroaryls include pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
As used herein, the term "heteroaryla lkyl" refers to a group of formula -Ci·j alkyl- (heteroaryl). In some embodiments, heteroarylalkyl 5-10 membered heteteroaryl-Ci. , alkyl, wherein the heteroaryl portion is monocyclic or ic and has 1, 2, 3, or 4 heteroatom ri ng members independently selected from en, sulfur and oxygen. In some embodiments, the heteroarylalkyl is 5-6 membered heteteroaryl-Ci.i alkyl or 5-6 ed heteteroaryl-Ci.a alkyl, wherein the heteroaryl portion is monocyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfu r and oxygen.
As used herein, the term "heterocycloalkyl," employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which optionally contains one or more alkenylene groups as part of the ring structure, and which has at least one heteroatom ring member independently ed from nitrogen, sulfur and oxygen. When the cycloalkyl groups ns more than one heteroatom, the heteroa toms may be the same or different.
Heterocycloalkyl groups can include mono- or clic (e.g., having 2, 3 or 4 fused rings) ring systems, 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 can be attached at either an atom in the aromatic or non-aromatic portion. The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized (e.g. have one or two oxo substituents) to form a carbonyl, or sulfonyl group (or other oxidized linkage) or a nitrogen atom can be nized. In some embodiments, the heterocycloalkyl group is 5- to I 0- l O membered, which can be monocyclic or bicyclic and which has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfu r and oxygen. In some embodiments, the cycloalkyl group is 5- to 6-membered or 5- to 7-membered. es of hetero cycloalkyl groups include 1, 2, 3, 4-tetrahydroq uinoline, dihydrobenzofuran, azetidine, e, pyrrolidine, piperidine, pipera zine, morpholine, thiomorpholine, and pyran. Furt her examples of hetero cycloalk yl gro ups include 2-oxotetrnhydrofuranyl, 2-oxopyrrolidinyl, 2-oxoimidazolidinyl, 1-oxo-1,2,3,4-tetra hydroi soquinolinyl, and 2-oxo-1,3-dioxolanyl.
As used herein, the term "heterocycloalkylalkyl" refers to a group of formula+Csj alk yl­ (heterocycloalkyl). In some embodiments, heterocycloalkylalkyl is 5-10membered heterocycloalkyl-Ci., alkyl or 5-10 membered heterocycloalkyl-Ci.a alkyl, wherein the heterocycloalkyl n is clic or bicyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from ni trogen, sulfur and oxygen. In some embodiments, heterocycloalkylalkyl is 5-6 ed heterocycloalkyl-Ci.a alkyl wherein the heterocycloalkyl portion is monocyclic and has 1, 2, 3, or 4 heteroatom ri ng members independently selected from nitrogen, sulfu r and oxygen.
The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as omers and diastereoisomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in lly active or racernic forms. Methods on how to prepare lly active forms from optically inactive starting materials are known in the mt, such as by resolution of ra cemic mixtures or by stereoselective sis. Many geometri c isomers of olefins, C:=:: N double bonds, and the like can also be present in the nds described herein, and all such stable isomers are contemplated in the present ion. Cis and trans geometric isomers of the compounds of the present invention may be isolated as a mixture of isomers or as separated isomeric forms.
Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization s 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 P-camphorsulfonic acid.
Other resolving agents suitable for fractional crystallization s include stereoisomerically pure forms of c-rnethylbenzylamine (e.g., Sand R forms, or reoisomerically pure forms), 2-phenylglycinol, edrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.
Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.
Compounds of the ion can also include tautomeric forms. Tautomeric forms result fr om the swapping of a single bond with an adjacent double bond together 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 JH-imidazole, 1H-, 2H- and 4H­ l , 2, azole, 1H- and 2H- isoindole, and 1H- and 2H-pyra zole.
Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or fi nal compounds. Isotopes e those atoms having the same atomic number but different mass numbers. For example, isotopes of hydro gen e m and deuteri um.
The term "compound," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the stru ctures depicted. Compounds herein identifi ed by name or stru cture as one ular eric form are intended to e other tautomeric forms unless otherwise specifi ed. nds herein identifi ed by name or stru cture without specifying the particular uration of a stereocenter are meant to encompass all the possible configurations at the stereocenter, For example, if a ular stereocenter in a compound of the invention could be R or S, but the name or structure of the nd does not designate which it is, than the stereocenter can be either R or S.
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.
In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By "substantially ed" is meant that the compound is at least partially or substantially separated from the nment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds of the invention.
Substantial separation can e itions 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 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof.
Methods for isolating compounds and their salts are routine in the art.
The phr ase "pharmaceutically acceptable" is ed herein to refer to those compounds, materi als, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irri tation, ic response, or other problem or complication, surate with a reasonable benefit/risk ratio.
The expressions, "ambient tempera ture" and "ro om temperature," as used herein, are understood in the art, and refer genera lly to a ature, e.g., a reaction tempera ture, that is about the tempera ture of the ro om in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C.
The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used , aceutically accepta ble salts" refers to deri vatives of the disclosed nds wherein the parent compound is modifi ed by convert ing an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, minera l or organic acid salts of basic residues such as ami nes; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorgani c or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be ed by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, EtOAc, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (CH3CN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17111 Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J Phann. Sci., 1977, 66(1), 1-19, and in Stahl et al., ok of Pharmaceutical Salts: ties, Selection, and Use, (Wiley, 2002).
The below Table is a key to some abbreviations used throughout.
Abbreviations atm atmosphere BOC tert-butyl-oxy-carbonyl CAS# Chemical Abstra ct Service registry number CBS Corey-Bakshi-Shibata (catalyst) CH3CN Acetonitrile CBZ Carbobenzyloxy DIPEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DME ylether DMF dimethyl ide dppf l , l '-bis(diphenylphosphino)ferrocene EDCI 1-ethyl(3-dimethylaminoprop yl)carbodiimide hloride ee enantiomeric excess EtOAc ethyl acetate h hour(s) min minute(s) HOAT I-hydroxyazabenz otri azole HOAc acetic acid HPLC high-performance liquid chromatography KO Ac potassium acetate LAH lithium aluminum hydride LDA lithium diisopropylamide mCPBA 3-meta-chloroperoxybenzoic acid MeOH Methanol MS mass spectrometry MTBE methyl t-butyl ether NH40H ammonium hydroxide NMP 1-methylpyrrolidone PAH pulmonary arterial hypertension PE petroleum ether PheOH alanine hydro xylase Prep-TLC ative thin-layer chromatography p-TSA para-toluene sulfonic acid RT room temperature SNAr nucleophilic aromatic substitution TBAF tetrabutylammonium fluoride tBuOH tert-butanol TBTU O-(benzotriazolyl)-N N1-tetramethyluronium tetrafluoroborate TEA Triethylamine TFA trifl uoroacetic acid TH tyrosine hydroxylase TI-IF Tetrahydrofura n TLC thin-layer chr raphy TMS Trimethylsilyl TMSI Trimethylsilyl iodide TPH tryptophan hydroxylase Synthesis Procedur es for making compounds described herein are provided below with reference to Schemes 1-10. Optimum reaction conditions and on times may vary depending on the particular reactants used. Unless otherwise specifi ed, solvents, temperatures, pressures and other reaction conditions are readily selected by one of ordinary skill in the art. Specific procedures are ed in the Examples section. Compounds are named using the "structure to name" function ed in ChemDraw® v.12 (Perkin-Ebner).
Typically, on progress may be monitored by thin layer chromatography (TLC) or HPLC-MS if desired. Intermediates and ts may be ed by chromatography on silica gel, recrystallization, HPLC and/or reverse 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 avoid their unwanted 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 afford compounds of Formula I. The protecting groups depicted in the schemes are used as examples, and may be replaced by other compatible alternative . Starting materials used in the following schemes can be purchased or prepared by methods described in the chemical literature, or by adaptations thereof, using s kn own by those skilled in the art. The order in which the steps are performed can vary depending on the protecting or onal groups introduced and the ts and reaction conditions used, but would be apparent to those skilled in the art.
Compounds of Formula I can be prepared as shown in genera l in Scheme 1. Briefl y, in step 1, an alcohol (where the ring substituted by RA, R8, Re, R0 corresponds to ring A of Formula I) (see, e.g., Intermediate 1) in dioxane is treated with a dichloro heterocycle (e.g., 2- amino-4,6-dichloropyrimidine) in the presence of a base (e.g., Cs2C03), and heated for several hours (e.g. 12-24 h) at refl ux. In step 2, a spiro cycle of formula B (e.g., benzyl 3-ethyl 2,8- diazaspiro[4.5]decane-2,3-dicarboxylate) is added to a solution of nd A in a solvent (e.g., dioxane) in the presense of a base (e.g, ), and heated to reflux to provide a compound of formula C. In step 3, the amino pro g gro up (P) (e.g. CBZ or BOC) of a compound of formula C is removed (e.g. with TMSI, tra nsition metal-catalyzed hydrogenation, or strong acid depending on the nature of the pro tecting group). In step 4 , a compound of formula D is obtained by ester hydrolysis (e.g. with LiOH in aqueous THF). In some instances, the sequence of steps 3 and 4 can be reversed.
Step 2 P = amino protecting group (e.g. CBZ or BOC) Steps 3 & 4 Scheme 1 Alcohols (e.g., Intermediate 1) used in Scheme 1 can be prepared as shown in Scheme 2.
Briefly, in step 1, to a solution of base (e.g. potassium t-butoxide) in a solvent (e.g. DMSO) is added 3-methyl pyrazole and an aryl bromide E (e.g., l,4-dibromo:fluorobenzene), and the mixture is heated for several hours (e.g. 12-24 h) to provide a nd of formula F. In step 2, a compound of formula F is treated with a a Grignard t (e.g., Cl) in a solvent (e.g., THF), then reacted with ethyl trifluoroacetate in a solvent (e.g., THF) to provide a ketone of formula G.
Alternatively, a ketone of formula G can be obtained by treating first a fluoro aromatic compound of formula El with a strong base (e.g., LDA), then trapping the intermediate aryl lithium with trifluoroacetic acid ethyl ester to give a compound of a Fl (Step la). In a subsequent step 2a, 3-methyl pyra zole can be introduced onto a ketone of formula Flvia an SNAr reaction in the presence of base (e.g., K2C03) under solvent reflu x (e.g., toluene). In step 3, a ketone of formula G is converted specifi cally into a chiral alcohol of formula H via either chiral tra nsfer hydrogenation (e.g., with potassium formate) in the ce of a tra nsition metal catalyst (e.g., pentamethyl entadienyl iridium (III) chloride dimer) and a chiral ligand (e.g., (1R,2R)-(-)-N-(4-toluene sulfonyl)-1,2-diphenyl ethylene e) in a solvent (e.g., acetonitrile), or alternatively with a borane reagent (e.g. catechol ) and a chiral catalyst (e.g. (S)methyl-CBS oxazaborolidine) in a solvent (e.g., THF). Alternatively, an alcohol of formula K can be made in a similar n 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., trimethy1(trifluoromethyl)silane) in the presence of a fluoride source (e.g., TBAF) in an inert solvent (e.g., THF).
Step 1a RB RA mplex" R-c ��)y� TBAF orCBS )/. 0 OH oxazaborolidine R0 cF Step tc Step 2c K Scheme2 Other types of oxygen or nitrogen linker groups (L-groups) can be installed as shown in Scheme 3. Briefly, in step 1, to a spirocyclic compound ofB (e.g., (S)benzyl 3-ethyl 2,8- diazaspiro[ 4.5]decane-2,3-dicarboxylate) in dioxane is added a di-halo heterocycle (e.g., 2- 4,6-dichloropyrimidine) in the pre sence of a base (e.g., Cs2C03) under solvent reflu x (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., Cs2C03). After heating at reflux for several hours (e.g., 12-24 h), a compound of formula Pis obtained. In step 3, the amino ting group (P) (e.g., CBZ or BOC) of a compound of formula Pis removed (e.g., with TMSI, transition metal-catalyzed hydrogenation, or acid). Then, in step 4, a compound of formula Q is obtained by ester hydrolysis (e.g., with LiOH in aqueous THF). In some instances, the sequence of steps 3 and 4 can be reversed.
L = 0 or NR4 Step 1 M (e:�;ABOC)P = protecting group )-_�R' Rc�LvW� (Jt,r�- _3_) T_M_S_l_o_r_H_2 _or_H_+_ RD R2 R3 II � X,y�N 4) UOH p Steps 3 & 4 Scheme 3 For certain tuents and substitution patterns, palladium-mediated coupling ons (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., s dioxane) is added a boronic acid or te (e.g.,phenyl boronic acid) in the presence of a ium catalyst (e.g., PdCh(dppt)­ CH2Ch) and a base (e.g., KHCOJ), and the mixture heated to refl ux 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)of 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 instances, the sequence of steps 2 and 3 can 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 a W or AA, respectively (Schemes 4b and 4c).
P = amino protecting group Step 1 (e.g. CBZ or BOC) ?<".:::::; NH 2) TMSI or H2 or W Rc_1 n 3) LiOH RA y Steps 2 & 3 Scheme 4a O RI BrorCl'?x (}1�-;r: Pd (cat) I � L w R8-8(0Hh or µNR2 R3 JI y X, �N u3 u Step 1 P = protecting group {e.g CBZ or BOC} 2) TMSl or H2 or W 3) UOH Steps 2 & 3 Scheme 4b P = amino ting group {e.g. CBZ or BOC) c?.o A OH 2} TMSI or H2 or W YYL11 WyN N R2 R3 X --N 3) LiOH Steps 2 & 3 "P -:: Scheme 4c Various substitutions of the central 6-membered ring (e.g., the ring containing W; X, and Y) can be accomplished as shown in Scheme 5. Briefly, in step 1, to a solution of a methyl e of formula AB in an inert t (e.g., CI-hCh) is added an oxidant (e.g., ).
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 a AC in a t (e.g., dioxane) is added a spirocyclic compound of formula B (e.g., (S)benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3- dicarboxylate) in the presence of a base (e.g., Cs2COJ), 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 saponifi ed (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., Cs2C03) for several hams (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.
Step 2 4) amine or alcohol ) TMSI or H2 or H+ Steps 4 & 5 Scheme 5 Ester group substituents can be introduced by the l method of Scheme 6. Briefly, in step 1, to a solution of an acid of formula AG in an inert solvent (e.g., CH2Ch) is added a coupling reagent (e.g., EDCI and DMAP), followed by an l (e.g., propanol) to provide a compound of formula AH. In step 2, the benzyl groups of the benzyl ester and of the N-CBZ group can be removed with reagents such as TMSI or by transition metal-catalyzed hydrogenation (e.g., H2 with Pd/C), affording a compound of formula Al. 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 the final deprotection.
Rb�OA cR-: Re A n R-OH o11 wyN TMSI or H2 RD R2 R3 I ------ EDCI, DMAP X,y�N [3) If N-P = BOC then H"] AG Step 1 AH Step 2 [& 3) P = amino protecting group (e.g. CBZ or BOC) \_�RA )-OH RcvJx,o w Ot1�" Ro R2 R3 II y X,y,:. N Scheme 6 Ethyl esters can be generally prepared according to Scheme 7. Briefly, deprotection of the amino group in a compound of formula AJ, can be accomplished either with the use of a lating agent (e.g., TMSI) or via transition metal-catalyzed hydrogenation (e.g., H2 with Pd/C) if the protecting group is CBZ, or with a strong acid (e.g., TF A or HCl), if the ting group is BOC, to provide AK. It will be recognized by those skilled in the art that many other protecting groups can be used alternatively (for example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)).
R�A :t: R' R ' :;:r RCVJxo w Ot1�- TMSI or H' Rc�o w Ot1�" R0 R2 R3 O "r ------ Ro R2 R31 r x ...Y�N Step 1 'y" AJ AK P :::: amino protecting group (e.g. CBZ or BOC) Scheme 7 Various esters can be made via direct alcohol ng to the acid, as shown in Scheme 8, or via alkylation of the acid, as shown in Scheme 9. Briefly, an amino acid of formula AL is dissolved in an alcoholic solvent (e.g., n-octanol), optionally in the presence of a co-solvent (e.g., toluene), and heated in the ce of acid (e.g., p-TSA) for l hours (e.g., 12-24 h), optionally in the presence of a water trapping material (e.g., molecular sieve) or apparatus (e.g., Dean-Stark trap) to produce an ester of formula AM. atively, in step 1, an acid of formula AN is dissolved in a t (e.g., DMF) in the presence of a base (e.g., K2C03) 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 (e.g., with an acid like TF A in an inert solvent such as CH2Ch in case of a BOC protecting gro up) provides an ester of formula AP. Other compatible deprotection methods apparent to those skilled in the art can be applied for other types of amino pro tecting groups.
Re"\/' L W �OHR'OH R'�L W �d � YI �Ro R2 R3 ----· RD R2 R3 Yi y X,y�NII I x W N AL Step 1 AM Scheme 8 Cl'R, Rc�L W �<ct- ---�- Ro R2 R3 II y K2C03 X,y�N AN Step 1 AO Step 2 Scheme 9 !-Butyl esters can be made via direct alcohol coupling to the acid, as shown in Scheme 10. Briefly, in step 1, an acid of formula AQ is dissolved in a t (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 a AR. In step 2, removal of the amino protecting group is achieved as described earlier to afford a compound of formula AS.
Step2 Scheme 10 A1ethods of Use The compounds of the invention can be used to inhibit the activity of the TPHl enzyme in a cell by contacting the cell with an inhibiting amount of a compound of the invention. The cell can be part of the tissue of a living organism, or can be in culture, or isolated from a living organism. Additionally, the nds of the invention can be used to inhibit the activity of the TPHI enzyme in an animal, individual, or patient, by stering an inhibiting amount of a compound of the ion to the cell, animal, individual, or patient.
Compounds of the ion can also lower eral 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, the compounds of the invention can lower levels of peripheral serotonin (e.g., 5-HT in the GI tract) selectively over non-peripheral serotonin (e.g., 5IT in the CNS). In some embodiments, the selectivity is 2-fold or more, 3- fold or more, 5-fold or more, 10-fold or more, SO-fold or more, or 100-fold or more.
As TPH1 inhibitors that can lower peripheral serotonin , the compounds of the invention are useful in the treatment and prevention of various diseases associated with abnormal expression 01· activity of the TPHl enzyme, or diseases associated with elevated or al periphera l serotonin levels. In some embodiments, the treatment or prevention includes administering to a patient in need thereof a therapeutically effective amount of a TPHl inhibitor of the invention.
Biological , some of which are described herein, can be used to determine the inhibitory effect of compounds against TPH (such as TPHI) in vitro and/or in vivo. In vitro biochemical assays for human, mouse, and rat TPHl and human TPH2, PheOH, and TH may be used to measure inhibition of enzyme activity and the ivity among TPHI, TPH2, PheOH, and TH. In addition, the efficacy of these compounds can be determined, for example, by measuring their effect on intestinal 5-HT levels in rodents after oral administration.
Diseases ble or preventable by administering a TPHI tor of the invention l O include bone disease such as, for example, osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, fractures, and bone metastasis. 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). 1 5 The present invention further includes methods of treating or preventing bone fracture such as, for example, osteoporot ic or traumatic fracture, or surgical fractures associated with an edic procedure (e.g., limb ening, bunion removal, an increase in bone formation associated with a prosthesis, bone metastasis, or spinal fusion).
Further es 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 also inclu ding PH associated with or bro ught on by other diseases or ions. In some embodiments, the PH disease is pulmonary arterial hypertension (PAH).
The types of PAH treata ble according to the methods of the invention include (1) idiopathic (IPAH) , (2) familial (FP AH), and (3) ated (AP AH ) which is the most common type of PAH. The latter is PAH which is associated with other medical ions including, for example, (1) collagen ar disease (or conn ective tissue disease) which include autoimmune diseases such as scleroderma or lupus; (2) congenital heart and lung diseas e; (3) portal hypertension (e.g., resulting fr om liver disease); (4) HIV infection; (5) drugs (e.g., appetite suppressants, cocaine, and amphetamines; (6) other conditions including thyroid disorders, glycogen storage disease, r disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myelopro1iferative disorders.and splenectomy. AP AH can also be PAH associated with abnormal narrowing in the pulmonary veins and/or capillaries such as in pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis. Another type of PAH is associatead with persistent ary hypertension of the newborn (PPHN).
Further diseases ble or preventable by the methods of the invention include metabolic diseases such as diabetes and hyperlipidemia; pulmonary 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's syndrome, pancreatic cholera me, pancreatic insufficiency , pheochromacytoma, scleroderma, zation disorder, Zollinger-Ellison Syndrome, or other gastrointestinal infl ammatory conditions; liver diseases such as chronic liver disease; cancers such as liver , breast cancer, cholangiocarcinoma , colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, and bone cancer (e.g., osteosarcoma, chrondrosarcoma, Ewings a, osteoblastoma, osteoid osteoma, osteochondro ma, dro ma, omyxoid fi broma, smal bone cyst, unicameral bone cyst, giant cell tumor, and bone tumors); blood diseases (e.g., myeoloproliferative syndrome, myelodysplastic syndrome, Hodgkin's lymphoma, dgkin's lymphoma, myeloma, and anemia such as aplastic anemia and anemia ted with kidney disease; and blood cancers (e.g., ias such as acute lymphocytic leukemia (ALL), c lymphocytic leukemica (CLL), acute myeloid leukemia (AML), and chronic myeloid ia (CML)).
The compounds of the invention are also useful in the treatment and prevention of sero tonin syndrome.
In some embodiments, the present invention includes methods of lowering plasma cholesterol, lowering plasma triglycerides, loweri ng plasma glycero l, lowering plasma free fatty acids in a patient by administering to said t a thera peutically effective amount of a compound of the invention.
The compounds of the invention are also usefu l in the treatment and prevention of infl ammatory disease, such as allergic airway infl ammation (e.g., asthma).
As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo or in vivo.
In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can 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.
As used herein, the term cting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" the enzyme with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having the TPHI enzyme, as well as, for example, introducing a compound of the invention into a sample containing a cellular or ed preparation containing the TPHlenzyme.
As used herein, the term idual" or "patient," used interchangeably, refers to any animal, ing mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
As used , the phrase "therapeutically effective amount" refers to the amount of active compound or ceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a cher, veterinarian, medical doctor or other clinician.
As used herein the term "treating" or "treatment" refers to l) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experi encing or ying the pathology or symptomatology of the disease, condition or disorder (i.e., arr esting furt her development of the pathology and/ or symptomatology), or 2) ameliora ting the disease; for e, ameliora ting a disease, condition or disorder in an individual who is experiencing or displaying the ogy or symptomatology of the e, condition or disorder (i.e., reversing the pathology and/or symptomatology).
As used herein the term "preventing" or "prevention" refers to inh ibiting onset or worsening of th e disease; for example, in an individual who may be predisposed to the e, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
Combination Therapv One or more additional pharmaceutical agents or ent s can be used in combination with the compounds of the present invention for treatment or prevention of various diseases, disorders or conditions disclosed 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.
Example pharmaceutical agents that may be useful in a combination y for blood disorders like blood cancers include parathyroid hormone, anti-sclerostin antibodies, kathepsin K inhibitors, and anti-Dickopff 1.
Example pharmaceutical agents that may be useful in a combination therapy for cancer e leuprolide, goserelin, buserelin, ide, nilutamide, ketoconazole, aminoglutethimide, mitoxantrone, estramustine, doxorubicin, etoposide, vinblastine, paclitaxel, carboplatin, and vinorelbine. ies that can be combined with TPH inhibition include radiation therapy, high- intensity d ultrasound, or y (e.g., removal of diseased tissues). Other drug s for use in treating cancer include testolactone, ozole, letroz ole, exemestane, vorozole, formestane, fadrozole, GnRH- analogues, temozolomide, ximab, cyclophosphamide, fluo rouracil, fulvestrant, gefi tinib, trastuzumab, IGF-1 antibodies, lapatinib, methotrexate, olapari b, BSI-201, pazopanib, rapamycin, ribavirin, sorafenib, sunitinib, tamoxifen, docetaxel, vatalinib, zumab, and octreotide.
Example pharmaceutical agents that may be usefu l in combination y for cardiovascular or pulmonary diseases e endothelin receptor antagonists such as ambrisentan, BMS-193884, bosentan, darusentan, SB-234551, sitaxsentan, tezosentan an d macitentan. agulants such as warfarin, acenocoumarol, phenprocoumon , phenindione, heparin, fondaparinux, argatroban, bivalirudin, lepirudin, and ximelagatran may also be useful in combination therapy. Pharmaceutical agents for combination y further e calcium channel blockers like amlodipine, felodipine, nicardipine, nifedipine, nimodipin e, nisoldipine, nitrendipine, lacidipine, lercanidipine, phenylalkylarnines, vera pamil, gallopamil, diltiazem, and menthol. Prostacyclins like epoprostenol, iloprost and treprostinil may also be combined with the TPH inhibitors of the invention. Further pharmaceutical agents for combination therapy in vascular or pulmonary diseases include PDE5 inhibitors like sildenafi l, tadalafi l, and vardenafil; diuretics like furo semide, ethacrynic acid, tora semide, bumetanide, hydrochlorothiazide, spironolactone, mannitol, nitric oxide or nitric oxide releasers, and soluble guanylate e stimulators, such as riociguat. Yet further pharmaceutical agents for combination therapy include APJ receptor agonists (WO 201 3 /1111 1O); IP receptor agonists (; ; ; ; ; ); and PDGF receptor tors ().
Example pharmaceutical agents that may be useful in combination therapy for metabolic disorders include HSL inhibitors such as those disclosed in International Patent Publications W02006/074957; W02005/073 l99; \.V02004/11 1031; W02004/111004; W02004/035550; W02003/051841; /051842; and W02001/066531.
Example pharmaceutical agents that may be useful in combination therapy for bone disorders and diseases include bisphosphantes such as nate, clodronate, tiludronate, pamidronate, neridronate, olpadronate, alendronate, ibandronate, risedronate, cimadronate, zoledronate, and the like. Serotonin receptor modulators, such as 5-HTts, S-HT2A, and 5-HT2B agonists or antagonists, may also be useful in combination thera py for bone disease. Other useful agents for combination y include selective serotonin reuptake tors (SSRI), anti-serotonin dies, and beta blockers such as IPS339, ICil 18,551, buta xamine, metipranolol, nadol, oxprenolol, penbutolol, pindolol, prop ranolol, timolol, and sotalol. Further useful agents for combination therapy for the treatment of bone disorders, such as orosis, include ratide, strontium ranelate, raloxifene, and denosumab.
Administration. Pharmaceutical Formulations. Dosage Forms The compounds of the ion can be administered to patients (animals and humans) in need of such treatment in riate dosages that will provide prophylactic and/ or therapeutic effi cacy. The dose required for use in the treatment or prevention of any particular disease or disorder will typically vary from patient to patient depending on, for example, particular compound or composition selected, the route of administra tion, the nature of the condition being treated, the age and ion of the patient, rent medication or l diets then being followed by the patient, and other factors. The riate dosage can be determined by the treating physician.
A compound of this invention can be administered , subcutaneously, topically, parenterally, by inhalation spra y or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration can involve subcutaneous injections, enous or intramuscular injections or infusion techniques.
Treatment duration can 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 can terminate when a d result, for example a particular therapeutic effect, is ed. Or a treatment period can be continued indefinitely.
In some embodiments, the pharmaceutical compositions can be prepared as solid dosage forms for oral stration (e.g., capsules, tablets, pills, dragees, powders, granules and the like). A tablet can be ed by compression or g. ssed tablets can 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, can include IO coatings, such as enteric coatings.
Compositions for inhalation or insuffl ation e solutions and suspensions in pharmaceutically acceptable aqueous or c solvents, or mixtures f, and s.
Liquid dosage forms for oral admin istra tion can include, for example, ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Suspensions can include one or more suspending agents Dosage forms for tra nsdermal administration of a subject composition e powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
Compositions and compounds of the present invention can be administered by aero sol which can be administered, for example, by a soni c nebulizer.
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 can be in the form of a sterile powder which can be reconstituted into a sterile able solutions or dispersion just prior to use.
The invention will be described in greater detail by way of specifi c examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any mann er. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modifi ed to yield essentially the same results. The compounds of the Examples were found to be tors ofTPHl as described below.
EXAMPLES The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. in the description of the tic methods described below, it is to be understood that. all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions rd for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not ible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are ore indicated. The starting materials for the examples are either commercially available or are readily prepared by rd methods from known materials. tH NMR Spectra were acquired on one or more of three instruments: (1) Agilent Unitylnova 400 MHZ spectrometer equipped with a 5 mm Automation Triple Broadband (ATB) probe (the ATE probe was aneously tuned to 1H, 19F and 13C); (2) Agilent Unitylnova 500 MHZ spectrometer; or (3) Varian Mercury Plus 400 MHz spectrometer. Several NMR probes were used with the 500 MHZ NMR spectrometer, ing both 3 mm and 5 mm 'H, 19F and 13C probes and a 3 mm X‘H19F NMR probe (usually 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 32768 complex points were ted during the 5.1 second acquisition time, and the recycle delay was set to 1 second. Spectra were collected at 25 °C. .H NMR Spectra were lly processed with 0.3 Hz line broadening and zero-filling to about 131072 points prior to Fourier transformation. Chemical shifts were expressed in ppm relative to cthylsilane. The following abbreviations are used herein: hr = broad signal, s = singlet, d = doublet, dd = double doublet, ddd = double double doublet, dt = double triplet, t = triplet, td = triple doublet, tt = triple t q = quartet, m = multiplet.
Liquid chromatography - mass spectrometry (LCMS) ments to determine retention times and ated mass ions were 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 pm, was used at a temperature of 50 °C and at a flow rate of 1.5 mL/min, 2 uL injection, mobile phase: (A) water with 0.1% formic acid and 1% itrile, mobile phase (B) MeOH with 0.1 % formic acid; retention time given in minutes. Method A details: (I) ran on a Binary Pump G13128 with UVNis diode array detector G13l5C and Agilent 6130 mass spectrometer in positive and negative ion electrospray mode with UV PDA detection with a gradient of 15-95% (B) in a 2.2 min linear gradient (II) hold for 0.8 min at 95% (B) (III) decrease from 95-15% (B) in a 0.1 min linear nt (IV) hold for 0.29 min at 15% (B); Method B: An Agilent Zorbax Bonus RP, 2.1 x 50 mm, 3.5 pm, was used at a temperature of 50 °C and at 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) ran on a Binary Pump with UV/Vis diode array detector G1315C and Agilent 6130 mas s spectrometer in positive and negative ion electro spray mode with UV-detection at 220 and 254 nm with a gradient of 5-95% (B) in a 2.5 min linear gradient (II) hold for 0.5 min at 95% (B) (III) decrease from 95-5% (B) in a 0.1 min linear gradient (IV) hold for 0.29 min at 5% (B).
Method C: An API 150EX mass spectrometer link ed to a Shimadzu LC-1OAT LC system with a diode array or was used. The spectrometer had an electrospray source operating in positive and negative ion mode. LC was carried out using an Agilent ZORB AX XDB 50 x 2.1 mm C18 column and a 0.5 ml/minute fl ow ra te. 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; 4.2�6.0 min: 2% solvent (B).
Microwave experiments were carried out using a Biotage Initiatort'", whi ch uses a single­ mode resonator and dynamic fi eld . Temperatu res from 40-250 °C were achieved, and pressures ofup to 20 bars were reached.
Preparative HPLC purifi cation was carried out using either a Cl8-reverse-phase column from Genesis (Cl 8) or a C6-phenyl column from enex (C6 Ph) (100 x 22.5 mm i.d. with 7 micron particle size, UV detection at 230 or 254 nm, flow 5-1 SmL/min), eluting with gradients from 100-0 to 0-100 % water/acetonitrile or water/MeOH containing 0.1%formic acid. Fra ctions containing the required product (identifi ed by LCMS analysis) were pooled, the c fraction removed by a tion, and the ing aqueous fraction lised, to give the product.
Chiral HPLC was d out using a Chiralpak AD column, 4.4 mm x 250 nun, particle size 5 micron Compounds which required column chromatography were purified manually or fully automatically using either a Biotage SPI™ Flash Purification system with Touch Logic Control™ or a Combiflash ion® with pre-packed silica gel !solute® SPE cartridge, Biotage SNAP cartridge or Redisep® Rf cartridge respectively. ation of alcohols and amines The chiral alcohols drawn below are shown in their absolute configuration (unless otherwise shown). Their enantiopurity (% ee) can be determined via Mosher ester is and analyzed as described in the literature (Dale, J. A. & Mosher, H. S. Nuclear Magnetic Resonance Enantiomer Regents. Configurational Correlations Via Nuclear Magnetic Resonan ce Chemical Shift s OfDiastereomeric Mandelate, 0-Methyhnandelate, and alpha-Methoxy alpha­ Trifl uoromethylphenylacetate (MTPA) Esters. J. Am. Chem. Soc. 95, 512-519 (1973)). The chiral alcohols of the invention are preferably enantiomerically enriched, for example, to 2: 95% Representative Mosher ester ation Toa solution of (R)(4-chloro(3-methyl-1 H-pyrazolyl)phenyl)-2,2,2- oroethanol (46 mg, 0.20 mmol, Intermediate 3) was added pyridine (138 mg, 1.7 mmol) fo1lowed by the addition of either (S or R)-u-methoxy-u-tri:fl uoromethyl-phenylacetyl chloride (10 mg, 0.40 mmol). The reaction was stirred for 12 h, then the material was purified ly on silica gel chromatogra phy (EtOAc/h eptane) to provide the "Mosher ester" which was analyzed by 1 H NMR for enantiomeric purity. ediate 1: (4-Bromo(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethanol Step 1: Potassium xide (16.3 g, 145 mmol) was ved 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-Dibromofluorobenzene (31 g, 120 mmol) was then added and the on stirred at 50 °C for 16 h. The on was cooled to RT and extracted with water and EtOAc, washed with brine, dried over Na2S04, and then filtered and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 1-(2,5- dibromophenyl)methyl-lH-pyrazole.
Step 2: -dibromophenyl)methyl-lH-pyrazole (23.0 g, 73 mmol) from Step 1 was dissolved in 200 mL ofTHF and cooled to O °C. i-Propyl magnesium chloride (2.0 MinTHF, 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 O °C, then 10% HCl is added dro pwise (400 mL). The reaction was extracted with water and EtOAc, washed with brine, dri ed over Na2S04, filtered , and then concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 1-(4-bro mo(3-methyl-lH-pyrazol-l-yl)phenyl)- 2,2,2-triflu oroethanone.
Step 3: METHOD A: Pentamethylcyclopenta dienyl iridium (III) chl oride dimer (CAS# 12354- 84-6) (10.4 mg) and (1R,2R)-(-)-N-(4-toluene sulfonyl)-1,2-diphenyl ethylene diamine (CAS# 1442224) (9.2 mg) were combined in water (120 ml.), then heated to 50 °C for 5 h to provide the "Iridium complex." 1-(4-Bromo(3-methyl-lH-pyra zolyl)phenyl]-2,2,2- trifluoroethanone (16 g, 48 mmol) was dissolved in acetonitrile (120 mL) to which the Ir idium complex and potassium formate (3.1 g, 3.7 mmol) were added. The reaction mixture was heated to 50 °C for 8 h. The reaction mixture was then cooled to RT, ioned n water and EtOAc, and extracted. The combined organic layers were washed with brine, dried over Na2S04, filtered , and concentrated in vacuo. Recrystallization from hot heptane (200 mL) provided the title compound.
METHOD B: Altern atively, the trifl uoro methyl (or other prochiral) ketones of formula G or J (scheme 2) were asymme tri cally reduced as follows (see for e: Corey, E. J. & Link, J. 0.
A General,Catalytic, and Enantioselective Synthesis of Alpha-amino Acids. J. Am. Chem. Soc. 114, 1906-1908 (1992)): ol borane (95 mL, 1 Min THF) and (S)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(3-methyl- lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethanone (16 g, 48 mmol) in THF (150 mL) was added dropwise over 2 h. The on was then warmed to -36 °C and held 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 wanned to O °C and H202 (30%, I00 mL) was added over 30 min, then warmed to RT for 4 h. The reaction mixture was quenched with 1 N NaOH, extracted with ether, washed with brine, dri ed over Na2S04, and IO concentrated in vacuo. cat ion on normal phase silica gel chromatography (EtOAc/heptane) provided the product as a viscous oil.
Intermediate 2: (R)(5-Bromo(3-methyl-lH-pyrazolyl)phenyl)-2,2,2- trifluoroethanol QifCF Br 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 Minhexanes, 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-bromofl uorobenz ene (5 g, 28.6 mmol) in THF (6.0 mL) was added, and the reaction was stirred at -78 °C for 1 h. Trifl uoro acetic acid ethyl ester (3.73 mL, 31.4 mmol) in THF (6.0 mL) was then added, an d the reaction was slowly warmed to O °C over an hour. The reaction was quenched with NH4Cl (aq. sat), and extracted with EtOAc, washed with brine, and dried over Na2S04, fi ltered, and concentrated ;,1 vacuo. Purifi cation by normal phase silica gel column tography (EtOAc/heptane) provided romofl enyl)-2,2,2-trifluoroe thanone.
Step 2: 1-(5-bromofl uorophenyl)-2,2,2-triflu oroethanone (2.20 g, 8.12 mmol) from Step 1, K2C03 (1.68 g, 12.2 mmol), and 3-methyl-lH-pyraz ole (I .33 g, 16.2 mmol) were stirr ed in toluene (IO 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 , filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided l-[5-bromo(3-methyl-pyrnzolyl)-phenyl]-2,2,2-trifluoroethanone.
Step 3: The title compound was prepared using the Iridium complex-catalyzed hydrogenation as bed for ediate 1, (R)(4-bromo(3-methyl-lH-pyrazol- l-yl)phenyl)-2,2,2- tritl uoroethanol.
Intermediate 3: (4-chloro(3-mcthyl-lH-pyrazolyl)phcnyl)-2,2,2-trifluorocthanol :0 CF CIA) Step I: Potassium /-butoxlde (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-Bro mochlorofl uorobe nzene (4.6 g, 0.22 mm ol) was then added and the reaction was stirr ed at 50 °C for 16 h. The reaction was cooled to RT and extracted with water and EtOAc, washed with brine, and dried over Na2S04, filtered and concentra ted in vacuo.
Purifi cation by normal phase silica gel column chromatogra phy (EtOAc/heptane) provided 1 -(2- bromochlorophenyl)methyl-1H-pyra zole and 1-(2-bro mochlorophenyl)methyl-lH­ pyrazole as a 4: 1 mixture that was used in the next step directly.
Step 2: The mixture from Step I (8 g, 0.39 mmol) was dissolved in 160 mL ofTHF and cooled to 0 °C. i-Propyl magnesium chlori de (2.0 MinTHF, 23 mL) was added dropwise and the on stirred for 45 min, then ethyl trifluoroacetate (6 mL) was added. The reaction was stirred for 30 min at O °C, then 10% HCl was added dropwise (40 mL). The reaction was extracted with water and EtOAc, washed with brine, and dried over Na2S04, filtere d, and concentrated in vacuo.
Purification by normal phase silica gel column tography (EtOAc/heptane) provided 1-(4- chloro(3-methyl-1 H-pyrazolyl)phenyl)-2,2,2-trifluoroethanone as a white solid.
Step 3: The title nd was prepared using the Iridium complex-catalyzed hydrogenation, as described for Intermediate 1 (R)(4-bromo(3-methyl-lH-pyrazolyl)phenyl)-2,2,2- trifluoroethanol.
Intermediate 4: (R)(5-chloro(2,2,2-trifl u orohydroxyethyl)phenyl)pyrrolidinone of) QF3 Cl�OH To a solution of (R)(4)-2,2,2-trifluoroethanol (300 mg, 1.04 mmol)in toluene (7 mL) was added pyrrolidinone (89 mg, 1.04 mmol), ( I N 1,N2-dimethylcyclohexane-1,2-diamine (74 mg, 0.52 mmol), Cul (50 mg, 0.26 mmol) and K2C03 (360 mg, 2.6 mmol). The reaction was heated in a sealed tu be to 130 °C for 12 hand then cooled to RT. The solids were filte red and the pro duct was purifi ed by normal phase silica gel chr omatography (EtOAc:petroleum ether) to to pro vide the title nd as a white solid.
Intermediate 5: (R)-2,2,2-Trifluoro(2-methyl-lH-benzo[d]imidazolyl)ethanol '>=N QF3 HN�(J Step 1: 4-Bromomethyl-IH-benzimidazole (500 mg, 2.37 mmol) was dissolved in THF (8 mL) and cooled to -78 °C. n-Butyllithium (2.3 ml., 2.5 Min hexanes, 5.7 mmol) was added dropwise and the reaction was stirr ed at -78 °C for 30 min. Trifl uoroacetic acid ethyl ester (339 µL, 2.8 mmol) was added and the reaction was stirred at O °C for 1 h. The reaction was quenched with HCI (2 N, 4 mL), then extra cted with water and EtOAc, washed with brine, dri ed over Na2S04, fil tered, and concentrated in vacuo. Purifi cation by normal phas e silica gel column chromatography (CH2Ch/M eOH/NH40H) provided 2,2,2-triflu oro-l-(2-methyl-lH­ benzoimidazo1y1)-ethanone.
Step 2: The title compound was prepared using the m complex-catalyzed hydrogenation, as described for Intermediate 1 (R)(4-bromo(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethanol.
Intermediate 6: 1-(4-Chloro(3-methyl-1H-pyrazolyl)phenyl)ethanol c,HoHQ Step 1: 1-(2-bromochlorophenyl)methyl-1 H-pyrazole/1-(2-bromochlorophenyl) methyl-1H-pyrazole e (Intermediate 3, step 1) (1.00 g, 3.68 mmol) was dissolved in THF (6 mL) and cooled to O °C. i-Propyl magnesium chloride (2.76 mL, 2.0 Min THF, 5.52 mmol) was added dropwise and allowed to warm to RT over 30 min. The reaction was then cooled to -15 °C. Acetyl chloride (481 µL, 5.5 mrnol) was added and the reaction was warmed to RT for 3 h. The reaction was ed with HCl (2 N, 4 mL), then extracted with water and EtOAc, washed with brine, and dried over Na2S04, fi ltered, and concentrated in vacuo. Purifi cation by normal phase silica gel column chromatogra phy (EtOAc/heptane) provided 1-[4-chloro(3- methyl-pyra zol-l-yl)-phenyl]-ethanone.
Step 2: 1-[4-Chloro(3-methyl-pyrazolyl)-phenyl]-ethanone (400 mg, 1.70 rnm ol) from Step 1 was dissolved in MeOH (10 mL) and cooled to O °C. NaBH4 (129 mg, 3.41 mmol) was added portionwise, then the reaction was warmed to RT, stirred for 30 min, then ed with acetone. The MeOH was removed in vacuo then the residue was partitioned n water and EtOAc and extracted several times. The combined organic layers were washed with brine, drie d over Na2S04, fi ltered, and concentrated in vacuo. Purifi cation by normal phase silica gel column chromatography (CH2Ch/M eOH/NH40H) provided the title nd.
Intermediate 7: 1-(2,6-dibromophenyl)ethanol To a on of 1-(2,6-dibromophenyl)-2,2,2-trifluoroethanone (CAS# 12080782) (3 g, 9 mmol) in EtOH (50 mL) was added NaBH4 (340 mg, 9 mmol) at 5 °C. The reaction was warmed to RT for I h, then extracted with EtOAc NaHC03, brine, and dried over Na2S04 filtered and concentrated in vacuo to provide l-(2,6-dibromopheny))-2,2,2-trifluornethanol as a light yellow oil.
Intermediate 8: 1-(2,5-dibromophenyl)ethanol ifOH Br This compound was made as described above for Intermediate 7, 1-{2,6-dibromophenyl)-2,2,2- trifluoroethanol, starting with -dibromophenyl)-2,2,2-trifluoroethanone to provide a light yellow oil.
Intermediate 9: (4-Chloro(3-methyl-lH-pyrazol-l-yl)phcnyl)methanol Cl2rOH Step 1: 1-(2-bromochlorophenyl)methyJ-lH-pyrazole/1-(2-bromochlorophenyl) methyl-lH-pyraz ole mixture (Intermediate 3, step 1) (1.00 g, 3.68 mmol) was dissolved in THF (6 mL) then cooled to O °C. yl magnesium chloride (2.76 mL, 2.0 M inTHF, 5.52 mmo1) was added dropwise and the reaction was warmed to 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 to RT and stirred for 1 h. DMF (500 mL) was added and the reaction was stirred for an additional 1 h. The on was quenched with HCl (2 N, 4 mL), diluted with water, extracted with EtOAc, washed with brine, dried over Na2S04, filtered, and trated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 4-chloro(3-methyl-pyrazol-l-yl)-benzaldehyde.
Step 2: ro(3-methyl-pyrazolyl)-benzaldehyde (446 mg, 2.03 mmol) from Step 1 was dissolved in MeOH (14 mL) and cooled to O °C. NaBH4 (175 mg, 4.61 mmol)) was added portionwise. The reaction mixture was allowed to warm to RT, and after 90 min was quenched with acetone. The MeOH was removed in vacuo. The residue was ioned between water and EtOAc and then extracted. The combined organic layers were washed with brine, dri ed over Na2S04, fi ltered, and concentrated in vacuo. Purifica tion by normal phase silica gel column chromato gra phy (EtOAc/heptane) provided the title compound.
Using the procedure described for Intermediate 3, (R )(4-chloro(3-methyl-lH­ pyra zolyl)phenyl)-2,2,2-triflu oroethanol, the following alcohols (Intermediates 10-15) shown in the Table below were prepared starting with the appropriately substituted 1-bromo fl uorobenzene.
LCMS Name No. ure (MH+) (R)-2,2,2-triflu oro(4-methyl(3- methyl- azol Intermediate yl)phenyl)ethanol h ffoH'N CF- 3 271 (R)- 2,2,2-trifl uoro (4-methoxy (3-methyl-lH-pyrazol Intermediate h yl)phenyl)ethanol u:HN CF 287 (R)(3-chloro(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2- ediate trifluoroethanol '21'h 291 12 Cl OH (R)-2,2,2-trifluoro(2-(3-methyl- 1H-pyrazol-l-yl)(trifluoromethyl) Intermediate h phenyl)ethanol lf�H'N CF 325 (R)-2,2,2-trifluoro(4-fluoro(3- methyl-lH-pyrazol Intermediate h yl)phenyl)ethanol N' 274 14 OH (R)-2,2,2-trifluoro(6-methyl(3- methyl-lH-pyrazol-l-yl)pyridin Intermediate h yl)ethanol 'N CF- 3 272 ffoH Intermediate 16: (2-Phcnoxy(piperidinyl)pheuyl)methanamine Step 1: To a solution of phenol (415 mg, 4.5 mmol) in 60 mL ofDMF was added NaH (60%, 6.0 mmol) at O °C. The reaction was stirred for 1 h, then 2-flu oro(pip eridin-l-yl)benzonitrile (CAS# 6469896) (612 mg, 3.0 mmol) was added and the reaction stirred for 48 hatRT.
The reaction mixture was then diluted with water and ted with EtOAc. The combined c layers were washed with brine, dried over Na2S04, then concentrated in vacuo.
Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 2- phenoxy(piperidinyl)benzonitrile as an off-white solid.
Step 2: To 2-phenoxy(piperidinyl)benzonitrile (250 mg, 0.9 mmol) from Step 1 in 20 mL ofMeOH was added Raney Nickel (5%) and NH40H (2 mL). The reaction was stirred under 1 atm of H2 at RT for 2 h. The solid was filtered away and the filtrate was concentrated in vacuo to provide the title compound as a viscous oil.
Intermediate 17: (4-Chloro(2-mctboxyethoxy)pheuyl)-2,2,2-trifluoroethanol Clu�H0lo CF Step 1: 1-Bromochloro(2-methoxy-ethoxy)-benzene (CAS# 35) (5.00 g, 18.8 rnmol) was dissolved in THF (30 mL) and cooled to O °C. i-Propylmagnesium bromide (11.3 ml., 2.0MinTHF, 22.6 mmol) was added dropwise, and the reaction was stirred at 10 °C for 30 min, then wannedto RT for 16 h. The reaction was then cooled to - 1 5 °C and trifl uoroacetic 1 5 acid ethyl ester (3.37 rnl., 28.2 mm ol) was added. The reaction was stirred at 10 °C for 1 h. The reactionwas quenched with HCI (2 N, 38 mL) at O °C. The reaction mixture was diluted with water and extra cted with EtOAc. The combined organic layers were washed with brine, dried overNa2SOi1, then concentrated in vacuo. Purifi cation by normal phase silica gel column chro matography(EtOAc/heptane) provided 1-(4-chloro (2-methoxyethoxy)phenyl)-2,2,2- trifluoroethanone, Step 2: The title compound was prepared using the Iridium complex-catalyzed hydrogeneation as describedfor Intermediate 1 (R)(4-bromo(3-methyl-1H-pyraz ol-l-yl)phenyl)-2,2,2- oroethanol. ediate 18: (R)-l-(5-chloro-[1,1'-biphcnyl]yl)-2,2,2-trifluoroethanol To a on of (R)-l-(2-bromochlorophenyl)-2,2,2-trifluoroethanol (300 mg, 1.1 nunol) in dioxane (12 mL) was added phenyl boronic acid (185 mg, 1.5 mmol), Pd2(dppf)Ch (35 mg, 0.07 mmol) and Na2C03(3 mL, 2.0 M, aq). The reaction was heated to 90 °C for 2 h, then cooled to RT, and concentrated in vacuo. The residue was taken up in CH2Ch, washed with brine, and extracted with CH2Ch. The combined organic layers were dried over Na2S04. Purification by normal phase silica gel column (EtOAc/hexanes) to provide a white solid.
Intermediate 19: (R)(4-chloro(5-chlorothiophenyl)phenyl)-2,2,2-trifluoroethanol Cl This nd was made in the same way as described for Intermediate 18 (R)-l-(5-chloro­ [1,1'-biphenyl]yl)-2,2,2-trifl uoro l to provide a whi te solid.
Intermediate 20: 2,2-trifluoro(6-methyl(3-methyl-lH-pyrazolyl)pyridin yl)cthanol ffoHQ CF - 3 Step 1: To the solution of2-chloromethylni cotinic acid (5 g, 29.1 mmol) in CI-hCh (40 mL) was added oxalyl dichlori de (8.1 g, 63.8 mmol) at O °C and the reaction mixture was stirr ed for 2 h. The mixture was concentrated and 40 mL of methanol was then added at O °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 Na2S04, fil tered, and concentrated in vacuo to provide methyl 2-chloromethylnicotinate that is used without further purification as a light yellow solid.
Step 2: To a solution of 3-methyl-lH-pyrazole (1.1 g, 13.4 mmol)in DMF (5 ml) was added sodium hydride ( 1.0 g, 60% in oil) at O °C. The reaction mixture was stirred for 1 h at O °C and then . A solution of methyl 2-chloromethylnicotinate (4.3 g, 23.16 mmol) in DMF (5 mL) was added se to the reaction mixture at O °C. After on, the mixture was heated to 80 °C and stirred for 12 h. After this time, the mixture was poured into ice-water and extracted and extracted with EtOAc. The combined c layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo and then purified by normal phase silica gel column (EtOAc/h epate) to provide methyl 6-methyl(3-methyl-lH-pyrazolyl)nicotinate as a brown semi-solid.
Step 3: To a solution of methyl 6-methyl(3-methyl-IH-pyrazol-l-yl)nicotinate (3.7 g, 16 nun ol) and trimethyl(trifl uoromethyl)silane (11.4 g, 80.2 mmol) in toluene (60 ml), was added drop wise at - 78°C and then the solution of tetrabutyl um fl uoride (1.6 ml., 1 .0 M in THF) was added dropwise to the reaction mixture at -78 °C. After addition, the e was warmed slowly up to RT and stirr ed for 12 h. The reaction mixture was trated and the resulting residue was dissolved in methanol (30 mL). 6 N 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.NaHCOJ and extra cted with EtOAc. The combined organic layers were washed with brine, dri ed over , fi , and concentra ted in vacuo and purifie d by normal phase silica gel column (EtOAc/h epate) to provide 2,2,2-triflu oro(6-methyl(3-methyl-lH­ pyrazolyl)pyridinyl)ethanone as a brown semi-solid.
Step 4: A solution of (S)-(-)Butyl-CBS-oxazaboro lidine solution (3.0 ml 1.0 Min toluene) and catecholborane (30 ml 1 .0 Min THF) was d at RT for 30 min. The mixture was then cooled to -70 °C and 2,2,2-triflu oro-l-(6-methyl(3-methyl-lH-pyra zolyl)pyridin yl)ethanone (1 g, 2.9 mmol) in THF (16 mL) was added dropwise. Aft er addition, the reaction mixture was warmed up to -32 °C and stirred for 12 h. After this time, 3N NaOH (18 mL) was added followed by H202 ( 18 mL) and the temperature of the re action mixture was increased to RT for 30 min and then extracted with ethyl. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo and purified by normal phase silica gel column (EtOAc/hepate) to provide the title compound as a yellow solid.
Intermediate 38: (R)(5-bromo-[1,l '-biphenyl]yl)-2,2,2-trifluorocthanol Step 1: A solution of2,4-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 e of NMP/water (100 mL) was heated to 70 °C for 2 d. After this time, the reaction mixture was cooled to RT, and the reaction mixture was adjusted to pH= 4-5 with 3 N HCI. The mixture was then extracted with ethyl acetate and the combined organic layers were washed with brine, dri ed over Na2S04, fil tered, and concentrated in vacuo and purifie d by normal phase silica gel column (EtOAc/PE 10:1 to 1 : 1 ) to afford 5-bro mo-[1,1'-biphenyl]carboxylic acid as a colorless oil.
Step 2: To a solution of 5-bromo -[1,1'-biphenyl]carboxylic acid (5 g, 18.2 mmol) in MeOH (30 mL) was added SOCh (10 mL) dropwise, The on mixture was heated to 70 °C for 2 h, then cooled to RT. The e was concentra ted, adjusted to pH= 7-8 with saturated aqueous NaHC03 and extra cted with ethyl acetate. The ed organic layers were washed with brine, dried over Na2S04, fil tered, and concentra ted in vacuo and purifie d by normal phase silica gel column (EtOAc/PE 50: 1) to aff ord afford methyl 5-bromo-[1,1 '-biphenyl]carboxylate as a colorless oil.
Step 3: A solution of methyl 5-bromo-[l, l '-biphenyl]carboxylate (2.2 g, 6.9 mmol) in THF (SO mL) was cooled to O °C. LiA1H.t (380 mg, 10 mmol) was added slowly. The reaction mixture was stirre d at RT for 2 h, aft er which water (1 mL) was added slowly to quench the on. The solid was removed by fi ltration and the filtrate was trated in vacuo to provide (5-bromo­ [1,1'-biphenyl]yl)methanol as a white solid that was used directly without r purifi cation.
Step 4: To a solution of (5-bromo-[1,l'-biphenyl]yl)methanol (2.0 g, 8.4 mmol) in CH2Ch (30 mL) was added Dess-Martin inane (4.3 g, 10 mmol). The on mixture was stirred at RT for 2 hand then the solids were filtered and the resultant :filtrate was trated in vacuo.
Purification by normal phase silica gel column (EtOAc:PE = 1 :50) afforded o-[1, 1 '- biphenyl]carbaldehyde as a colorless oil.
Step 5: To a solution of 5-bromo-[1,1'-biphenyl]carbaldehyde (1.9 g, 7.3 mmol) and was added TMSCF3 (l.2g, 8.7 mmol) in THF (20 mL) and cooled to O °C. To this solution was added TBAF (1.46 mL, IM in THF) and the reaction mixture was warmed to RT for 3 h. After this time, the mixture was treated with 3 N HCl (5 mL) and d for 12 h. Then the reaction mixture was diluted with water and extra cted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S04, fi , concentrat ed in vacuo and purifi ed by normal phase silica gel column (EtOAc:PE = 1:10) to afford 1-(5-bromo-[1,1'-biphenyl]yl)- 2,2,2-triflu oroethanol as a colorless oil.
Step 6: To a on of 1-(5-bromo-[1, 1 '-biphenyl]yl)-2,2,2-triflu oroethano (1.8 g, 5.5 mmol) in CH2Ch (30 mL) was added Dess-Martin Peri odinane (3g, 7.1 mmol), The reaction mixture was stirred at RT for 2 hand then the solids were fi ltered. The ant filtrate was concentrated in vacuo. Purifi cation by normal phase silica gel column (EtOAc:PE = 1 :50) afforded 1-(5- bromo-[l,l1-bipheny1]yl)-2,2,2-trifl uoroethanone as a colorless oil.
Step 7: 1-(5-Bromo-[1,l'-biphenyl]yl)-2,2,2-triflu oro ethanone (1.3 g, 3.9 mmol) in CH3CN (10 mL) was reduced to the chiral alcohol using the chiral iri dium catalyst (METHOD A) at RT.
The reaction mixture was then charged with potassium formate (725 mg, 8.6 mmol) and the mixture was stirr ed at 40 °C for 12 h. Then the reaction was diluted with water and extra cted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S04, filtered , concentrated in vacuo and purifi ed by normal phase silica gel column (E tOAc:PE = 1:10) to afford the title compound as a colorless oil.
Using the procedure described for Intermediate 3, (R)(4-chloro(3-methyl-IH­ pyrazolyl)phenyl)-2,2,2-trifluoroethanol, the ing alcohols mediates 39-42) shown in the Table below were prepared starting with the appropriately substituted pyrazole.
LCMS Name Structure No. (MH+) (R)(4-chloro(3- F3C ( orornethy1)-1Hspyrazol-l- Intermediate yl)phenyl)-2,2,2-trifluoroethanol u�HN NhCF 345 (R)(2-(3-(tert-butyl)-IH-pyrazol l'.1 yl)chlorophenyl)-2,2,2- trifluoroethanol Intermediate u�H'N CF 334 (R)(4-chloro(3-isopropyl-1 H- pyrazol-l-yl)phenyl)-2,2,2- trifluoroethanol Intermediate �H' (R)(4-chloro (3-cyclopropyl-1 H- b pyrazolyl)phenyl)-2,2,2- trifl uoroethan ol Intermediate N CF 317 42 u�H Intermediate 43: (R)(2-bromochlorophenyl)-2,2,2-trifluoroethanol Clu:H A solution of dichloro(pentamethylcyclopentadienyl)iridium (III) dimer ([Cp*lrCb]2, 14 mg, 0.02 mmol) and (JR,2R)-(+(4-toluenesulfonyl)-1,2-diphenylethylenediamine (14 mg, 0.04 mmol) in water (7 mL) was prepared at RT. The resulting e was heated to 40 °C for 3 h to provide a homogeneous orange solution. To this active catalyst solution at 40 °C was added ium formate (143 mg, 171 mmol), and a solution of romochlorophenyl)-2,2,2 - trifluoroethanone (CAS# 10338050, 98 mg, 0.34 mmol) in CH3CN (70 mL). The reaction mixture was then stirred at 40 °C for 2 hand then cooled to RT and the layers were separated.
The aqueous layer was extracted with MTBE and the combined organic layers were dried over Na2S04, fi , and concentra ted in vacuo to pro vide the title compound that was used without further purifi cation.
The following alcohols and amines in the table below arc useful in preparing compounds of the invention. They are either commercially available or can be prepared by kn own tic procedures. CAS ry numbers are provided for each.
No. Name CAS Registry # Structure Ex# 21 (R)-2,2,2-trifl uoro-l-(2-(3- 10338050 methyl-I H-pyrazol 0 yl)phenyl)ethanol 21' lOa & 22 (R)-l-(2-bromo·4- 10338052 chlorophenyl)-2,2,2- u�H 34a- trifluorcethanol 34ae 23 (R} 1-(5-chloro- 2-(3-methyl- 10338059 lH-pyrazolyl)phenyl)- 0 2,2,2-trifluoroeth anol ifN CF- 3 lOk 24 l-(adamantan 133924 yl)ethanamine lbl< 38 (adamantan-l- 177681 yljmethanamine &h 41c 26 [1,1'-biphenyl] 177976 7 °v ylmethanamine NH2 39d 27 naphthalen-z-ylmethanarnine 20188 C(J'NH2 39a 28 1-(adamantanyl)ethanol 267503 IG--(H 41c 29 (R)(naphthalen 6-9 yl )ethanamine cdNH2 39e 2,2-trifluoro 682000 QF3 (naphthalenyl)ethanol 59b 31 [Ll-biphenylj=l- -5 ylmethanamine e-: 39b �NH2 32 (2-(piperidin 54-6 ():NH2 y1)phenyl)methanamine 0 41a 33 (R)(4-bromophenyl)-2 ,2,2- 804188 QF3 trifluoroethanol 55a- MOH 55db No.= Intermediate number; Ex#= Used in the preparation of the following example(s) Preparation of boi·onic acids and esters The boronic acids and esters used in biaryl couplings are either commercially available or can be readily synthesized from the corresponding bromide using routine synth etic methods.
The ing Intermediate 34 is a representative example.
Intermediate 34: 6-(4,4,5,5-Tetramethyl-1,3,2-clioxaborolanyl)-3,4-dihydroquinolin- 2(1H)-one OyN��rr To a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (200 mg, 0.89 mmol) in 5 mL of acetonitrile was added pinacoldiboron (300 mg, 1.2 mmol), Pd(dppt)2CI (30 mg, ol), KOAc (250 mg, 2.1 mmol) and triethyl amine (1 mL). The reaction was heated to 87 °C for 24 h, then cooled to RT. The solids were ed away, and the solvent was removed in vacuo, then extracted with EtOAc, water, brine and dried over Na2S04. The solvent was removed in vacuo to provide an off-white solid which was used without further purification.
Spirocyclic amino esters preparation Intermediate 35: (S)Benzyl 3-ethyl 2,8-cliazaspiro[4.5]decane-2,3-dicarboxylate HN�8) Step 1: (3S)Tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate [Example 24 in US Pat. Pub. No. 2012/0101280] (50 g, 160 mmol) in CH2Ch (500 mL), and EtJN (51.7 g, 512 mmol) was cooled to O °C. Benzyl chloroformate (34.1 g, 205 mmol) was added drop wise and the mixture was stirred at O °C for 3 h. The reaction mixture was washed with water, ted with CH2Ch, dried over Na2S04, and concentrated in vacuo to pro vide 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 .
Step 2: To a solution of (S)benzyl 8-tert-butyl 3-ethyl 2,8-diazaspiro[4.S]decane-2,3,8- tricarboxylate (79 g, 160 rn mol, Step 1) in CH2Ch (400 mL) was added TFA (182 g, 1600 mmol) se at RT. The on mixture was stirred for 3 h then concentrated in vacuo. The residue was quenched with saturated NaHCOJ and solid NaHC03 was added until no further gas evolution was noted. The mixture was extracted with EtOAc and the combined organic layers were concentrated in vacuo. cation by normal phase silica gel column chromatography (CH2Ch/MeOH/NH40H) provided the title compound as a light yellow solid.
Intermediate 36: (S)Tcrt-butyl 3-etltyl 2,8-diazaspiro[4.S]clecane-2,3-clicarboxylateKN�; Step 1: (S)Benzyl l 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (2.4 g, 6.9 mmol) in HCl/dioxane (50 mL, 3.3 N) was stirred for 2 hat RT. The solvent was then removed in vacuo to provide (S)benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate hydrochloride which was used directly without further purification.
Step 2: To a solution of (S)benzyl 3-ethyl 2,8-diazaspiro[4.5Jdecane-2,3-dica rboxylate hydrochloride and BOC20 (1.5 g, 6.9 mmol) in EtOH (50 mL) was added Pd/ C (10%, 2.4 g) and HOAc (cat.). The mixture was degassed and blanked under H2 then stirred at 45 °Cat 50 psi of 1-h for 12 h. The solid was fi ltered away and the fi ltrate concentrate d in vacuo to provide the title compound as a s solid.
Intermediate 37: Methyl azaspiro[S.S]undccanecarboxylate To a solution of 3,9-diazaspiro[5.5]undecanecarboxylic acid, methoxyphenyl)methyl] (ph enylmethyl)-methyl ester [CAS# 13143883] (50 mg, 0 .12 mmol) in MeOH (2 mL) and water (2 mL) was added a catalyt ic amount of TFA. The mixture was hydrogenated using a H­ eube apparatus under 80 °CI 80 bar 2 cycles. The reaction mixture was cooled to RT then concentrated in vacuo to provide the title compound as a white solid which is used directly.
General synthetic methods s for removal of N-Carbobenzyloxy ) protecting group Method A - Hydrogenation over Pd/C: To a solution ofN-CBZ protected compound (1 eq.) in EtOAc was added HOAc (100 µL) and 5% (w/w) Pd/C (5 mol%). The reaction mixture was degassed, blanketed under H2 (balloon) 3 times, then stirred at RT for 2 h. The reaction was then filtered h a pad of celite that was rinsed with 1 :9 MeOH:EtOAc. The te was concentratedin vacuo. The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (H20:HOAc:99: I to MeOH:AcOH 99: 1 ).
Method B - Dealkylation with T.MSI: To a solution Z protected nd (I eq.) in CH3CN was added a solution ofTMSI (2.2 eq.) in CH3CN (0.2 M). The reaction mixture was IO stirre d at RT for 2 h then quenched with 1 N HCI to pH 1. The product was purifie d by column chromatography using an Isco Gold reversed phase silica cartridge (H20:HOAc:99: 1 to MeOH:AcOH 99:1).
General ester hydrolysis with lithium hydroxide: To a solution of an ethyl ester compound (I eq) in THF (0.18 M) an d water (1.4 M) was added LiOH-H20 (10 eq). The mixture was stirred at RT for 1 h. Water was added and the pH was adjusted to 6.5 with 1 N HCI. THF was removedin vacuo, then the solid was precipitated, washed with water, and dried in vacuo to yield the corresponding carboxylic acid.
The compounds of the examples were isolated either in the neutral zwitterionic form or as a TFA or HCI salt.
Example 1u: (S)(2-amino((R)-2,2,2-trifluor o(3-(3-methyl-lH-pyrazol-l-yl)-[1,1 '­ biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5] decanecarboxylic acid Step 1: To a solution of (R)(4-bromo(3-methyl-1 H-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethanol (160 mg, 0.2 mmol, Intermediate 1) in dioxane (2 mL) was added 2-amino-4,6- dichloropyrimidine (100 mg, 0.16 mmol) and Cs2C03 (48 ,g, 0.16 mmol). The reaction was heated to 80 °C for 16 h, cooled to RT, and filtered. The solvent was removed in vacuo and the residue was ved in a mixture of CH2Ch and heptane, concentrated to half the volume, filtered, and concentrated again in vacuo. cation via normal phase silica gel chromatography /Heptane) provided 4-[( lR)[4-bromo(3-methylpyraz ol yl)phenyl]-2,2,2-triflu oro-ethoxy)chloro- pyrimidinamine as an off-white solid.
Step 2: To a solution of 4-[(lR)[4-bromo(3-methylpyrazolyl)phenyl]-2,2,2-triflu oro­ ethoxy]chloro-p yrimidinamine (125 mg, 0.3 mmol, Step 1) in dioxane (3 mL) was added (S)benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (95 mg, 0.3 mmol) and Na2C03 (182 mg, 0.35 mmol). The reaction was heated to 90 °C for 130 h, then cooled to RT, fi ltered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)benzyl 3-ethyl 8-(2-amino((R)(4-bro 3-methyl-lH­ pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidiny1)-2,8-diazaspiro[4. 5]decane-2,3- dicarboxylate as a white solid.
Step 3: To a solution of (S)benzyl 3-ethyl 8-(2-amino((R)(4-bromo(3-methyl-lH- pyrazol- l-yl)phenyl)-2,2,2-trifl uoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3- oxylate (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added phenylboronic acid (143 mg, 0.8 mmol), PdCh(PPh3)2 (41 mg, 0.058 mmol), and Cs2C03 (390 mg, 1.2 mmol). The reactionwas heated to 60 °C for 16 h, then cooled to RT, fi ltered through celite and tratedin vacuo. cation by normal phase silica gel column (EtOAc/h eptane) provided (S)benzyl 3-ethyl 8-(2-amino((R)-2,2,2-triflu oro(3-(3- methyl-lH-pyrazolyl)-[1, l '-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane- 2,3-dicarboxylate as a white solid.
Step 4: A solution of benzyl 3-ethyl 8-(2-amino((R)-2,2,2-trifl uoro(3-(3-methyl-lH- pyrazol-l-yl)-] 1, 1'-biphenyl]yl)ethoxy)pyl'i midinyl)-2,8-diazaspiro[4.5]decane-2,3- dicarboxylate (240 mg, 0.4 mmol, Step 3) in EtOAc (5 mL) was hyrogenated using an H-Cube apparatus 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((R)-2,2,2-trifluoro methyl- Hl-pyrazol-l-ylj-Il , 1 '-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decanecarboxy1ate.
Step 5: To a on of (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyra zol- 1-yl)-[1, l'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.S]decanecarboxylate (50 mg, 0.08 mmol) from Step 4 in THF (2.0 mL) and water (0.2 mL), was added lithium hydroxide monohydrate (58 mg, 0.05 mmol). The reaction mixture was stirred at RT for 2 h, then the solution was neutralized with 1 N HCl, and tra ted in vacuo. Purific ation by normal phase silica gel column /heptane) provided the title compound as an off-white solid as the zwitterionic form.
Exampie lm: (S)(2-amino((R)(3' ,4'-dimethyl(3-methyl-lH-pyrazolyl)-[1,1 '- biphcnyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro [4. 5] dccane carboxylic acid Step 1 : To a solution of (S)benzyl 3-ethyl mino((R )(4-bromo(3-methyl-lH­ pyrazolyl)phenyl)-2,2,2-trifl uoro )pyri midinyl)-2,8-diazaspiro[4.S]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 (3,4-dimethylphenyl)boronic acid (120 mg, 0.8 mmol), PdCh(PPh3)2 (41 mg, 0.058 mmol), and Cs2C03 (390 mg, 1.2 mmol). The reaction was heated to 60 °C for 16 h, then cooled to RT, filt ered through celite and concentrated in vacuo. Purifi cation by normal phase silica gel column (EtOAc!he ptane) provided (S)benzyl 3-ethyl 8-(2-amino((R)(3',4'- dimethyl(3-methyl-lH-pyrnzolyl)-[l, l'-biphenyl]yl)-2,2,2-trifl uoro ethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Step 2: A solution of benzyl 3-ethyl mino((R)(3',4'-dimethyl(3-methyl-lH­ lyl)-[1, l'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate (220 mg, 0.3 mmol) in EtOAc (5 mL) was hydrogenated using an H-Cube apparatus 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((R)(3',4'-dimethyl(3-methyl-1H-pyrazolyl)-[1, 1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidiny1)-2,8-diazaspiro [4. 5]decanecarboxylate.
Step 3: To a solution of (S)-ethyl 8-(2-amino((R)-l-(3',4'-dirn ethyl(3-methyl-lH-pyraz ol yl)-[1,1 '-biphenyl]yl)-2,2,2-trifluo ro )pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate (50 mg, 0.08 mm ol) from Step 2 in THF (2.0 mL) and water (0.2 ml.), was added lithium hydroxide monohydrate (58 mg, 0.05 mmol). The reaction mixture was stirred at RT for 2 h, then the solution was neutralized with 1 N HCl and concentra ted in vacuo. Purifi cation by normal phase silica gel column (EtOAc/he ptane) provided the title compound as an off-whit e solid as the zwitterionic form.
Exampie 1cq: (S)(2-amino((R)-2,2,2-trifluo ro-l-(3 '-(hydroxymethyl)-4'-methyl(3- methyl-Hl-pyrazol-l-ylj-]1,1 '-biphenyJ]yl)cthoxy)pyrimidinyl)-2,8- diazaspiro ccanecarboxylic acid Step 1: To a solution of (S)benzyl 3-ethyl 8-(2-amino((R)(4-bromo(3-methyl-lH­ pyra zo 1yI)pheny1)-2,2 ,2-trifl uoroethoxy)pyrimidinA-yl)-2,8-diazaspiro [4.5]decane-2,3- dicarboxyl ate (Step 2, Example lu) (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added (3-(hydroxymethyl)methylphenyl)boronic acid (CAS# l4513910; 120 mg, 0.7 mmol), PdCh(PPh3)2 (41 mg, 0.058 mmol), and Cs2C03 (390 mg, 1.2 mm ol). The reaction was heated to 60 °C for 16 h, then cooled to RT, filtered through celite and trated in vacuo. cation by normal phase silica gel column (EtOAc/heptane) provided (S) benzyl 3-ethyl 8-(2-amino((R)-2,2,2-trifluoro(31-(hydroxymethyl)-4 1-methyl(3-methyl- 1H-pyrazolyl)-[1, l1-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3- dicarboxylate a white solid.
Step 2: A solution of (S)benzyl 3-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'­ (hydroxymethyl)-4'-methyl(3-methyl-1H-pyrazolyl)-[1, 1'-biphenyl] yl)ethoxy)pyri midinyl)-2,8-diazaspiro(4.5]decane-2,3-dicarboxylate (200 mg, 0.24 mmol,) in EtOAc (5 mL) was hydrog enated using an I-I-Cube apparatus and a 10% (w/w) PcVC cartridge with a fl ow rate of 1.0 mL/min at RT. Purific ation on normal phase silica gel (EtOAc/h eptane) ed (S)-ethyl 8-(2-amino((R)-2,2,2-triflu oro(3 '-(h methyl)methy1(3- methyl-1Il-pyrazol-l-yl)-]1,l1-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane- 3-carboxylate.
Step 3: To a solution of (S)-ethyl 8-(2-amino((R)-2,2,2-trifl uoro (3'-(hyclroxym -4'­ methyl(3-methyl-1H-pyrazolyl)-[1, 1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylate (50 mg, 0.08 mmol) from Step 2 in THF (2.0 mL) and water (0.2 mL), was added m hydroxide monohydrate (58 mg, 0.05 mmol). The reaction mixture was stirred at RT for 2 h, then the so]ution was neutralized with 1 N HCI, and concentrated in vacuo. Purifi cation by normal phase silica gel column (Et OAc/he ptane) provided the title compound as an off-white solid as the zwitterionic form.
Example 1er: (S)(2-amino((R)-2,2,2-trifluoro( 4'-(hydroxymcthyl)-3'-methyl(3- mcthyl-lH-pyrazolyl)-[l,1'-biphcnyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5Jdccauccarboxylic acid The title compound was made as described for (S)(2-amino((R)-2;2,2-trifluoro(3'­ (hydroxymethyl)-4'-methyl(3-methyl-1 zolyl)-[1,1'-biphenylJ yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5Jdecanecarboxylic acid (Example 1 cq) using (4- (hydroxymethyl)methylphenyl)boronic acid (CAS# 12187905).
Using the generic scheme below, the following examples of Table 1 a were prepared as described above for (S)(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1 H-pyrazolyl)-[1, l'­ yl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.S]decanecarboxylic acid (Example lu). The boronic acid was genera ly used to make the analogues below, however, where it was not available, the corr esponding boronate was used.
STEP l STEP2 Table la.
Ex. Cy CASName LCMS No. o-ff (MH+) (3S)(2-amino(( 1R)-2,2,2-trifluoro-l-(3- (3-methyl-1H-pyrazolyl)-4'-(methylsulfinyl)- la 'S 671 [ 1,1'-biphenyl]yl)ethoxy)pyrimidinyl)- ff 2,8-diazaspiro[4.S]decanecarboxylic acid (S)(2-amino((R)-2,2,2-trifluoro(3-(3- methyl-IH-pyrazol-l-yl)-4'-(methylthio)-[l,l 1- lb 's 655 biphenyl]yl) ethoxy)pyrimidinyl)-2,8- c¢o diazaspiro [4.S]decanecarboxylic acid (S)(2-amino((R)(3'-carboxy(3- methyl-IH-pyrazolyl)-[ 1, l'-biphenyl]yl)- le 652 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- o� diazaspiro[4.5]decanecarboxylic acid HO (S)(2-amino( (R)- l -(3'-carboxy(3- methyl-IH-pyrazolyl)-[l, l'-biphenyl]yl)- Id trifluoroethoxy)py rimidinyl)-2,8- 652.5 diazaspiro]4.5]decanecarboxylic acid o� (S)(2-amino((R)(4'-carboxy(3- methyl-lH-pyrazol-l-yl)-[1,1 '-biphenyl]yl)- le 652.6 trifl uoroe thoxy)pyrimidinyl)-2,8- OH diazaspiro]4.5ldecanecarboxylic acid (2-amino((R)-2,2,2-trifl uoro (2-(3- H� methyl-lH-pyrazol-l-yl)(1,2,3,6- 1f tetrahydropyridin=l- 613.5 yl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro [4.5]decanecarboxylie acid (2-amino((R)-2,2,2-triflu oro(2-(3- I ,,:: methyl- IH-pyrazol-l-yl)(pyridin lg � 609.6 yl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro[ 4.5ldecanecarboxylic acid \ (S)(2-amino((R)-2,2,2-trifl uoro (2-(3- -lH-pyraz ol-l-yl)(1-methyl-lH- lh N� 612.6 pyrazo]yl)phenyl)ethoxy)pyri midiny])- 2,8-diazaspiro[ 4.5]decanecarboxylic acid (S)(2-amino((R)-2,2,2-trifluoro(4- 1i o� (isoxazolyl)(3-methyl- lH-pyrazol 599.6 yl)phenyl)ethoxy)pyrimidinA-yl)-2,8- diazaspiro]4.5Jdecanecarboxylic acid (S)(2-amino((R)(4-(3,6-dihydro-2H- pyranyl)(3-methyl-lH-pyrazol lj � 614.6 nyl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.S]decanecarboxylic acid 0 (S)(6-((R)(4-(l-acetyl-1,2,3,6- tetrahydropyridinyl)(3-methyl-1 H- lk ,Jl� pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)-2 - 655.7 yrimidiny l)-2,8- diazaspiro]4.S]decanecarboxylic acid (S)(2-amino((R)-2,2,2-triflu oro(4'- 11 "r°Vy isopropoxy(3-methyl-1H-pyra zolyl)-[ 1,l1- 666.7 yl]yl)ethoxy)pyrimidinyl)-2,8- M piro]4.5]decanecarboxylic acid (S)(2-amino((R)(3',4'-dimethyl(3- lm methyl- lH-pyrazolyl)-[1,l '-biphenyl]yl)- 636.7 2,2,2-trifl uoroethoxy)pyrimidinyl)-2,8- .o, diazaspiro]4.S]decanecarboxylic acid (S)(2-amino((R)-2,2,2-triflu oro(4-(2- h methoxypyridinyl)(3-methyl-1 Il-pyrazol- In 0 639.6 I 1-yl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decanecarboxylic acid H (S)(2-amino((R)-2,2,2-triflu oro-l-(4-(3- methyl-lH-indazolyl)(3-methyl-1H- lo 662.3 pyra yl)phenyl)ethoxy)pyl'imidinyl)- � 2,8-diazaspiro[ 4.5]decanecarboxylic acid (S)(2-am ino((R)(41-(tert-butyl )(3- methyl-lH-pyra zolyl)-[1, 1 '-biphenyl]yl)- lp 664.8 2,2,2-trifl uoroeth oxy)pyrimidinyl)-2,8- ��OVy diazaspiro[4.5]decanecarboxylic acid (S)(2-amino((R )(4'-ethoxy(3- methyl-lH-pyra lq l h zolyl)-[1,1 '-biphenyl]yl)- 652.7 2,2,2-trifl hoxy)pyrimidinyl)-2,8- ,Ar()y diazaspiro]4.5ldecanecarboxylic acid (S)(2-arn ino((R)-2,2,2-trifl uoro(4-(2- Ir N ,..,-::. ypyri midinyl)(3-methyl-1H- 639.6 pyrazolyl)phenyl)ethoxy)pyrimidinyl)- /01Jy 2,8-diazaspiror4.5]decanecarboxylic acid (S)(2-amino((R)-2,2,2-triflu oro- l-(4-(6- I " methoxypyridinyl)(3-methyl-lH-pyrazol- ls � 639.6 1-yl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro]4.S]decanecarboxylic acid c. (S)(2-amino((R)-2,2,2-trifluoro(3-(3- methyl-lH-pyrazol-l-yl)-[1,1 '-bipheny1] lu 608.6 yl)ethoxy)pyrimidinyl)-2,8- diazaspil'or4.5]decanecarboxylic acid (S)(2-amino((R)-2,2,2-trifluoro-l-(3-(3- methyl-lH-pyrazol-l-yl)-2',3',4',5'-tetrahydro- lv � 636 [I, 1'-biphenyl]yl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5ldecanecarboxylic acid N (S)(2-amino((R)(3'-cyano(3-methy1- lH-pyrazolyl)-[l ,l '-biphenyl]yl)-2,2,2- lw o roethoxy)pyrimidinyl)-2,8- 633 diazaspiro[4. 5]decanecarboxylie acid 0 (S)(6-((R)(4'-(acetamidomethyl)(3- Ix ,)l�u),, - IH-pyrazolyl)-( 1, 1'-biphenyl]yl)- 2,2,2-trifl uoroethoxy)aminopyrimidinyl)- 2,8-diazaspiro[4.5]decanecal'boxylic acid Yo (S)(6-((R )(4'-(2-acetamidoethyl)(3- methyl-lH-pyrazolyl)-[1, l enyl]yl)- ly HN� 2,2,2-trifluo xy)aminopyrimidinyl)- 693 I ---::: 2,8-diazaspiro [4.5]decanecarboxylic acid (S)(2-amino((R)-2,2,2-triflu oro(2-(3- -lH-pyrazol-l-yl)(quinolin lz 659 yl)phenyl)ethoxy)pyrimidinyl)-2,8- � diazaspiro[4.5]decanecar boxylic acid H (S)(6-((R)(4-(1H-indolyl)(3-methyl- lH-pyrazolyl)phenyl)-2,2,2-trifluor oethoxy)- 2-aminopyri midinyl)-2,8- 567 �H2Nu),, diazaspiro [4.S]decanecarboxylic acid (S)(2-amino((R )(4'-(aminomethyl) (3-rn eth yl-lH-pyrazoJyl)-[l, 1 '-biphenyl] lab 637 yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspir o[ 4.5]decanecarboxylic acid F (2-amino((R)-2,2,2-triflu oro(3 '- fl uoro- 3-(3-methyl-lH-pyrazolyl)-[1, 11- lac 626 yl]yl)ethoxy)pyrimidinyl)-2,8- � diazaspiro[4.5]decanecarboxylic acid (S)(2-amino((R)-2,2,2-trifl uoro- 1-(2-(3- methyl-IH-pyrazol-l-yl)(quinolin lad 659 yl)phenyl)ethoxy)pydmidinyl)-2,8- � diazaspiro r4.5ldecanecarboxylic acid 'o, (S)(2-amino((R)-2,2,2-tri fl uoro(4'- methyl(3-methyl- lH-pyrazolyl)-[1, 1 '- lae 622 biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid c1Vy (S)(2-amino((R)(3',4'-dichloro(3- methyl-lH-pyrazolyl)-[l, 1'-biphenyl]yl)- laf Cl :::::-..._ 677 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- F:(\, diazaspiro[4.S]decanecarboxylic acid (S)(2-amino((R)(3',4'-difluoro(3- lag s, F I methyl-lH-pyrazolyl)-[1,1 '-biphenyl]yl)- 2,2,2-trifluoroethox y)pyrimidinyl)-2,8- CIC,, diazaspiro[4.S]decanecarboxylic acid (S)(2-amino((R)(4'-chloro(3- :::::-.... I methyl-lH-pyrazolyl)-[1,1'-biphenyl]yl)- lah 643 2,2,2-trifluoroethoxy)pyri midiny1)-2,8- diazaspiro]4.S]decanecarboxylic acid "� (S)(2-amino((R)-2,2,2-trifluoro(2-(3- l ai N ,,.-::. methyl-lH-pyrazol-l-yl)(pyri midin yl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiroj-l.Sjdecane-Lcarboxylic acid F (2-amino((R)(3 ro(3- methyl-I H-pyrazolyl)(triflu oromethyl)- lak (1, l'-biphenyl)yl)-2,2,2- 7 11 I trifluoroethoxy)pyrimi diny1)-2,8- "'OMCl� diazaspiro[4.Sldecanecarboxylic acid (S)(2-amino((R)(3'-chloro -4'-ethoxy (3-methyl-lH-pyrazolyl)-[1,1'-biphenyl] lal Cl� 687 yl)-2,2,2-trifluoroet hoxy)pyrimidinyl)-2,8- diazaspiro [4.5]decanecarboxylic acid A (S)(2-amino((R)-2,2,2-trifl uoro(3-(3- methyl-IH-pyrazolyl)-3'-(trifluo romethyl)- lam 676 F F [1, henyl]yl)ethoxy)pyrimidinyl)- 2,8-diazaspiro [4.S'[decane-Svcarboxylic acid (S)(2-amino((R)- l-(3'-chloro -5'-methyl hyl-lH-pyra zolyl)-(1, 1 '-biphenyl] Ian 657 Cl yl)-2,2,2-triflu oroethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decanecarb oxylic acid F (S)(2-amino((R)(4'-chloro-3 1-flu oro hyl-1 H-pyrazolyl)-[l, 1 '-biphenyl] lao 'o,� I 661 yl)-2,2,2-trifl uoroethoxy)pyrimidinyl)-2,8- .o, diazaspiro]4.S]decanecarboxylie acid (2-amino((R)(3'-ethoxy(3- methyl-IH-pyrazolyl)-[1,1'-biphenyl]yl)- lap --...,0 652 2,2,2-trifl uoroethoxy)pyrimidinyl)-2,8- diazaspiro[ 4.5]decanecarboxylie acid My (S)(2-amino((R)-2,2,2-trifl uoro(3'- fl uoro-4' -methyl(3-methyl-1 H-pyrazolyl)- laq F 640 [ 1 ,1'-biphenyl]yl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.S]decanecarboxylic acid Cl (S)(2-amino((R)(3'-chloro-4'-fluoro (3-methyl-1 H-pyrazol-l-yl)-[l .l1-biphenyl] lar F�� I 661 yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspirof4.S]decanecarboxylie acid (S)(2-amino((R)-2,2,2-trifluoro(3-(3- las F�� methyl-IH-pyrazolyl)-3'-(trifluoromethoxy)- 692 F O [1, 1'-biphenyl]yl)ethoxy)pyrimidinyl)- A 2,8-diazaspiro[4.S]decanecarboxylic acid (S)(2-amino((R)(3',5'-dimethyl(3- methyl-lH-pyrazolyl)-[1,11-biphenyl]yl)- lat 637 2,2,2-triflu oroethoxy)pyrimidinyl)-2,8- F:(\, diazaspiro]4.Sldecanecarboxylic acid (2-amino((R)(3',4'-difl uoro(3- lau � ' methyl-I H-pyrazolyl)-[1, 1'-biphenyl]yl)- F 644 2,2,2-triflu oroethoxy)pyrimidinyl)-2,8- piro [4.S]decanecarboxylic acid F (2-arn ino((R)(3',5'-diflu oro(3- methyl-IH-pyrazolyl)-[1,l -biphcnylj-d-yl)- lav °'° 644 2,2,2-triflu oroethoxy)pyrimidinyl)-2,8- piro [4.5]decanecarboxylic acid M (2-amino((R)-2,2,2-triflu oro(4'- F fl uoro(3-methyl- lH-pyraz olyl)-3'- law F F u oromethyl)-[l, l '-biphenyl] 694 yl)ethoxy)pyrimidinyl)-2,8- :(\, diazaspiro [4.5]decanecarboxylic acid (S)(2-am ino((R)-2,2,2-tri fl uoro(3 '- lax � I flu -isopro poxy(3-methyl-lH-pyrazol- F 684 1-yl)-[1, 1'-biphenyl]yl)ethoxy)pyri midin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid lo (S)(2-amino((R)(3'-ethoxy-5'-fl uoro- 3- (3-methyl-1H-pyra zolyl)-[1,1 '-biphenyl] lay .o, yl)-2,2,2-trifl uoro ethoxy)pyrimidinyl)-2,8- 670 diazaspiro [4.5)decanecarboxylic acid AF (S)(2-amino((R )(3'-(tert-butyl)(3- methyl-IH-pyrazolyl)-[1 ,11-biphenyl]yl)- laz 664 2,2,2-triflu oroethoxy)pyrimidinyl)-2,8- FM, diazaspiro]4.S]decanecarboxylic acid (S)(2-amino((R)-2,2,2-triflu oro(41- � I flu oro-3 '-methyl(3-methyl-1H-pyrazolyl)- lba 640 [l,1'-biphenyl]yl)ethoxy)pyrimidinyl)- A 2,8-diazaspiro r4.S]decanecarboxylic acid (S)(2-amino((R )-2,2,2-trifl uoro(3'- isopro pyl(3-methyl-1 zol-Lyl)-] 1,1'- lbb 650 biphenyl]yl)ethoxy)pyrimid inyl)-2,8- diazaspiro]4.S]decanecarboxylic acid (S)(2-amino((R)-2,2,2-trifluoro(3 1- lbc Ao� isopropoxy(3-methyl-lH-pyrazolyJ)-[l, l 1- CM biphenyl)yl)ethoxy)pyrimidinyl)-2,8- diazaspiro] 4.5]decanecarboxylic acid �' (2-amino((R)(4'-chloro-3'-methyl (3-methyl-1 H-pyrazolyl)-[1, 1 '-biphenyl] lbd 656 yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- H,NA diazaspiro[4.5]decanecarboxylic acid (S)(2-amino((R)(3'-carbamoyl(3- methyl-lH-pyrazolyl)-[1, 1'-biphenyl]yl)- lbe 651 0 2,2,2-triflu oroethoxy)pyrimidinyl)-2,8- diazaspiro ecanecarboxylie acid AF (S)(2-amino((R )-2,2,2-triflu oro(3-(3- methyl-lH-pyra zol-l-yl)-3' ,51- lbf bis(trifl uoromethyl)-[1,1 '-biphenyl] 744 F yl )ethoxy)pyrimidinyl)-2,8- F F diazaspiro[4.5]decanecarboxylic acid 'X\, (S)(2-amino((R)(3 '-ethoxy-4'-flu oro lbg ./"'-o � (3-methyl-lH-pyrazolyl)-[1,l enyl] I 670 yl)-2,2,2-triflu oroe thoxy)pyrimidinyl)-2,8- .o, diazaspiro[4.5]decanecarboxylic acid � ' (S)(2-amino((R) -chloro-3 ',5'- dimethyl(3-methyl-IH-pyrazol-l-yl)-[1, 1 '- lbh biphenyl]yl)-2,2,2- 671 triflu oroethoxy)pyrimidinyl)-2,8- diazaspiro [4.S]decanecarboxylic acid Ct (2-amino((R)- 5'-dichloro(3- methyl-lH-pyrazol-l-yl)-[1,1 '-biphenyl]yl)- lbi o, 677 2,2,2-triflu oroethoxy)pyrimidinyl)-2,8- diazaspiroj-l. Sjdecane-Lcarboxylic acid (S)(2-amino((R) (3'-(tert-butyl) methyl(3-methyl-lH-pyrazolyl)-[ 1 , 1'- 1 bj A biphenyl]yl)-2,2,2- 778 trifl uoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decanecarboxylic acid (S)(2-amino((R)(3 '-chloro(3- ClVy methyl-lH-pyrazolyl)-[1,l'-biphenyl]yl)- lbk 642 2,2,2-trifluo roethoxy)pyrimidiny1)-2,8- diazaspiro[4.S]decanecarboxylic acid (S)(2-amino((R)(3'-chloro(3- methyl- azolyl)-4'-(triflu oromethyl)- lbl C l � [l,1'-biphenyl]yl)-2,2,2- 71 1 trifluoro ethox y)pyrimidiny1)-2,8- diazaspiro [4. 5]decanecarboxylic acid �o� (S)(2-amino((R)-2,2,2-trifluoro- l-(41- lbm � I y(3-methyl-lH-pyrazolyl)-[1,11- biphenyl]yl)ethoxy)pyrimidinyl)-2,8- '-'OX\, diazaspiro[4.5]decanecarboxylic acid (S)(2-amino((R)-l-(4'-ethoxy-3'-fluoro lbn � I (3-methyl-IH-pyrazolyl)-[1, 1 '-biphenyl] F 670 yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro]4.S]decanecarboxylic acid F (S)(2-amino((R)-2,2,2-trifluoro- I-(3',4',5'- trifluoro(3-met hyl-lH-pyrazolyl)-[l, I'- lbo F��' 662 yl)yl)ethoxy)pyrimidinyl)-2,8- diazaspiro r4. 5ldecanecarboxylic acid (S)(2-amino((R)(3'-chloro-4'-methyl lbp cNy (3-methyl-IH-pyrazolyl)-[ 1,1'-biphenyl] yl)-2,2,2-trifl uoroethoxy)pyrimidinyl)-2,8- diazaspiro]4.Sldecanecarboxylic acid '.x,o� (S)(2-amino((R)-2,2,2-trifluoro (3 '- f F I methyl(3-methyl-lH-pyrazolyl)-4'- lbq � u hoxy)-[ 1,1'-biphenyl] 706 yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid F (S)(2-amino((R)-2,2,2-trifl uoro(3 '- fl uoro-5'-isopropoxy(3-methyl-1 Il-pyrazol- lbr AoA 684 1-yl)-[1,1 '-biphenyl]yl)ethoxy)pyrimidin yl)-2,8-diazaspiro[4.51decanecarboxylic acid F (S)(2-amino((R)(31-chloro-S1-fluoro hyl-1H-pyra zolyl)-[1,1 '-biphenyl] lbs 661 yl)-2,2,2-trifl uoroethoxy)pyrimidinyl)-2,8- A diaza spiro [4.5]decanecarboxylic acid (S)(2-amino((R)( 4'-chloro- 3-(3- F methyl-lH-pyrazolyl)(trifl uoromethyl)- lbt F F [1,I'-biphenyl]yl)-2,2,2- 710 trifl uoroethoxy)pyrimidinyl)-2,8- diazaspiro]4.5]decanecarboxylic acid AF (S)(2-amino((R)-2,2,2-trifl uoro (31- :flu oro- 3-(3-methyl-IH-pyra zolyl)-5'- lbu (trifluorometlryl)-] 1, 1'-biphenyl] 694 F F yl)ethoxy)pydmidinyl)-2,8- diazaspiro]4.51decanecarboxylic acid 'OM (S)(2-amino((R)(3'-chloro-4'- isopropoxy(3-methyl- lH-pyra zolyl)-[1, l '- lbv Cl , biphenyl]yl)-2,2,2- 701 trifl uoroethoxy)pyri midinA-y1)-2,8- diazaspiro]4.5]decanecarboxylic acid co, (2-amino((R)-2,2,2-trifluoro(2-(3- methyl-I H-pyrazol-l-yl)(naphthalen lbw ::::::-.. 659 yl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro]4. Sldecanecarboxylic acid Qo� (S)(2-amino((R)-l-(4'-(benzyloxy) fluoro(3-methyl-lH-pyrazolyl)-[l, 1'- lbx -.. I biphenyl]yl)-2,2,2- 733 F trifluoroethoxy)pyrimidinyl)-2,8- diazaspirof4.5ldecanecarboxylic acid '(:(Ry (S)(2-amino((R)-2,2,2-trifluoro(4'- lby � I isopropoxy-3'-methyl(3-methyl-lH-pyrazol- [l, l1-biphenyl]yl)ethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxy1ic acid �o� (S)(2-amino((R)-2,2,2-triflu (31 - l h fl uoro(3-methyl-IH-pyrazolyl)-4'- lbz F propoxy-] 1, 1'-biphenyl]yl)ethoxy)pyrimidin- 685 4-yl)-2,8-diazaspiro[ 4.5]decanecarboxylic acid �o� (S)(2-amino((R)(4'-butoxy-3'-fl uoro lea ::::::-.. I (3-methyl-lH-pyrazolyl)-[1,1 '-biphenyl] F 698 yl)-2,2,2-trifl uoroethoxy)pyrimidinyl)-2,8- diazaspiro]4.Sldecanecarboxylic acid (S)(2-amino((R)-2,2,2-triflu oro- 1-(3 '- -f� fl uoro(5-methyl-1,3,4-oxadiazolyl)(3- lcb o -7' I methyl-IH-pyra zolyl)-[1) 1-biphenyl] 709 F � yl)ethoxy)pyrimidinyl)-2,8- diazaspiro]4.Sldecanecarboxylic acid O'Vy0 (S)(2-amino((R)-2,2,2-triflu oro(3-(3- methyl- a zolyl)(methylsulfonyl)- lee 687 [1, 1'-biphenyl]yl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decanecarboxylic acid �o� (S)(2-amino((R)-2,2,2-trifl uoro(3-(3- ::::::-.. I methyl-lH-pyrazolyl)-4'-propoxy-[1, l 1- led 668 biphenyl]yl)ethoxy)pyri midinyl)-2,8- diazaspiro[ canecarboxylic acid 01 0 (S)(2-amino((R)-2,2,2-triflu oro(3-(3- l____,Nv"'�� methyl-I H-pyrazolyl)-4'-((2- Ice morpholinoethyl)carbamoyl)-[1, 1 '-biphenyl] 764 yl)ethoxy)pyrimidinyl)-2,8- diazaspiro I4.S]decanecarboxylic acid H2N,8,0 (S)(2-amino((R)-2,2,2-trifl uoro(3-(3- lcf O'Vy methyl-lH-pyra zol-l-yl)-4'-sulfamoyl-[1, l '- 689 biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid NH2 (S)(2-amino((R)(4'-carbamoyl(3- methyl-lH-pyrazolyl)-[l, 1'-biphenyl]yl)- leg "o,�' 652 trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4 .51decanecarboxylic acid 0 (S)(2-amino((R)-2,2,2-trifluoro(3-(3- - lH-pyrazol-l-yl)-4'-(methylcarbamoyl)- lch '"'� 666 H � I [I, l'-biphenyl]yl)ethoxy)pyrimidinyl)- azaspiro [4. 5Idecane-f-carboxylic acid (S)(2-amino((R)-2,2,2-trifluoro-l-(3'- I ci � I fluoro-4'-methoxy(3-methyl-1 Il-pyrazol-l- F 657 yl)-[1,1 '-biphenyl]yl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decanecarboxylic acid 0 (S)(2-amino((R)-2,2,2-trifl uoro(3-(3- f'N� methyl-I H-pyrazolyl)-4'-(pipera zine-llcj HN---..) carbonyl)-[1, l 1-biphenyl] 721 yl)ethoxy)pyrimidinyl)-2,8- diazas piro [4.S]decanecarboxylic acid 0 (S)(2-amino((R)-l-(41- 'N� (dimethylcarbamoyl)(3-methyl-lH-pyrazollck I s, I 1-yl)-[1,l1-biphenyl]yl)-2,2,2- 680 triflu oroethoxy)pyr imidinyl)-2,8- diazaspiro]4.Sldecanecarboxylic acid (2-amino((R)-2,2,2-triflu oro(4'- ,,(_,o� lcl � I isobutoxy(3-methyl-1 H-pyra zolyl)-[1,11- biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro]4.Sldecanecarboxylic acid lNJ (S)(2-amino((R)(4'- ylcarbamoyl)(3-methyl-lH-pyrazol lcm yl)-[1, 1'-biphenyl]yl)-2,2,2- 707 o� trifl uoroethoxy)pyrimidinyl)-2,8- diazasnirof4.5[decane-Svcarboxylic acid (S)(2-amino((R)-2,2,2-trifl uoro(3-(3- )Co� 1cn � I methyl-1 H-pyrazolyl)(neopentyloxy)- [ 1, 1'-biphenyl]yl)ethoxy)pyrimidinyl)- co, 2,8-diazaspiro r4.5ldecanecarboxylie acid (S)(2-amino((R)-l-(4-(chromanyl) (3-methyl-1H-pyrazolyl)phenyl)-2,2,2- lco 665 triflu oroe thoxy)pydmidinyl)-2,8- co, diazaspiro [4.Sldecanecarboxylic acid (S)(2-amino((R)- cinnolinyl) (3-methyl-1H-pyrazolyl)phenyl)-2,2,2- lcp � � 661 trifl uoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decanecarboxylic acid -. (S)(2-amino((R)-2,2,2-trifluoro- l-(3 '- xyrnethyl)-4'-methyl(3-methyl-1 H- lcq � pyrazolyl)-[1,1'-biphenyl] 652 h yl)ethoxy)pyrimidinyl)-2,8- diazaspirof4.5]decanecarboxylic acid (S)(2-amino((R)-2,2,2-trifluoro(4'- (hydroxymethyl)-3'-methyl(3-methyl-1 H- lcr HO� pyrazol-l-ylj-j l ,T'-biphenylj=l- 653 oxy)pyrimidinyl)-2,8- diazasnirol4.Sjdecane-Lcarboxylic acid l (S)(2-amino((R)(4-(6-ethoxypyridin yl)(3-methyl-1H-pyraz olyl)phenyl)-2,2,2- 1 cs o�I " triflu oroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid (S)(2-amino((S)-l-(3' ,4'- HO bis(hydroxymethyl)(3-methy1-1H-pyrazol 1 ct � yl)-[1, 1 '-biphenyl]yl)-2,2,2- 669 .,,.-,,:, trifl uoro ethoxy)pyrimidiny1)-2,8- � diazaspiro]4.5]decanecarboxylic acid Table lb. 1H NMR Data for Compounds of Table la Ex. 1HNMR la 1H NMR (MeOH-d4): o ppm 1.29 (m, 3H), 1.68 (q, J = 6.3 Hz, 4H), 2 .10 (dd, J = 13 .6, 8.1 Hz, IH), 2.41 (s, 4H), 2.85 (s, 3H), 3.24 (m, 2H), 3.62 (m, IH), 3 .71 (s, 2H), 3.79 (dd, J = 13. 7, 5.8 Hz, 2H), 4.44 (t, J = 8.5 Hz, HI), 4.83 (s, 2H), 6.44 (d, J = 2.4 Hz, 1H), 6.92 (q, J = 6.2 Hz, lH), 7.88 (m, 8H) lb 1HNMR (400 MHz, MeOI-I-d4): 8 ppm 1 .3 1 (m, 3H), 1.6 0 (t, J = 5.6 Hz, 4H), 2.06 (dd, J = 13.4 , 7.0 Hz, IH), 2.40 (s, 4H), 2 .51 (s, 3H), 2.80 (s, 1 H) , 3 . 13 (d, J = 11 . 5 Hz, lH), 3.25 (d, J = 1 LO Hz, lH), 3 .53 (dd, J = 22 .1, 9.7 Hz, 2H), 3.69 (d, J = 14.9 Hz, 2H), 4.1 4 (t, J = 8 . 1 Hz, lH), 4.93 (s, lH), 6.42 (d, J = 2.3 Hz, lH), 6.79 (q, J = 6.5 Hz, HI), 7.34 (m, 2H), 7.63 (dd, J = 8.9, 2 .1 Hz, 3H), 7.77 (m, 2H), 7.97 (d, J = 2.3 Hz, lH) le 1H NMR (400 MHz, MeOH-d4): o ppm 1 .4 (d, J = 18 .0 Hz, lH), 1 .68 (q, J = 6.8, 5 .6 Hz, 4H), 2.4 (dd, J = 13 .6, 8 .1 Hz, lH), 2.41 (s, 4H), 2.85 (s, IH), 3.25 (m, 2H), 3 .64 (m, lH), 3.72 (s, lH), 3.79 (d, J = 13 .8 Hz, 2H), 4.44 (q, J = 8.6 Hz, 11-1), 6.5 (d, J = 2.4 Hz, lH), 6.92 (dd, J = 1 0.5 , 4.4 Hz, lH), 7.95 (m, SH), 8 .1 (d, J = 2.5 Hz, IH), 8.4(m, Jd 1H NMR (400 MHz, MeOH-d4): s ppm 1.68 (dt, J = 9.0, 5 .8 Hz, 4H), 2.09 (dd, J = 13.6, 8.1 Hz, lH), 2.41 (s, 4H), 3.24 (m, 2H), 3.72 (m, 4H), 4.45 (t, J = 8 .5 Hz, 1 H), 6.44 (d, J = 2.3 Hz, lH), 6.90 (q, J = 6.2 Hz, lH), 7.61 (t, J = 7.8 Hz, IH), 7.75 (d, J = 1 . 7 Hz, 1 H), 7. 85 (m, 2H), 7 .98 (m, 2H), 8.08 (dt, J = 7 .8, 1 .3 Hz, 1 H), 8.34 (t, J = 1 . 8 Hz, lH) le 1H NMR (400 MHz, MeOH-d4): 8 ppm 1 .68 (dt, J = 9.0, 5 .8 Hz, 4H), 2.09 (dd, J = 13.6, 8 .1 Hz, 1H), 2.41 (s, 4H), 3.24 (m, 2H), 3.72 (m, 4H), 4.45 (t, J = 8.5 Hz, JI-I ), 6.44 (d, J = 2.3 Hz, lH), 6.90 (q, J = 6.2 Hz, lH), 7.61 (t, J = 7.8 Hz, lH), 7.75 (d, J = 1.7 Hz, l H), 7.85 (m, 2H), 7.98 (m, 2H), 8.08 (dt, J = 7.8, 1.3 Hz, lH), 8.34 (t, J = 1.8 Hz, lH) 1f 1H NMR (400 MHz, MeOH-d4): o ppm 1.47 - 1.69 (m, 4 H) 1.97 - 2.13 (m, 1 H) 2.19 - 2.35 (m, 1 H) 2.37 (d, J=0.34 Hz, 0 H) 2.66 - 2.81 (m, 2 H) 3.05 - 3.17 (m, 1 H) 3.18 - 3.28 (m, 1 H) 3.33 - 3.40 (m, 2 H) 3.41 - 3.72 (m, 4 H) 3.73 - 3.83 (m, 2 H) 3.99- 4.13 (m, 1 H) 5.71 (s, 1 H) 6.32 (d, J=0.39 Hz, 1 H) 6.41 (d, J=2.29 Hz, 2 H) 6.67 - 6.79 (m, 1 H) 7.49 (d, J=l.81 Hz, 1 H) 7.55 - 7.64 (m, 1 H) 7.72 (d, J=8.40 Hz, 2 H) 7.92 (d, J=2.29 Hz, 1 H) lg 1H NMR (400 MHz, MeOH-d4): o ppm 1.49 - 1.69 (m, 4 H) 2.06 (dd, 7, 7.03 Hz, 1 H) 2.31 (dd, J=13.42, 9.32 Hz, 1 H) 2.41 (s, 3 H) 3.12 (d, J=l2.00 Hz, 1 H) 3.25 (d, J=l 1.76 Hz, 1 H) 3.38 - 3.57 (m, 2 H) 3.58- 3.76 (m, 2 H) 4.08 (dd, J=9.13, 7.17 Hz, 1 H) 5.74 (s, 1 H) 6.44 (d, 1=2.34 Hz, 1 H) 6.87 (q, J=6.62 Hz, 1 H) 7.75 - 7.80 (m, 2 H) 7.82 (s, 1 H) 7.89 (s, 2 H) 8.02 (d, J=2.34 Hz, 1 H), 8.57 - 8.69 (m, 2 H) lh 1H NMR (400 MHz, Me0H-d4): o ppm 1.61 - 1.84 (m, 5 H) 2.10 (dd, 1=13.62, 8.49 Hz, 1 H) 2.40 (s, 3 I-I) 2.47 (dd, J=13.76, 8.88 Hz, 1 H) 3.25 - 3.29 (m, 2 H) 3.73 - 3.91 (m, 4 H) 3.94 (s, 3 H) 4.53 (t, J=8.64 Hz, 1 H) 6.42 (d, J=2.39 Hz, 1 H) 6.81 (q, J=5.94 Hz, 1 H) 7.61 - 7.70 (m, 2 H) 7.71 - 7.78 (m, 1 H) 7.90 - 7.96 (m, 2 H) 8.12 (s, 1 H) li IH NMR (400 MHz, 4): s ppm 1.35 - 1.40 (m, 5 H), 1.60-1.65 (m, 8 H), 2.40 (m, 5 H) 2.47 (dd, 1=13.76, 8.88 Hz, 1 H) 3.25 - 3.29 (m, 2 H) 3.73 - 3.91 (m, 4 I-I) 3.94 (s, 3 H) 4.53 (t, J=8.64 Hz, 1 H), 5.6 (s, lH), 6.42 (d, J=2.39 Hz, 2 H) 6.70 (m, 1 H) 7.61 - 7.70 (m, 2 H) 7.71 - 7.78 (m, 1 H) 7.90 - 7.96 (m, 2 H) 8.12 (s, 1 H) 1'J 1H NMR (400 MHz, MeOH-d4): o ppm 1.58 - 1.86 (m, 4 H) 2.01 - 2.20 (m, 1 H) 2.40 (s, 3 H) 2.43 - 2.61 (m, 3 H) 3.61 - 3.75 (m, 2 H) 3.86 (s, 4 H) 3.93 (t, J=5.44 Hz, 2 H) 4.25 - 4.37(m, 2 H) 4.49 - 4.69 (m, 1 H) 6.42 (d, J=2.24 Hz, 2 H) 6.52 (br, s., 1 H) 6.77 - 6.88 (m, 1 H) 7.51 (d, J=l.32 Hz, 1 H) 7.60 - 7.73 (m, 2 H) 7.91 (d, J=2.34 Hz, 1 H) lk 1H NMR (400 MHz, MeOH-d4): s ppm 1.72 (d, J=18.21 Hz, 4 H) 2.09 (dd, J=13.62, 8.49 Hz, 1 H) 2.18 (d, J=14.50 Hz, 3 I-I) 2.39 (s, 3 H) 2.48 (dd, J=13.64, 8.91 Hz, 1 H) 2.58 (br.s., 1 H) 2.66 (br. s., 1 H) 3.60" 3.95 (m, 6 H) 4.24 (br. s., 2 H) 4.55 (t, J=8.71 Hz, 1 H) 6.33 (br. s., 1 H) 6.42 (d, J=2.34 Hz, 1 H) 6.46 (br. s., 1 H) 6.75 - 6.87 (m, l H) 7.52 (s, 1 H) 7.62 - 7.74 (m, 2 H) 7.92 (d, J=2.34 Hz, 1 H) 1 1 11-I NMR (400 MHz, MeOH-d4): 8 ppm 1.29 (d, J=6.05 Hz, 6 H) 1.49 (d, J=5.47 Hz, 4 H) 1.70 - 1.86 (m, 1 H) 1.98 - 2.15 (m, 1 H) 2.37 (s, 3 H) 2.69 (d, J=l 1.13 Hz, 1 H) 2.93 (s, 1 H) 3.35 - 3.52 (m, 2H) 3.53 - 3.64 (m, 2 H) 3.64 - 3.73 (m, 1 H) 4.59 (s, 1 H) 5.71 (s, 1 H) 6.38 (d, J=2.15 Hz, 1 H) 6.68 - 6.82 (m, 1 H) 6.93 (d, J=8.79 Hz, 2 H) 7.44 - 7.58 (m, 3 H) 7.64 (d, J=l.37 Hz, 1 H) 7.67 - 7.78 (m, 1 H) 7.93 (d, J=2.15 Hz, 1 H) lm 1H NMR (400 MHz, Me0H-d4): s ppm 1.51 (d, J=5.47 Hz, 4 H) 1.71 " 1.86 (m, 1 H) 2.01 " 2 . 17 (m, 1 H) 2.28 (s, 3 H) 2.31 (s, 3 H) 2.39 (s, 3 H) 2.64 - 2.78 (m, 1 H) 2.90 - 3.05 (m, 1 H) 3.36 - 3.54 (m, 2 H) 3.55 - 3.79 (m, 3 H) 5.73 (s, 1 H) 6.41 (d, J=2.15 Hz, 1 H) 6.69 - 6.87 (m, 1 H) 7.20 (s, 1 H) 7.33 - 7.40 (m, 1 H) 7.43 (s, 1 H) 7.59 (d, J=I.37 Hz, 1 H) 7.70 (s, 1 H) 7.75 (s, 1 H) 7.96 (d,J=2.15 Hz, 1 H) ln 1H NMR (400 MH z, Me0H-d4): s ppm 1.53 (d, J=5.86 Hz, 4 H) 1.75 - 1.87 (m, 1 H) 2.04 - 2.17 (m, 1 H) 2.41 (s, 3 H) 2.64 - 2.76 (m, 1 H) 2.91 - 3.04 (m, 1 H) 3.38 - 3.54 (m, 2 H) 3.55 - 3.74 (m, 3 H), 3.95 (s, 3 H) 5.72 (s, 1 H) 6.44 (d, J=2.34 Hz, 1 H) 6.79 - 6.92 (m, 1 H) 7. 12 (s, 1 H) 7.23 - 7.31 (m, 1 H) 7.74 (d, J = l.17 Hz, 1 H) 7.79 - 7.89 (m, 2 H) 8.02 (d, J=2.15 Hz, 1 H) 8.15 - 8.25 (m, 1 H) lo 1H NMR (400 MHz, Me0H-d4): o ppm 1.60 (br. s., 4 H) 2.02 - 2.17 (m, 1 H) 2.24 - 2.39 (m, 1 H) 2.43 (s, 3 H) 2.53 - 2.66 (m, 4 H) 3.07 - 3.17 (m, I H) 3.21 - 3.29 (m, 1 H) 3.40- 3.59 (m, 2 H) 3.61- 3.80 (m, 2 H) 4.00 - 4.18 (m, 1 H) 5.77 (s, 1 H) 6.45 (d, J=2.15 Hz, 1 H) 6.75 - 6.90 (m, 1 H) 7.36- 7.56 (m, 1 H) 7.73 (d, J=4.10 Hz, 2 H) 7.77 - 7.89 (m, 4 H) 8.01 (d, J=2.15 Hz, 1 H) lp 1H NMR (400 MHz, MeOH-d4): o ppm 1.24 - 1.42 (m, 9 H) 1.60 (br. s., 4 H) 2.02 - 2.12 (m, l H) 2.42 (s, 4 H) 3.05 - 3.17 (m, 1 H) 3.20 - 3.29 (m, 1 H) 3.41 - 3.79 (m, 4 H) 4.02-4.17 (m, 1 H) 5.78 (s, 1 H) 6.43 (d, J=2.15 Hz, 1 H) 6.73 -6.88 (m, 1 H) 7.51 (d, J=8.40 Hz, 2 H) 7.57-7.69 (m, 3 H) 7.78 (s, 2 H) 7.98 (d, J=2.15 Hz, 1 H) lq 1H NMR (400 MHz, MeOH-d4): o ppm 1.41 (t, J=7.03 Hz, 3 H) 1.60 (br, s., 4 H) 1.95 - 2.14 (m, 1 H) 2.27 -2.38 (m, 1 H) 2.41 (s, 3 H) 3.14 (s, 1 H) 3.20- 3.29 (m, 1 H) 3.41- 3.59 (rn, 2 H) 3.60 - 3.83 (m, 2 H) 3.99 - 4.20 (m, 3 H) 5.77 (s, 1 H) 6.43 (d, J=2.34 Hz, 1 H) 6.71 - 6.85 (m, lH) 7.00 (d, J=8.79 Hz, 2 H) 7.52 - 7.65 (m, 3 H) 7.72 (d, J=l .56 Hz, 1 H) 7.76 (s, 1 H) 7.97 (d, J=2.34 Hz, 1 H) Ir 1HNMR (400 MHz, MeOH-d4): s ppm 1.62 (d, J=4.88 Hz, 4 H) 2.02 - 2.13 (m, 1 H) 2.27 - 2.38 (m, 1 H) 2.42 (s, 3 H) 3.16 (s, 1 H) 3.26 (s, lH) 3.41 - 3.59 (m, 2 H) 3.60 - 3.78 (m, 2 H) 3.99 - 4.19 (m,4 H) 5.76 (s, 1 H) 6.45 (d, J=2.34 Hz, 1 H) 6.82 - 6.96 (m, 1 H) 7.74 (d, J=l.56 Hz, 1 H) 7.81 (d, J=l.56 Hz, l H) 7.86 (s, 1 H) 8.03 (d, J=2.15 Hz, 1 H) 8.92 (s, 2 H)) ls 1HNMR (400 MHz, Me0H-d4): 8 ppm 1.59 (br. s., 4 H) 2.01 - 2.14 (m, 1 H) 2.31 (br. s., 1 H) 2.41 (s, 3 H) 3.07 - 3.17 (m, 1 H) 3.21 - 3.29 (m, 1 H) 3.40 - 3.59 (m, 2 H) 3.67 (d, J=5.47 Hz, 2H) 3.95 (s, 3 H) 4.09 (d, J=l.17 Hz, 1 H) 5.75 (s, 1 H) 6.43 (d, J=2.15 Hz, 1 H) 6.82 (d, J=6.44 Hz, 1 H) 6.88 (d, J=8.79 Hz, 1 H) 7.64 (d, J=l.56 Hz, 1 H) 7.68 - 7.76 (m, 1 H) 7.77 - 7.87 (m, 1 H) 7.93 - 8.07 (m, 2 H) 8.45 (d, J=2.34 Hz, 1 H) lu 1H NMR (400 MHz, MeOH-d4): o ppm 1.42 - 1.74 (m, 4 H) 2.05 (dd, J=13.50, 7.20 Hz , 1 H) 2.40 (s, 4 H) 3.07 - 3.16 (m, 1 H) 3 .17 - 3.29 (m, 1 H) 3.38 - 3.59 (m, 2 H) 3.59 - 3.78 (m, 2 H) 4.11 (dd, , 7.25 Hz, 1 H) 6.42 (d) J=2.34 Hz, 1 H) 6.74 - 6.86 (m, 1 H) 7.34 - 7.41 (m, 1 H) 7.42 - 7.50 (m, 2 H) 7.60 - 7.69 (rn, 3 H) 7.71 - 7.77 (m, 1 H) 7.77 - 7.83 (m, 1 H) 7.97 (d, J=2.00 Hz, 1 H) Iv 1H NMR (400 MHz, MeOH-d4): s ppm 1.24 (t, J=7.59 Hz, 3 H) 1.50 - 1.69 (m, 4 H) 2.06 (dcl, J=13.42) 7.13 Hz, 1 H) 2.32 (dd, J=13.45, 9.20 Hz) 1 H) 2.37 (s, 3 H) 2.72 (q, J=7.61 Hz, 2 H) 3.08 - 3.27 (m, 2 H) 3.39 - 3.78 (m, 4 H) 4.08 (dd, J=9.13, 7.17 Hz, 1 H) 5.74 (s, 1 H) 6.36 (d, J=2.34 Hz, 1 H) 6.71 (q, 1=6.65 Hz, 1 H) 7.26 - 7.34 (m, 1 H) 7.35 - 7.44 (m, 1 H) 7.56 (s, 1 H) 7.82 (d, J=2.29 Hz, 1 H) lw 1H NMR (400 MHz, 4): o ppm 1.51 - 1.64 (m, 4 H) 1.96 (s, 2 H) 2.04 (dd, 1=13.23, 7.32 Hz, 1 H) 2.25 - 2.34 (m, 1 H) 2.38 (s, 3 H) 3.09 (d, 1=11.67 Hz, 1 H) 3.23 (d, J=l 1.81 Hz, I H) 3.38 - 3.56 (m, 2 H) 3.59 - 3.73 (m, 2 H) 4.00 - 4.10 (m, 1 H) 5.73 (s, l H) 6.41 (d, J=2.34 Hz) 1 H) 6.79 - 6.89 (m, 1 H) 7.61 w 7.67 (m, 1 H) 7.69 - 7.88 (m,4 H) 7.96 - 8.02 (111, 2 H) 8.08 (t, J=l.59 Hz) 1 H) lx 1H NMR (400 MHz, MeOH-d4): s ppm 1.49 - 1.64 (m, 4 H) 1.97 (s, 3 H) 1.98 (s, 3 H) 2.04 (dd, J=13.35, 7.15 Hz, 1 I-I) 2.29 (dd, J=13.47, 9.18 Hz, 1 H) 2.38 (s, 3 H) 3.05 w 3.26 (m, 2 H) 3.39 - 3.73 (m, 4 H) 4.05 (dd, 1=9.18, 7.22 Hz, I H) 4.38 (s, 2 H) 5.73 (s, 1 H) 6.40 (d, 1=2.29 Hz, 1 H) 6.77 (q, J=6.67 Hz, 1 H) 7.37 (d, J=8.40 Hz, 2 H) 7.59 w 7.66 (m, 3 H) 7.71 - 7.81 (m, 2 H) 7.95 (d, J=2.34 Hz, 1 H) ly 1H NMR (400 MHz, MeOH-d4): s ppm 1.57 (t, J=4.44 Hz, 4 H) 1.89 (s, 3 H) 1.97 (s, 4 H) 2.04 (dd, J=13.37, 7.13 Hz, 1 H) 2.29 (dd, J=l3.28, 9.18 Hz, 1 H) 2.38 (s, 3 H) 2.82 (t,J=7.32 Hz, 2 H) 3.06 - 3.25 (m, 2 H) 3.40 (t, J=7.32 Hz, 2 H) 3.43 - 3.73 (m, 4 H) 4.05 (dd, J=9.18, 7.27 Hz, I I-I) 5.74 (s, 1 H) 6.40 (d, J=2.25 Hz, 1 H) 6.77 (q, J=6.80 Hz, 1 H) 7.31 (d, J=8.30 Hz, 2 H) 7.57 - 7.63 (m, 3H) 7.70 - 7.80 (m, 2 H) 7.95 (d, J=2.34 Hz, 1 H) lz 1H NMR (400 MHz, MeOI-I-d4): s ppm 1.53 - 1.61 (m, 4 H) 1.97 (s, 3 H) 2.04 (dd, J=l3.32, 7.03 Hz, 1 H) 2.30 (dd, J=13.59, 9.30 Hz, 1 H) 2.40 (s, 3 H) 3.06 - 3.26 (m, 2 H) 3.40 - 3.72 (m, 4 H) 4.06 (dd, J=8.91, 7.25 Hz, 1 H) 5.76 (s, 1 H) 6.42 (d, J=2.29 Hz, 1 H) 6.85 (q, J=6.51 Hz, 1 H) 7.55 (dd, J=8.27, 4.32 Hz, 1 H) 7.82 (d, J=l.71 Hz, 1 H) 7.85 - 7.99 (m, 3 H) 8.00 - 8.07 (m, 2 H) 8.29 (s, 1 H) 8.39 (d, J=7.61 Hz, 1 H) 8.88 (dd, J=4.30, 1.66 Hz, 1 H) laa 1H NMR (400 MHz, Me0H-d4): o ppm 1.59 (d, J=4.69 Hz, 4 H) 1.99 - 2.13 (m, 1 H) 2.24-2.39 (m, 1 H) 3.03 - 3.14 (m, 1 H) 3.17 - 3.27 (m, 1 H) 3.38- 3.54 (m, 2 I-I) 3.55 - 3.75 (m, 2 H) 3.99 - 4.14 (m, 1 H) 5.56 (s, 1 H) 6.46 (d, J=2.93 Hz, 1 H) 6.58 - 6.71 (m, 1 H) 7.27 (d, J=3.12 Hz, 1 H) 7.29 - 7.36 (m, 1 H) 7.54 - 7.66 (m, 4 H) 7.70 (d, 1=8.20 Hz, 2H) lab 1HNMR (400 MHz, MeOH-d4): o ppm 1.52 - 1.62 (m, 4 H) 1.92 (s, 5 H) 1.99 - 2.09 (m, 1 H) 2.27 (dd, J=13.42, 9.22 Hz, 1 I-1) 2.38 (s, 3 I-1) 3.06 - 3.26 (m, 2 H) 3.39 - 3.73 (m,4 H) 4.00 - 4.08 (m, 1 H) 4.13 (s, 2 I-I) 5.72 (s, 1 I-I) 6.41 (d, J=2.29 Hz, 1 H) 6.78 .49 Hz, l H) 7.53 (d, J=8.30 Hz, 2 H) 7.66 (d, J=l.66 Hz, 1 H) 7.73 - 7.84 (m, 4 H) 7.97 (d, J=2.25 Hz, l H) lac 1H NMR (400 MHz, MeOH-d4): o ppm 1.51 - 1.70 (m, 4 H) 2.06 (dd, 7, 7.13 Hz, 1 H) 2.31 (dd, J=13.28, 9.37 Hz, 1 H) 2.41 (s, 3 H) 3.08 - 3.19 (m, 1 H) 3.20 -1 29 (m, 1 H) 3.39 - 3.78 (m, 4 H), 4.01 -4.19 (m, 1 H) 5.75 (s, 1 H) 6.43 (d, J=2.15 Hz, 1 H) 6.84 (d, J=6.64 Hz, 1 I-I) 7.06 - 7.19 (m, 1 H) 7.37 - 7.52 (m, 3 H) 7.65 (d, J=l.56 Hz, I H) 7.70 - 7.77 (rn, 1 H) 7.78 - 7.86 (m, 1 H) 8.00 (d, J=2.15 Hz, 11- 1) lad 1H NMR (400 MHz, MeOH-d4): o ppm 1.53 - 1.68 (m, 4 H) 2.00 - 2.1 1 (m, 1 H) 2.25 - 2.36 (m, 1 H) 2.44 (s, 3 I-I) 3.03 - 3 . 13 (m, 1 H) 3.18 - 3.26 (m, 1 H) 3.42 - 3.60 (m, 2 H) 3.62- 3.80 (m, 2 H) 3.98 - 4.12 (m, 1 H) 5.73 - 5.86 (m, 1 H) 6.38 - 6.53 (m, 1 H) 6.80- 6.96 (m, 1 H) 7.56 - 7.64 (m, 1 H) 7.82 - 7.93 (m, 2 H) 7.93 - 8.00 (m, 1 H) 8.03 - 8.09 (m, 1 I-D 8.16 (s, 2 I-I) 8.28 - 8.38 (m, 1 H), 8.42 - 8.55 (m, 1 H) 8.80 - 8.97 (m, 1 H) lae 11-I NMR (400 MHz, MeOH-d4): o ppm 0.89 (t, J = 6.7 Hz, lH), 1.30 (d, J = 16.8 Hz, 3H), 1.57 (q, J = 8.1, 5.5 Hz, 4H), 1.98 (m, lH), 2.24 (m, lH), 2.38 (d, J = 10.5 Hz, 6H), 2.99 (d, J = 11.6 Hz, 1H), 3.16 (d, J = 11.5 Hz, ll-1), 3.48 (ddt, J = 20.2, 13.1 , 6.1 Hz, 3H), 3.65 (dd, J = 13.9, 6.2 Hz, 2H), 3.96 (t, J = 8.0 Hz, lH), 5.75 (s, lH), 6.41 (d, J = 2.3 Hz, lH), 6.77 (q, J = 6.6 Hz, lH), 7.26 (d, J = 7.8 Hz, 2H), 7.58 (m, 3H), 7.74 (m, 2H), 7.96 (d, J = 2.4 Hz, II-I) laf lH NMR (400 MHz, MeOH-d4): o ppm 0.90 (m, lH), 1.27 (m, SH), 1.51 (dt, J = 10.5, .6 Hz, 4H), 1.75 (dd, J = 13.1 , 7.2 Hz, lH), 2.09 (dd, J = 13.1, 8.7 Hz, lI-I), 2.40 (s, 3H), 2.76 (d, J = 11.0 Hz, IH), 2.90 (d, J = 11.0 Hz, lH), 3.54 (m, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, IH), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.73 (s, lH), 6.43 (d, J = 2.4 Hz, lH), 6.84 (q, J = 6.5 Hz, lH), 7.64 (m, 3H), 7.80 (m, 3H), 8.01 (d, J = 2.4 Hz, lH) lag 1H NMR (400 MHz, MeOH-d4): s ppm 1.29 (d, J = 14.8 Hz, lH), 1.58 (s, 8H), 2.05 (m,2H), 2.39 (s, 8H), 3.12 (d, J = 1 1.1 Hz, 2H), 3.24 (d, J = 11.2 Hz, 3H), 3.47 (s, 3H), 3.53 (s, lH), 3.64 (s, 4H), 4.11 (s, 2H) , 4.96 (s, 11-I), 6.42 (d, J = 2.0 Hz, 2H), 6.83 (q, J = 6.6 Hz, 2H), 7.33 (q, J = 9.0 Hz, 2H), 7.47 (t, J = 6.1 Hz, 2H), 7.65 (m, 6I-I), 7.79 (d, J = 8.1 Hz, 2H), 7.99 (d, J = 2.0 Hz, 2H) lah 1HNMR (400 MHz, 4): s ppm 1.29 (d, J = 10.2 Hz, 1H), 1.57 (t, J = 5.3 Hz, 5H), 2.04 (dd, J = 13.2, 6.9 Hz, 1H), 2.34 (m, 5H), 3.09 (d, J = 11.8 Hz, l+I), 3.22 (m, 2H), 3.48 (dd, J = 25.5, 12.5 Hz, 3H), 3.64 (s, 3H), 4.06 (t, J = 7.9 Hz, lH), 4.83 (s, 2H), 4.93 (s, lH), 5.74 (s, lH), 6.41 (d, J = 2.4 Hz, lH), 6.81 (q, J = 6.7 Hz, lH), 7.45 (d, J = 8.2 Hz, 2H), 7.65 (m, 3H), 7.76 (m, 3H), 7.98 (d, J = 2.3 Hz, lH) lai 1H NMR (400 MHz, Me0H-d4): s ppm 0.91 (tt, J = 8.8, 4.7 Hz, IH), 1.32 (m, 3H), 1.58 (h, J = 5.2, 4.4 Hz, 8H), 1.99 (m, 2H), 2.25 (dd, J = 13.4, 9.0 Hz, 2H), 2.40 (s, 6H), 3.03 (d, J= 11.5 Hz, 2H), 3.18 (d, J = 11.5 Hz, 2H), 3.48 (ddt, J = 21.1, 13.0, 5.9 Hz, 51-I), 3.62 (dt, J = 11.3, 6.3 Hz, 4H), 3.98 (t, J = 7.9 Hz, 2H), 5.73 (s, 2H), 6.44 (d, J = 2.4 Hz, 2H), 6.90 (q, J = 6.6 Hz, 2H), 7.86 (m, 6H), 8.04 (d, J = 2.4 Hz, 2H), 9.15 (d, J = 11.9 Hz, 6H) lak 1H NMR (400 MHz, MeOH-d4): s ppm 1.28 (s, IH), 1.67 (dt, J = 11.3, 5.3 Hz, 4H), 2.08 (dd, J = 13.6, 8.1 Hz, lH), 2.40 (m, 4H), 3.25 (q, J = 11.8, 9.3 Hz, 3H), 3.67 (m, 4H), 4.43 (t, J = 8.5 Hz, IH), 6.44 (d, J = 2.4 Hz, IH), 6.95 (q, J = 6.3 Hz, l H), 7.77 (dt, J = 5.4, 1.8 Hz, 2H), 7.86 (d, J = 1.4 Hz, 2H), 7.96 (m, lH), 8.05 (d, J = 2.4 Hz, 2H) lal 1H NMR (400 MHz, MeOH-d4): s ppm 1.28 (s, lH), 1.44 (t, J = 7.0 Hz, 3H), 1.57 (t, J = 5.6 Hz, 4H), 2.02 (dd, J = 13.4, 7.0 Hz, lH), 2.28 (dd, J = 13.3, 9.1 Hz, lH), 2.39 (s, 3H), 3.06 (d, J = 11.6 Hz, IH), 3.21 (d, J = 11.6 Hz, lH), 3.47 (dd, J = 22.4, 13.7 Hz, 3H), 3.65 (dd, J = 13.8, 6.9 Hz, 2H), 4.03 (t, J = 8.1 Hz, lH), 4.14 (q, J = 7.0 Hz, 2H), 4.93 (s, 2H), 5.75 (s, lH), 6.41 (d, J = 2.3 Hz, lH), 6.78 (q, J = 6.6 Hz, lH), 7.12 (d, J = 8.7 Hz, lH), 7.57 (m, 2H), 7.73 (m, 3H), 7.98 (d, J = 2.4 Hz, lH) lam 1H NMR (400 MHz, MeOH-d4): o ppm 1.29 (d, J = 3.7 Hz, 2H), 1.55 (m, 4H), 1.92 (dd, J = 13.4, 7.2 Hz, 11-I) , 2.19 (t, J = 10.6 Hz, 1H), 2.40 (s, 3H), 2.88 (d, J = 11.4 Hz, lH), 3.10 (d, J = 11.5 Hz, 1 H), 3.47 (dd, J = 22.2, 15.6 Hz, 3H), 3.64 (s, 3H), 3.85 (t, J = 8.1 Hz, IH), 5.74 (s, lH), 6.43 (d, J = 2.4 Hz, lH), 6.83 (q, J = 6.6 Hz, lH), 7.69 (m, 3H), 7.82 (m, 2H), 7.99 (rn, 3H) lan 1H NMR (400 MHz, MeOH-d4): B ppm 1.17 (t, J = 7.0 Hz, lH), 1.29 (m, lH), 1.57 (d, J = 5.9 Hz, 4H), 2.00 (dd, J = 13.4, 7.0 Hz, lH), 2.26 (dd, J = 13.1, 9.4 Hz, lH), 2.38 (d, J = 9.1 Hz, 6H), 3.03 (d, J = 11 . 6 Hz, IH), 3.18 (d, J = 11.5 Hz, 11-I ), 3.47 (ddt, J = 20.8, 13.2, 6.0 Hz, 2H), 3.62 (h, J = 7.1, 6.4 Hz, 3H), 4.00 (t, J = 7.9 Hz, lH), 4.89 (s, 9H), .74 (s, lH), 6.41 (d, J = 2.3 Hz, lH), 6.82 (q, J = 6.9, 6.4 Hz, lH), 7.21 (s, lH), 7.40 (s, IH), 7.45 (s, lH), 7.60 (d, J = 1.9 Hz, lH), 7.68 (dd, J = 8.0, 1.8 Hz, 1H), 7.78 (d, J = 8.2 Hz, IH), 7.99 (d, J = 2.3 Hz, IH) tao 1H NMR (400 MHz, MeOH-d4): s ppm 1 .28 (m, 2H), 1.55 (q, J = 7.5, 5.1 Hz, 4H), 1.94 (dd, J = 13.2, 6.9 Hz, lH), 2.21 (dd, J = 13.1, 8.9 Hz, lH), 2.39 (s, 3H), 2.94 (d, J = 11.5 Hz, lH), 3.12 (d, J= 11.2 Hz, IH), 3.46 (ddt, J = 20.2, 13.0, 5.9 Hz, 2H), 3.63 (dd, J = 13.7, 6.1 Hz, 2H), 3.90 (t, J = 8.0 Hz, lH), 4.85 (d, J = 9.0 Hz, IH), 5.73 (s, lH), 6.42 (d, J = 2.4 Hz, l H), 6.83 (q, J = 6.6 Hz, lH), 7.57 (m, 4H), 7.77 (m, 2H), 8.00 (d, J = 2.4 Hz, lH) lap 1HNMR (400 MHz, MeOH-d4): o ppm 1.29 (d, J = 11.9 Hz, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.59 (t, J = 5.7 Hz, 4H), 2.05 (dd, J = 13.4, 7.2 Hz, lH), 2.39 (s, 4H), 3.12 (d, J = 11.6 Hz, lH), 3.24 (d, J = 11.7 Hz, IH), 3.51 (ddt, J = 25.1, 13.2, 5.8 Hz, 2H), 3.67 (dd, J = 13.8, 5.7 Hz, 2H), 4.10 (dq, J = 14.0, 7.7, 7.0 Hz, 3H), 6.41 (d, J = 2.3 Hz, lH), 6.79 (q, J = 6.6 Hz, HI), 6.93 (dd, J = 8.2, 2.5 Hz, HI), 7.19 (m, 21-1), 7.34 (t, J = 7.9 Hz, lH), 7.62 (d, J = 1.8 Hz, IH), 7.75 (m, 2H), 7.97 (d, J = 2.4 Hz, IH) laq 11-I NMR (400 MHz, Me0H-d4): s ppm 0.89 «, J = 7.2 Hz, IH), 1.28 (s, 4H), 1.58 (t, J = 5.6 Hz, 4H), 2.05 (dd, J = 13.5, 7.1 Hz, lH), 2.29 (d, J = 1.8 Hz, 4H), 2.39 (s, 3H), 3.10 (d, J = 11.8 Hz, lH), 3.24 (d, J = 11.5 Hz, lH), 3.49 (ddt, J = 21.1, 12.9, 5.8 Hz , 3H), 3.68 (ddt, J = 18.9, 12.4, 6.2 Hz, 3H), 4.07 (m, lH), 5.75 (s, lH), 6.41 (d, J = 2.3 Hz, lH), 6.80 (q, J = 6.5 Hz, lH), 7.37 (m, 3H), 7.63 (d, J = 1.8 Hz, lH), 7.76 (m, 2H) , 7.98 (d, J = 2.3 Hz, l H) l ar 1HNMR (400 MHz, MeOH-d4): o ppm 1.57 (t, J = 5.8 Hz, 4H), 1.99 (dd, J = 13.3, 7.0 Hz, lH), 2.25 (dd, J = 13 .3, 9.1 Hz, lH), 2.39 (s, 3H), 3.00 (d, J = 11.3 Hz, lH), 3.17 (d, J = 11.5 Hz, lH), 3.31 (d, J = 2.4 Hz, 4H), 3.49 (m, 2H), 3.65 (dd, J = 13.8, 6.6 Hz, 2H), 3.97 (t, J = 8.1 Hz, lH), 5.74 (s, lH), 6.42 (d, J = 2.3 Hz, lH), 6.83 (q, J = 6.6 Hz, lH), 7.33 (t, J = 8.8 Hz, lH), 7.65 (m, 2H), 7.73 (dd, J = 8.2, 1 .9 Hz, lH), 7.82 (m, 2H), 8.00 ( d, J = 2.3 Hz, lH) las 1H NMR (400 MHz, 4): s ppm 1.28 (s, lH), 1.60 (m, 4H), 2.05 (dd, J = 13.4, 7.1 Hz, l H), 2.32 (dd, J = 13.4, 9 .1 Hz, 11-I), 2.40 (s, 3H), 3.12 (d, J = 11.7 Hz, lH), 3.24 (d, J = 1 1 .7 Hz, lH), 3.51 (dq, J = 24.6, 7.3, 6.5 Hz, 2H), 3.66 (dt, J = 11.7 , 6.2 Hz, 2H), 4.11 (dd, J = 9.1, 7.1 Hz, IH), 6.42 (d, J = 2.3 Hz, lH), 6.83 (q, J = 6.3 Hz, lH), 7.32 (m, lH), 7.58 (dd, J = 15.5, 7.5 Hz, 2H), 7.69 (m, 2H), 7.80 (m, 2H), 8.01 (d, J = 2.3 Hz, lH) lat 11-I NMR (400 MHz, MeOH-d4): s ppm 1.28 (s, lH), 1.57 (m, 4H) , 1.97 (dd, J = 13.1, 6.8 Hz, lH), 2.23 (m, 2H), 2.37 (d, J = 18.2 Hz, 9H), 2.98 (d, J = 1 1.6 Hz, lH), 3.15 (d, J = 11.5 Hz, lH), 3.48 (ddt, J = 20.5, 13.0, 5.8 Hz, 2H), 3.65 (dd, J = 13.4, 5.8 Hz, 2H), 3.94 (dd, J = 9.1, 7.1 Hz, lH), 5.75 (s, lH), 6.41 (d, J = 2.3 Hz, lH), 6.78 (q, J = 6.6 Hz, 11-I), 7.03 (s, lH), 7.27 (ct, J = 1.6 Hz, 21-I), 7.59 (ct, J = 1.8 Hz, lH), 7.73 (m, 2H), 7.97 (d, J = 2.4 Hz, lH) lau 1H NMR (400 MHz, Me0H-d4): 8 ppm 1.29 (d, J = 3.4 Hz, 2H), 1.60 (t, J = 5.7 Hz, 4H), 2.06 (dd, J = 13.5, 7.2 Hz, lH), 2.39 (s, 4H), 3.13 (d, J = 11 .7 Hz, lH), 3.25 (d, J = 11.7 Hz, lH) , 3.52 (m, 2H), 3.67 (dt, J = 12.0, 6.4 Hz, 2H), 4.14 (dd, J = 9.1 , 7.2 Hz, 11-1); 4.91 (s, ll-D, 6.42 (d, J = 2.4 Hz, IH), 6.83 (q, J = 6.6 Hz, lH), 7.36 (dt, J = 10.4, 8.4 Hz, lH), 7.51 (ddt, J = 8.1, 3.9, 1.6 Hz, IH), 7.65 (m, 2H), 7.77 (m, 2H), 7.99 (d, J= 2.3 Hz, lH) lav 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.57 (dt, J = 6.7, 3.0 Hz, 4H), 1.98 (dd, J = 13.3, 7.0 Hz, lH), 2.24 (dd, J = 13.4, 9.2 Hz, lH), 2.40 (s, 3H), 2.99 (d, J = 11.5 Hz, II-I), 3.16 (d, J = 11.5 Hz, lH), 3.48 (ddt, J = 20.5, 13.2, 5.9 Hz, 2H), 3.65 (dq, J = 11.1, .0 Hz, 2H), 3.95 (t, J = 8.2 Hz, lH), 5.74 (s, lH), 6.42 (d, J = 2.4 Hz, lH), 6.84 (q, J = 6.6 Hz, lH), 6.99 (tt, J = 9.0, 2.3 Hz, lH), 7.35 (m, 2H), 7.68 (d, J = 1.9 Hz, IH), 7.79 (m, 2H), 8.02 (d, J = 2.4 Hz, IH) law 1HNMR (400 MHz, Me0H-d4): s ppm 0.89 (m, lH), 1.30 (d, J = 13.3 Hz, 2H), 1.51 (q, J = 6.5, 5.7 Hz, SH), 1.77 (dd, J = 13.0, 6.9 Hz, l H), 2.05 (dd, J = 13.0, 8.9 Hz, lH), 2.40 (s, 3H), 2.62 (d, J = 11 .0 Hz, IH), 2.93 (d, J = 11.0 Hz, lH), 3.42 (d, J = 14.2 Hz, 2H), 3.49 (s, lH), 3.62 (dt, J = 16.7, 6.6 Hz, 3H), 5.72 (s, lH), 6.42 (d, J = 2.4 Hz, 11-l), 6.83 (q, J = 6.6 Hz, lH), 7.44 (m, IH), 7.69 (d, J = 1.9 Hz, lH), 7.81 (m, 2H), 8.01 (m, lax 1H NMR (400 MHz, MeOH-d4): 8 ppm 0.89 (m, 2H), 1.32 (m, 13H), 1.57 (t, J = 5.4 Hz, 4H), 2.01 (m, nn, 2.29 (dd, J= 13.4, 9.2 Hz, lH), 2.39 (s, 3H), 2.80 (s, lH), 3.07 (d, J = 11.6Hz, 1 H), 3 .17 (s, lH), 3.50 (m, 2H), 3 .66 (d, J = 13.8 Hz, 2H), 4.03 (t, J = 8.1 Hz, lH), 4.65 (p, J = 6.1 Hz, 1H), 5.75 (s, lH), 6.41 (d, J = 2.4 Hz, lH), 6.78 (q, J = 6.6 Hz, II-I), 7.16 (t, J = 8.6 Hz, IH), 7.45 (m, 2H), 7.61 (d, J = 1.8 Hz, lH), 7.74 (m, 2H), 7.98 (d, J = 2.4 Hz, lH) lay 1H NMR (400 MHz, 4): s ppm 0.88 (m, 2H), 1.28 (s, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.59 (d, J = 5.6 Hz, 4H), 2.04 (dd, J = 13.5, 7.1 Hz, IH), 2.39 (s, 4H), 3. 10 (d, J = 11.7 Hz, lH), 3.24 (m, lH), 3.49 (ddt, J = 25.3, 13.1 , 5.9 Hz, 2H) , 3.66 (dq, J = 12.1, 5.6 Hz, 2H), 4.07 (dq, J = 12.7, 7.2 Hz, 3H), 5.75 (s, lH), 6.42 (d, J = 2.4 Hz, UI), 6.71 (dt, J = 10.8, 2.2 Hz, lH), 6.80 (p, J = 6.6 Hz, lH), 7.01 (m, 2H) , 7.63 (d, J = 1.8 Hz, lH), 7.76 (m, 2H), 8.00 (d, J = 2.4 Hz, lH) 1H NMR (400 MHz, MeOH-d4): 8 ppm 0.90 (m, lH) , 1.36 (s, 13H), 1.59 (m, 4H), 2.05 (dd, J = 13.4, 6.9 Hz, IH), 2.33 (dt, J = 13.7, 6.0 Hz, 1H), 2.40 (s, 3H), 3 .12(d , J=11. 4 Hz, IH), 3.24 (d, J = 12.1 Hz, lH), 3.40 (s, IH), 3.53 (d, J = 14.7 Hz, lH), 3.68 (d, J = laz 13.4 Hz, 2H), 4.10 (s, lH), 4.76 (m, SH), 4.83 (s, 2H), 5.01 (s, lH), 6.42 (d, J = 2.2 Hz, lH), 6.77 (q, J = 6.6 Hz, lI-I), 7.42 (m, 3H), 7.65 (m, 4H) , 7.76 (m, 2H), 7.98 (d, J = 2.3 Hz, lH) 1H NMR (400 MHz, MeOH-d4): o ppm 1.30 (d, J = 12.1 Hz, 3H), 1.59 (t, J = 5.2 Hz, Iba 4H), 2.05 (dd, J = 13.4, 7.0 Hz, lH), 2.34 (m, 7H), 3.11 (d, J = 11.7 Hz, lH), 3.24 (d, J = 11. 8 Hz, lH), 3 .5 1 (m, 2H), 3.68 (dt, J = 13 .1 , 6.3 Hz, 2H), 4.09 (dd, J = 9.2, 6.9 Hz, lH), 6.41 (d, J = 2.3 Hz, lH), 6.79 (q, J = 6.7 Hz, lH), 7.11 (t, J = 9.1 Hz, lH), 7.55 (m, 31-l), 7.74 (m, 2H), 7.98 (d, J = 2.3 Hz, lH) 1H NMR (400 MHz, MeOH-d4): o ppm 1.28 (d, J = 6.9 Hz, 6H), 1.59 (t, J = 5.6 Hz, 4H), 2.05 (dd, J = 13.4, 6.9 Hz, IH), 2.32 (dd, J = 13.4, 8.9 Hz, lH), 2.40 (s, 3H), 2.96 (h, J = 6.8 Hz, 1 H), 3.12 (d, J = 11.8 Hz, lH), 3.24 (d, J = 11.7 Hz, l H), 3.51 (m, 2H), 3.67 (m, 2H), 4.10 (t, J = 8.3 Hz, lH), 6.41 (d, J = 2.3 Hz, lH), 6.78 (q, J = 6.5 Hz, lH), 7.27 (m, lH), 7.37 (t, J = 7.7 Hz, lH), 7.48 (m, 2H), 7.62 (d, J = 1.8 Hz, lH), 7.76 (m, 2H), 7.98 (d, J = 2.4 Hz, lH) 1HNMR (400 MHz, MeOH-d4): o ppm 0.89 (m, lH), 1.29 (m, 9H), 1.55 (d, J = 5.8 Hz, 4H), 1.99 (m, 1H), 2.26 (dd, J = 13.4, 9.1 Hz, lH), 2.39 (s, 3H), 3.04 (d, J = 11.6 Hz, lH), 3.17 (d, J = 11.6 Hz, 11-I), 3.47 (ddt, J = 20.9, 13.0, 5.9 Hz, 2H), 3.62 (dq, J = 11.5, .7 Hz, 2H), 4.01 (m, lH), 4.64 (hept, J = 5.9 Hz, IH), 5.74 (s, lH), 6.41 (d, J = 2.4 Hz, lH), 6.79 (q, J = 6.6 Hz, lH), 6.91 (dd, J = 8.1, 2.4 Hz, lH), 7.16 (ddd, J = 8.5, 5.3, 1.7 Hz, 2H), 7.32 (t, J = 7.9 Hz, lH), 7.64 (m, 3H), 7.77 (d, J = 8.3 Hz, IH), 7.97 (d, J = 2.4 Hz, lH) 1HNMR (400 MHz, 4): s ppm 1.28 (s, lH), 1.59 (d, J = 5.6 Hz, 4H), 2.05 (dd, J= 13.4, 7.0Hz, lH), 2.31 (dd,J= 13.4,9.3 Hz, lH),2.41 (d,J= 11.1 Hz,6H), 3.11 (d, J = 11.7 Hz, lH), 3.24 (d, J = 11.7 Hz, lH), 3.49 (ddd, J = 27.1, 12.8, 5.9 Hz, 2H), 3.66 ] bd (dq, J = 13.8, 6.0 Hz, 2H), 4.07 (dd, J = 9.2, 7.0 Hz, lH), 5.75 (s, lH), 6.42 (d, J = 2.4 Hz, lH), 6.80 (q, J = 6.6 Hz, lH), 7.45 (m, 2H), 7.63 (dd, J = 7.2, 2.0 Hz, 2H), 7.76 (m, 2H), 7.98 (d, J = 2.3 Hz, lH) 1H NMR (400 MHz, MeOH-d4): o ppm 1.29 (d, J = 3.9 Hz, 4H), 1.59 (t, J = 5.8 Hz, 7H), 2.05 (dd, J = 13.3, 7.0 Hz, 2H), 2.31 (dd, J = 13.4, 9.2 Hz, 2H), 2.40 (s, SH), 3.11 (d, J = 11.7 Hz, 2H), 3.24 (m, 4H), 3.50 (dq, J = 23.7, 7.4, 6.5 Hz, 4H), 3.67 (dq, J = 13.1, 6.4 Hz, 4H), 4.09 (t, J = 8.1 Hz, 2H), 4.84 (s, lH), 4.93 (s, IH), 6.42 (d, J = 2.3 Hz, 2H), 6.84 (q, J = 6.5 Hz, 2H), 7.57 (t, J = 7.8 Hz, 2H), 7.74 (s, 2H), 7.88 (m, 7H), 7.99 (d, J = 2.4 Hz, 2H), 8.19 (t, J = 1.9 Hz, 2H) 1H NMR (400 MHz, MeOH-d4): s ppm 1.57 (t, J = 5.7 Hz, 4H), 1.99 (dd, J = 13.3, 7.0 Hz, lH), 2.25 (dd, J = 13.3, 9.1 Hz, IR), 2.41 (s, 3H), 3.01 (d, J = 11.6 Hz, lH), 3.17 (d, J = 11.5 Hz, lH), 3.48 (dq, J = 23.5, 7.0, 6.5 Hz, 2H), 3.64 (dd, J = 13.0, 5.8 Hz, 2H), 3.97 (dd, J = 9.0, 7.1 Hz, lH), 5.73 (s, 1H), 6.44 (d, J = 2.4 Hz, lH), 6.87 (q, J = 6.6 Hz, lH), 7.79 (d, J = 1.8 Hz, lH), 7.88 (m, 2H), 8.00 (s, lH), 8.07 (d, J = 2.3 Hz, lH), 8.29 (s, 2H) 1H NMR (400 MHz, MeOH-d4): s ppm 1.28 (s, IH), 1.43 (t, J = 7.0 Hz, 3H), 1.64 (q, J = 5.8 Hz, 4H), 2.08 (dd, J = 13.5, 7.7 Hz, IH), 2.40 (s, 4H), 3.23 (m, 21-I ), 3.64 (m, 4H), lbg 4. 18 (q, J = 7.0 Hz, 2H), 4.32 (t, J = 8.4 Hz, lH), 6.42 (d, J = 2.4 Hz, lH), 6.83 (q, J = 6.4 Hz, lH), 7.20 (m, 2H), 7.36 (dd, J = 8.0, 2.1 Hz, IH), 7.65 (d, J = 1.6 Hz, lH), 7.77 (m, 2H), 7.99 (d, J = 2.4 Hz, lH) 1HNMR (400 MHz, 4): s ppm 1.28 (s, lH), 1.59 (d, J = 5.4 Hz, 4H), 2.04 (dd, J = 13.4, 7.0 Hz, IH), 2.29 (m, 2H), 2.41 (d, J = 9.6 Hz, 9H), 3 . 1 0 (d, J = 1 1 . 7 Hz, lH), lbh 3.24 (m, lH), 3.49 (ddt, J = 20.7, 13.0, 6.0 Hz, 2H), 3.65 (dt, J = 13.2, 7.2 Hz, 2H), 4.06 (dd, J = 9.2, 7.1 Hz, lH), 5.75 (s, lH), 6.41 (d, J = 2.4 Hz, lH), 6.79 (q, J = 6.6 Hz, lH), 7.45 (s, 2H), 7.62 (d, J = 1.8 Hz, lH), 7.75 (m, 2H), 7.98 (d, J = 2.4 Hz, IH) 1!-I NMR (400 MHz, Me0H-d4): s ppm 1.57 (m, 4H), 1.99 (dd, J = 13.4, 7.1 Hz, lH), 2.26 (dd, J = 13.3, 9.1 Hz, ll-I), 2.40 (s, 3H), 3.02 (d, J = 1 1 . 6 Hz, l H), 3.18 (d, J = 1 1 . 6 Hz, lH), 3.48 (dq, J = 2 3 . 5 , 7.1 , 6.6 Hz, 2H), 3.64 (dq, J = 11.4, 5.5 Hz, 2H), 3.99 (dd, J = 9.2, 7.0 Hz, IH), 5.73 (s, IH), 6.42 (d, J = 2.4 Hz, IH), 6.85 (q, J = 6.6 Hz, lH), 7.46 (t, J = 1.9 Hz, I H), 7.66 (t, J = 1.8 Hz, 31-I), 7.73 (dd, J = 8.3, 2.0 Hz, lH), 7.82 (d, J = 8.1 Hz, lH), 8.02 (d, J = 2.4 Hz, IH) 1HNMR (400 MHz, Me0H-d4): 8 ppm 1.28 (m, lH), 1.34 (s, lOH), 1.61 (t, J = 5.9 Hz, 4H), 2.06 (dd, J = 13.5, 7.3 Hz, lH), 2.39 (m, 7H), 3 . 14 (d, J = 11.6 Hz, lH), 3.25 (m, 1 bj lH), 3.55 (m, 2H), 3.68 (s, 2H), 4 . 1 8 (dd, J = 9.0, 7.3 Hz, IH), 6.42 (d, J = 2.3 Hz, lH), 6.78 (q, J = 6.5 Hz, lH), 7.28 (m, 2H), 7.45 (t, J = 1.7 Hz, lH), 7.60 (d, J = 1.8 Hz, lH), 7.75 (m, 2H), 7.98 (d, J = 2.3 Hz, lH) 1H NMR (400 MHz, MeOH-d4): s ppm l.28 (s, 2H), 1.5 8 (t, J = 5.5 Hz, 4H), 2.04 (dd, J = 13.3, 6.9 Hz, lH), 2.30 (dd, J = 13 .3, 9. 1 Hz, lH), 2.40 (s, 3H), 3.09 (d, J = 1 1 . 7 Hz, lbk lH), 3.23 (d, J = 12.2 Hz, IH), 3.51 (m, 21-1), 3.66 (dd, J = 13.9, 6.6 Hz , 2H), 4.05 (t, J = 8.2 Hz, l H), 4.62 (s, lH), 5. 75 (s, lH), 6.42 (d, J = 2.4 Hz, lH), 6.82 (q, J = 6.5 Hz, lH), 7.43 (m, 2H), 7.63 (m, 21-I ), 7.75 (m, 3H), 8.00 (d, J = 2.3 Hz, lH) 1H NMR (400 MHz, Me0H-d4): s ppm 1.57 (t, J = 5.6 Hz, 4H), 2.00 (dd, J = 13. 5 , 7.0 Hz, lH), 2.26 (dd, J = 13.3, 9.1 Hz, lH), 2.40 (s, 3H), 3.03 (d, J = 1 1 . 6 Hz, IR), 3.18 (d, lbl J = 1 1 . 5 Hz, lH), 3.47 (ddd, J = 20.9, 14 .0, 6.5 Hz, 2H), 3.64 (t, J = 7.4 Hz, 2H), 3.99 (dd, J = 9.1, 7.1 Hz, lH), 5.74 (s, lH), 6.43 (d, J = 2.3 Hz, lH), 6.86 (q, J = 6.6 Hz, lH), 7.81 (m, SH), 7.98 (d, J = 1.6 Hz, lH), 8.03 (d, J = 2.4 Hz, lH) 1H NMR (400 MHz, MeOH-d4): s 1.54 (d, J=2.93 Hz, 4 H), 1.82 - 1.99 (m, 1 H), 2.09 - 2.24 (m, 1 H), 2.40 (s, 3 H), 2.79 - 2.93 (m, 1 H), 2.99 - 3 .14 (m, 1 H), 3.37 - 3.55 (m, 2 H), 3.56 - 3.72 (m, 2 H), 3.82 (s, 4 H), 5.74 (s, 1 H), 6.41 (d, J=2.15 Hz, 1 H), 6.70 - 6.84 (m, 1 H), 6.99 (d, J=8.79 Hz, 2 H), 7.5 0 - 7.63 (m, 3 H), 7.64 - 7. 71 (m, 1 H), 7.71 - 7.80 (m, 1 H), 7.95 (d, 1=2.15 Hz, 1 H) 1H NMR (400 MHz, MeOH-d4): s ppm 0.8 9 (m, lH), 1 .28 (s, 2H), 1.42 (t, J = 7.0 Hz, 3H), 1 .58 (t, J = 5.2 Hz, 4H), 2.05 (dd, J = 13.4, 7.0 Hz, lH), 2. 31 (dd, J = 13.4, 9.0 Hz, lH), 2.39 (s, 3H), 3 . 1 1 (d, J = 1 1. 8 Hz, lH) , 3.24 (d, J = 1 1 . 7 Hz, IH), 3.51 (m, 2H), 1 bn 3.67 (m, 2H), 4.13 (m, 3H), 4.63 (s, lH), 5.75 (s, lH), 6.41 (d, J = 2.3 Hz, lH), 6.78 (q, J = 6.6 Hz, lH), 7 . 1 5 (t, J = 8.6 Hz, 11-I ), 7.45 (rn, 2H), 7.60 (d, J = 1.8 Hz, lH), 7.73 (m, 2H), 7.97 (d, J == 2.4 Hz, lH) 1 1 0 1H NMR (400 MHz, MeOH-d4): o ppm 1.29 (d, J = 8.3 Hz, lH), 1.59 (t, J = 5.3 Hz, 4H), 2.05 (dd, J = 13.5, 7.0 Hz, lH), 2.32 (dd, J = 13.6, 9.2 Hz, lH), 2.39 (s, 3H), 3.12 (d, J = 11.6 Hz, 1 I-I), 3.25 (m, lH), 3.49 (ddd, J = 24.6, 12.8, 5.8 Hz, 2H), 3.66 (dq, J = 12.7, 6.0 Hz, 2H), 4.09 (t, J = 8.1 Hz, lH), 5.76 (s, lH), 6.42 (d, J = 2.3 Hz, lH), 6.85 (q, J = 6.6 Hz, lH), 7.54 (m, 2H), 7.68 (d, J = l.8 Hz, lH), 7.78 (m, 2H), 8.01 (d, J = 2.3 Hz, lH) 1H NMR (400 MHz, Me0H-d4): o ppm 1.29 (d, J = 8.6 Hz, lH), 1.59 (d, J = 5.9 Hz, 4H), 2.05 (dd, J = 13.5, 7.3 Hz, lI-I), 2.39 (m, 7H), 3.13 (d, J = 11.6 Hz, lH), 3.24 (m, lbp 2H), 3.52 (dq, J = 25.3, 6.3 Hz, 2H), 3.68 (dd, J = 13.7, 5.9 Hz, 2H), 4.16 (m, lH), 6.42 (d, J = 2.3 Hz, lH), 6.82 (q, J = 6.5 Hz, lH), 7.37 (d, J = 7.9 Hz, lH), 7.51 (dd, J = 7.9, 2.0 Hz, lH), 7.63 (d, J = 1.9 Hz, lH), 7.73 (m, 3H), 7.98 (d, J = 2.4 Hz, lH) 1HNMR (400 MHz, 4): o ppm 1.29 (d, J = 8.0 Hz, IH), 1 . 59 (m, 4H), 2.05 (dd, J = 13.4, 7.0 Hz, lH), 2.38 (d, J = 13.7 Hz, 7H), 3.13 (d, J = 11.7 Hz, lH), 3.25 (d, J = lbq 11.6 Hz, lH), 3.53 (dt, J = 31.7 , 10.3 Hz, 2H), 3.67 (dd, J = 13.5, 7.0 Hz, 2H), 4.15 (m, UI), 4.89 (s, 17H), 6.42 (d, J = 2.4 Hz, lH), 6.82 (q, J = 6.6 Hz, lH), 7.32 (m, lH), 7.61 (m, 4H), 7.76 (m, 2H), 7.99 (d, J = 2.3 Hz, lH) 1 H NMR (400 MHz, MeOH-d4): s ppm 0.90 (s, 1 I-1), 1.29 (m, 8H), 1.60 (d, J = 7.7 Hz, 4H), 2.02 (m, 2H), 2.39 (s, 4H), 3. 14 (d, J = 11 .6 Hz, lH), 3.25 (d, J = 11 .4 Hz, lH), 3.51 (m, 2H), 3.66 (dd, J = 13.6, 6.6 Hz, 2H), 4.1 1 (dt, J = 21.0, 7.6 Hz, lH), 4.65 (h, J lbr = 6.0 Hz, lH), 6.42 (d, J = 2.3 Hz, lH), 6.69 (dt, J = 10.9, 2.2 Hz, lH), 6.82 (q, J = 6.3 Hz, lH), 6.99 (m, 2H), 7.61 (d, J = 1.8 Hz, 1!-l), 7.7 1 (m, lH), 7.78 (d, J = 8.1 Hz, lH), 7.99 (d, J = 2.3 Hz, lH) 1HNMR (400 MHz, Me0H-d4): s ppm 0.09 (s, lH), 0.90 (q, J = 8.4, 7.7 Hz, lH), 1.29 (d, J = 8.6 Hz, 3H), 1.59 (d, J = 5.7 Hz, SH), 2.05 (dd, J = 13.5, 6.9 Hz, lH), 2.31 (dd, J = 13.6, 9.4 Hz, lH), 2.40 (s, 3H), 3 . 13 (d, J = 11 . 6 Hz, lH), 3.25 (m, HI), 3.61 (m, SH), I bs 4.08 (m, lH), 5.74 (s, lH), 6.43 (d, J = 2.4 Hz, lH), 6.85 (q, J= 6.7 Hz, 11-I), 7.24 (dt, J = 8.5, 2.1 Hz, 11:1 ), 7.45 (dt, J = 9.6, 2.0 Hz, lH) , 7.58 (t, J = 1.7 Hz, lH), 7.68 (d, J = 1.9 Hz, lH), 7.79 (m, 2H), 8.02 (d, J = 2.3 Hz, lH) 1H NMR (400 MHz, MeOH-d4): s ppm 1.28 (d, J = 1.7 Hz, HI), 1.58 (t, J = 5.7 Hz, 4H), 2.03 (dd, J = 13.4, 7.0 Hz, IH), 2.29 (dd, J = 13.4, 9.2 Hz, IH), 2.40 (s, 31-l), 3.07 1 bt (d, J = 1 1 . 6 Hz, lH) , 3.22 (d, J = 1 1 . 6 Hz, lH), 3.49 (m, 2H), 3.65 (dd, J = 13.0, 6.7 Hz, 2H), 4.04 (dd, J = 9.2, 7.0 Hz, lH), 5.73 (s, IH), 6.43 (d, J = 2.4 Hz, lH), 6.84 (q, J = 6.6 Hz, lH), 7.77 (m, SH), 7.92 (dd, J = 8.4, 2.2 Hz, 1H), 8.04 (dd, J = 14.2, 2.3 Hz, 2H) 11-I NMR (400 MHz, MeOH-d4): s ppm 1.60 (d, J = 5.4 Hz, 41-1), 2.05 (dd, J = 13.5, 7.1 Hz, lH), 2.40 (s, 4H), 3 . 11 (d, J = 11.7 Hz, IH), 3.24 (d, J = 11.7 Hz, lH), 3.49 (ddt, J = lbu 21.1 , 13.3, 6.0 Hz, 2H), 3.67 (dt, J = 12.9, 6 . 1 Hz, 2H), 4.07 (dd, J = 9.2, 7.1 Hz, lH), .74 (s, lH), 6.43 (d, J = 2.4 Hz, IH), 6.86 (q, J = 6.6 Hz, IH), 7.50 (m, lH), 7.80 (m, SH), 8.04 (d, J = 2.4 Hz, lH) 1H NMR (400 MHz, MeOH-d4): s ppm 1.35 (d, J = 6.0 Hz, 7H), 1 .55 (d, J = 5.9 Hz, 4H) , 1.98 (dd, J = 1 3.3, 7.0 Hz, lH), 2.25 (dd, J = 13. 3, 9.1 Hz, lH), 2.39 (s, 2H), 3.01 (d, J = 11.5 Hz, 1 H), 3.17 (d, J = 11.6 Hz, lH), 3.47 (ddt, J = 20.8, 13.0, 6.0 Hz, 2H), 3.64 (dd, J = 13.9, 6.3 Hz, 2H), 3.98 (dd, J = 9.2, 7.1 Hz, lH), 4.67 (p , J = 6.1 Hz, lH), 4.89(s, l lH), 5.74 {s, lH), 6.41 (d, J = 2.4 Hz, lH), 6.79 (q, J = 6.6 Hz, IH), 7.13 (d, J = 8.7 Hz, lH), 7.55 (m, 2H), 7.71 (m, 4H), 7.98 (d, J = 2.4 Hz, II- I) 1HNMR (400 MHz, Me0H-d4): o ppm 1 . 54 (t, J = 5.7 Hz, 4H), 1.95 (dd, J = 13.3 , 7.0 Hz, lH), 2.22 (dd, J = 13.3, 9.0 Hz, HI), 2.41 (s, 3H), 2.95 (d, J = 11 . 5 Hz, lH), 3.13 (d, 1 1 1 J = 11.4 Hz, lH), 3.47 (ddt, J = 19.9, 12.9, 5.9 Hz, 2H), 3.64 (dd, J = 13.3, 6.4 Hz, 2H), 3.94 (t, J = 8.1 Hz, IH), 4.91 (s, lOH), 5.77 (s, IH), 6.43 (d, J = 2.3 Hz, lH), 6.83 (q, J = 6.6 Hz, IH), 7.49 (m, 2H), 7.83 (m, 7H), 8.01 (d, J = 2.4 Hz, lH), 8.13 (d, J = 1.9 Hz, 1H NMR (400 MHz, MeOH-d4): o ppm 1.59 (m, 4H), 2.05 (dd, J = 13.5, 7.2 Hz, lH), 2.39 (s, 4H), 3.12 (d, J = 11.7 Hz, lH), 3.24 (d, J = 11.8 Hz, lH), 3.51 (m, 2H), 3.67 lbx (dd, J = 13.7, 6.2 Hz, 2H), 4.13 (dd, J = 9.1, 7.2 Hz, lH), 5.19 (s, 2H), 6.41 (d, J = 2.3 Hz, lH), 6.79 (q, J = 6.5 Hz, IH), 7.21 (t, J = 8.6 Hz, 1H), 7.42 (m, 7H), 7.60 (d, J = 1.8 Hz, lH), 7.72 (m, 2H), 7.97 (d, J = 2.3 Hz, lH) 1 H NMR (400 MHz, MeOH-d4): o ppm 1.33 (dd, J = 6.1, 1.6 Hz, 6H), 1.58 (t, J = 5.2 Hz, 4H), 2.04 (dd, J = 13.5, 7.1 Hz, IH), 2.22 (s, 3H), 2.35 (m, 4H), 3.10 (d, J = 11.8 Hz, l H), 3.23 (d, J = 11.8 Hz, IH), 3.49 (ddt, J = 20.8, 13.6, 5.9 Hz, 2H), 3.66 (dd, J = 13.6, 6.9 Hz, 2H), 4.07 (dd, J = 9.2, 7.1 Hz, lH), 4.63 (p, J = 6.1 Hz, lH), 5.76 (s, lH), 6.41 (d, J = 2.4 Hz, lH), 6.75 (q, J = 6.7 Hz, 1H), 6.97 (d, J = 8.2 Hz, lH), 7.45 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 1.8 Hz, lH), 7.71 (m, 2H), 7.96 (d, J = 2.3 Hz, ll-1 ) 11-I NMR (400 MHz, 4): o ppm 1.06 (t, J = 7.4 Hz, 3H), 1.29 (m, 1 H), 1.58 (d, J = 5.9 Hz, 4H), 1.83 (h, J = 7.1 Hz, 2H), 2.02 (dd, J = 13.4, 6.9 Hz, II-I), 2.29 (dd, J = 13.3, 9.1 Hz, lH), 2.39 (s, 3H) , 3.08 (d, J = 11.6 Hz, lH), 3.21 (d, J = 11 . 5 Hz, lH), lbz 3.48 (ddd, J = 21.8, 12.6, 5.8 Hz, 2H), 3.65 (dd, J = 13.6, 7.3 Hz, 2H), 4.04 (q, J = 7.1, 6.4 Hz, 3H), 4.97 (s, lH), 5.75 (s, lH), 6.41 (d, J = 2.3 Hz, lH), 6.78 (q, J = 6.5 Hz, lH), 7.14 (t, J = 8.6 Hz, lH), 7.44 (m, 2H), 7.59 (d, J = 1.9 Hz, lH) , 7.72 (m, 2H), 7.98 (d, J = 2.3 Hz, lH) 1H NMR (400 MHz, MeOH-d4): s ppm 0.99 (t, J = 7.4 Hz, 3H), 1.53 (m, 6H), 1.79 (dq, J = 8.6, 6.5 Hz, 2H), 1.93 (dd, J = 13.2, 7.0 Hz, lH) , 2.20 (dd, J = 13.3, 9.1 Hz, lH), 2.39 (s, 3H), 2.91 (d, J = 1 1. 4 Hz, IH), 3 .11 (d, J = 11.4 Hz, lH), 3.47 (ddt, J = 20.0, lea 13.0, 5.9 Hz, 2H), 3.64 (dd, J = 13.8, 5.7 Hz, 2H), 3.88 (t, J = 8.0 Hz, lH), 4.07 (t, J = 6.4 Hz, 2H), 5.75 (s, 1H), 6.41 (d, J = 2.4 Hz, l H), 6.78 (q, J = 6.7 Hz, lH), 7.14 (t, J = 8.6 Hz, IH), 7.43 (m, 2H) , 7.59 (d, J = 1.9 Hz, lH), 7.71 (rn, 2H), 7.98 (d, J = 2.4 Hz, 1H NMR (400 MHz, MeOH-d4): s ppm 0.89 (s, IH), 1.28 (s, lH), 1.62 (d, J = 6.2 Hz, SH), 2.06 (dd, J = 13.3, 7.3 Hz, 2H), 2.41 (s, 8H), 2.65 (s, SH), 3.15 (d, J = 12.0 Hz, lcb 2H), 3.25 (m, 2H), 3.52 (s, 3H), 3.58 (s, 2H), 3.70 (d, J = 13.3 Hz, 4H), 4.21 (t, J = 8.4 Hz, 21-I), 5.89 (s, lH), 6.00 (m, lH), 6.44 (d, J = 2.3 Hz, 2H), 6.89 (q, J = 6.4 Hz, 2H), 7.80 (m, IOH), 8.04 (d, J = 2.3 Hz, 2H), 8.12 (t, J = 7.9 Hz, 2H) 1HNMR (400 MHz, Me0H-d4): s ppm 1.29 (d, J = 6.2 Hz, lH), 1.57 (m, 4H), 1.99 (dd, J = 13.4, 7.0 Hz, lH), 2.25 (dd, J = 13.4, 9.1 Hz, lH), 2.40 (s, 3H), 3.01 (d, J = 11.6 Hz, lee 1H), 3.1 5 (m, 4H), 3.32 (s, lH), 3.48 (ddt, J = 20.3, 12.8, 5.9 Hz, 2H), 3.65 (dd, J = 13.9, 7.0 Hz, 2H), 3.97 (dd, J = 9.1 , 7.0 Hz, lH), 4.89 (m, 2H), 5.75 (s, 1H), 6.44 (d, J = 2.4 Hz, lH), 6.85 (q, J = 6.6 Hz, lH), 7.75 (d, J = 1.7 Hz, lH) , 7.84 (m, 2I-I), 7.94 (d, J = 8.5 Hz, 2H), 8.03 (m, 3H) 1H NMR (400 MHz, MeOH-d4): s ppm 1.05 (t, J = 7.4 Hz, 3H), 1.51 (q, J = 6.5, 5.7 Hz, 4H), 1.80 (h, J = 6.7, 6.1 Hz, 3H), 1.89 (d, J = 1.5 Hz, 1H), 2.07 (dd, J = 12.7, 9.2 Hz, lH), 2.39 (s, 3H), 2.67 (d, J = 11.2 Hz, lH), 2.94 (t, J = 1 1.8 Hz, lH), 3.40 (m, 3H), 3.64 (m, 3H) , 3.96 (t, J = 6.4 Hz, 2H), 4.89 (m, l H), 5.75 (s, lH), 6.41 (d, J = 2.3 Hz, lH), 6.75 (m, lH), 6.99 (m, 2H), 7.59 (dd, J = 9.0, 2.0 Hz, 3H), 7.71 (m, 2H), 7.97 (d, J = 2.4 Hz, lH) 11 2 1H NMR (400 MHz, MeOH-d4): s ppm 1.30 (d, J = 16.9 Hz, 4H), 1.57 (s, SH), 2.02 (m, lH), 2.27 (dd, J = 13.3, 8.8 Hz, lH), 2.40 (s, 3H), 2.60 (m, 6H), 3.06 (d, J = 11.4 Hz, lH), 3.20 (d, J = 11.3 Hz, lH), 3.34 (s, lH), 3.48 (s, 3H), 3.56 (t, J = 6.7 Hz, 2H), 3.70 (m, 7H), 4.02 (s, ll-1), 4.98 (d, J = 6.2 Hz, lH), 5.76 (s, lH), 6.43 (d, J = 2.3 Hz, lH), 6.82 (q, J = 6.5 Hz, lH), 7.71 (s, lH), 7.80 (m, 4H), 7.93 (d, J = 8.0 Hz, 2H), 8.01 (d, J = 2.3 Hz, IH) 1HNMR (400 MHz, MeOH-d4): o ppm 0.90 (t, J= 6.4 Hz, lH), 1.30 (dd, J= 12.6, 4.9 Hz, 6H), 1.55 (m, SH), 1.93 (dd, J = 13.2, 7.0 Hz, lH), 2.19 (qd,J = 9.4, 3.3 Hz, lH), 2.40 (s, 3H), 2.92 (d, J = 11.4 Hz, lH), 3.11 (d, J = 11.3 Hz, lH), 3.48 (m, 2H), 3.65 (dd, J = 13.7, 6.3 Hz, 2H), 3.88 (dd, J = 8.9, 7.2 Hz, lH), 4.87 (d, J = 12.3 Hz, lH), 4.97 (d, J = 12.9 Hz, 2H), 5.75 (s, lH), 6.43 (d, J = 2.3 Hz, IH), 6.83 (q, J = 6.7 Hz, lH), 7.73 (s, lH), 7.84 (m, 4H), 8.00 (m, 3H) 11-I NMR (400 MHz, MeOH-d4): o ppm 1.29 (s, lH), 1.58 (d, J = 5.9 Hz, 4H), 2.03 (dd, J = 13.4, 6.9 Hz, IH), 2.30 (dd, J = 13.3, 9.2 Hz, lH), 2.40 (s, 3H), 3.11 (d, J = 11.7 Hz, leg lH), 3.23 (d, J = 11.5 Hz, lH), 3.48 (ddd, J = 28.3, 12.4, 5.7 Hz, 2H), 3.65 (dd, J = 13.7, 7.2 Hz, 2H), 4.07 (m, lH), 5.76 (s, 1H), 6.43 (d, J = 2.3 Hz, lH), 6.82 (q, J = 6.5 Hz, lH), 7.70 (d, J = 1.7 Hz, 1H), 7.79 (dt, J = 13.1 , 8.1 Hz, 4H), 7.99 (m, 3H) 1H NMR (400 MHz, Me0H-d4): s ppm 1.29 (d, J = 3.6 Hz, lH), 1.63 (q, J = 5.8 Hz, SH), 2.07 (dd, J = 13.5, 7.5 Hz, lH), 2.37 (dd, J = 13.5, 9.0 Hz, lH), 3.04 (s, 31-1), 3.15 (d, J = 24.6 Hz, 6H), 3.27 (m, lH), 3.52 (dt, J = 24.6, 8.3 Hz, 2H), 3.65 (m, 2H), 4.23(t, J = 8.1 Hz, lH) , 6.66(q, J = 7.0 Hz, lH), 7 .51 (d, J = 8.1 Hz, 2H), 7.68 (m, 6H) 1HNMR (400 MHz, MeOH-d4): s ppm 1.58 (d, J = 5.6 Hz, 4H), 2.03 (dd, J = 13.3, 7.1 Hz, IH), 2.30 (dd, J = 13.4, 9.2 Hz, 1H), 2.39 (s, 3H), 3.09 (d, J = 11.7Hz, lH), 3.22 (d, J= 1 1.7 Hz, lH), 3.49 (ddd, J = 21. 1 , 12.5, 5.6 Hz, 2H), 3.66 (dd, J = 13.7, 6.7 Hz, 2H), 3.90 (s, 3H), 4.06 (dd, J = 9.2, 7.1 Hz, II-I) , 5.76 (s, UI), 6.41 (d, J = 2.3 Hz, IH), 6.78 (q, J = 6.6 Hz, 1H), 7.17 (t, J = 8.9 Hz, lH), 7.46 (m, 2H), 7.60 (d, J = 1.8 Hz, lH), 7.73 (m, 2H), 7.98 (d, J = 2.3 Hz, lH) 1H NMR (400 MHz, MeOH-d4): s ppm 1.30 (d, J = 17.0 Hz, lH), 1.57 (d, J = 5.5 Hz, 4H), 2.01 (dd, J = 13.2, 7.0 Hz, lH), 2.28 (dd, J = 13.3, 9.0 Hz, lH), 2.40 (s, 3H), 2.79 (s, 2H), 2.91 (s, 2H), 3.07 (d, J = 12.1 Hz, lH), 3.20 (d, J = 11.4 Hz, lH), 3.49 (rn, 4H), 3.65 (dd, J = 13.5, 6.9 Hz, 2H), 3.74 (s, 2H), 4.02 (t, J = 8.1 Hz, lH), 4.99 (s, lH), 5.76 (s, l H), 6.43 (d, J = 2.4 Hz, II-I ), 6.82 (q, J = 6.6 Hz, l H), 7.52 (d, J = 7.9 Hz, 2H), 7.76 (m, SH), 8.01 (d, J = 2.4 Hz, lH) 1HNMR (400 MHz, 4): o ppm 1.30 (d, J = 11.1 Hz, lH), 1.51 (q, J = 6.8, 6.0 Hz, 4H), 1.78 (dd,J = 13.0, 7.0 Hz, lH), 1.89 (s, 2H), 2.07 (dd, J = 13.1, 9.1 Hz, II-I ), 2.40 (s, 3H), 2.68 (d,J = 11.1 Hz, lH), 2.95 (d, J = 1 1 .1 Hz, IH), 3.03 (s, 3H), 3.11 (s, 3H), 3.22 (s, 2H), 3.45 (m, 3H), 3.63 (q, J = 7.9, 7.5 Hz, 3H), 5.75 (s, lH), 6.43 (d, J = 2.4 Hz, 1 H), 6.82 (q, J = 6.6 Hz, 1 H), 7.53 (d, J = 7. 9 Hz, 2H), 7.70 (m, lH), 7.80 (m, 4H), 8.01 (d, J= 2.5 Hz, IH) 1H NMR (400 MHz, MeOH-d4): s ppm 1.04 (d, J = 6.7 Hz, 6H) , 1.29 (m, lH), 1.60 (d, J = 6.0 Hz, SH), 2.05 (ddd, J = 13.7, 7.0, 3.9 Hz, 2H), 2.36 (m, 4H), 3.13 (d, J = 11.9 Hz, lH), 3.24 (d, J = 11.6Hz, lH), 3.51 (ddd, J = 25.5, 14.3, 7.1 Hz, 2H), 3.69 (d, J = 13.8 Hz, 3H), 3.77 (d, J = 6.4 Hz, 2H), 4.14 (t, J = 8.3 Hz, lI-1), 4.93 (s, 8H), 6.41 (d, J = 2.3 Hz, lH), 6.77 (q, J = 6.6 Hz, lH), 6.99 (m, 2H), 7.60 (m, 3H), 7.72 (m, 2H), 7.96 (d, J = 2.3 Hz, IH) lcm 1HNMR (400 MHz, McOH�d4): s 1.14 (t, J=7.1 Hz, 3H), 1.26 (t, J = 7.3 Hz, 3H), 1.55 (q, J = 4.8 Hz, 4H), 1.90 (m, 1I-I), 2.18 (dd, J = 13.2, 9.0 Hz, lH), 2.40 (s, 3H), 2.87 (d, J = 11.4 Hz, lH), 3.09 (d, J = 11.3 Hz, lH), 3.30 (m, 4H), 3.54 (dddd, J = 37.2, 30.6, .1, 5.9 Hz, 6H), 3.84 (dd, J = 9.0, 6.9 Hz, lH), 5.76 (s, lH), 6.42 (d, J = 2.3 Hz, lH), 6.83 (q, J = 6.6 Hz, lH), 7.48 (m, 2H), 7.70 (d, J = 1.6 Hz, HI), 7.80 (m, 4H), 8.01 (d, J = 2.3 Hz, lH) 1H NMR (400 MHz, Me0H-d4): 8 ppm 0.84 (s, 3H), 1.06 (s, lOH), 1.30 (m, 11-l), 1.56 (t, J = 5.4 Hz, 4H), 2.00 (dd, J = 13.4, 6.8 Hz, lH), 2.27 (dd, J = 13.2, 9.0 Hz, HI), 2.41 (s, 3H), 3.04 (d, J = 11.5 Hz, l H), 3.19 (d, J= 11.4 Hz, lH), 3.48 (ddt, J =20.4, 13.0, .9 Hz, 2H), 3.65 (s, 4H), 4.03 (t, J = 8.1 Hz, lH), 5.77 (s, IH), 6.43 (d, J=2.2Hz, lH), 6.79 (q, J = 6.6 Hz, lH), 6.98 (d, J = 8.4 Hz, 2H), 7.60 (m, 4H), 7.75 (d, J = 8.2 Hz, IH), 7.97 (d, J = 2.3 Hz, lH) 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.28 (d, J = 5.8 Hz, lH), 1.55 (t, J = 5.7 Hz, 4H), 1.98 (m, 3H), 2.25 (dd, J = 13.3, 9.2 Hz, lH), 2.39 (s, 3H), 2.80 (t, J = 6.5 Hz, 2H) , 3.02 (d, J = 11.6 Hz, lH), 3. 17 (d, J = 1 1 .6 Hz, lH), 3.47 (ddt, J = 20.5, 13.0, 5.9 Hz, lco 2H), 3.64 (dt, J = 13.8, 5.9 Hz, 2H), 4.00 (dd, J = 9.2, 7.1 Hz, lH) , 4.16 (m, 2H), 5.75 (s, IH), 6.40 (d, J = 2.3 Hz, lH), 6.76 (m, 2H), 7.33 (d, J = 6.5 Hz, 2H), 7.54 (d, J = 1.8 Hz, lH), 7.63 (dd, J = 8.3, 1.9 Hz, lH), 7.71 (d, J = 8.3 Hz, lH), 7.95 (d, J = 2.4 Hz, 1H NMR (400 MHz, Me0H-d4): s ppm 1.59 (t, J = 5.3 Hz, 4H), 2.05 (dd, J = 13.5, 7.1 Hz, lH), 2.31 (dd, J = 13.4, 9.3 Hz, lH), 2.42 (s, 3H), 3.11 (d, J= 11.7 Hz, lH), 3.24 (d, J = 11.7 Hz, lH), 3.51 (m, 2H), 3.67 (s, 21-I) , 4.07 (dd, J = 9.3, 7.1 Hz, lH), 4.89 (s, lH) , .78 (s, lH), 5.99 (m, lH), 6.46 (d, J = 2.3 Hz, lH), 6.89 (q, J = 6.5 Hz, lH), 7.91 (m, 2H), 8.00 (dd, J = 8.3, 2.0 Hz, lH), 8.07 (d, J = 2.4 Hz, lH), 8.34 (m, 3H), 8.55 (d, J = 8.9 Hz, IH) , 9.33 (d, J = 5.9 Hz, lH) 1H NMR (400 MHz, MeOH-d4): o ppm 7.97 (s, lH), 7.77 (s, 2H), 7.67 (d, J = 15.8 Hz, 2H), 7.51 (s, 11-I), 7.26 (d, J= 7.8 Hz, HI), 6.42 (s, lH), 4.69 (s, 2H), 4.14 (s, IH), 3.68 (s, 2H), 3 .51 (s, 3H), 3.23 (s, 1H), 3.13 (d, J = 11.6 Hz, lH), 2.38 (d, J = 14.0 Hz, 6H), 2.05 (s, IH), 1.60 (s, 4H), 1.29 (s, 3H) 11-I NMR (400 MHz, Me0H-d4): s ppm 7.97 (s, 2H), 7.74 (q, J = 8.3 Hz, 41-l ), 7.62 (s, 2H), 7.46 (d, J = 7.4 Hz, SH), 6.78 (q, J = 6.7 Hz, 2H), 6.41 (s, 2H), 5.75 (s, 2H), 4.65 (s, 3H), 4.07 (t, J = 8.1 Hz, 2H), 3.64 (s, 4H), 3.52 (d, J = 6.9 Hz, lH), 3.46 (d, J = 16.2 l cr Hz, 4H), 3.22 (d, J = 11.8 Hz, 2H), 3.10 (d, J = 11 . 8 Hz, 2H), 2.38 (d, J = 7.9 Hz, lOH), 2.29 (s, lH), 2.03 (dd, J = 13.4, 7.0 Hz, 21-I), 1.58 (d, J = 5.6 Hz, 7H), 1.30 (d, J = 13.4 Hz, SH) 1H NMR (400 MHz, MeOH-d4): s ppm 8.43 (d, J = 2.5 Hz, lH), 7.99 (q, J = 3.3 Hz, 21-I ), 7.79 (d, J = 8.3 Hz, lH), 7.72 (d, J = 8.1 Hz, lH), 7.63 (s, lH), 6.83 (dd, J = 20.4, 7.6 Hz, 2H), 6.42 (d, J = 2.3 Hz, lH), 5.74 (s, lH), 4.35 (q, J = 7.0 Hz, 2H), 3.96 (d, J = 8.9 Hz, lH), 3.64 (s, 3H), 3.48 (dd, J =25.9, 11.9 Hz, 2H), 3 .15 (d, J = 1 1.7Hz, IH), 2.99 (d, J = 11. 4 Hz, lH), 2.39 (s, 3H), 2.24 (s, lH), 2.02- 1.94 (m, lH), 1.56 (s, 4H), 1.3 8 (t, J = 7.1 Hz, 3H), 1.28 (s, IH).
Example 1cp: (S)(2-amino((R)(3',4'-dimethyl(3-(trifluoromethyl)-lH-pyrazol ,11-biphenyl]y1)-2,2,2-trifluoroe thoxy)pyrimidinyl)-2,8-diazaspiro [4.5]dccane carboxylie acid The title nd was prepared as described for (S)(2-amino((R)-2,2,2-trifluoro(3-(3- methyl-l H-pyrazolyl)-[ l, 1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid (Example 1u) starting with (2-amino((R)(4-chloro(3-methyl- lH- pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[ 4.S]decane carboxylic acid (Example 1 Od). 1HNMR (400 MHz, MeOH-d4): o ppm 1.57 (br, s., 4H) 1.91 - 2.01 (m, l H) 2 .18 - 2.27 (m, 1 H) 2.33 (d, J=l 1.71 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: (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-lH-pyrazolyl) (piperidiuyl)phenyl)cthoxy)pyrimidinyl)-2,8-diazaspiro [4.5] dccanecarboxylic acid Step 1: A solution of (S)benzyl 3-ethyl 8-(2-amino((R)-2,2,2-triflu oro(2-(3-methyl­ lH-pyrazol-l-yl)( 1,2,3,6-tetrahydro pyridinyl)phenyl)ethoxy)pyrimidinyl)-2,8- piro[4.5]decane-2,3-dicarboxylate (Example lf) (150 mg, 0.15 mmol) inMeOH (5 mL) was hydrogenated in an H-Cube appara tus using a I0% (w/w) Pd/C cartridge with a fl ow ra te of 1.0 mL/min at RT. The resulting eluent was concentra ted in vacuo and The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (I00% CH2Ch to 90:9: 1 CH2Ch:MeOH:conc. NH40H) to provide (S)benzyl 3-ethyl 8-(2-amino ((R)-2,2,2-tri (2-(3-methyl-lH-pyrazol-l-yl)(1,2,3,6-tetrahydropyridin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.
Step 2: Hydrolysis of (S)benzyl 3-ethyl 8-(2-amino((R)-2,2,2-tritluoro(2-(3-methyl-lH­ pyrazolyl)(1,2,3,6-tetrahydropyridinyl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate using the LiOH general method ed the title compound as an off-white solid. 1H NMR (400 MHz, MeOH-d4): o ppm 1.49 - 1.69 (rn, 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 I-I) 3.08 (d, J=0.44 Hz, 2 H) 3.10 - 3.18 (rn, 2 H) 3.25 (d, J=l 1.71 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=I.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, l=2.20 Hz, 1 H). LCMS (MH+): 613.
Example 3a: (S)(2-amino((R)-2,2,2-trifluoro(2-(3-mcthyl-1H-pyrazol-l-yl)(1- (mcthylsulfonyl)piperidinyl)phcnyl)ethoxy)pyrimidinyl)-2,8-cliazaspiro[4.SJdccane carboxylic acid Step 1: To a solution of (S)benzyl 3-ethyl 8-(2-amino((R)-2,2,2-triflu oro(2-(3-methyl- 1H-pyrazolyl)( 1,2,3 ,6-tetrahydropyridinyl)phenyl)ethoxy)pyri midinyl)-2,8- diazaspiro]4.5]decane-2,3-dicarboxylate (320 mg, 0.413 mmol) in CH2Ch (5.0 mL) was added methanesulfonyl chloride (47 mg, 0.41 mmol) and triethylamine (94 mg, 0.83 mmol), and the reaction was stirr ed for 1.5 hat RT and then tra ted in vacuo. The product was purifi ed by column chromatogra phy using an Isco Gold reversed phase silica cartridge (100% CH2Ch to 90:9:1 CH2Cb:MeOH:conc. Nl-1.,0H) to e (S)benzyl 3-ethyl 8-(2-amino((R)-2,2,2- trifluoro(2-(3-methyl-1H-pyrazol-l-yl)(1-(methylsulfonyl)-1,2,3 ,6-tetrahydropyridin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxy1ate as an off-white solid.
Step 2: A solution of (S)benzyl 3-ethy1 8-(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-lH­ lyl)(l-(methylsulfony1)-1,2,3,6-tetrahydropyridinyl)phenyl)ethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxy1ate (290 mg, 0.340 mmol, Step 1) in MeOH (10 mL) was hydrogenated in an H-Cube apparatus using a 10% (w/w) Pd/ C cartridge with a fl ow rate of 1 .0 rnL/ min at RT. The resulting eluent was concentrated in vacuo and The product was purifi ed by column chromatography using an Isco Gold reversed phase silica cartridge (100% CH2Ch to 90:9:1 CH2Ch:MeOH:conc. NH40H) to provide (S)-ethyl 8-(2-amino((R)-2,2,2- tdflu oro(2-(3-methyl-lH-pyrazol-l-yl)(1-(methylsulfonyl)piperidin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5)decanecarboxylate.
Step 3: Hydro lysis of (S)-ethyl 8-(2-amino((R)-2,2,2-trifl -(2-(3-methyl-lH-pyrazol-lyl )( 1-(me thy lsulfonyl)piperidinyl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro]4.5]decanecarboxylate using the LiOH general method ed the title compound as an off-white solid. lH NMR (400 MHz, Me0H-d4): 6 ppm 1.53 - 1.65 (m, 4 H) 1.80 (qd, J=l2.57, 3.98 Hz, 2 H) 1.94 -2 .02 (rn, 2 H) 2.02 - 2 . 12 (m, 1 H) 2.31 (dd, J=l3.42, 9.27 Hz, 1 I-I) 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, I H) 6.64 - 6.82 (m, 1 H) 7.31 (d, J=l.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.
Using the generic scheme below, the following examples of Table 2a can be ed as described above for (S)(2-amino((R)-2,2,2-trifluoro- 1-(2-(3-methyl-1 H-pyrazolyl)(1- (methylsulfonyl)piperidiny1)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5Jdecane carboxylic acid (Example 3a).
R,°'Qy �Ot (SJ � � N-{ ---- I O N O ---- STEP I � � STEP2 N CF3 N"'?'N z= N Z=N I Z"'O STEPS 2 & 3 Table 2a.
Ex. Cy CASName LCMS (MH+) 3b ,,!!_°"0 (S)(6-((R)(4-(1-acetylpiperidinyl)(3- 656.7 -lH-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)aminopyrimidinyl)-2,8- o. diazaspiro[4.5]decanecarboxylic acid 3c (S)(2-amino((R)-2,2,2-trifluoro(2 -(3-methyl- 615.6 1H-pyrazolyl)(tetrahydro-2H-pyran yl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decanecarboxylic acid Table 2b.
NMR Data for Compounds of Table 2a Ex. lHNMR 3b 1H NMR (400 MHz, MeOH-d4): o ppm 1.54 - 1.82 (m, 6 H) 1 . 86 - 1 . 99 (m, 2 H) 2.05 - 2.18 (m, 4 H) 2.36 - 2.38 (m, 3 H) 2.48 (dd, J=l3.69, 8.86 Hz, 1 H) 2.66 - 2.81 (m, 1 H) 2.88 - 3.03 (m, 1 H) 3.19-3 . 27 (m, l H) 3 . 3 1 - 3.40 (m, 1 H) 3.60- 3.95 (m, 4 H) 4.05 (d, 8 Hz, 1 H) 4.55 (t, J=8.66 Hz, 1 H) 4.67 (d, J=13.13 Hz, 1 H) 6.39 (d, 1=2.39 Hz, 1 H) 6.50 (br. s., 1 H) 6.79 - 6.87 (rn, 1 H), 7.36 (s, 1 H) 7.47 (dd, J=8.22, 1.64 Hz, 1 H) 7.64 (d, J=8.30 Hz, 1 H) 7.86 (d, J=2.39 Hz, 1 H) 3c 1H NMR (400 MHz, Me0H-d4): o ppm 1.59 (d, J=S.08 Hz, 4 H) l .72 - 1.89 (m, 4 H) 2.06 (dd, J=l3.45, 7.15 Hz, 1 H) 2.32 (dd, J=13.45, 9.25 Hz, 1 H) 2.38 (s, 3 H) 2.82 - 2.95 (m, 1 H) 3.07 - 3.16 (m, 1 H) 3.25 (d, Jr= l 1.76 Hz, I H) 3.36 - 3.74 (m, 6 H) 4.03 (dt, J=l 1.16, 2.96 Hz, 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) 6.72 (q, J=6.75 Hz, l H) 7.29 (d, J=l .71 Hz, 1 H) 7.41 (dd, , 1.76 Hz, 1 H) 7.67 (d, J=8.10 Hz, 1 H) 7.88 (d, J=2.34 Hz, 1 H) Exam pie 4: (2-amino((R)-2,2,2-trifl uoro(3 '-methoxy-4'-(methoxycarbonyl)(3- methyl-lH-pyrazolyl)-[1,1 '-biphcnyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro [4.5]decanecarboxylic acid '-..0 Step 1: To a solution of (S)(2-amino((R)(4-bromo(3-methyl-l H-pyrazol yl)phenyl)-2,2,2-trifluoroethoxy )pyrimidinyl)((benzyloxy)carbonyl)-2,8- diazaspiro[4.5]decanecarboxylic acid (pro duct of Step 3, Example 10m) (135 mg, 0.18 mmol) in dioxane (2 mL) was added (3-methoxy(methoxycarbonyl)phenyl)boronic acid (84 mg, 0.4 mmol) and Cs2C03 (48 mg, 0 .16 mmol). The reaction was heated to 80 °C for 16 h, cooled to RT, and fil tered. The solvent was removed in vacuo. Purifi cation via normal phase silica gel chromatogra phy (CH2Ch/Heptane) provided (S)(2-amino((R)-2,2,2-triflu oro- 1-(31- methoxyA'-(methoxycarbonyl)(3-methyl-l H-pyrazolyl)-[1,l '-biphenyl] yl)ethoxy)pyrimidinyl)((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decanecarboxylic acid as an off-white solid. 1 1 9 Step 2: N-CBZ Deprotection was accomplished via method B to yield (S)(2-amino((R)- 2,2,2-trifluoro(3'-methoxy-4'-(methoxycarbonyl)(3-methyl-l H-pyrazolyl)-[ I, 1'­ biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid as an off­ white solid. 1HNMR (400 MHz, MeOH-d4): o 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 Sa: (S)(2-amino((R)-l-(3' xycarbonyl)(3-methyl-lH-pyrazol-l-yl)­ [l,1 '-biphcnyl]y l)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]dccane carboxylic acid The title nd was made according to the procedures described for (S)(2-amino((R)- 2,2,2-tritluoro-l-(3'-methoxy(methoxycarbonyl)(3-methyl-lH-pyrazolyl)-[1, l1- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid (Example 4). 1H NMR (400 MHz, MeOH-d4): o ppm 1.42 (t, J=7.13 Hz, 3 H) 1.61 (hr. 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=l.56 Hz, 1 H) 7.80 (d, J=l.56 Hz, l 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 Sb: (S)(2-amino((R)(4'-(cthoxycarbonyl)(3-methyl-lH-pyrazolyl)­ biphenyI]yl)-2,2,2-trifluoroethoxy)pyrimidiny1)-2,8-diazaspiro [4.5] dccane carboxylic acid /"'--o The title compound was made ing to the procedures described for (S)(2-amino((R)- 2,2,2-trifluoro(31-methoxy-4'-(methoxycarbonyl)(3-methyl-lH-pyrazolyl)-[1, 1'­ biphenyl)yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid (Example 4). 11-I NMR (400 MHz, MeOH-d4): o ppm0.88 (m, 4H), 1.30 (d, J = 17.4 Hz, lOH), 1.40 (t, J = 7.1 Hz, 4H), 1.59 (d, J = 5.8 Hz, SH), 2.05 (dd, J = 13.5, 7.2 Hz, IH), 2.35 (m, SH), 3 . 1 1 (d, J = 11.7 Hz, lH), 3.24 (d, J = 1 1 .7 Hz, lH), 3.49 (ddd, J = 28.1, 12.7, 5.7 Hz, 21-1), 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, lH), 4.91 (s, 2H), .75 (s, 1 H), 6.42 (d, J = 2.4 Hz, 1 H), 6.83 (q, J = 6.5 Hz, lH), 7.72 (d, J = 1.6 Hz, 1 H), 7.81 (m, 4H), 8.00 (d, J = 2.4 Hz, 1H), 8.10 (m, 2H). LCMS (MH+): 681.
Example 6: (S)(2-amino((R)-l-(4-(3-carboxypropyl)(3-mcthyl-lH-pyrazol yl)pheny1)-2,2,2-trifl uoroethoxy)pyrimidinyl)-2,8-diazaspiro [4.5]deeane-S-carboxylie acid Step I: To a solution of 9-borabicyclo[3.3.l]nonane (2.0 mL, 0.5 MinTHF, 1.0 mmol) was added methyl butenoate (100 µL, 1.0 mmol) and stirred at RT for 2 h to prepare the 9- tane solution.
Step 2: To a on of (S)(2-amino((R)(4-bromo(3-methyl-1 H-pyrazol-l­ yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)((benzyloxy)carbonyl)-2,8-diazaspiro [4.S]decanecarboxylic acid (product of Step 3, Example lOm) (250 mg, 0.32 mmol) in THF (2 mL) was added sequentially PdCh(dppf)CH2Ch (8 mg, 0.01 mmol), NaOEt (66 mg, 1 mmol) and the prepared 9-BBN/butene solution from Step 1. The reaction was heated to 65 °C for 2 h, then cooled to RT. The reaction was extracted with EtOAc, brine and dried over Na2S04 and concentrated in vacuo. The product was purified by column chro a phy using an Isco Gold reversed phase silica cartridge (100% CH2Ch to 90:9:1 CH2Ch:MeOH:conc. NH40H) to provide (S)benzyl 3-ethyl 8-(2-amino((R)-2,2,2-trifl uoro-l-(4-(4-methoxyoxobutyl)(3- methyl-I H-pyraz olyl)phenyl)ethoxy) dinyl)-2,8-diazas piro[4.S]decane-2,3- dicarboxylate as an off-white solid.
Step 3: N-CBZ Deprotection was accomplished via method B to provide (Sj-ethyl 8-(2-amino ((R)-2,2,2-trifluo ro(4-(4-methoxyoxobutyl)(3-methyl-lH-pyrazolyl)phenyl) ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5] decanecarboxylate as an off-white solid.
Step 4: Hydrolysis of (S)-ethyl 8-(2-amino((R)-2,2,2-triflu oro- 4-methoxyoxobutyl)- 2-(3-methyl-l H-pyrazolyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[ 4.5]decane carboxylate was carried out using the LiOH genera l method pro viding the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6): o 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 (hr. s., I H) 5.71 (br. s., 1 I-I) 6.00 (br. s., 2 H) 6.38 (d, 1=2.20 Hz, 1 H) 7.00 (q, J=6.87 Hz, 1 H) 7.29 (d, J=l .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. e 7: (S)(2-amino((R)(4-(2-carboxyethyl)(3-methyl-lH-pyrazol yl)p heny1)-2,2,2-tl'ifl uoroethoxy)pyri midiny1)-2,8-diazaspiro [4.5] decanecarboxylic acid The title compound was made as described for (2-amino((R)(4-(3-carboxypropyl) (3-methyl-1H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid (Example 6). 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.56 (t, J=S.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=l 1 .86 Hz, 1 H) 3.39 - 3.55 (m, 2 H) 3.57 - 3.75 (111, 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, l H) 6.71 (q, J=6.61 Hz, 1 H) 7.28 (d, J=l.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.
Exampie 9: (S)(2-amino((R)(4-(3-ethoxyoxop1·opyl)(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-triflu orocthoxy)pyrimidinyl)-2,8-diazaspiro[4.S]decanecarboxylic acid Step 1: To a solution of (S)(2-amino((R)(4-bromo(3-methyl-1H-pyrazol-l­ yl)phenyl)-2,2,2-triflu oro ethoxy)pyrimidinyl)((benzyloxy )carbonyl)-2,8- diazaspim[4.5]decanecarboxylic acid (product of Step 3, Example 1 Om) (240 mg, 0.33 mmol) in ethanol (8 mL) was added (E)-ethyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)acrylate (110 mg, 0.49 mmol), PdCh(PPh3)2 (20 mg, 0.049 mmol) and KHC03 (170 mg, 0.05 mmol).
The reaction was heated to 80 °C for 2 h, cooled to RT, and filtered. The solvent was removed in vacuo. Purification via normal phase silica gel chromatography (CH2Ch/heptane) provided ((S)(2-amino((R)-l-(4-((E)ethoxyoxopropenyl)(3-methyl-1 Il-pyrazol-I­ yl)phenyl)-2,2,2-triflu oro )pyrimidinyl)((((2E,4Z)vinylhexa-2,4-dien yl)oxy)carbonyl)-2,8-diazaspiro[ 4.5]decanecarboxylic acid as a white solid.
Step 2: To a solution of ((S)(2-amino((R)-l-(4-((E)ethoxyoxoprop-l-enyl)(3- -I H-pyrazol-l-yl)phenyl)-2,2,2-triflu oroethoxy)pyrimidinyl)((((2E,4Z) vinylhexa-2,4-dien-l-yl)oxy)carbonyl)-2,8-diazaspiro[4.5]decanecarboxylic acid (180 mg, 0.15 mmol) in MeOH (5 mL) was hydrogenated in an H-Cube apparatus using a 10% (w/w) Pd/C dge with a fl ow rate of 1.0 mL/min at RT. The resulting eluent was concentrated in vacuo and the product was purifi ed by column chromatogra phy using an Isco Gold reversed phase silica cartridge (100% CH2Ch to 90:9: 1 CH2Ch:MeOH:conc. l) to provide the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4): 6 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=l 1.76 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=l.61 Hz, 1 H) 7.35 (dd, J=8.15, 1.61 Hz, 1 H) 7.62 (d, J=8.05 Hz, I H) 7.83 (d, J=2.34 Hz, I H). LCMS (MH+): 632.1 Example lOcl: (S)(2-amino((R)(4-chloro(3-mcthyl-lH-pyrazolyl)phenyl)-2,2,2- trifl uoroethoxy)pyrimidinyl)-2,8-cliazaspiro f4.5] decanecarboxylic acid Step I: To a solution of ( lR)[4-chloro(3-methylpyrazolyl)phenyl]-2,2,2-trifluoro­ ethanol (40 g, 138 mmol) in e (400 mL) was added 4,6-dichloropyrimidinamine (113 g, 690 mmol) and Cs2C03 (132 g, 405 . The mixture was heated for 24 h at 80 °C. The reaction was then cooled to RT and filtered. The solvent was removed in vacuo, then CI-bCh and heptane was added. The solvent volume was reduced until a solid precipitated out. The solid was filtered and the procedure repeated several times to provide 4-chloro[(lR)(4-chloro (3-rnethylpyrazolyl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidinamine as a white solid.
Step 2: To a solution of 4-chloro[(lR)[4-chloro(3-methylpyrazolyl)phenyl]-2,2,2- trifl uoroethoxy]pyrimidinamine (57.3 g, 137 nun ol, Step 1) in dioxane (500 mL) was added benzyl 3-ethy1 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (48 g, 124.9 mmol), and NaHC03 (31 .5 g, 375 mmol). After 5 h, an additional amount of NaHC03 (31.5 g, 375 mmol) was added and the reaction mixture was heated to 90 °C for 36 h. The reaction was then cooled to RT and fi ltered. Purifi cation by normal phase silica gel column (EtOAc/heptane) ed (S)benzyl 3-ethyl 8-(2-amino((R)-l-(4-chloro(3-methyl-1 H-pyrazolyl)phenyl)-2,2,2- triflu oroethoxy)pyri midinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Step 3: N-CBZ Deprotection was accomplished via method B to provide (S)-ethyl 8-(2-amino ((R)(4-chloro(3-methyl- lH-pyrazol-l-yl)phenyl)-2,2,2-trifl uoroethoxy)pyrimidinA-yl)- 2,8-diazaspiro[4.5]decanecarb e an off-white solid.
Step 4: Hydrolysis of (S)-ethyl 8-(2-amino((R)(4-chloro(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-triflu oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate using the LiOH general method provided the title nd as an off-white solid.
Using the generic scheme below, the following examples of Table 3a were prepared as described above for (S)(2-amino((R)(4-chloro(3-methyl-1 Il-pyrazol-l-yljphenyl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[ 4.5]decanecarboxylie acid (Example lOd). ;:rO r_p_l STEP2 H�N-0 Table 3a.
* Stereochemistry defined in name in table below Ex. R' R" R"' CASName LCMS No. (MR+) 10a H H H mino((R)-2,2,2-trifluoro(2-(3-methyl-lH- 532 pyrazol-l-yljphenyljethoxy)pyrimidinyl)-2,8- diazaspiro]4.5]decanecarboxylic acid lOb H Cl H mino((R)(4-chloro(3-methyl-1 H- 566 l-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro [4. 5]decanecarboxylie acid lOc H Cl H (R)(2-amino((R)(4-chloro(3-methyl-1 H- 566 pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decanecarboxylic acid R-Spiro 10d H Cl H (S)(2-amino((R)(4-chloro(3-methyl-1 H- 566 pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decanecarboxylic acid lOe H H H (S)(2-amino((R)-2,2,2-triflu oro(2-(3-methyl- 532 lH-pyrazol-l-yl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro]4.S]decanecarboxylic acid lOf H H Cl (S)(2-amino((R)- hloro(3-methyl-lH- 566.9 pyrazolyl)phenyl)-2,2,2- trifl uoroethoxy)pyrimidiny1)-2,8- diazaspiro [4. 5]decanecarboxylic acid IOg I-I CF3 H (S)(2-amino((R)-2,2,2-triflu oro(2-(3-methyl- 600.6 lH-pyrazol-l-yl) (trifl uoromethyl)phenyl)ethoxy)pyrimidiny1)-2,8- piro]4.S]decanecarboxylic acid lOh H CI-b H (S)(2-amino((R)-2,2,2-triflu oro- 1-(4-methyl 546.6 (3-methyl-lH-pyra zolyl)phenyl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro [4.S]decanecarboxylic acid lOi H F H 8-(2-amino((R)-2,2,2-triflu oro - l-(4-flu oro(3- 550.5 methyl-lH-pyra zol-l-yl)phenyl)ethoxy)pyrimidin yl)-2,8-diazaspiro [4.S]decanecarboxylic acid lOj H ,...,or' H 8-(2-amino((R)-2,2,2-tri fl uoro-l-(4-methoxy(3- 564.6 methyl-lH-pyra yl)phenyl)ethoxy)pyri midin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid IOk Cl H H 8-(2-amino((R )(5-chloro(3-methyl-1H- 566.9 pyrazolyl)phenyl)-2,2,2- tri fl uoroethoxy)pyrimidinyl)-2,8- diaza spiro(4.5]decanecarboxylic acid 101 H ,......or' H (S)(2-amino((R)-2,2,2-triflu oro(-l-rnethoxy- 564.6 ethyl-1 H-pyrazol yl)phenyl)ethoxy)pyri midinyl)-2,8- diazaspiro[ 4.5]decanecarboxylic acid 1 Om H Br H (S)(2-amino((R)(4-bromo(3-methyl-1H- 611 pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidiny1)-2,8- diazaspiro]4.5]decanecarboxylic acid lOn Br H H (S)(2-amino((R)-l-(5-bromo(3-methyl-lH- 611.5 pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro [4. necarboxylic acid Table 3b.
NMR Data for Compounds of Table 3a Ex. NMR IO a 1HNMR (400 MHz, MeOH-d4): o ppm 1.59 (br. s., 4 H) 1.97 - 2 .12 (m, 1 H) 2.24 - 2.35 (m, 1 H) 2.39 (s, 3 H) 3 . 11 (s, 1 H) 3.22 (s, 1 H) 3.40 - 3.58 (m, 2 H) 3.66 (hr. s., 2 H) 3.95 - 4.17 (m, 1 H), 5.73 (s, 1 H) 6.39 (s, 1 H) 6.70 - 6.88 (m, 1 H) 7.42 (d, J=7.52 Hz, 1 H) 7.53 (dd, J=l2.93, 7.57 Hz, 2 H) 7.75 (d, J=7.52 Hz, 1 H) 7.87 (s, 1 H) lOb 1H NMR (400 MHz, MeOH-d4) o ppm 1.44 - 1.74 (m, 4 H) 1.88 - 2.06 (m, 1 H) 2 .17 - 2.31 (m, 1 H) 2.39 (s, 3 H) 2.86 - 3.04 (m, 1 H) 3.09 3.21 (m, 1 H) 3.41-3.57 (m, 2 H) .77 (m, 2H) 3.85-4.05 (m, IH) 5.63-5.76 (m, 1 H )6.36-6.48 (m, 1 H) 6.76 6.91 (m, 1 H) 7.46-7.60 (m, 2 H) 7.67 - 7.79 {m, 1 H) 7.90 - 8.03 (m, 1 H) lOc 1H NMR (400 MHz, Me0H-d4): o ppm 1.62 (br. s., 4 H) 2.04 - 2 . 17 (m, 1 H) 2.41 (s, 4 H) 3.10 - 3.21 (m, 1 I-I) 3.27 (s, 1 H) 3.44 - 3.58 (m, 2 H) 3.60 - 3.79 (m, 2 H) 4.05 - 4 .18 (m, 1 H) 5.71 (s, 1 H) 6.44 (d, J:==2.15 Hz, 1 H) 6.75 - 6.91 (m, 1 H) 7.52 (s, 2 H) 7.66 - 7.80 (m, 1 H) 7.96 (d, J=2.15 Hz, 1 H) 10d 1H NMR (400 MHz, MeOH-d4): s ppm 1.59 (t, J=5.30 Hz, 4 H) 1 .97 - 2.12 (m, 1 H) 2.31 (dd, J=13.45, 9.25 Hz, 1 H) 2.38 (s, 3 H) 3 . 11 (d, J=l 1.76 Hz, I H) 3.25 (d, J=l 1 .71 Hz, 1 H) 3.38 - 3.57 (m, 2 H), 3.58 - 3.74 (m, 2 H) 4.08 (dd, J=9.15, 7 .15 Hz, 1 H) 5.69 (s, 1 H) 6.41 (d, J=2.39 Hz, 1 H) 6.82 (q, J=6.61 Hz, 1 H) 7.44 - 7.57 (m, 2 H) 7.71 (d, 1=8.35 Hz, 1 H) 7.93 (d, J=2.34 Hz, 1 H) toe 1HNMR(400 MHz, Me0H-d4): s ppm 1.71 (dt, J=l8.13, 5.48 Hz, 4 H) 2.08 (dd, J=l3.62, 8.49 Hz, 1 H) 2.37 (s, 3 H) 2.47 (dd, J=13.59, 8.96 Hz, 1 H) 3.62 - 3.90 (m, 4 H) 4.54 (t, J=8.71 Hz, 1 H) 6.38 (d, J=2.34 Hz, 1 H) 6.48 (br. s., 1 H) 6.85 (q, J=6.04 Hz, 1 H) 7.46 (dd, J=7.86,l.07 Hz, 1 H) 7.52 - 7.59 (m, 1 H) 7.61 � 7.67 (m, 1 H) 7.70 (d, J=7.76 Hz, I H) 7.84 (d, J=2.39 Hz, l H) lOf 'n NMR (400 MHz, MeOH-d4): o ppm 1.49 - 1.68 (m, 4 H) 2.04 (dd, J=13.45, 7.15 Hz, 1 H) 2.30 (dd, J=13.45, 9.25 Hz, 1 H) 2.35 (s, 3 H) 3.05 - 3.26 (m, 2 H) 3.38 - 3.77 (rn, 5 H) 4.06 (dd, J=9.10, 7.15 Hz, 1 H) 5.60 (s, l H) 6.18 (q, 1=6.56 Hz, 1 H) 6.39 (d, J=2.34 Hz, 1 H) 7.49 - 7.59 (m, 1 H) 7.60 - 7.74 (m, 3 H) lOg 1H NMR (400 MHz, 4): 8 ppm 1 .51 - 1.64 (m, 4 H) 2.03 (dd, J=13.45, 7 .15 Hz, 1 H) 2.29 (dd, J=13.47, 9.27 Hz, 1 H) 2.37 (s, 3 H) 3.03 - 3.25 (m, 2 H) 3.37 - 3.54 (m, 2 H) 3.56 - 3.75 (m, 2 H), 4.04 (dd, J=9.08, 7.22 Hz, 1 H) 5.66 (s, 1 H) 6.42 (d, J=2.34 Hz, 1 H) 6.90 (q, J=6.54 Hz, 1 H) 7.73 (s, 1 H) 7.78 (d, J=8.25 Hz, 1 H) 7.91 (d, J=8.35 Hz, 1 H) 7.98 (d, J=2.34 Hz, I H) IOh 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.58 (t, 1=5.25 Hz, 4 H) 2.05 (dd, 5, 7.15 Hz; 1 H) 2.30 (dd, J=l.00 Hz, 1 H) 2.37 (s, 3 H) 2.40 (s, 3 H) 3.05 - 3.17 (m, 1 H) 3.21 - 3.29 (m, 1 H) 3.36 - 3.75 (m, 4 H) 4.09 (dd, 1=9.10, 7.25 Hz, 1 H) 5.73 (s, 1 H) 6.37 (d, 1=2.25 Hz, 1 H) 6.71 (d, J=6.69 Hz, l I-I) 7.23 (d, J=0.68 Hz, 1 H) 7.31 (d, J=8.10 Hz, 1 H) 7.60 (d, J=8. 05 Hz, 1 H) 7.84 (d, J=2.29 Hz, 1 H) lOi 1H NMR (400 MHz, MeOH-d4): o ppm 1.52 - 1.91 (m, 4 H) 2.05 - 2.16 (m, 1 H) 2.40 (s, 3 H) 2.45 - 2.69 (m, 1 H) 3.52 - 4.13 (m, 4 H) 4.57 (d, J=l 7.28 Hz, 1 H) 6.43 (d, J=2.25 Hz, 1 H) 6.88 - 7.09 (m, 1 H) 7.23 - 7.51 (m, 2 H) 7.68 - 7.83 (m, 1 H) 7.92 (d, 29 Hz, 1 H) lOj 'H NMR (400 MHz, MeOH-d4): 8 ppm 1.59 (d, J=4.54 Hz, 4 H) 2.00 - 2.12 (m, 1 H) 2.27 - 2.35 (m, 1 H) 2.38 (s, 3 H) 3.05 - 3.17 (m, 1 H) 3.25 (d, 1=11.71 Hz, 1 H) 3.48 (dd, J=l.17, 0.20 Hz, 2 H) 3.66 (d, 1=5.52 Hz, 2 H) 3.85 (s, 3 H) 4.08 (dd, 1=9.08, 7.27 Hz, 1 H) 5.72 (s, 1 H) 6.38 (d, J=2.29 Hz, 1 H) 6.67 (d, J=6.69 Hz, I H) 6.94 (d, J=2.64 Hz, 1 H) 7.06 (dd, J=8.83, 2.59 Hz, 1 H) 7.63 (d, J=8.83 Hz, 1 H) 7.87 (d, J=2.29 Hz, 1 H) I Ok 1H NMR (400 MHz, CHLOROFORM-d): 8 ppm 1.18-1.36 (m, 3 H) 1.43 (t, J=6.74 Hz, 3 H) 1.54-2.29 (m, 6 H) 2.39 (br.s., 3 H) 3.78 (hr. s., 4 H) 4.26 (hr. s., 2 H) 4.42 (d, J =6.15 Hz, 2 H) 5.53 (br. s., 1 H), 6.36 (s, 1 H) 6.59 (br. s., 1 H) 7.48 (d, J=7.96 Hz, I H), 7.61 (br. s. I H) 8.16 (d, J =8.05 Hz, l H) 8.34 (hr. s., 1 H) 101 1R NMR (400 MHz, DICHLOROMETRANE-d2): o ppm 1.40 - 1.61 (m, 4 H) 1.95 (dd, 1=12.89, 5.86 Hz, 1 H) 2.14 - 2.28 (m, 1 H) 2.36 (s, 3 H) 3.07 (d, 1=1.00 Hz, I H) 3.16 (d, J=l.00 Hz, 1 H) 3.36 (br. s., 2 H), 3.54 (br. s., 2 H) 3.79 (s, 3 H) 4.08 (t, J=7.71 Hz, 1 H) 4.71 - 5.04 (m, 2 H) 5.47 (s, 1 H) 6.30 (d, J=2.10 Hz, 1 H) 6.65 (q, J=7.11 Hz, 1 H) 6.87 (d, J=2.64 Hz, 1 H) 6.95 (dd, J=8.86, 2.6 1 Hz, 1 H), 7.61 (d, 1=8.74 Hz, 1 H) 7.65 (d, J=2.20 Hz, 1 H) 10111 1R NMR (400 MHz, MeOH-d4): 8 ppm 1.64 (d, 1=4.69 Hz, 4 H) 2.03 - 2 .15 (m, 1 H) 2.40 (s, 4 H) 3.12 - 3.31 (m, 2 H) 3.43 - 3.63 (m, 2 H) 3.64 - 3.78 (m, 2 H) 4.16 -4.34 (m, 1 H) 6.43 (d, J=2.34 Hz, , 1 H) 6.76 - 6.91 (m, 1 H) 7.67 (dd, J=5.76, 4.20 Hz, 3 H) 7.94 (d, J=2.l 5 Hz, 1 I-I) lOn 1H NMR (400 MHz, DMSO-d6): o ppm 1.47 - 1.71 (m, 4 I·I) 1.90 (dd, J=13.15, 9.15 Hz, I H) 2.24 - 2.39 (m, 4 H) 3.13 (t, 1=5.25 Hz, 2 H) 3.66 (br. s., 4 H) 4.39 - 4.51 (m, 2 H) 6.05 (s, 1 H) 6.42 (d, J=2.34 Hz, 1 H) 7.25 (d, J=S.27 Hz, 1 H) 7.51 (d, J=8.59 Hz, I H) 7.78 (s, 1 H) 7.85 (dd, J:=8.54, 2.29 Hz, I H) 8.11 (d, J=2.34 Hz, l H) 8.95 (d, J=6.69 Hz, 1 H) 10.20 (br. s., 1 H) Example 100: (S)(2-amino((R)(4-bromo(3-methyl-lH-pyraz olyl)phenyl)-2,2,2- trifluorocthoxy)pyrimidinyl)-2,8-diazaspiro [4.5]dccanecarboxylic acid The title compound was prepared as described for (2-amino((R)(4-chloro(3- methyl-1 H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid (Example 10d) starting with (R)-l-(5-bromo-[1,1'­ biphenyl]yl)-2,2,2-trifluoroethanol (Intermediate 38). 1H NMR (400 MHz, MeOH-d4): s 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, lH), 2.36 (dd, J = 13.5, 9.1 Hz, IH), 3.15 (d, J = 11.9 Hz, 1H), 3.26 (d, J = 11.7 Hz, IH), 3.47 (ddt, J = 21.7, 13.4, 5.8 Hz, 2H), 3.63 (m, 2H), 4.18 (t, J = 8.2 Hz, lH), 6.63 (q, J = 6.8 Hz, lH), 7.50 (m, 7H). LCMS (MH+): 607.
Example lOp: (S)(2-amino((R)(4-chloro(3-(trifluoromethyl)-lH-pyrazol yljphenyl)-2,2,2-trifluorocthoxy)pyrimidiny1)-2,8-diazaspiro [4.5] clecanccarboxylie acid Cl� NH �OyYN �:Noµ CF3 NyN The title compound was prepared as described for (2-amino((R)(4-chloro (3- methyl- IH-pyra zolyl)phenyl)-2,2,2-triflu oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5] decanecarboxylic acid (E xample lOd) starting with (R)(4-chloro(3-(trifl uoromethyl)- 1 H-pyrazol-l-yl)phenyl)-2,2,2-trifluo roethanol (Intermediate 39). 1H NMR (400 MHz, 4): s ppm 1.53 (d, J=S.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) .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=l.37 Hz, 1 H). LCMS (MH+): 620.
Example lOpa: (2-amino((R)(2-(3-(tert-butyl)-lH-pyrazolyl)chlorophenyl)- 2,2,2-trifluoroethoxy)pyrimidiny1)-2,8-diazaspiro [4.5] carboxylie acid The title compound was prepared as described for (S)(2-amino((R)(4-chloro(3- methyl- I H-pyrazolyl)phenyl)-2,2 ,2-trifluoroethoxy)pyrirnidinyl)-2,8-diazaspir o[4.5] decanecarboxylic acid (Example 1 Od) starting with (2-(3-(tert-butyl)-1 Il-pyrazol-l-yl)- 4-chlorophenyl)-2,2,2-triflu oroethan ol (Intermediate 40). 1H NMR (400 MHz, MeOH-d4): o 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, I H) 5.57 (s, I H) 6.52 (d, J=2.34 Hz, 1 H) 7.15 - 7.28 (m, I H) 7.44 - 7.53 (m, 1 H) 7.56 (d, J=l.95 Hz, 1 H) 7.68 - 7.79 (m, 1 H) 7.95 (d, J=2.34 Hz, 1 H). LCMS (MH+): 609.
Example 1Oq: (S)(2-amino((R)( 4-chloro(3-isopropyl-lH-pyrazolyl)phenyl)- 2,2,2-trifluoroethoxy)py rimidinyl)-2,8-diazaspiro [4.5]deeanccarboxylic acid The title compound was prepared as described for (S)(2-amino((R)(4-chloro(3- methyl-l Il-pyrazol- l -yl)phenyl)-2,2,2-triflu oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5] 1 31 decanecarboxylic acid (Example lOd) starting with (R)(4-chloro(3-isopropyl-lH­ pyrazolyl)phenyl)-2,2,2-trifluoroethanol (Intermediate 41). 1H NMR (400 MHz, MeOH-d4): o 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,21-1) 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, I H) 7.54 (s, 2 H) 7.67 - 7.78 (m, 1 H) 7.91 - 8.02 (m, 1 H). LCMS (MH+): 595.
Example 1Or: (S)(2-amiuo((R)(4-chloro(3-cyclopropyl-lH-pyrazolyl)phenyl)- 2,2,2-triflu orocthoxy)pyrimidinyl)-2,8-diazaspiro[4.S]dccanecarboxylic acid The title compound was prepared as described for (S)(2-amino((R)(4-chloro- 2-(3- -IH-pyrazolyl)phenyl)-2,2,2-trifl uoro ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5] decanecarboxylic acid (Example 1 Od) starting with (R)(4-chloro (3-cyclopropyl-l H- pyrazolyl)phenyl)-2,2,2-trifluoroe thanol (Intermediate 42). 1H NMR (400 MHz, MeOH-d4): o 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, I H) 3.00 - 3.11 (m, 1 H) 3.3 8- 3.69 (m, 4 H) 3.72- 3.84 (m, I 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. e 11: (S)(2-amino((R )-2,2,2-triflu oro(6-mcthyl(3-mcthyl-1H-pyrazol yl)pyridinyl)ethoxy)pyl'imidiuy1)-2,8-diazaspil'o[ 4.5] dccanecarboxylie acid The title nd was prepared as described for (S)(2-amino((R)-l-(4-chloro(3- methyl-IH-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[ canecarboxylic acid (Example lOd) starting with (S)-2,2,2-trifluoro(6- methyl(3-methyl-1 H-pyrazolyl)pyridinyl)ethanol (Intermediate 20) Example 12a: (2-amino((R)(4-ethyl(3-methyl-lH-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro [4.5)clecanecarboxylic acid Step 1: To a solution of (S)benzy} 3-ethyl 8-(2-amino((R)(4-bromo(3-methyl-lH­ pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3- dicarboxylate (300 mg, 0.388 mmol, see Example l u) in EtOH:H20 (15 mL) was added 4,4,5,5- tetrame thylvinyl-1,3,2-dioxaborolane (90 mg, 0.58 mmol), KHC03 (389 mg, 3.88 mmol), and PdCh(PPh3)2 (41 mg, 0.058 mmol), The reaction mixture was heated to 80 °C for 1 h, then cooled to RT. The reaction was diluted with water, extracted with EtOAc. The combined organic layers were washed with brine, dri ed over Na2SO,i, filtered, and concentra ted in vacuo.
Purifi cation with a 40 g Isco RediSep silica cartridge (EtOAc:heptane) provided (S)benzyl 3- ethyl 8-(2-amino((R)-2,2,2-triflu oro(2-(3-methyl-1H-pyraz olyl) vinylphcnyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Step 2: N-CBZ Deprotection was lished via method A, which also reduced the olefin, to provide (S)benzyl l 8-(2-amino((R)-l-(4-ethyl(3-methyl-1 H-pyrazol yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Step 3: Hydrolysis of (S)benzyl 3-ethyl 8-(2-amino((R)-l-(4-ethyl(3-methyl- lH­ pyrazo1y1)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspil'o[4.S]decane-2,3- dicarboxylate using the LiOH general method provided the title compound as a white solid.
Using the same scheme below, the following examples of Table 4a were prepared as described above for (S)(2-amino((R)(4-ethyl(3-methyl- lH-pyrazolyl)phenyl)- 2,2,2-trifluo xy)pyrimidinyl )-2,8-diazaspiro [4.S]decanecarboxylic acid (Example 12a).
R' = H, Me, Et Table 4a.
Ex. R CASName LCMS(MH+) 12a r (S)(2-amino((R)(4-ethyl(3-methyl-lH- 560 pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 12b � (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl- lH- 575 pyrazolyl)propylphenyl)ethoxy)pyrimidinyl)-2 ,8- diazaspiro[4.5]decanecarboxylic acid 12c � (S)(2-amino((R)-l-(4-butyl(3-methyl-IH- 588 pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro [4.5]decanecarboxylic acid Table 4b.
NMR Data for Compounds of Table 4a Ex. NMR 12a 1H NMR (400 MHz, Me0H-d4): o ppm 1.26 (t, J = 7.59 Hz, 3 H), 1.50 - 1.69 (m, 4 H), 2.01 - 2.35 (m, 2 H), 2.37 (s, 3 H), 2.72 (q, J = 7.57 Hz, 2 H), 3.05 - 3.28 (m, 2 H), 3.40 - 3.76 (m, 4 H), 4.08 (dd, J = 8.88, 7.32 Hz, 1 H), 5.72 (s, l H), 6.38 (d, J = 2.25 Hz, 1 H), 6.71 (q, J = 6.70 Hz, 1 H), 7.25 (d, J = 1.56 Hz, 1 H), 7.35 (dd, J = 8.18, 1.59Hz, 1 H), 7.63 (d, J = 8 .15 Hz, 1 H), 7.85 (d, J = 2.29 Hz, 1 H) 12b 1H NMR (400 MHz, 4): o ppm 0.96 (t, J = 7.35 Hz, 3 H), 1.49 - 1.62 (m, 4 H), 1.62 - 1.77 (m, 2 H), 2.01 - 2.35 (m, 2 H), 2.37 (s, 3 H), 2.59 - 2.74 (m, 2 H), 3.06 - 3.29 (m, 2 H), 3.39 - 3.77 (m, 4 H), 4.08 (dd, J = 9.05, 7.30 Hz, 1 H), 5.72 (s, 1 H), 6.37 (d, J = 2.29 Hz, l H), 6.71 (q, J = 6.72 Hz, 1 H), 7.23 (d, J = 1.56 Hz, 1 H), 7.33 (dd, J = 8.15, 1.56 Hz, 1 H), 7.63 (d, J = 8.05 Hz, 1 H), 7.85 (d, J = 2.29 Hz, 1 H) 12c 1H N"MR (400 MHz, MeOH-d4): o ppm 0.94 (t, J = 7.35 Hz, 3 H), 1 .38 (dq, J = 14.92, 7.39 Hz, 2 H), 1.49 - 1.72 {m, 6 H), 2.01 - 2.35 (m, 2 H), 2.37 (s, 3 H), 2.60 - 2.74 (m, 2 H), 3.07 - 3.28 (m, 2 H), 3.40 - 3.74 (m, 4 H), 4.08 (dd, J = 9.15, 7.20 Hz, 1 H), 5.71 (s, 1 H), 6.38 (d, J = 2.15 Hz, 1 H), 6.63 - 6.77 (m, 1 H), 7.23 (d, J = 1.61 Hz, 1 H), 7.33 (dd, J = 8.10, 1.66 Hz, 1 H), 7.63 (d, J = 8.05 Hz, 1 H), 7.85 (d, J = 2.29 Hz, 1 H) Example 13: (3S)(2-amino((lR)(4-(1,2-clihydi·oxyethyl)(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-trifluorocthoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanccarboxylic acid Step 1: To a on of (S)benzyl 3-ethyl 8-(2-amino((R)-2,2,2-trifluoro(2-(3-methyl- 1H-pyrazol- l-yl)vinylphenyl)ethoxy)pyrimid inyl)-2,8-diazaspiro[4.5)decane-2,3- dicarboxylate (product of Step 1, Example 12b)(373 mg, 0.518 mmol) in 4: 1 acetone.Hio (20 mL) was added Os04 (313 µL of a 4% (w/w) s 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 reactlon was stirred at RT for 24 h, concentrated in vacuo, and th e residue was purifi ed by chromatography on a 50 g Isco Gold RediSep reversed phase silica cart ridge (H20:HOAc: 99:1 to EtOH:HOAc 99:1). A second purifi cation on a 40 g Isco RediSep silica cartridge eluting (CH2Ch 100% to 90:9:1 CI-hCh:EtOH:NH4QH) ed -benzyl 3-ethyl 8-(2-amino (( lR)(4-( 1,2-dihydro xyethyl)(3-methyl-lH-pyrazolyl)phenyl)-2,2,2- trifl uoro ethoxy)pyrimidinyl)-2,8-diazaspiro[4.S]decane-2,3-dicarboxylate as a white solid.
Step 2: N-CBZ deprotection was lished via method A to provide (3S)-ethyl 8-(2-amino- 6-((1R)(4-(1,2-dihydroxyethyl)(3-methyl-lH-pyraz olyl)phenyl)-2,2,2- trifluoroeth oxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate as a white solid.
Step 3: Hydrolysis of (3S)-ethyl 8-(2-amino((lR)(4-(1,2-dihydroxyethyl)(3-methyl-lH­ pyra zolyl)phenyl)-2,2,2-triflu oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.S]decane carboxylate using the LiOH general method provides the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4): 8 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, 1=4.20, 2.34 Hz, 1 I-I). LCMS (MH+): 592.
Example 14: (S)(2-amino((R)(4-cyauo(3-methyl-lH-pyrazolyl)phenyl)-2,2,2- trifl u oxy)pyrimidinyl)-2,8-diazaspiro [4.5]decanecarboxylic acid Step 1: To a solution of (38)benzyl 3-ethyl 8-(2-amino(1-(4-chloro(3-methyl-IH- pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro [4.5]decane-2,3- dicarboxylate (730 mg, 1.0 mmol), was added 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 vial at 1 1 5 °C for 2 h, then cooled to RT, fi ltered, and concentrat ed in vacuo.
Purifi cation by normal phase silica gel column (EtOAc/hepate) provided (3S)benzyl l 8-(2-amino( 1-(4-cyano(3-methyl-1H-pyrazolyl)phenyl)-2 ,2,2-trifluoroethoxy) pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a viscous oil.
Step 2: N-CBZ Deprotection was accomplished via Method A to provide (3S)-ethyl 8-(2-amino- 6-( 1-(4-cyano(3-methyl-lH-pyrazolyl)phenyl)-2,2,2-trifl uoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylate as an off-white solid.
Step 3: ysis of (3S)-ethyl 8-(2-amino(1-(4-cyano(3-methyl-1 H-pyrazol yl)phenyl)-2,2,2-triflu oxy)pyrimidinyl)-2,8-diazaspiro[4.5Jdecanecarboxylate using the LiOH genera l method provides the title compound as an off-white solid. 1H NMR (400 MHz, MeOH-d4): o ppm 1.47 - 1.71 (m, 4 H) 1.95 - 2.10 (m, 1 H) 2.20 - 2.33 (m, 1 I-I) 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)(2-amino((R)(4-carbamoyl(3-mcthyl-1H-pyrazolyl)phenyl)- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro [4.5]dccanecarboxylic acid Step 1: To a on of (3S)benzyl 3-ethyl 8-(2-amino(1-(4-cyano(3-methyl-lH- pyrazol- l-y])phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-dia zaspiro[4.S]decane-2,3- dicarboxylate (150 mg, 0.2 mmol, see Ex. 14) in toluene (10 mL) was added acetaldehyde oxime (240 mg, 4 mmol) and In Ch (44 mg, 0.2 mmol). The reaction was heated to l 10 °C for 3 h, then cooled to RT, and concentrate d in vacuo. Purific ation by normal phase silica gel column (EtOAc/h epate) provided (3 S)benzy1 3-ethyI 8-(2-amino( 1-(4-carbamoyl(3-methy1-1H- pyrazol-l-yl)phenyl)-2,2,2-triflu oroethoxy)pyrimidinyl)-2,8-diaza spiro[4.5]decane-2,3- dicarboxylate as a white solid.
Step 2: N-CBZ Deprotection was accomplished via Method A to provide (3S)-ethyl mino- 6-(1-(4-carbamoyl(3-methyl-lH-pyrazolyl)phenyl)-2,2,2-trifl uoroethoxy)pyri midinyl)- 2,8-diazaspiro[4.5]decanecarboxylate as a white solid.
Step 3: Hydrolysis of (3S)-ethyl 8-(2-amino(1-(4-carbamoyl(3-methyl-1 H-pyrazol ny1)-2,2,2-trifluoro ethoxy)pyrimidinyl)-2,8-diazaspiro [4.5]decanecarboxylate using the LiOH general method provides the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4): 6 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=l 1.71 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)(2-amino((R)(4-carboxy(3-methyl-1H-pyrazolyl)phcnyl)- 2,2,2-trifluoroethoxy) pyrimidinyl)-2,8-cliazaspiro{4.5Jdecanccarboxylic acid Step I: To a solution of -benzyl 3-ethyl mino(1-(4-cyano(3-methyl-lH- pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-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) was added LiOH-H20 (0.20 g, 5 mmol). The mixture was heated to 50 °C overnight. The reaction was then cooled to RT, and the reaction was i ed with 6N HCI to pH=l. Concentration in vacuo followed by reverse phase HPLC purifica tion (MeOHJ water/HOAc) provided (3S)(2-amino- 6-( 1-(4-carboxy(3-methyl-1 H-pyrazolyl)phenyl)-2,2,2-trifl uoroet hoxy) pyrimidinyl) ((benzyloxy)carbonyl)-2,8-diazaspiro[4. 5]decanecarboxylic acid as a white solid.
Step 2: N-CBZ Deprotection was accomplished via Method A to prov ide the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4): 6 ppm 1 . 57 (t, 1=5.42 Hz, 4 H) 2.03 (dd, 1=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) 3.1 6 - 3.25 (m, 1 T-1) 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, I H) 6.78 - 6.89 (m, I H) 7.76 (d, J=8.15 Hz, 1 H) 7.90 (d, J=2.34 Hz, 1 H) 7.95 (d, J=l.42 Hz, 1 H) 8.04 (dd, 1=8.13, 1.59 Hz, 1 H). LCMS (MH+): 576. e 17: (S)(2-amino((R)-l-(4-(ethoxycarbonyl)(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-trifluoroethoxy)pyl'imidinyl)-2,8-diazaspiro[4.5]clecanccarboxylic acid Step 1: To a solution of (S)benzyl 3-ethyl 8-(2-amino((R)-l-(4-bromo(3-methyl-lH­ pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro [4. 5]decane-2,3- dicarboxylate (1.50 g, 1.94 mmol, See Ex. l u) in THF (20 ml.), MeOH (10 rnL) and water (10 mL) was added LiOH-H20 (0.80 g, 19.4 mmol), and the reaction was stirred at RT for 4 h. The pH of the reaction mixture was adjusted to 6.5 with 6 N HCl, and the organic solvents were removed in vacuo to provide a white solid that is filtered away. The reaction mixture was then partitioned between water and EtOAc, and extracted. The combined organic layers were washed with bri ne, dried over Na2S04, fi ltered, then concentrated in vacuo to e (2S)[2-amino [(1 R)[4-bromo(3-methylpyrazol- l -yl)phenyl]-2,2,2-triflu oro-ethoxy]pyrimidinyl] benzyloxycarbonyl-3,8-diazaspiro[4.5]decanecarboxylie acid as a white solid that is used directly t further purifi cation.
Step 2: To a solution of (2S)[2-amino[(lR)[4-bromo(3-methylpyrazol-l-yl)phenyl]- 2,2,2-trifl uoro-ethoxy]pyrimidinyl]benzyloxycarbonyl-3,8-diazaspiro [4.S]decane carboxylic acid (74 mg, 0.10 mmol, Step 2) in EtOH (4 mL) was added KHCOJ (84 mg, 1 .0 mmol). The reaction e was degassed, fitted with a 1 atm CO balloon, then treated with PdCh(PPh3)2 (14 mg, 0.02 mmol). The on was degassed once more with 1 atm CO and then heated to 80 °C for 12 h. The reaction was cooled to RT, concentrated in vacuo and the residue was partitioned between water and EtOAc, and extra cted. The combined organic layers were washed with brine, dried over Na2S04, fi ltered, and concentrated in vacuo. Purific ation by normal phase silica gel column (CH2Ch/AcOH/E tOH) provided (2S)[2-amino[(1R)[4- ethoxycarbonyl(3-methylpyrazol- l -yl)phenyl]-2,2,2-tri:fluoro-ethoxy] pyrimidinyl] benzyloxycarbonyl-3,8-diazaspiro [4.5]decanecarboxyIic acid as a white solid.
Step 3: N-CBZ Deprotection was accomplished via Method A to e the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4): s 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, I 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=l.61 Hz, 1 H) 8.09 (dd, J=8.27, 1.68 Hz,1 H). LCMS (MH+): 604.
Example 18a: (S)(2-amino((R)-2,2,2-triflu (4-(((1,1,1,3,3,3-hexafluorn methylpropanyl)oxy)carbonyl)(3-methyl-lH-pyrazolyl)phenyl)ethoxy)pyrimicUn yl)-2,8-diazaspiro[4.5] clecanecarboxylic acid Step 1: To a solution of (S)(2-amino((R)- I-(4-bro mo(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-trifl uoroethoxy)pydrnidinyl)((benzyloxy)carbonyl)-2,8- diazaspiro[4.5 ]decanecarboxylic acid (product of Step 3, Example lOm) (1.2 g, 1.6 mmol) in DMF (16 mL) was added benzyl bromide (0.27 g, 1.6 mmol) and NaHC03 (0.67 g, 8.0 mmol).
The reaction was then heated to 60 °C for 2 h, cooled to RT, and stirr ed for 12 h. The precipitate was fi ltered, washed with EtOAc and the fi ltrate concentra ted in vacuo. The residue was partitioned between water and EtOAc, and extra cted. The combined c layers were washed with brine, dried over , fi ltered, and concentrated in vacuo. Puri fi cation by normal phase silica gel column (EtOAc /heptane) provided (S)-dibenzyl 8-(2-amino((R)(4-bromo(3- methyl-I H-pyrnzolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin -2,8- diazaspiro[4.5]decane-2,3-dicarboxylate as the white solid.
Step 2: To a solution of (S)-dibenzyl 8-(2-amino((R)-l-(4-bromo(3-methyl-1 H-pyrazol yl)phenyl)-2 ,2,2-trifluoroethoxy)pyrimidiny1)-2, 8-d iazaspiro]4.5]decane-2,3-dicarboxylate from Step 1 (415 mg, 0.50 mmol) in 1,4-dioxane (8 mL) and water (4 mL) was added KHC03 (420 mg, 5.0 mmol), and the reaction was degassed with 1 atm CO. Then PdCh(PPh3)2 ( 140 mg, 0. 10 mmol) was added and the reaction mixture was treated with 1 atm CO (bal loon). The reaction mixture was heated to 80 °C for 12 h, then cooled to RT, and concentrated in vacuo.
The residue was ioned between water and EtOAc, and extra cted. The ed organic layers were washed with brine, dried over Na2S04, fi ltered, and trat ed in vacuo.
Purifi cation by normal phase silica gel column (CH2Cb/M 40H) provided 4-[( 1R)[2-amino[(2S)-2,3-bis(benzyloxycarbonyl)-3,8-diazaspiro[4.S]decan yl]pyrimidinyl]oxy-2,2,2-tri fl uoro-ethyl](3-methylpyraz olyl)benzoic acid as a white solid.
Step 3: To a solution of 4-[(1R)[2-amino[(2S)-2,3-bis(benzyloxycarbonyl)-3,8- diazaspiro[ 4.5]decanyl]pyrimidinyl]oxy-2,2,2-triflu oro- ethy1](3-methylpyrazol yl)benzoic acid (80 mg, 0.1 mmol) in CH2C'2 ( 4 mL) was added DMAP (73 mg, 0.6 mmol), (CF3)2MeCOH (108 mg, 0.6 mmol), ed by EDCI ( 1 1 4 mg, 0.6 mmol). The reaction mixture was stirred at RT for 12 h, diluted with CH2Ch and washed with water. The aqueous solution was extracted with CH2Ch. The combined organic layers were washed with brine, dried over , fi ltered, and concentrated in vacuo. Pur ific ation by normal phase silica gel column (EtOAc I heptane) provided dibenzyl (2S)[2-amino[(1R)-2,2,2-trifl uoro- 1-[2-(3- methylpyrazolyl)[2,2,2-trifl uoromethyl(trifl uorometh yl)ethoxy[carbonyl-phenyl] ethoxy]pyrimidinyl]-3 ,8-diazaspiro[4.S]decane-2,3-dicarboxylate as a white solid.
Step 4: N-CBZ Deprotection was accomplished via Method A to prov ide the title compound as a white solid.
Using the generic scheme below, the following es of Table Sa were prepared as described above for (S)(2-amino((R)-2,2,2-trifluoro(4-(((1,1,1,3,3,3-hexafluoro methylpropanyl)oxy)carbonyl)(3-methyl-1 H-pyrazolyl)phenyl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.S]decanecarboxylic acid (Example l 8a).
Table Sa.
Ex. R CASName LCMS No. (MH+) 18a ::rrF (S)(2-amino((R)-2,2,2-trifluoro(4- 740 (((1, 1,1,3,3,3-hexafluoromethylpropan yl)oxy)carbonyl)(3-methyl-1 H-pyrazol F F F nyl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid 18b l (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl- 618 azol-l-yl) (propoxycarbonyl)phenyl)ethoxy)pyrirnidinyl)-2,8- o)y diazaspiro[4.5]decanecarboxylic acid 18c \0 (S)(2-amino((R)(4-(butoxycarbony l)(3- 632 methyl-IH-pyrazol-l-y])phenyl)-2,2,2- trifl uoroethoxy)pyrirnid inyl)-2,8- c()y diazaspiro [4. necarboxylic acid )lo� (S)(2-amino((R)(4-(tert-butoxycarbonyl)(3- 632 rn ethyl-1H-pyrazoly1)phenyl)-2,2,2- trifl uoroethoxy)pyrirn idinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid 18e "( (S)(2-amino((R)-2,2,2-tri fl uoro-l-(4- 632 (isobutoxycarbonyl)(3-methyl- lIf-pyrazol-lyl )phenyl)ethoxy)pyri midinyl)-2,8- co�o� diazaspiro]4.5ldecanecarboxylic acid 18f (S)(2-amino((R)- (cyclopentyloxy)carbonyl)- 644 2-(3-methyl-1H-pyra zolyl)phenyl)-2,2,2- triflu oroethoxy)pyrimidiny])-2,8- diazaspiro[4.5ldecanecarboxylic acid Table Sb.
NMR Data for Compounds of Table Sa Ex. NMR 18a 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.58 (br. s., 4 H) 1.97 (s, 1 H) 2.04 (dd, J=l3.50, 7.20 Hz, 1 H) 2.12 (s, 3 H) 2 .31 (dd, J=13.45, 9.30 Hz, I H) 2.38 (s, 3 H) 3.04 - 3.27 (rn, 2 H) 3.38 - 3 .55 (m, 2 H) 3.64 (dd, J=l3.23, 5.56 Hz, 2 H) 4.07 (t, J=8.08 Hz, 1 H) 5.67 (s, 1 H) 6.43 (d,J=2.34 Hz, l H) 6.85 (q, J=6.69 Hz, 1 H) 7.90 (d, 1=8.20 Hz , 1 H) 7.96 (dd, 1=8.20, 2.00 Hz, 2 H) 8.06 (dd, J=8.27, 1.73 Hz, I H) 18b 1H NMR (400 MHz, Me0H-d4): 8 ppm 1.01 (t, J=7.44 Hz, 3 H) 1.58 (d, 1=4.49 Hz, 4 H) 1.72 - 1.85 (m, 2 H) 1.97 (s, 1 H) 2.04 (dd, J=13.35, 7.25 Hz, 1 H) 2.30 (dd, J=13.52, 9.13 Hz, 1 H) 2.38 (s, 3 H), 3 .06- 3.26 (m, 2 H) 3.38 - 3.72 (m, 4 H) 4.00-4 .12 (m, 1 H) 4.29 (t, J=6.64 Hz, 2 I-I) 5.68 (s, 1 H) 6.42 (d, J=2.44 Hz, 1 H) 6.84 (q, J=6.57 Hz, 1 H) 7.84 (d, J=8.20 Hz, 1 H) 7.95 (d, J=2.34 Hz, lH) 7.98 (d, J=l.61 Hz, I H) 8.09 (dd, , 1.64 Hz, 1 H) 18c 1H NMR (400 MHz, Me0H-d4): 8 ppm 0.97 (t, J=7.42 Hz, 3 H) 1.46 (dq, J=lS.01, 7.48 Hz, 2 H) 1.58 (d, J=4.83 Hz, 4 H) l.68 - 1.82 (m, 2 H) 1.97 (s, l H) 2.04 (dd, J=13.52, 7.03 Hz, 1 H) 2.30 (dd, 1=13.42, 9.18 Hz, 1 H) 2.38 (s, 3 H) 3.07- 3.25 (m, 2 J-1) 3.38 - 3.71 (m, 4 H) 4.06 (dd, J:=9.15, 7.00 Hz, 1 H) 4.33 (t, J=6.61 Hz, 2 H) 5.68 (s, 1 H) 6.42 (d, J=2.39 Hz, 1 H) 6.84 (q, 1=6.44 Hz, 1 H) 7.84 (d, J=8.30 Hz, 1 H) 7.95 (d, J=2.29 Hz, 1 H) 7.98 (d, J:=,J .61 Hz, 1 H) 8.08 (dd, J=8.25, 1.71 Hz, 1 H) 18d 1H NMR (400 MHz, 4): o ppm 1.57 (s, 13 H) 1.97 (s, 2 H) 2.04 (dd, J=13.50, 7.15 Hz, 1 H) 2.30 (dd, J=14.06, 9.96 Hz, 1 H) 2.38 (s, 3 H) 3.08 - 3.26 (rn, 2 H) 3.38 - 3.74 (m, 4 H) 4.01 - 4.14 (m, 1 H) 5.68 (s, 1 H) 6.41 (d, J=2.34 Hz, 1 H) 6.80 (q, 1=6.64 Hz, 1 H) 7.80 (d, J=8.15 Hz, 1 H) 7.92 (dd, J=7.88, 1.93 Hz, 2 H) 8.02 (dd, J=8.27, 1.59 Hz, 1 I-1) 18e 1H NMR (400 MHz, Me0H-d4): o ppm 1.00 (d, J=6.74 Hz, 6 H) 1.52 - 1.64 (m, 4 H) 1.97 (s, 2 H) 2.00 - 2.12 (m, 2 H) 2.30 (dd, J=13.45, 9.35 Hz, 1 H) 2.38 (s, 3 H) 3.07 - 3.26 (m, 2 H) 3.37 - 3.55 (m, 2 H) 3.58 - 3.70 (m, 2 H) 4.06 (dd, J=9.03, 7.17 Hz, 1 J-1) 4.12 (d, J=6.59 Hz, 2 H) 5.68 (s, 1 H) 6.42 (d, J=2.39 Hz, 1 H) 6.84 (q, J=6.51 Hz, 1 H) 7.84 (d, J=8.35 Hz, 1 H) 7.95 (d, J=2.34 Hz, 1 H) 7.98 (d, J=l.61 Hz, 1 H) 8.09 (dd, J=8.27, 1.68 Hz, 1 H) 18f 1H NMR (400 MHz, MeOH-d4): o ppm 1.54 - 1.94 (m, 11 H) 1.97 (s, 3 H) 2.04 (dd, J=l3.35, 7.15 Hz, 1 H) 2.24 -2.35 (m, 1 H) 2.38 (s, 3 H) 3.02- 3.27 (m, 2 H) 3.37 - 3.81 (rn, 4 H) 3.95 - 4.22 (m, l H) 5.32 - 5.44 (m, 1 H) 5.67 (s, 1 H) 6.41 (d, J=2.39 Hz, 1 H) 6.82 (d, J=6.39 Hz, 1 H) 7.82 (d, J=8.30 Hz, 1 H) 7.94 (d, J=l.85 Hz, 2 H) 8.06 (dd, J=8.15, 1.71 Hz, 1 H) Example 19a: (S)(2-amino((R )-2,2,2-trifluoro (2-(3-methyl-lH-pyrazolyl) henyI) cthoxy)pyrimidiny1)-2,8-diazaspi ro [ 4 .5] dccanecarboxy lic acid Step 1: To a solution of (S)benzyl 3-ethyl 8-(2-amino((R)(5-bromo(3-methyl-1H­ pyrazol-Lyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro [4.5Jdecane-2,3- dicarboxylate (500 mg, 0.65 mmol) in 4:1 EtOH:H20 (25 mL) was added 4,4,5,5-tetramethyl vinyl-1,3,2-dioxaborolane (150 mg, 0.971 mmol), KHC03 (648 mg, 6.47 mmol), and IO PdCh(PPh3)2 (68 mg, 0.097 . The reaction e was heated to 80 °C for 1.75 h, then cooled to RT, and extract ed with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, fi ltered, and concentrat ed in vacuo. Purifi cation via a 40 g Isco RediSep silica cartridge g (EtOAc/hepate) provides (S)benzyl 3-ethyl 8-(2-amino((R)-2,2,2- trifluoro(2-(3-methyl-lH-pyrazolyl)vinylphenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Step 2: N-CBZ Deprotection was accomplished via Method B to provide (Sj-ethyl 8-(2-amino ((R)-2,2,2-trifluoro- l-(2-(3-methyl-1H-pyrazol-l-yl)vinylphenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylate as an off-white solid.
Step 3: Hydro lysis of (S)-ethyl 8-(2-amino((R)-2,2,2-tdfluo 2-(3-methyl-1 H-pyra zol yl)vinylphenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.S]decanecarboxylate using the LiOH genera l method provided the title compoun d as a white solid.
Using the c scheme below, the following examples of Table 6a were prepared as described above for (S)(2-amino((R)-2,2,2-trifl uoro(2-(3-methyl-lH-pyrazolyl) vinylphenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid (Example l 9a).
R' = H, Me, Et, COOH STEP2 Table 6a.
Ex. R CASName LCMS No. (MH+) 19a (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H- 558.6 � pyrazolyl)vinylphenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro(4.5]decanecarboxylie acid 19b (2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1 H- 572.6 pyrazolyl)((E)-propen � yl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspirolq.Sldecane-Sccarboxylic acid 19c \ (S)(2-amino((R)(5-((E)-butenyl)(3- 585.5 methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin yl)-2,8- diazaspiro]4.5]decanecarboxylic acid 19d (S)(2-amino((R)(5-((E)carboxyvinyl)(3- 602.6 o� methyl-lH-pyrazolyl)phenyl)-2,2,2- trifluoroe thoxy)pyri midinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid Table 6b.
NMR Data for Compounds of Table 6a Ex. NMR 19a 1H NMR (400 MHz, MeOH- d4): s ppm 1.59 (m, 4 H) 2.06 (dd, J=13.42, 7.17 Hz, 1 H) 2.31 (dd, 2, 9.18 Hz, 1 H) 2.38 (s, 3 H) 3 . 1 8 (m,2 H) 3.59 (m, 4 H) 4.07 (dd, J=9.20, 7.20 Hz, 1 H) 5.36 (d, J=l0.98 Hz, 1 H) 5.75 (s, 1 H) 5.85 (d, J=l 7.62 Hz, 1 H) 6.39 (d, J=2.34 Hz, 1 H) 6.80 (m, 2 H) 7.38 (d, J=8.30 Hz, 1 H) 7.63 (dd, J=B.25, 2.00 Hz, 1 H) 7.74 (s, 1 H) 7.87 (d, J=2.29 Hz, 1 H) 19b 1H NMR (400 MHz, MeOH- d4): s ppm 1.59 (m, 3 H) 1.90 (dd, J=6.32, 1.20 Hz, 3 H) 2.06 (dd, 7, 7.13 Hz, 1 H) 2.31 (dd, 1=13.45, 9.25 Hz, 1 I-1) 2.37 (s, 3 H) 3 .18 (m, 2 H) 3.57 (m, 4 H) 4.08 (dd, J=9.18, 7 .17 Hz, 1 H) 5.75 (s, 1 H) 6.39 (m, 3 H) 6.75 (q, J=6.67 Hz, I H) 7.32 (d, J=8.25 Hz, 1 H) 7.52 (dd, J=8.30, 2.00 Hz, I H) 7.65 (s, l H) 7.84 (d, J=2.34 Hz, 1 H) 19c 1H NMR (400 MHz, MeOH- d4): s ppm 1.11 (t, J=7.47 Hz, 3 H) 1 .59 (d, J=4.59 Hz, 4 H) 2.06 (dd, J=l3.37, 7.22 Hz, 1 H) 2.28 (m, 3 H) 2.37 (s, 3 H) 3.18 (m, 2 H) 3.59 (m, 4 H) 4.07 (dd, J=9.10, 7.20 Hz, 1 H) 5.76 (s, 1 H) 6.40 (m, 3 H) 6.76 (m, 1 H) 7.33 (d, J=&.25 Hz, 1 H) 7.54 (dd, J=8.30, 2.05 Hz, 1 H) 7.66 (s, 1 H) 7.84 (d, J=2.29 Hz, 1 H) 19d 11-1 NMR (400 MHz, MeOH-d4): 8 ppm 1.57 (t, J=5.44 Hz, 4 H) 1.97 (s, 3 H) 2.04 (dd, J=13.72, 7.27 Hz, 1 H) 2.30 (dd, J=13.32, 9.18 Hz, lH) 2.37 (s, 3 H) 3.07 - 3.25 (m, 2 H) 3.40 - 3.55 (rn, 2 H) 3.65 (dd, , 4.73 Hz, 2 H) 4.07 (t, J=7.98 Hz, 1 H) 5.75 (s, 1 H) 6.40 (d, J=2.34 Hz,1 H) 6.51 (d, J=l6.20 Hz, 1 H) 6.94 (q, J=6.52 Hz, 1 H) 7.46 (d, J=8.30 Hz, 1 H) 7.66 (d, J=15.86 Hz, 1 H) 7.78 (dd, , 1.88 Hz, 1 H) 7.87 (s, 1 H) 7.92 (d, J=2.34 Hz, 1 H) Using the generic scheme below, the following examples of Table 7a can be prepared as described above for (S)(2-amino((R)-2,2,2-trifl uoro(2-(3-methyl-1H-pyra zolyl) vinylphenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid (Example 19a), by substituting the alkylidene borolane with a boronic acid or ester.
Table t« I CASName ILCMS (MH+) 19e (S)(2-amino((R)-l-(3',4'-dimethyl(3-methyl-1 H- 536.7 pyrazolyl)-[1, 1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane- � 3-carboxylic acid 19f HO (S)(2-amino((R)-l-(3'-carboxy(3-methyl-1 H- 652 pyrazolyl)-[1, henyl]yl)-2,2,2- �o trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid 19g 2" (S)(2-amino((R)(4'-carboxy(3-methyl-1 H- 652 pyrazolyl)-[1, henyl]yl)-2,2,2- � I trifluoro )pyrimidinyl)-2,8-diazaspiro[4.5]decane- ::::-... 3-carboxylic acid 19h OH (S)(2-amino((R)(3 '-((E)carboxyvinyl)(3- 678 '0 methyl-IH-pyrazol yl)-[1, henyl]yl)-2,2,2- I trifl uoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane- I --.:::: 3-carboxylic acid 19i O� OH (S)(2-amino((R)(4'-((E)carboxyvinyl)(3- 678 methyl-lH-pyrazolyl)-[1,1'-biphenyl]yl)-2,2,2- � trifluoroe thoxy)pyrimidiny1)-2,8-diaza spiro [4.S]decane- � I 3-carboxylic acid ::::-... 19j OH (S)(2-amino((R)(3 '-(2-carboxyethyl)(3-methyl- 680 '0 1H-pyrazolyl)-[1,1'-biphenyl]yl)-2,2,2- trifl uoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane- I --.:::: 3-carboxylic acid 19k 0:,-... OH (S)(2-am ino((R )(4'-(2-carboxyethyl)(3-methyl- 680 1H-pyrazolyl)-[1, l '-biphenyl]yl)-2,2,2- tri fluoroethoxy)pyrimidiny1)-2,8-diazaspiro [4.5]decane- � I 3-carboxylic acid 191 f (S)(2-amino((R)-2,2,2-trifluo ro(41- 652 (hydroxymethyl)-3 '-methyl(3-methyl-lH-pyra zol-l-yl)- ".:::: biphenyl]yl)ethoxy)pyrimidinyl)-2,8- � diazaspiro[ 4.5]decanecarboxylic acid 19m ¢' (S)(2-amino((R)-2,2,2-trifluoro(3'- 652 "'-::: (hydroxymethyl)-4'-methyl(3-methyl-1 H-pyrazolyl)- h [1, 1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid 1911 9 (S)(2-amino((R)-2,2,2-trifluoro(4-(3-methyl-1 H- 608 pyrazolyl)-[l, l'-biphenyl]yl)ethoxy)pyrimidinyl)- 2,8-diazaspiro(4.S]decanecarboxylic acid 190 ·�F (S)(2-amino((R)(3',4'-difluoro(3-methyl-1 H- 644 pyrazolyl)-[1, 11-biphenyl]yl)-2,2,2- l h trifluoroethoxy)pyrimidiny1)-2, 8-diazaspiro[4. ne- oxylic acid 19p Cl (S)(2-amino((R)(3',4'-dichloro(3-methyl- lH- 677 �J°' pyraz l)-[1, 1 '-biphenyl]yl)-2,2,2- h triflu oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane- 3-carboxy1ic acid 19q 2Cl (S)(2-amino((R)(4'-chloro(3-methyl-l H- 643 pyrazolyl)-[1, henyl]yl)-2,2,2- trifl uoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid 19r "9 (S)(2-amino((R)-2,2,2-trifl uoro-l-(4'- 639 (hydroxymethyl)(3-methyl-1 H-pyra zolyl)-[1, 1'- I "'-::: biphenyl]yl)ethoxy)pyrimidinyl)-2,8- h diazaspiro[4.5]decanecarboxylic acid Table 7b.
NMRData for Compounds of Table 7a Ex. NMR 19e 1H NMR (400 MHz, MeOH- d4): o ppm 1 .5 7 (m, 4 H) 2.04 (dd, J=13.62, 6.98 Hz, 1 H) 2.32 (d, J=ll .96 Hz, 6 H) 2.40 (s, 3 H) 3.1 6 (m, 2 H) 3.55 (m, 4 H) 4.07 (dd, J=9.l8, 7.22 Hz, 1 H) 5.79 (s, 1 H) 6.40 (d, J=2.29 Hz, 1 H) 6.85 (m, 1 H) 7.21 (d, J=7.76 Hz, 1 H) 7.31 (m, 1 H) 7.36 (s, 1 H) 7.45 (d, J=8.25 Hz, 1 H) 7.75 (dd, J=8.27, 2.12 Hz, 1 H) 7.90 (d, J=2.20 Hz, 2 H) 19f 1H NMR (400 MHz, Me0H-d4): 8 ppm 1 .53 - 1.67 (m, 4 H) 2.05 (dd, J=13.42, 7.1 7 Hz, 1 H) 2.30 (dd, J=13.42, 9.22 Hz, 1 H) 2.40 (s, 3 H) 3.06 - 3.27 (m, 2 H) 3.39 - 3.74 (m, 4 I-I) 4.08 (dd, J=9.13, 7.27 Hz, 1 H) 5.79 (s, 1 H) 6.42 (d, J=2.29 Hz, 1 H) 6.92 (q, J=6.62 Hz, 1 H) 7.53 (d, J=8.25 Hz, 1 H) 7.57 (t, J=7.76 Hz, 1 H) 7.77 - 7.87 (m, 2 H) 7.94 (d, J=2.34 Hz, 1 H) 7.97 (d, J=l .42 Hz, 1 H) 8.04 (dt, J=7.79, 1.23 Hz, 1 H) 8.24 (t, J=l .61 Hz, 1 H) 19g 1H NMR (400 MHz, MeOH-d4): o ppm 1.47 - 1.6 7 (m, 4 H) 2.05 (dd, J=13.45, 7.20 Hz, 1 H) 2 .31 (dd, J=13.37, 9.27 Hz, I H) 2.40 (s, 3 H) 2.99 - 3.28 (m, 2 H) 3.39 - 3.78 (m, 4 H) 4.08 (dd, J=9.08, 7.27 Hz, 1 H) 5.79 (s, 1 H) 6.42 (d, J=2.29 Hz, 1 H) 6.86 - 7.01 (m, 1 H) 7.53 (d, J=8.30 Hz, 1 H) 7.64 - 7.77 (m, 2 H) 7.85 (dd, J=8.30, 2.15 Hz, 1 H) 7.94 (d, J=2.34 Hz, I H) 7.99 (d, J=l .32 Hz, 1 H) 8.08 - 8.18 (m, 2 H) 19h 1H NMR (400 MHz, MeOH-d4): s ppm 1.59 (t, J=5.54 Hz, 4 H) 2.04 (dd, J=13.45, 7.39 Hz, 1 H) 2.32 (dd, J=13.50, 9.25 Hz, 1 H) 2.41 (s, 3 H) 3.07 - 3.26 (m, 2 H) 3.41 - 3.76 (m, 4 H) 4.08 (dd, J=9.01, 7.30 Hz, 1 H) 5.81 (s, 1 H) 6.42 (d, J=2.29 Hz, 1 H) 6.57 (d, J=16.0l Hz, 1 H) 6.86 - 6.97 (m, 1 H) 7.48 - 7.57 (m, 2 H) 7.60 - 7.68 (m, 2 H) 7.73 (d, 1=16.01 Hz, 1 I-I) 7.77 (bs, 1 H) 7.83 (dd, J=8.25, 2.10 Hz, I H) 7.93 - 7.96 (m, 2 H) 19i 1H NMR (400 MHz, MeOH-d4): s ppm 1.50 - 1.65 (m, 4 H) 2.05 (dd, J=13.45, 7.20 Hz, 1 H) 2.31 (dd, J=13.40, 9.30 Hz, 1 H) 2.40 (s, 3 H) 3.05 - 3.28 (m, 2 H) 3.40 - 3.74 (m, 4 H) 4.07 (dd, J=9.10, 7.25 Hz, 1 H) 5.79 (s, 1 H) 6.42 (d, J=2.29 Hz, I H) 6.54 (d, 1 Hz, 1 H) 6.91 (q, J=6.72 Hz, 1 H) 7.51 (d, 1=8.25 Hz, 1 H) 7.61 - 7.75 (m, 5 H) 7.82 (dd, J=8.30, 2.15 Hz, 1 H) 7.93 (d, J=2.34 Hz, 1 H) 7.97 (s, 1 H) 19j 1HNMR (400 MHz, MeOH-d4): o ppm 1.51 - 1.66 (m, 4 H) 2.04 (dd, J=13.50, 7.15 Hz, 1 H) 2.31 (dd, J=13.37, 9.18 Hz, l H) 2.40 (s, 3 H) 2.65 (t, J=7.61 Hz, 2 H) 2.99 (t, J=7.59 Hz, 2 H) 3.06 - 3.27 (m, 2 I-I) 3.40 - 3.78 (m, 4 H) 4.08 (dd, J=8.98, 7.42 Hz, 1 H) 5.80 (s, 1 H) 6.41 (d, J=2.34 Hz, 1 H) 6.88 (q, J=6.61 Hz, 1 H) 7.27 (d, J=,7.32 Hz, 1 H) 7.35 - 7.41 (m, 1 H) 7.41 - 7.51 (m, 3 H) 7.77 (dd, J=8.27, 2.12 Hz, 1 H) 7.88 - 7.97 (m, 2 H) 19k 1H NMR(400 MHz, Me0H-d4): s ppm 1.57 (d, J=3.37 Hz, 4 H) 2.04 (dd, J=13.40, 7.20 Hz, 1 H) 2.30 (dd, J=13.35, 9.20 Hz, 1 H) 2.40 (s, 3 H) 2.63 (t, J=7.61 Hz, 2 H) 2.96 (t, J=7.57 Hz, 2 I-1) 3.03 - 3.26 (m, 2 H) 3.39 - 3.76 (m, 4 H) 4.07 (dd, , 7.32 Hz, l H) .78 (s, 1 H) 6.41 (d, J=2.29 Hz, 1 H) 6.86 (q, J=6.54 Hz, 1 H) 7.34 (d, J=8.25 Hz, 2 H) 7.46 (d, J=8.30 Hz, 1 H) 7.52 (d, J=8.25 Hz, 2 H) 7.76 (dd, J=8.27, 2.12 Hz, I H) 7.89 - 7.92 (m, 2 H) 191 1HNMR (400 MH z, Me0H-d4): o ppm 1.45 - 1.65 (m, 4 H) 2.00 - 2.09 (m, 1 H) 2.30 (dd, 0, 9.25 Hz, 1 H) 2.40 (s, 6 H) 3.03 - 3.27 (m, 2 H) 3.39 - 3.76 (m, 4 H) 4.07 (dd, J=9.10, 7.25 Hz, 1 H), 4.67 (s, 2 H) 5.79 (s, 1 H) 6.41 (d, J=2.25 Hz, 1 H) 6.86 (q, J=6.64 Hz, 1 H) 7.36 - 7.53 (m, 4 H) 7.77 (dd, J=8.30, 2.15 Hz, 1 H) 7.91 (d, J=2.44 Hz, 2 19m 1H NMR (400 MHz, Me0H-d4) : o ppm 1.46 - 1.69 (m, 4 H) 2.00 - 2.10 (m, 1 H) 2.30 (dd, J=13.45, 9.25 Hz, 1 H) 2.37 (s, 3 H) 2.40 (s, 3 H) 3.03 - 3.27 (m, 2 H) 3.39 - 3.76 (m, 4 H) 4.07 (dd, J=9.13, 7.22 Hz, 1 H) 4.70 (s, 2 H) 5.78 (s, 1 H) 6.41 (d, J=2.25 Hz, 1 H) 6.85 (q, J=6.57 Hz, 1 H) 7.26 (d, J=7.91 Hz, 1 H) 7.43 (dd, J=7.81, 1.95 Hz, 1 H) 7.47 (d, J=8.30 Hz, I H) 7.64 (d, J=l.81 Hz, 1 I-I) 7.79 (dd, J=8.27, 2.12 Hz, 1 H) 7.91 (d, J=2.29 Hz, 1 H) 7.94 (s, 1 H) 19n 1H NMR (400 MHz, MeOH-d4): o ppm 1.29 (d, J = 7.2 Hz, HI), 1.56 (d, J = 6.3 Hz, 4H), 2.03 (d, J = 12.8 Hz, lH), 2.30 (d, J = 12.4 Hz, lH), 2.39 (s, 3H), 3.09 (d, J = 11.5 Hz, lH), 3.22 (d, J = 11.7 Hz, lH), 3.47 (t, J = 18.6 Hz, 2H), 3.63 (s, 2H), 4.07 (s, lH), 4.64 (s, lH), 5.78 (s, lH), 6.41 (d, J = 2.1 Hz, lH), 6.87 (q, J = 6.5 Hz, IH), 7.44 (m, 4H), 7.59 (d, J = 7.4 Hz, 2H), 7.64 (s, lH), 7.77 (m, IH), 7.91 (m, 2H) 190 1H NMR (400 MHz, MeOH-d4): s ppm 1.30 (d, J = 18.0 Hz, lH), 1.57 (d, J = 6.1 Hz, 4H), 2.04 (dd, J = 13.9, 6.4 Hz, lH), 2.30 (dd, J = 13.5, 8.4 Hz, 1H), 2.39 (s, 3H), 3 . 11 (d, J = 11.6 Hz, IH), 3.23 (d, J = 11 .4 Hz, lH), 3.48 (dq, J = 21.6, 7.6, 6.8 Hz, 2H), 3.64 (dd, J = 13.8, 6.9 Hz, 2H), 4.08 (m, lH), 4.87 (s, 12H), 5.78 (s, lH), 6.41 (d, J = 2.0 Hz, lH), 6.91 (q, J = 6.6 Hz, lH), 7.36 (m, 2H), 7.50 (t, J = 9.3 Hz, 2H), 7.74 (dd, J = 8.3, 2.2 Hz, lH), 7.90 (dd, J = 7.9, 2.1 Hz, 2H) 19p 1H NMR (400 MHz, MeOH-d4): o ppm 1.27 (s, lH), 1.44 (s, lH), 1.52 (q, J = 5.9 Hz, 4H), 1.85 (m, 1H), 2.11 (dd, J = 13.2, 8.8 Hz, lH), 2.39 (s, 3H), 2.77 (d, J = 11.3 Hz, lH), 3.01 (d, J = 11.3 Hz, lH), 3.45 (ddt, J = 19.8, 12.8, 5.8 Hz, 2H), 3.61 (m, 2H), 3.74 (t, J = 8.0 Hz, lH), 5.78 (s, lH), 6.42 (d, J = 2.4 Hz, lH), 6.93 (q, J = 6.6 Hz, lH), 7.54 (m, 3H), 7.75 (m, 2H), 7.92 (dd, J = 11.1, 2.0 Hz, 2H) 19q 1H NMR (400 MHz, MeOH-d4): s ppm 1.28 (s, lH), 1.57 (t, J = 5.0 Hz, 4H), 2.03 (dd, J = 13.3, 6.9 Hz, lH), 2.29 (dd, J = 13.4, 9.0 Hz, lH), 2.39 (s, 3H), 3.08 (d, J = 11.6 Hz, lH), 3.22 (d, J = 11.6 Hz, lH), 3.48 (ddt, J = 20.4, 13.2, 5.9 Hz, 2H), 3.65 (dd, J = 13.7, 6.5 Hz, 2H), 4.05 (t, J = 8.0 Hz, II-I), 5.77 (s, 1 H), 6.41 (d, J = 2.3 Hz, lH), 6.89 (q, J = 6.6Hz, lH), 7.47(m,3H), 7.58(m,2H), 7.77(dd,J=8.3,2.2Hz, lH), 7.91 (t,J=2.4 Hz, 2H) 19r 1H NMR (400 MHz, Me0H-d4): s ppm 7.94 - 7.80 (m, 9H), 7.60 (d, J = 8.1 Hz, 6H), 7.50 (dd, J = 20.7, 8.1 Hz, 9H), 6.94 (q, J = 6.2 Hz, 3H), 6.42 (d, J = 2.3 Hz, 3H), 4.66 (s, SH), 4.38 (t, J = 8.4 Hz, 3H), 3.73 (s, 6H), 3.63 - 3.55 (m, lH), 3.29- 3.18 (m, SH) , 2.40 (s, 9H), 2.07 (dd, J = 13.5, 7.8 Hz, 3H), 1.70 - 1.61 (m, lOH), 1.28 (s, lH).
Example 20: (2-amino((R)(2'-(ethoxycarbonyl)(3-methyl-lH-pyrazolyl)­ [1,1'-biphenyl]yl)-2,2,2-trifh101·oeth oxy)pyrimiclinyl)-2,8-diazaspiro [4.5] decane carboxylic acid The title compound was made using the procedure described for (S)(2-amino((R)-l-(3'­ ycarbonyl)(3-methyl-IH-pyrazol-l-yl)-[1, 1'-biphenyl]yl)-2,2,2- trifluo roethoxy)pyrimidinyl)-2,8-diazaspiro[4.S]decanecarboxylic acid (Ex ample Sa) starting with (S)(2-amino((R )-l-(5-bromo(3-methyl-lH-pyra zol-l-yl)phenyl)-2,2,2- trifluo roethoxy)pyrim idinyl)((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decanecarboxylic acid. 1I-I NMR (400 MHz, MeOH-d4): s ppm 0.89 (t, J=7.15 Hz, 3 H) 1.60 (t, J=S.54 Hz, 4 H) 2.06 (dd, 1=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 (rn, I 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)(2-amino((R)-l-( 4'-(ethoxycarbonyl)(3-methyl-lH-pyrazolyl)­ [1,1'-biphenyl]yl)-2,2,2-trifluoroethox y)pyrimidinyl)-2,8-diazaspiro [4.5Jdccane carboxylic acid The title compound was made using the proc edure describ ed for (S)(2-amino((R)(31- (ethoxycarbonyl)(3-methyl-1H-pyrazolyl)-[1,11-biphenyl]yl)-2,2,2- trifl hoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid (Exa mple 5) ng with (S)(2-amino((R)(5-bromo(3-methyl-lH-pyrazol- l-yl)phenyl)-2,2,2- trifluoroethoxy) pyrimidinyl)((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decanecarboxylic acid. 1H NMR (400 MHz, MeOH-d4): o 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=l3.42, 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, 1=2.25 Hz, 1 H) 6.86 - 7.01 (m, 1 H) 7.53 (d, J=8.30 Hz, I 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=l .51 Hz, 1 H) 8.06 - 8.17 (m, 2 H).
LCMS (MH+): 680.
Example 22a: (S)(2-amino((R)(5-ethyl(3-methyl-lH-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.S]decanccarboxylic yycitOH µN'N CF3 NyN Step 1: (S)-Ethyl 8-(2-amino((R)-2,2,2-trifluoro-l-(2-(3-methyl- lH-pyrazolyl) vinylphenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate (100 mg, 0.171 mmol) in MeOH (2 mL) was hydrogenated via an H-Cube apparatus 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 resisdue was lized from 1:1 H20:CH3CN to provide (S)-ethyl 8-(2-amino((R)-l-(5-ethyl(3-methyl-lH-pyrazolyl)phenyl)-2,2,2- tri:flu oxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate as a white solid which was used ly in the next step.
Step 2: Hydrolysis of (S)-ethyl 8-(2-amino((R)- I-(5-ethyl(3-methyl-lH-pyra zol yl)phenyl)-2,2,2-tri:flu oroethoxy)pyrimidinyl)-2,8-diazas piro[4.5]decanecarboxylate using the LiOH genera l method provided the title compound as a white solid.
Using the same generic scheme below, the following examples of Table 8a can be prepared as described above for (S)(2-amino((R)-l-(5-ethyl(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-trifluoro ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid (Example 22a).
STEP 1 R'=H, Me, Et STEP2 Table Sa.
Ex. R CAS Name LCMS No. (MH+) 22a \J (S)(2-amino((R)(5-ethyl(3-methyl-1 H-pyrazol 561 yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxy1ic acid 22b S, S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-lH- 575 pyrazolyl)propylphenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro]4.S]decanecarboxylic acid 22c \ (S)(2-amino((R)(5-butyl(3-methyl-1 zol 589 yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro] 4.S]decanecarboxylic acid Table Sb.
NMR Data for Compounds of Table Sa 22a 1H NMR (400 MHz, MeOH-d4): o ppm 1.24 (t, J=7.59 Hz, 3 H) 1.57 (m, 4 H) 2.06 (dd, J=13.42, 7.13 Hz, 1 H) 2.32 (dd, J=13.45, 9.20 Hz, 1 H) 2.37 (s, 3 H) 2.72 (q, J=7.61 Hz, 2 H) 3.18 (rn, 2 H) 3.57 (m, 4 H) 4.08 (dd, J=9.13, 7.17 Hz, 1 H) 5.74 (s, 1 H) 6.36 (d, J=2.34 Hz, 1 H) 6.71 (q, J=6.65 Hz, 1 H) 7.31 (m, 1 H) 7.39 (rn, 1 H) 7.56 (s, 1 H) 7.82 (d, J=2.29 Hz, 1 H) 22b 1H NMR (400 MHz, MeOH-d4): o ppm 0.91 (t, J=7.35 Hz, 2 H) 1.62 (m, 6 H) 2.06 (dd, J=13.52, 7.17 Hz, 1 H) 2.31 (dd, J=13.45, 9.25 Hz, 1 H) 2.37 (s, 3 H) 2.66 (t, J=7.52 Hz, 2 H) 3.18 (m, 2 H) 3.56 (m, 4 H) 4.08 (dd, , 7.17 Hz, 1 H) 5.74 (s, 1 H) 6.36 (d, J=2.29 Hz, 1 H) 6.70 (q, J=6.70 Hz, 1 H) 7.31 (m, 1 H) 7.37 (m, 1 H) 7.53 (s, 1 H) 7.82 (d, J=2.29 Hz, I H) 22c 1H NMR (400 MHz, MeOH-d4): 3 ppm 0.92 (t, J=7.37 Hz, 2 H) 1.32 (dq, J=14.94, 7.38 Hz, 2 H) 1.60 (m, 6 H) 2.06 (dd, J=13.37, 7.22 Hz, 1 H) 2.31 (dd, J=13.45, 9.25 Hz, 1 H) 2.37 (s, 3 H) 2.69 (t, J=7.59 Hz, 2 H) 3.18 (m, 2 H) 3.58 (m, 4 H) 4.08 (dd, J=9.20, 7.25 Hz, I H) 5.75 (s, I H) 6.36 (d, J=2.15 Hz, 1 H) 6.69 (q, J=6.62 Hz, 1 H) 7.30 (m, 1 H) 7.37 (rn, 1 H) 7.53 (s, 1 H) 7.82 (d, J=2.29 Hz, 1 H) Example 23: (S)(2-Amino((R)(5-(ethoxycarbonyl)(3-methyl-lH-pyrazol yl)phenyl)-2,2,2-trifluoroctho xy)pyrimidinyl)-2,8-diazaspiro(4.5]clecanecarboxylic acid Step 1: To a solution of (S)(2-amino((R)(5-bromo(3-methyl-IH-pyrazol y y 1)-2,2,2-trifluoroe thoxy)pyrimidiny1)((benzyloxy)carbonyl)-2,8- diazaspiro [4.5]decanecarboxylie acid (product of Step 3, Example 1Om) (180 mg, 0.24 mmol) in ethanol (2 mL) was added Pd(PPh3)2C'2 (34 mg, 0.048 mmol), KHC03 (242 mg, 2.4 mmol).
Aballoon of CO was fitt ed and the reaction mixture was heated to 80 °C for 20 h, then cooled to RT. The on was quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine , dried over MgS0,1, fi ltered, and concentrated in vacuo.
Purifica tion by normal phase silica gel column /MeOH/AcOH) provided (S)(2-amino- 6-((R)(5-(ethoxycarbonyl)(3-methyl- 1H-pyrazolyl)phenyl)-2,2,2-triflu oroethoxy) pyrimidinyl)((benzyloxy)carbonyl)-2,8-diazaspiro[4.S]decanecarboxylic acid as an off­ white solid.
Step 2: N-CBZ Deprotection of (S)(2-amino((R)(5-(ethoxycarbonyl)(3-methyl-1 H­ pyrazolyl)phenyl)-2,2,2-trifluoroethoxy) pyrimidinyl)((benzyloxy)carbonyl)-2,8- diazaspiro[4.5]decanecarboxylic acid was lished via Method A to provide the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6): o ppm 1.34 (t, J=7.10 Hz, 3 H) 1.51 - 1.71 (m, 4 H) 1.90 (dd, 8, 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. e 24: (S)(2-Amino((R)-l-(5-carboxy(3-mcthyl-lH-pyrazolyl)pheuyl)- 2,2,2-frifluoroethoxy) pyrimidinyl)-2,8-diazaspfrof4.5)decauccarboxylic acid Hydrol ysis of (S)(2-amino((R)(5-(ethoxycarbonyl)(3-methyl-1 H-pyra zol yl)phenyl)-2,2,2-trifluoro ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxy1ic acid (Example 23) using the LiOH general method provides the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): o ppm l.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=S.80 Hz, 1 H) 7.67 (d, J=8.35 Hz, 1 H) 8.11 (dd, J=8.35, 1.95 Hz, l H) 8.21 (d, J=2.39 Hz, I H) 8.25 (s, 1 H) 8.93 (m, .!=4.40 Hz, 1 H) I 0.09 (br. s., 1 H). LCMS (MH+): 576.
Exampie 25: (S)(2-Amino((R)-2,2,2-trifluoro(4-(hydroxymethyl)(3-methyl-1H­ pyrazo1yl)phcnyl)ethoxy) pyrimidinyl)-2,8-diazaspiro[4.S]clecanccarboxylic acid Step 1: To a solution of (S)benzyl l 8-(2-amino((R)(4-bromo(3-methyl-lH­ pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro [4.S]decane-2,3- dicarboxylate (386 mg, 0.50 mmol) in DMF (10 mL) and EtJN (0.35 rnl., 2.5 mmol) was added (n-octyl)3SiH (368 mg, 1.0 mmol). The mixture was degassed under 1 atm of CO n and PdCh(PPh,)2 (72 mg, 0.10 mmol) was added, then degassed again with I attn of CO, and heated to 80 °C for 12 h. The reaction was cooled to RT and trated in vacuo. The residue was diluted with water then extracted with EtOAc. The combined organic layers were dri ed over Na2S04, fi ltered, and concentrated in vacuo. Normal phase column chro matography on silica gel IO (EtOAc I heptane) provided benzyl 3-ethyl 8-(2-amino((R )-2,2,2-trifluoro (4-formyl- 2-(3-methyl-1H-pyrazolyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3- dicarboxylate as a light yellow solid contaminated with about 25% of (S)benzyl 3-ethyl 8-(2- amino((R)-2,2,2-trifluo ro- 3-methyl-1H-pyrazoly!)phenyl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as by-pro duct. The mixture was used directly in the next step.
Step 2: To a solution of (S)benzyl 3-ethyl 8-(2-amino((R )-2,2,2-triflu oro(4-formyl(3- methyl-IH-pyrazolyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3- dicarboxylate (36 mg, 0.05 mmol) in dichloroethane (2 mL ) was added NaCNBH3 (IM in THF, 1 mL, 0.5 mmol), followed by a few drops of HOAc. The mixture was stirred at RT for3 h then concentrated in vacuo. The residue was dissolved in MeOH and purifi ed on reverse phase HPLC (MeOHIH20/H OAc) to provide (S)benzyl l 8-(2-amino((R)-2,2,2-trifl uoro(4- xymethyl)(3-methyl- 1H-pyrazol- l-yl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro]4.5]decane-2,3-dicarboxylate as a sticky solid that was used without further purifi cation.
Step 3: N-CBZ Deprotection was accomplished via Method B to provide hyl mino ((R)-2,2,2-trifluoro(4-(hydroxymethyl)(3-methyl-lH-pyrazol-lyl )phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro(4.5]decanecarboxylate as a white solid.
Step 4: Hydrolysis of (S)-ethyl 8-(2-amino((R)-2,2,2-h·ifluoro(4-(hydroxymethyl)(3- methyl-1 H-pyrazolyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.S]decanecarboxylate using the LiOH general method provided the tide compound as a white solid. 1H NMR (400 MHz, MeOH-d4): s ppm 1.57 (t, J=S.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 1-1) 3.07 - 3.26 (rn, 2 H) 3.39- 3.54 (m, 2 H) 3.58 - 3.70 (m, 2 H) 3.99 -4.1 3 (m, 1 H) 4.65 (s, 2 H) 5.71 (s, I 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, l H) 7.68 (d, J=8.10 Hz, 1 H) 7.84 (d, J=2.34 Hz, 1 H).
LCMS (MH+): 562.
Example 26: (S)(2-amino((R)(4-((dimethylamino)mcthyl)(3-methyl-lH-pyrazol- 1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid Step 1: To a solution of (S)benzyl 3-ethyl 8-(2-amino((R)-2,2,2-trifluor o(4-formyl(3- methyl- I H-pyrazolyl)phenyl)ethoxy)pyri midinyl)-2,8-diazaspirof4.S]decane-2,3- dicarboxylate (166 mg, 0.23 mmol, see Ex. 25) in dichloroethane (4 mL) and HOAc (10mg) was added NaBH(OAc)3 (242 mg, 1 . 15 mmol) and Me2NH (2M in THF, 0.58 mL, 1 .15 mmol). The on mixture was stirred at RT for 20 h then concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and purifie d by e phase HPLC (MeOH/H20/HOAc) to pro vide (S)benzyl 3-ethyl 8-(2-amino((R)(4-((dimethylamino) methyl)(3-methyl-lH-pyrazol- l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro [4.5]decane-2,3-dicarboxylate as a white solid.
Step 2: N-CBZ Deprotection was accomplished via Method A to provide (S)-ethyl 8-{2-amino ((R)(4-((dimethylamino)methyl)(3-methyl-1 zol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate as a white solid.
Step 3: Hydrolysis of (S)-ethyl 8-(2-amino((R)-l-(4-((dimethylamino)methyl)(3-methyl­ lH-pyrazolyl)phenyl)-2,2,2-ttifl uoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate using the LiOH general method prov ided the title compound as a whi te solid. 1HNMR (400 MHz, 4): s ppm 1.66 - 1.8 1 (m, 4 H) 2. 10 (dd, J=13.62, 8.54 Hz, 1 H) 2.38(s, 3 H) 2.49 (dd, 1=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 I-I) 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.
Exam pie 27: (S)(6-((R)(4-Bromo(3-methyl-1H-pyrazolyl)pltenyl)-2,2,2- trifluorocthoxy)mcthylpyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid Br'Y) �OH p�oyy(},'NfCF3 N,f Step 1: To a solution of 1 (R)- 1-(4-bromo(3-methyl-lH-pyrazol-1 -yl)phenyl]-2,2,2- trifl uoro ethanol (15.7 g, 46.3 mmol, Intermediate 1) in dioxan e (200 mL) was added 4,6- dichloro-z-methylpyrimidine (30.6 g, 51 mmol) and Cs2C03 (61.2 g, 18 7 mmol). The reaction mixture was heated to 80 °C for 30 h, then cooled to RT, and fi ltered. The residue was concentrated in vacuo andpurifi ed by normal phase column chro matogra phy on silica gel (CH2Ch /heptane) to provide (R)(1-(4-bromo(3-methyl-lH-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)chlorornethylpyrimidine as a white solid.
Step 2: To a solution of (R)(1-(4-brorno(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)chloromethylpyrimidine (21 g) in e (200 ml) was added (S) benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (15 g) and Na2C03 (14 g). The reaction was heated to 90 °C for 48 h, then cooled to RT, filtered, and concentrated in vacuo.
Purification of the e on normal phase column chromatograp hy on silica gel (EtOAc /heptane) provided (S)benzyl 3-ethyl 8-(6-((R)(4-bromo(3-methyl-lH-pyrazol l O yl)phenyl)-2,2,2-trifl uoroethoxy)methylpyrimi dinyl)-2,8-diazaspiro[4.5]decane-2,3- dicarboxylate as an off-white solid.
Step 4: N-CBZ Deprotection was accomplished via Method A to provide (S)-ethyl 8-(6-((R)- 1- (4-bromo(3-methyl-1 H-pyra zolyl)pheny1)-2,2,2-trifluo xy)methylpyri midinyl)- 1 5 2,8-diazaspiro[4.5]decanecarboxylate an off-white solid.
Step 5: Hydrol ysis of (S)-ethyl 8-(6-((R)(4-bromo(3-methyl-IH-pyrazol-l-yl)phenyl)- 2,2 ,2-tri fluoroethox y)methylpyrimidiny1)-2,8-diazaspiro [4.5]decanecarboxy1ate using the LiOH general method provided the title nd as an off-white solid. 1H NMR (400 MHz, 4): 8 ppm 1.64 (br. s., 4 H) 2 .10 (d, J=7 .03 Hz, 1 H) 2.28 (s, 3 H) 2.35 (dd, 1=13.37, 9.27 Hz, 1 H) 2.39 (s, 3 H) 3 . 10 - 3.20 (m, 1 H) 3.28 (d, J=ll.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, l H) 7.58 - 7.75 (m, 3 H) 8.03 (d, 1=2.15 Hz, 1 H). LCMS (MH+): 609.
Example 28: (S)(6-((R)(4-chloro(3-methyl-1H-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)methyl pyrimidinyl)-2,8-diazaspiro[4.5]decanccarboxylic acid Cl'to ):OH "YYOY'Y�N� f1 CF, N,( The title compound was ed as described above for (S)(6-((R)-l-(4-bromo(3-methyl­ IH-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)methylpyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid (byr replacing I (R)(4-bromo(3-methyl-lH- pyrazolyl)phenyl]-2,2,2-trifluoroethanol with l(R)[4-chloro(3-methyl-lH-pyrazol yl)phenyl]-2,2,2-trifluoroethanol, Intermediate 3) and obtained as an off-white solid. 1HNMR(400 MHz, DMSO-d6): 8 ppm 1.34-1.54 (m, 4 H) 1.82 (dd, 1, 6.76 Hz, l 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=l 1.52 Hz, 1 H) 3.42 - 3.65 (m, 4 H) 3.70 (dd, J=8.91, 7.00 Hz, 1 H) 6.1 5 (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, 1=2.10 Hz, 1 H) 7.70 (d, J=S.44 Hz, 1 H) 8.1 9 (d, J=2.39 Hz, 1 H) 8.70 (br. s., 1 H). LCMS (MH+): 565.
General biatyl coupling (Suzuki) procedures Biaryl coupling method A Step 1: To a mixture of (S)((benzyloxy)carbonyl)(6-((R)(4-bromo(3-methyl­ lH-pyrazolyl)phenyl)-2,2,2-trifluoroetho methylpyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid (product of Step 3, Example 10m) (15 0 mg, 0.2 mmol), an arylboro nic acid (0.4 mmol), Pd(N ,N-dimethyl u-alaninate), (3.42 mg, 0.01 mmol), and K3PQ4 (128 mg, 0.6 mmol) were added water (3.0 mL) and EtOH (3.0 mL). The mixture was stirred at 50 °C for 12 h. The reaction was then cooled to RT, diluted with water, and extra cted with EtOAc. The combined organi c layers were dried over Na2SO,i, fi ltered, and concentrated in vacuo. The target biaryl compounds were purifi ed by normal phase silica gel column (CH2Ch:MeOH).
Step 2: Subsequent N-CBZ ection via method A aff orded the fi nal target spirocyclic amino acids.
Biaryl ng method B Step 1: To a e of (S)((benzyloxy)carbonyl)(6-((R)(4-bromo(3-methyl- 1H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)methylpyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid (product of Step 3, Example lOm) (150 mg, 0.2 mmol), an arylboronic acid (0.4 mmol), )2 • (1,1,3,3-tetramethylN-butylguanidine)2 (5.7 mg, 0.01 mmol), and K2C03 (83.5 mg, 0.61 mmo1) was added 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 to RT, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2S04, fil tered, and concentra ted in vacuo. The target biaryl compounds were purifi ed by normal phase silica gel column (CH2Ch:MeOH).
Step 2: Subsequent N-CBZ deprotection via method A afforded the final target spirocyclic amino acids.
Using the generic scheme below and employing the biaryl coupling method A, the Table 9.
Ex.No. Cy CAS Name LCMS(MH+) 29a o.0/ (S)(2-methyl((R)-2,2,2-trifluoro-l-(4-(2- 638 methoxypyridinyl)(3-methyl-l zol I � yl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.SJdecanecarboxyJic acid 29b ,1.0 (S)(2-methyl((R)-2,2,2-trifluoro(3-(3- 686 o1S�I methyl- IH-pyrazolyl)-4'-(methylsulfonyl)- -: [l ,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5ldecanecarboxylic acid 29c F (S)(6-((R}1-(3',4'-difluoro(3-methyl-1H- 645 � ' pyrazolyl)-[1, l'-biphenyl}4-yl)-2,2,2- F� trifl uoro ethoxy)methylpyrimidinyl)-2,8- diazaspiro]4.5]decanecarboxylic acid 29d M (S)(6-((R)-l-(3',4'-dimethyl(3-methyl-lH- 635 pyrazolyl)-[l ,1 '-biphenyl]yl)-2,2,2- trifl uoroethoxy)methylpyrimidinyl)-2,8- pirof4.5ldecanecarboxylic acid 29e ( (S)(6-((R)(3'-(ethoxycarbonyl)(3-methyl- 680 1Il-pyrazol-l-yl)-]1,l'-biphenyl]yl)-2,2,2- tri fl uoroethoxy)methylpyrimidinyl)-2,8- I "'=:: diazaspiro[4.S]decanecarboxylic acid ,,,.-:. 29f /0'(\,,... I (S)(2-methyl((R)-2,2,2-triflu oro- 1-(4-(6- 639 � methoxypyridinyl)(3-methyl-lH-pyrazol yl)phenyl)ethoxy)pyrimidinyl)-2,8- /oyJy diazaspiro[ 4.5ldecanecarboxylic acid 29g (S)(2-methyl((R)-2,2,2-trifl uoro(4-(2- 640 N:::-- I methoxypyrimidinyl)(3-methyl-lH-pyrazol- henyl)ethoxy)pyrimidinyl)-2,8- diazaspiro]4.S]decanecarboxylic acid 29h /0«I (S)(6-((R)-l-(2',4'-dimethoxy(3-methyl-IH- 668 � I pyra zolyl)-[l,1 enyl]yl)-2,2,2- triflu oro ethoxy)methylpyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid 29i 0 (S)(6-((R)-l-(4'-(ethoxycarbonyl)(3-methyl- 679 1 H-pyrazolyl)-[ 1,1'-biphenyl]yl)-2,2,2- /'o� trifluoroethoxy)methylpyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid 29j 0 (S)(6-((R)(41-(dimethylcarbamoyl)(3- 678 methyl-lH-pyrazolyl)-[1, 1'-biphenyl]yl)- 'N�I I ,,-:, c. 2,2,2-trifluoroethoxy)methylpyrimidinyl)- 2,8-diazaspiro[4.S]decanecarboxylic acid 29k (S){2-methyl((R)-2,2,2-trifluoro(4-(2- 639 N ypyridinyl)(3-methyl- lH-pyra zol ,......o yl)phenyl)ethoxy)pyrim idinyl)-2,8- piro[4.S]decanecarboxylic acid 291 F (S)(2-methy1((R)-2,2,2-trifl uoro(3'- 655.6 fl uoro-4'-methoxy(3-methyl-1 Il-pyrazol-Lyl)- -.. I [1,11-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decane- 3-carboxylic acid 29m I (S)(6-((R)(3 '-(dimethylcarbamoyl)(3- 679 methyl-IH-pyrazolyl)-[l,1 '-biphenyl]yl)- I � 2,2,2-tri fl uoroethoxy)methylpyrimidinyl)- ,,-:, 2,8-diazaspiro[4.S]decanecarboxylic acid Using the generic scheme above with the biaryl coupling method B, the following examples of Table 10 were prepared.
Table 10.
Ex. Cy CASName LCMS No. (MH+) 29n (S)(2-methyl((R)-2,2,2-triflu (2',4',6'- 650 trimethyl(3-methyl-l H-pyrazolyl)-[1,1'- � biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decanecarboxylic acid 290 '(o� (S)(2-methyl((R)-2,2,2-triflu oro(4'- 666 isopro -(3-methyl-lH-pyra zo1yl)-[l, I'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro]4.S]decanecarboxylic acid 29p (S)(2-methyl((R)-2,2,2-trifluoro-l-(2'-methoxy- 638 3-(3-methyl-1 H-pyrazolyl)-[1, l'-biphenyl] .,,,o yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane- 29q 'oA 3-carboxylic acid 0 (2-methyl((R)-2,2,2-trifluoro(3'-methoxy- 695 4'-(methoxycarbonyl)(3-methyl-lH-pyrazolyl)- I ,.,-:; [l, 1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decanecarboxylic acid 29r "o, (S)(6-((R)-l-(4'-(tert-butyl)(3-methyl-lH- 663 pyrazolyl)-[1, 1'-biphenyl]yl)-2,2,2- tri:fluo roethoxy)methylpyrimidiny l)-2,8- diazaspiro[4.5]decanecarboxylic acid 29s +o, (S)(6-((R)-l-(4'-ethoxy(3-methyl-lH-pyrazol-l- 652 I � , l '-biphenyl]yl)-2,2,2-triflu oroethoxy) methylpyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid 29t �;yo� (S)(2-methyl((R)-2,2,2-trifl uoro(3-(3-methyl- 692 F I � 1 H-pyra zolyl)-4'-(triflu oromethoxy)-[1, l 1- biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro [4.S]decanecarboxylic acid 29u OA (S)(2-methyl((R)-2,2,2-triflu oro(31- 666 (methoxycarbonyl)(3-methyl-1 H-pyra zolyl)- ,,,o [1 , 1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decanecarboxylic acid 29v N (S)(2-methyl((R)-2,2,2-triflu oro(2-(3-methyl- 609 No,� lH-pyra zol- l-yl)(pyrimidin yI)phenyl)ethoxy)pyrimidinyI)-2,8- diazaspiro [4.S]decanecarboxylic acid 29w (S)(2-methyl((R)-2,2,2-trifl -(3'-methoxy- 637 0 3-(3-methyl-l Il-pyrazo l-l-ylj-j l ,l '-biphenyl] I yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid 29x A (S)(2-methyl((R)-2,2,2-trifl uoro(3 ropyl- 650 3-(3-methyl-1H-pyrazolyl)-[1, l'-biphenyl] yl )ethoxy)pyrimidinyl)-2,8-diazaspiro [4.S]decane- 3-carboxylic acid 29y .o, (S)(2-methyl((R)-2,2,2-trifl uoro(3 '-fl uoro 626 hyl-lH-pyrazolyl)-[1,1 '-biphenyl] y xy)pyri midinyl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid 29z o, (S)(2-methyl((R )-2,2,2-trifl uoro(2-(3-methyl- 609 1 H-pyrazol- l-yl)(pyridin nyl)ethoxy)pyrimidinyl)-2,8- diazaspiro]4.5]decanecarboxylic acid (S)-8—(2-1nethyi((R)-2,2,2-trifluoro(3‘-methoxy~ 3-(3-methyl-1H-pyrazol~l -yl)-[1 ,1'-biphenyl]—4- yl)ethoxy)pyrimidinyl)—2,8-diazaspir0[4.S]decane— 3-carbox lie acid (S)(2-methyi((R)-2,2,2-trifluoro-1—(2—(3~methyl» 1 H-pyrazol—1-yl)—4-(pyridin—4— yl)phenyl)ethoxy)pyrimidin—4-y1)-2,8- diazaspiroI4.5]decane—3-carboxy1ic acid Example 30a: 8-(6-((R)(4‘cl1loro(3-methyl-1H-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)phenoxypyrimidin—4—yl)-2,8-diazaspiro[4.5] dccane—S-carboxylic acid arr/Y“ ”” N CF3N/N I..\ or: Step I: To a solution of (RM -[4—chloro(3-methylpyrazoiyl)phenyl]-2,2,2—trifluoroethanol (5.00 g, 17.2 mmol) and 4,6«dichloro(methylthio)pyrimidine (3.36 g, 17.2 mmol) in dioxane (250 mL) was added CszC03 (16.8 g, 51.6 mmol). The reaction e was then heated to 70 °C for 90 h, then cooled to RT. The reaction mixture was quenched with water and ted with EtOAc. The combined c layers were washed with brine, dried over Na2804, filtered, and concentrated in vacuo. Purification on a 120 g 1300 RediSep silica cartridge (EtOAc:heptane) provided 4-chloro-6—[(R)-i-[4-chloro~2-(3-1nethyipyrazol—1-yl)phenyl}-2,2,2- trifluoroethoxy]—2—methylsulfanylpyrimidine as a white solid.
Step 2: To a solution of4—chloro—6-[(R)[4-chlor0(3-methylpyrazoly1)phenyl]—2,2,2- roethoxy]-2~methylsulfanylpyrimidine (4 g, 8.95 mmol) in CHzClz (200 mL) was added for 15 h. m-CPBA (4.2 g of a 77% (w/w) source, 18.8 mmoi) and the reaction was stirred at RT The reaction was then diluted with saturated NaHCO3, and extracted with CH2C12. The combined organic layers were washed with brine, dried over NazSO4, filtered, and concentrated in vacuo. Purification on a 120 g Isco RediSep silica dge (EtOAczheptane) provided 4— chloro[(lR)[4-chloro(3-methylpyrazolyl)phenyl]-2,2,2-trifluoroethoxy] methylsulfonylpyrimidine as an off-white solid.
Step 3: To a solution of 4-chloro[(lR)[4-chloro(3-methylpyrazolyl)phenyl]-2,2,2- trifluoroethoxy]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), Cs2C03 (5.06 g, 15.5 mmol), and the reaction mixture was heated to 100 °C for 1.5 h. The reaction mixture was cooled to RT, quenched with brine, and extrac ted with EtOAc. The combined organic layers were dried over Na2S04, fi , and concentra ted in vacuo. Purifi cation on a 120 g Isco p silica dge (EtOAc:heptane) ed (S)benzyl 3-ethyl 8-(6-((R)-l­ (4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2-triflu oroethoxy)(methylsulfonyl) pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid (1.3 g) in addition to benzyl 3-ethyl 8-(4-chloro((R)-l-(4-chloro- 2-(3-methy}-lH-pyrazolyl)phenyl)- 2,2,2-trifl uoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.
Step 4: To a solution of2-benzyl 3-ethyl 8-(6-((R)(4-chloro(3-methyl-lH-pyrazol yl)phenyl)-2,2,2-triflu oroethoxy)(methylsulfonyl)pyrimidinyl)-2,8-diazaspiro(4.5Jdecane- 2,3-dicarboxylate (2.10 g, 2.65 nun ol) in 2: 1 THF:I-hO (90 mL) was added LiOH (127 mg, 5.3 rnm ol), and the reaction was stirred at RT for 21 h, afer which onal LiOH (65 mg, 2.6 mmol) was added, and the reaction was stirred for 8 h longer. The reaction was then quenched with 1 N HCI to pH<l, and extracted with EtOAc. The combined organic layers were dried over Na2S04, fi ltered, and concentra ted in vacuo to e 2-((benzyloxy)carbonyl)(6-((R)(4- chloro(3-methy1-1H-pyrazolyl)phenyl)-2,2,2-trifluoroeth oxy) (methylsulfonyl)pyrimidinyl)-2,8-diazaspiro [4.5]decanecarboxylic acid as an off-white solid which was used directly without further purifi cation.
Step 5: To a solution of 2-((benz yloxy)carbonyl)(6-((R)(4-ch\oro(3-methyl-lH-pyrazol- henyl)-2,2,2-trifl uoroethoxy)(methylsulfonyl)pyri midinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid (300 mg, 0.393 mm ol) in 1,4-dioxane (10 mL) was added phenol (74 mg, 0.79 mmol), Cs2C03 (512 mg, 1.5 mmol), and the reaction was heated to 70 °C for 21 h. The reaction was then cooled to RT, diluted with water, acidifi ed to pH<] with 1 N HCI, and extracted with EtOAc. The combined c layers were dried over Na2S04, filtered, and concentrated in vacuo. Purification on a 50 g Isco Gold RediSep reverse phase silica cartridge (H20:HOAc: 99:1 MeOH:HOAc 99:1) provided nzyloxy)carbonyl)(6- ((R)-l-(4-chloro(3-methyl-1 H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy) phenoxypyrimidinA-yl)-2,8-diazaspiro[4.S]decanecarboxylic acid as an off-white solid.
Step 6: N-CBZ ection was accomplished via Method B to provide the title compound as an off-white solid.
Using the generic scheme below, the following examples of Table 1 la were prepared as described above for 8-(6-((R)(4-chloro(3-methyl-l H-pyra zolyl)phenyl)-2,2,2- triflu oroethoxy)phenoxypyrim idinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid (Example 30a).
N/u CF:i STEP I STEP2 Table lla.
Ex. R CAS Name LCMS (MH+) 30a 8-(6-((R)(4-chloro(3-methyl-lH-pyrazol 644 yl)phenyl)-2,2,2-trifluoroethoxy)phenoxypyrimidin- � 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 30b tJ 8-(6-((R)(4-chloro(3-methyl-lH-pyrazol 649 nyl)-2,2,2-trifluoroethoxy) (cyclohexyloxy)pyrimidinyl)-2,8- diazaspiro]4.S]decanecarboxylic acid Table llb.
NMRData for nds of Table lla Ex. NMR 30a 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.57 (br. s., 4 H), 2.00 - 2.31 (m, 2 H), 2.32 (s, 3 H), 3.06- 3.28 (rn, 2 H), 3.36 - 3.71 (m, 4 H), 4.07 (dd, J= 8.83, 7.37 Hz, l H), 6. 11 (s, 1 H), 6.30 (d, J = 2.34 Hz, 1 H), 6.70 (q, J = 6.43 Hz, 1 H), 6.97 - 7.06 (m, 2 H), 7.10 - 7.20 (m, 1 H), 7.26-7 .36(m,2H), 7 .47(d,J=2 .15Hz , 1 H), 7.54(dd,J=8.54,2.15Hz, l H), 7.71 (d,J=8.54Hz, 1 H), 7 .86(d,J=2.39Hz, 1 H). 30b 1H NMR (400 MHz, Me0H-d4): o ppm I. I6 - 1.95 (m, I 4 H), 2.04 - 2.35 (m, 2 H), 2.36 (s, 3 H), 3.07 - 3.30 (m, 2 H), 3.43 - 3.82 (m, 4 H), 4.09 (dd, J = 8.86, 7.39 Hz, 1 H), 4.80 - 4.95 (m, I H), 5.98 (s, 1 H), 6.37 (d, J = 2.39 Hz, 1 H), 7.01 - 7.13 (m, 1 H), 7.45 - 7.55 (m, 2 H), 7.70 (d, J = 9.08 Hz, 1 H), 8.12 (d, J = 2.34 Hz, 1 H) Example 31: 8-(6-((R)(4-chloro(3-methyl-lH-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)(cyclohexylamino)pyrimidiny1)-2,8-diazaspiro [4.5]<lccane carboxylie acid The title nd was prepared as described above by replacing the alcohol in Step 5 of Example 30a with cyclohexyl amine. 1HNMR (400 MHz, MeOH-d4): 6 ppm 0.99 - 1.95 (m, 14 H), 2.02- 2.37 (m, 2 H), 2.38 (s, 3 I-I), 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, l H), 6.87 - 7.21 (m, l 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)(6-((R)(4-chloro(3-methyl-lH-pyrazolyl)phenyl)-2,2,2- trifluorocthoxy)(cyclobutanecarboxamido)pyrimidiuyl)-2,8-diazaspiro[4.S)decane carboxylic acid CIY) >:OH "Y"YOY!"Y�Nf �tJ) CF3 NYN / HNyD Step 1: To a solution of (S)(2-amino((R)-l-(4-chloro(3-methyl-l Il-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)((benzyloxy)carbonyl)-2,8- diazaspiro[4.5]decanecarboxyHc acid (product of Step 3, Example l Om) (300 mg, 0.412 mmol) in pyri dine (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 Na2S04, fi , and trated in vacuo. Purifi cation on a 40 g Isco RediSep silica cartridge (EtOAc/heptane) provides (S)benzyl 3-ethyl 8-(6-((R)-1�(4- chloro(3-methy1-1H-pyrazolyl)pheny1)-2,2,2-trifluoroethoxy)(cyclobutanecarboxamido) dinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Step 2: The title compound was prepared by the N-CBZ removal using the general method B to provide a white solid. 1H NMR (400 MHz, Me0H-d4): o 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, 1 H). LCMS (MH+): 649.
Example 33: (S)(2-amino((R)(4-chloro(2-oxopynoliclinyl)phenyl)-2,2,2- trifluoroethoxy) pyrimidinyl)-2,8-diazaspiro [4.5] dee auecarboxylic acid ClvYI >,OH "'-- O��Nf o� I I .I - CF3 NyN The title compound was ed as described for (S)(2-amino((R)(4-chloro(3- methyl-I H-pyrazolyl)phenyl)-2,2,2-triflu oroethoxy)pyrimidinyl)-2,8- diazaspiro [4.5)decanecarboxylic acid (Example 1Od) starting with (R)-l-(5-chloro(2,2,2- trifl uorohydroxyethyl)phenyl)pyrrolidinone. 1H NMR (DMSO-d6): s 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, IH), 3.47 (d, J = 6.9 Hz, 3H), 3.66 (m, 3H), 5.54 (s, lH), 6.09 (s, 2H), 6.74 (q, J = 6.9 Hz, IH), 7.55 (m, 3H).
LCMS (MH+): 570. e 34c: (S)(2-amino((R)(5-chloro-[1,11-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrim idiuy1)-2,8-diazaspiro f4.5] decanecarboxylie acid 0rOH Cl O"('ycf)H CF3 NyN Step 1: To a solution of (R)-l-(2-bromochlorophenyl)-2,2,2-trifluoroethanol (Intermediate 43) (400 mg, 1.4 mmol) in dioxane (25 mL) was added 4,6-dichloropyrimidinamine (1.1 g, 7 mmol) and Cs2C03 (1.3 g, 4 mmol). The e was heated for 24 hat 80 °C. The reaction was then cooled to RT and filtered. The solvent was removed in vacuo, then CH2Ch and heptane was added. The solvent volume was reduced until a solid precipitated out. The solid was filtered and the ure repeated several times to provide (R)(1-(2-bromochlorophenyl)- 2,2,2-trifluoroethoxy)chloropyrimidjnamine as a white solid.
Step 2: To a solution of (R)(l-(2-bromo chlorophenyl)-2,2,2-triflu oxy) chloropyrimidinamine (100 mg, 0.24 mmol, Step 1) in dioxane (5 mL) was added (S) benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (100 mg, 0.29 mrn ol), and NaHC03 (300 mg, 3.5 mmol). Aft er 5 h, an additional amount Q3 (300 mg, 3.5 mmol) was added and the reaction mixture was heated to 90 °C for 36 h. The rea ction was then cooled to RT and fil tered. Purifica tion by normal phase silica gel column (EtOAc/heptane) provided (S)benzyl 3-ethyl 8-(2-amino((R)-l-(2-bro mochtorophenyl)-2,2,2-triflu oroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5Jdecane-2,3-dicarboxylate as a white solid.
Step 3: To a on of (S)benzyl 3-ethyl 8-(2-amino((R) (2-bromochlorophenyl)- 2,2,2-trifl uoroe thoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2)-dicarboxylate (100 mg, 0.13 mmol) in 10: l dioxane:water (5 mL) was phenyl c acid (33 mg, 0.27 mmol), KHC03 (27 mg, 0.3 mmol), and PdCh(dppt}CH2Ch (6 mg, 0.007 mrn ol). The reaction was heated to 100 °C for 15 h, cooled to RT, and concentra ted in vacuo. The residue was diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2S04, fi ltered, and concentrated in vacuo. Purifi cation by normal phase silica gel column (EtOAc/heptane) provided (S)benzyl 3-ethyl 8-(2-amino((R )(5-chloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Step 4: N-CBZ Deprotection was accomplished via method B to provide (S)-ethyl 8-(2-amino ((R)(5-chloro-[1, l1-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin-4 -yl)-2,8- diazaspiro[4.5]decanecarboxylate an off-white solid.
Step 5: Hydrolysis of hyl 8-(2-amino((R)(5-chloro-[l, l1-biphenyl]yl)-2,2,2- oroethoxy)pyrimi yl)-2,8-diazaspiro[4.5]decanecarboxylate using the LiOH general method prov ided the title compound as an off-white solid as the zwitterionic form.
Example 34u: (S)(2-amino((R)-l-(5-chloro-3'-sulfamoyl-[1,1 '-biphenyl]yl)-2,2,2- trl fluoro ethoxy)pyrimidiuyl)-2,8-diazaspiro [4.5Jdecanecarboxylic acid Step 1: To a solution of (S)benzyl 3-ethyl 8-(2-amino((R)-l-(2-bromochlorophenyl)- 2,2,2-triflu oroethoxy)pyrim idinyl)-2,8-diazaspiro[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- dioxaboro lanyl)benzenesulfonamide (195 mg, 0.7 mmol), KHCOJ (207 mg, 2.06 mmol), and PdCh(dppf)- CH2Ch (56 mg, 0.069 mmol). The reaction was heated to 100 °C for 15 h, cooled to RT, and concentrated in vacuo. The residue was diluted with water, and ted with EtOAc. The combined organic layers were dried over Na2S04, fi ltered, and concentrated in vacuo. Purifi cation by normal phase silica gel column (EtOAc/hepta ne) provided benzyl 3-ethyl 8-(2-amino((R)(5-chlorosulfamoyl-[1, l1-biphenyl]yl)-2,2,2- triflu oroethoxy)pyrimidinA-yl)-2,8Mdiazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Step 2: N-CBZ Deprotection was accomplished via method B to provide (S)-ethyl mino ((R)(5-chlorosulfamoyl-[ 1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[ 4.5]decanecarboxylate as a white solid.
Step 3: Hydrolysis of (S)-ethyl 8-(2-amino((R)(5-chloro-3'-sulfamoyl-[1, 1'-biphenyl] 2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate using the LiOH l method provided the title compound as an off-white solid.
Using the generic scheme below, the following examples of Table 12a can be prepared as described above for (S)(2-amino((R )(5-chloro-3'-sulfamoyl-[l, 1 '-biphenyl]yl)-2,2,2- triflu oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid (Example 34u).
Table 12a.
ClyYO'](YN Cy CF3 NyN * Stereochemistry defined in name in table below Ex. Cy CASName LCMS No. (MH+) 34a 6 (2-amino((R)(3',5-dichloro-[1, 11- 597 biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.S]decanecarboxylic acid 34b & (S)(2-amino((R)(5-chloro-3'-methyHl, l1- 577 biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34c 0 8-(2-amino((R)(5-chloro-[1,l'-biphenyl]yl)- 563 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- piro [4. 5]decanecarboxylie acid 34d �"'6 8-(2-amino((R)(21-aminochloro-[1, 1 '- 577 biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin � I yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34e o,J) 8-(2-amino((R)(5-chloro- 31-nitro-[l, I'- 606 biphenyl]yl)-2,2,2-trifl hoxy)pyrim idin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34f J) 8-(2-amino((R)(3'-aminochloro-[ l ,1 '- 577 biphenyl]yl)-2 ,2,2-trifl uoroethoxy)pyrimid in yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34g ¢ 8-(2-amin o((R)(5-chloro nitro-[l, l 1- 607 biphenyl]yl)-2,2,2-tri fl uoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34h Q 8-(2-amino((R)(4'-aminochloro-[1,11- 577 biphenyl]yl)-2,2,2-triflu oroethoxy)pyrimidin yl)-2,8-diazaspiro(4.5]decanecarboxylic acid 34i ;) (S)(2-amino((R)(4-chloro(6- 578 methy 1pyridinyl)phenyl)-2,2,2- ,,,,:. trifluo roethoxy)pyrimidinyl)-2,8- diazaspiro]4.S]decanecarboxylic acid 34j (S)(2-amino((R)(5-chloro-3'-(ethylsulfonyl)- 655 [1, 1'-biphenyl]y 1)-2,2,2-trifl uoroethoxy)pyrimidin- 0,lu 4-y1)-2,8-diazaspiro[4.5]decanecarboxylic acid 34k (S)(2-amino((R)(5-chloro-3 '- 669 (propylsulfonyl)-[ 1, 11-biphenyl]yl)-2,2,2- js60d) trifluoroethoxy)pyrimidinyl)-2,8- piro]4.5]decanecarboxylic acid 341 o-J) (S)(2-amino((R)(3'-(butylsulfonyl)chloro- 682 ( 1, 1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid �s-' 34m p (S)(2-amino((R)(5-chloro-3 '- 592 (hydroxymethyl)-[1, 1 '-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid 34n (S)(2-amino((R)(5-chloro-3 '- 656 (methylsulfonamido)-[ 1, l'-biphenyl]yl)-2,2,2- triflu oroethoxy)pyrimidinyl)-2,8- HN� diazaspiro[4.5]decanecarboxylic acid O:S=O' 340 &h (2-amino((R)(5-chloro-3 '-(2- 646 oxopyrrolidinyl)-( 1 , l '-biphenyl]yl)-2,2,2- tritl hoxy)pyrimidiny1)-2, 8- diazaspiro[4.S]decanecarboxylic acid 34p )) (S)(2-amino((R)(5-chloro-3'-(3-methyl 660.5 oxoimidazolidinyl)-[1, 1 enyl]yl)-2,2,2- (N trifluoroethoxy)pyrimidiny1)-2,8- diazaspiro[4.S]decanecarboxylic acid 34q (S)(2-amino((R)- l- (5-chloro-3 '- 630 (triflu oromethyl)-(1, l '-biphenyl]yl)-2,2,2- F� triflu oroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxyl ic acid 34r 6 (S)(2-amino((R)-l-(5-chloro-[1, l '-biphenyl] 563 yl)-2,2,2-trifl uoroethoxy)pyrimidinyl)-2,8- diaza spiro[4.S]decanecarboxylic acid 34s (S)(2-amino((R)(4-chloro(5- 604 chlorothlophen-z-yljphenylj-z.z.z- triflu oro ethoxy)pyrimidinyl)-2,8- � diazaspiro[4.S]decanecarboxylic acid 34t Ni (S)(2-amino((R)-l-(4-chloro(1-methyl-lH- 566 pyrazolyl)phenyl)-2,2 )2- trifluoroe pyrimidinA-yl)-2,8- diazaspiro [4.5]decanecarboxylic acid 34u \J) (S)(2-amino((R)(5-chloro-3'-sulfamoyl-[1, l1- 641 biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.S]decanecarboxylic acid H N" .\ 2 0 34v b (S)(2-amino((R)-l-(5-chloro-3'-hydroxy-[1, I'- 578 biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34w o,J) (S)(2-amino((R)(5-chloro-3 '- 640 (methylsulfonyl)-[1, l'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidiny1)-2, 8- .,...s _, diazaspiro[4.5]decanecarboxylic acid 34x (S)(2-amino((R)(5-chloro-3 1-cyano-[l, 11- 587 yl]yl)-2,2,2-trifluoroethoxy)p yri midin yl)-2,8-diaza spiro[4.5]decanecarboxylic acid 34y ,0 (S)(2-amino((R)(5-chloro- 3'-methoxy-[1, 1 '- 592 yl]yl)-2,2,2-trifl uoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34z p (S)(2-amino((R )(3'-(aminomethyl)chloro- 591 [1,l1-biphenyl]yl)-2,2,2-tri fluo roethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34aa p (S)(6-((R)-l-(3'-(acrylamidomethyl)chloro - 645 [1, l'-biphenyl]yl)-2,2,2-trifl hoxy) aminopyrimidinyl)-2,8-diazaspiro(4.5]decane ;[NH carboxylic acid 34ab o� (S)(2-amino((R)(3'-carboxychloro-[1, l1- 606 biphenyl]yl)-2,2,2-triflu oroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 01-1 34ac oj, (S)(2-amino((R )-l-(3'-carbamoylchloro - 605 [1,1'-biphenyl]yl)-2,2,2-trifl uoroethoxy)pyrimidin- 2,8-diazaspiro [4.5]decanecarboxylic acid 34ad Q (S)(2-amino((R)-l-(5-chloro-4'- 640 (methylsulfonyl)-[1, l '-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid o=s=o 34ae Q (2-amino((R)-l-(5-chloroA'-sulfamoyl-[1, 1 '- 641 biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid o=s=o H2N. 34af 6 (S)(2-amino((R)-l-(4',5-dichloro-3 '-fluoro- 615 [1,l'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro [4.S]decanecarboxylic acid 34ag & (S)(2-amino((R)(5-chloro isopropoxy- 621 [1,l'-biphenyl]yl)-2,2,2-tri fl hoxy)pyrimidin- 4-yl)-2,8-diazaspiro [4.5]decanecarboxylic acid 34ah & (S)(2-amino((R)(5-chloro-3'-ethoxy-[l, l 1- 607 biphenyl]yl)-2,2,2-trifl uoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34ai (S)(2-amino((R)(3',5-dichl oro-4'-ethoxy- 642 [1, l'-biphenyl]yl)-2,2,2-triflu oro ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro [4.S]decanecarboxylic acid 34aj (S)(2-amino((R)(3',5-dichloro-4 '-methy1- 611 [1,1'-biphenyl]yl)-2,2,2-tdfl uoroethox y)pyrimidin- 2,8-diazaspiro[4.5]decanecarboxylic acid 34ak (S)(2-amino((R)(3',5-dichloro-4'- 655 poxy-] 1,l'-biphenyl]yl)-2,2,2- tri fluoro ethoxy)pyrimidiny1)-2,8- � diazaspiro]4.5] decane-J-carboxylie acid 34al (S)(2-amino((R)(5-chloro-3'-fluoro-4'- 639 isopropoxy-]1)'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8- lo F � diazaspiro[4. 5[decane-J-carboxyIi c acid 34am (S)(2-amino((R)(4',5-dichloro-3 '- 665 (trifluoromethyl)-[1, 1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8- � diazaspiro[4.5]decanecarboxylic acid F F Cl 34an 0 (S)(2-amino((R)(3',5-dichloro-5'-fluoro- 615 [1, henyl]yl)-2,2,2-trifl uoroethoxy)pyrimidin- 2,8-diazaspiro[4.5]decanecarboxylic acid F Cl 34ao xO (S)(2-amino((R)(3'-(tert-butyl)chloro- 619 [ 1,1'-biphenyl]yl)-2,2,2-triflu oroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34ap (S)(2-amino((R)(31,5-dichloro 665 (trifl uoromethyl)-[1, l '-biphenyl]yl)-2,2,2- triflu oroethoxy)pyrimidinyl)-2,8- F�Cl diazaspiro]4.5]decanecarboxylic acid 34aq (S)(2-amino((R)(5-chl oro-3'-fl uoro-5'- 648 (trifl uoromethyl)-[l,1 '-biphenyl]yl)-2,2,2- oro ethoxy)pyrimidinyl)-2,8- �F diazaspiro[4.5]decanecarboxylic acid F F 34ar ;3 593 (2-amino((R)(5-chloro- 3'-methoxy-[1, l'- biphenyl]yl)-2,2,2-triflu oroethoxy)pyrimidin 0 yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34as 0 (2-amino((R)(5-chlorofluo ro-[I,1'- 580 biphenyl]yl)-2,2,2-triflu oroethoxy)pyrimidin yl)-2,8-diazaspiro[ 4.S]decanecarboxylic acid 34at (S)(2-amino((R)(4',5-dichloro-3'-methyl- 61 1 °' [1, 1'-biphenyl]yl)-2,2,2-trifl uoro ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34au 0 (S)(2-amino((R)(5-chloro-31,51-difl uoro- 598 [1, l1-biphenyl]yl)-2,2,2-triflu oroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid F F 34av 0 (S)(2-amino((R)(3',5-dichloro-4'-fluoro- 615 [1, henyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34aw 0 (S)(2-amino((R)(5-chloro-3 ',4'-difluoro- 598 [1, 1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34ax :2 (2-amino((R)(3',5-dichloro-4'- 665 (trifluoromethyl)-[1, l '-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidiny1)-2,8- Cl diazaspiro]4.5]decanecarboxylic acid 34ay 1? (S)(2-amino((R)(5-chloro -3 ',4'-dimethyl- 591 [1,l'-biphenyl]yl)-2,2,2-triflu oroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34az Ql (S)(2-amino((R)(5-chloro-4'-ethoxy-3 '- 625 fluo ro -[1, 1 '-biphenyl]yl)-2,2,2- trifl uoroethoxy)pyrimidinyl)-2,8- F diazaspiro[4.5]decanecarboxylic acid 34ba n (S)(2-amino((R)-l-(5-chloro-3 ',5'-dimethyl- 591 p,1'-biphenyl]yl)-2,2,2-trifl uoroethoxy)pyri midin- 4-yl)-2,8-diazaspirn[4.5]decanecarboxylic acid 34bb (S)(2-amino((R)- hloro-3'-methyl-4'- 661 (trifl uoromethoxy)-[1,1'-biphenyl]yl)-2,2,2- trifl uoroethoxy)pyrimidinyl)-2,8- � diazaspiro[4.5]decanecarboxylic acid F O AF 34bc (S)(2-amino((R)(4',5-dichloro -3 ',5'- 625 dimethyl-j l ,1 '-biphenyl]yl)-2,2,2- trifl h oxy)pyrim idinyl)-2,8N diazaspiro [4.5]decanecarboxylic acid 34bd (S)N8N(2-amino((R)(5-chloro-4'-fluoro-3 1N 595 methyl-]1,1 '-biphenyl]yl)-2,2,2- trifl uoroethoxy)pyri midinyl)-2,8- � diazaspiro [4.5]decanecar boxylic acid 1 81 34be D (S)(2-amino((R)-l-(3',5-dichloro-5'-methyl- 611 [1, 1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34bf J) (S)(2-amino((R)(5-chloro-3',4',5'-trifluoro- 616 [1, 1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid F F 34bg h (S)(2-amino((R)(5-chloro-3 '- 696 (trifluoromethoxyj-] 1, 1'-biphenylJyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2 ,8- 0 diazaspiro[4.5]decanecarboxylic acid 34bh A (S)(2-amino((R)(5-chloro-3',5'- 698 bis(tri fl uoromethyl)-[1, 1 '-biphenyl]yl)-2,2,2- trifl uoroethoxy)pyrimidinyl)-2,8- piro[4.S]decanecarboxylic acid F lnF F F 34bi (S)(2-amino((R)-l-(5-chloroisopropyl-[t, 1 '- 605 biphenyl]yl)-2,2,2-trifl uoroethoxy) pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34bj 0 (S)(2-amino((R)-2,2,2-tritluoro(3 ',5,5'- 631 trichloro-I l , 1 '-biphenyl]yl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decanecarboxylic acid Cl Cl 34bk (S)(2-amino((R)(5-chloro-4'-flu oro-3'- 648 (trifl uoromethyl)-[l, 1 '-biphenyl]yl)-2,2,2- trifl uoroethoxyjpyrimidin-t-y1)-2,8- � diazaspiro]4.5]decanecarboxy1ic acid F F F 34bl D (S)(2-amino((R)(5-chl oro-3 '-fl uoro-5'- 639 isopropoxy-[ I, 1'-biphenyl]yl)-2,2,2- trifl hoxy)pyrimidinyl)-2,8- O F diazaspiro[4.5]decanecarboxylic acid 34bm p (S)(2-amino((R)-l-(3'-(tert-butyl)chloro -5'- 633 methyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroe thoxy)pyrimidinyl)-2,8- piro [4.S]decanecarboxylic acid 34bn (2-amino((R)-l-(5-chloro -3'-fl uoro-4'- 595 methyl-Il , l'-biphenyl]yl)-2)2,2- trifl uoroethoxy)pyrimidinyl)-2,8- F diazaspiro[4.S]decanecarboxylic acid 34bo 0 (S)(2-amino((R)-l-(4-chloro(pyridin 563 yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5Jdecanecarboxylic acid 34bp µ') (S)(2-amino((R)(5-chloro-3'-ethoxy 625 fluoro-[ l ,1 '-biphenyl]y})-2,2,2- oroethoxy)pyrimidiny1)-2,8- diazaspiro]4.S]decanecarboxylic acid 34bq J (S)(2-amino((R)(3'-(tert-butyl)chloro- 619 [ 1, 1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3 -carboxylic acid 34br J (S)(2-amino((R)(5-chloro-3 '-(prop- l-en 603 yl)-[1, l1-biphenyl]yl)-2,2,2-trifl uoroethoxy) pyrimidinyl)-2,8-diazaspiro [4.5]decane carboxylic acid 34bs '-N/ (S)(2-amino((R)(4-chloro(2- 603 (dimethylamino)pyridinyl)phenyl)-2,2,2- triflu oroethoxy)pyrimidinyl)-2,8- J9� diazaspiro]4.S]decanecarboxylic acid 34bt (2-amino((R)(4-chloro(naphthalen 613 yl)phenyl)-2,2,2-triflu oroethoxy)pyrimidinyl)-2,8- diazaspiro(4.5]decanecarboxylic acid 34bu .. (S)(2-amino((R )(4-chloro(2- 606 pylpyri dinyl)phenyl)-2,2,2- triflu oroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid 34bv 0 (S)(2-amino((R)(5-chloro-4'-fl uoro-[1) '- 525 biphenyl]yl)-2,2,2-triflu oxy)pyri 4- yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34bw 0 (S)(2-amino((R)(4' ,5-dichloro-[1,1 '- 597 biphenyl]yl)-2,2,2-tri:fl uoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34bx 9 (S)(2-amino((R )(5-chloro-4'-methyl-[1, 1'- 577 biphenyl]yl)-2,2,2-trifluoroetho xy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34by 0 (S)(2-ami no((R )(5-chloro-2',3',4',5'- 567 tetrahydro-[1,1 '-biphenyl]yl)-2,2,2- trifl uoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decanecarboxylic acid 34bz Q (S)(2-amino((R)(5-chloro-3'-isobutoxy-[ 1, 1'- 635 biphenyl]y1)-2,2,2-trifluoroethoxy)pyrimidin y yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34ca oh (S)(2-amino((R)- l-(5-chloro-3'-(pyrrolidine-l- 660 carbonyl)-[ 1, 1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8- 6 diazaspiro[4.5]decanecarboxylic acid 34cb b (2-amino((R)(5-chloro-3'- 647 (cyclopentyloxy)-[l ,l'-biphenyl]yl)-2,2,2- trifl uoroethoxy)pyrimidiny1)-2,8- 60 diazaspiro[4.5]decanecarboxylic acid 34cc �o (S)(2-amino((R)(5-chloro-3'-(((1R,4R) 740 hydroxycyclohexyl)carbamoyl)-[1, 1 enyl]yl)- 2,2,2-triflu oroethoxy)pyrimidinyl)-2,8- 0NH diazaspiro[4.S]decanecarboxylic acid HO'''' 34cd (\ (S)(2-amino((R)(5-chloroethyl-[l ,l1- 591 biphenyl]yl)-2,2,2-triflu oroethoxy)pyrimidin yl )-2 ,8-diazaspiro [4.5] decane-S-carboxylic acid 34ce Oy (S)(2-amino((R)-J-(5-chloro-3'-isoprop yl-[1, l '- 633 biphenyl]yl)-2,2,2-trifluoro ethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 34cf oy(] (S)(2-amino((R)(5-chloro-3'-((2-(py rrolidin- 703 thyl)carbamoyl)-[1, 1'-biphenyl]yl)-2,2,2- triflu oroethoxy)pyrimidiny1)-2,8- fNH diazaspiro[4.5]decanecarboxylic acid 34cg 2\0 (S)(2-amino((R)(5-chloro-3'-(morpholine 676 carbonyl)-[l, 1 '-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxy1ic acid 34ch (S)(2-amino((R)-l-(5-chloro-3'-(4- 689 methylpiperazine-l-carbonylj-Il ,l '-biphenyl]yl)- 2,2,2-tdfluoroethoxy)pyrimidinyl)-2,8- CN) diazaspiro[4.5]decanecarboxylic acid 34ci (2-amino((R)-l-(4-chloro(2- 584 methylthiazolyl)phenyl)-2,2,2- s�)=N trifluoroethoxy)pyrimidinyl)-2,8- diazaspirof4.Sldecanecarboxylic acid 34cj X)I (S)(2-amino((R)-l-(4-chloro(1-methyl 594 oxo-l,2-dihydropyridinyl)phenyl)-2,2,2- � I trifl uoroethoxy)pyrimidin- 4-yl)-2,8- diazaspiro]4.S]decanecarboxylic acid 34ck HN,I O (S)(2-amino((R)(5-chloro-3'-(N- 656 J6s:::: methylsulfamoyl)-[l,1 '-biphenyl]yl)-2,2,2- trifl uoroethoxy)pyrimidinyl)-2,8- piro]4.S]decanecarboxylic acid 34cl 'w",. (S)(2-amino((R)-l-(5-chloro-3'-(N,N- 670 0=8=0' dimethylsulfamoyl)-[1,1 enyl]yl)-2,2,2- triflu oroethoxy)pyrimidinyl)-2,8- diazaspiro]4.5]decane- 3-carboxylie acid 34cm );"I (S)(2-amino((R)(5-chloro-3 '- 620 (methylcarbamoyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroet hoxy)pyrimidinyl)-2,8- �! diazaspiro[4.5]decanecarboxylic acid 34cn Al (S)(2-amino((R)(5-chloro-3 '- 634 (dimethylcarbamoyl)-[1, 1 '-biphenyl]yl)-2,2,2- I triflu oxy)pyrimidinA-yl)-2,8- 0 diazaspiroj -l.S'[decane-Lcarboxylic acid 34co ( (S)(2-amino((R)-l "(S"chloro-3'- 662 ""' (diethylcarbamoyl)-] 1,I'-biphenyl]yl)"2,2,2- trifl uoro ethoxy)pyrimidiny 1)-2,8- diazaspiro[ 4.S]decanecarboxylic acid :::-..... l 34cp rNH (S)(6-((R)-l-(2-(1 H-benzo[d]imidazolyl) 603 )6 chlorophenyl)-2,2,2-trifluoroethoxy) yrimidiny1)-2,8-diazaspiro[4.5]decane carboxylic acid 34cq H (S)(2-amino((R)(5-chloro-3'-(piperazine 675 yl)-[1, 1 '-biphenyl]yl)-2,2,2- tri fluoroethoxy)pyrirnidinyl} 2,8- diazaspiro[4.S]decanecarboxylic acid :::::-... I 34cr J�("w�� (S)(2-amino((R)(5-chloro-3'-(4- 716 cyclopropylpiperazinecarbonyl)-[1, 1 '-biphenyl] yl)-2,2,2-triflu oroethoxy)pydmidinyl)-2,8- diazaspiro[4.S]decanecarboxylic acid ".:::: ;o,,.,:. 34cs (S)(2-amino((R )(4-chloro(pyridin 564 nyl)-2,2,2-trifl uoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid 34ct NJ (S)(2-amino((R)(4-chloro(pyrimidin- 2- 564 0N yl)phenyl)-2,2,2-trifl uoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decanecarboxylic acid 34cu (S)(2-amino((R )(4-chloro(p yrazin 565 N� yl)phenyl)-2,2,2-triflu oroethoxy)pyrimidinyl)-2,8- �N diazaspiro[4.5]decanecarboxylic acid 34cv .o (S)(2-amino((R)(5-chloro-3'-(2- 637 methoxyethoxy)-(1, 1 '-biphenyl]yl)-2,2,2- o�o, triflu oro ethoxy)pyrimidinyl)-2,8- diazaspiro[4.51decanecarboxylic acid Table 12b.
NMR Data for Compounds of Table 12a Ex. NMR 34a 11-I NMR (400 MHz, MeOH-d4): s ppm 1 .31 (d, J = 15.3 Hz, lH), 1.67 (d, J = 7.3 Hz, 4H), 2.10 (dd, J = 13 .6, 8.1 Hz, lH), 2.46 (m, IH), 3.25 (t, J = 12.0 Hz, 2H), 3.52 (s, 2H), 3.63 (m, 3H), 4.45 (t, J = 8.6 Hz, IH), 4.83 (d, J = 3.0 Hz, lH), 6.59 (q, J = 6.5 Hz, IH), 7.32 (q, J = 1 .8 Hz, IH), 7.39 (m, lH), 7.52 (m, 4H), 7.70 (d, J = 8.4 Hz, lH) 34b 1H NMR (400 MHz, MeOH-d4): s ppm 1.60 (q, J = 5 .6 Hz, 4H), 2.06 (dd, J = 13 .4, 7.2 Hz, 11-1), 2.33 (dd, J = 13.5, 9.2 Hz, lH), 2.43 (s, 3H), 3.1 3 (d, J = 1 1.8 Hz, II-I), 3.26 (d, J = 11 .7Hz, IH), 3.47 (m, 2H) , 3.62 (tt,J = 9.2, 4.9 Hz, 21-l), 4.10 (dd, J = 9.1, 7.1 Hz, 1 H), 4.61 (s, lH), 5.48 (s, lH), 6.66 (q, J " " 6 .9 Hz, 11-1), 7.27 (m, 4H), 7.42 (m, 2H), 7.67 (d, J = 8.5 Hz, II-I) 34c 1H NMR (400 MHz, MeOH -d4): s ppm 1 .62 (d, J=4.88 Hz, 4 H) 2.08 (dd, J=13.47, 7.22 Hz, 1 H) 2.34 (dd, J=13.37, 9.27 Hz, 1 H) 3.08 - 3.19 (m, lH) 3.28 (d, J=l 1.71 Hz, 1 H) 3.38 - 3.56 (m, 2 H) 3.63 (d, J=5.66 Hz, 2 H) 4.11 (dd, , 7.22 Hz, 1 H) 5.51 (s, 1 H) 6.66 (d, J=6.83 Hz, 1 H) 7.30 (d, J=2.15 Hz, 1 H) 7.41 - 7.52 (m, 4 H) 7.52 - 7.61 (m, 2 H) 7.69 (d, J=8.59 Hz, l H) 34d 1H-NMR (400 MHz, MeOH -d4): 8 ppm 1.9 (m,4H), 1.98 (m,lH), 2.26 (m,lH), 3.01 (m,lH), 3.17 , 3.48 (m,2H), 3.60 (m,2H), 3.95 (m,lH), 5.53-5.52 (d,IH), 6.26- 6.22 (q,lH), 6.97-6.69 (m, 3H), 7.31-7.17(m,2H), 7.47-7.44 (m,IH), 7.74-7.63 (m,lH) 34e 1H NMR (400 MHz, DMSO-d6): 8 ppm 1.61 (m, 4 H), 2.07-2.04 (m, 1 H), 2.37-2.33 (m, 1 H), 3.15-3.12 (d, 1 H, J=l 1.8 Hz), 3.25 (d, 1 H, J=l 1.8 Hz), 3.50-3.47 (m, 2 H), 3.67- 3.66 (m, 2 H), 4.11-4.07 (t, lH), 5.58 (s, 1 H), 6.58-6.53 (q, 1 H, J=6.8 Hz), 7.36 (s, 1 I-I), 7.53-7.51 (d, 1 H, J=8.4 Hz), 7.70-7.67 (d, 1 H, J=8.0 Hz), 7.82-7.78 (m, 2 I-I), 8.38-8.36 (d, 1 H, J=8.0 Hz), 8.58 (s, 1 H) 34f 1H NMR (400 MHz, MeOH -d4): 8 ppm 1.58 (m, 4 H), 2.05-2.02 (m, 1 H), 2.31-2.30 (m, 1 H), 3.28-3.21 (d, 1 H, J =11.8 Hz), 3.48-3.46 (m, 2 H, J = 11.8 Hz), 3.68-3.51 (m, 2 H), 4.08-4.01 (q, 1 H, J =7.0 Hz), 5.44 (s, 1 H), 6.76-6.69 (m, 4 H), 7.26-7.21 (m, 2 H), 7.41- 7.40 (d, l H, J =8.4 Hz), .64 (d, l H, J =8.4 Hz) 34g 1H-NMR 400 MHz, MeOH -d4): 8 ppm 1.28 (m,2H), 1.63 (m 4H) , 2.10-2.04 (m, lH), 2.42-2.36 (m,11-l ), 3.19-3 .16 (d, J =6.0,2H), 3.26 (s,lH), 3.65 (m,2H), 4.28-4.24 (t, J=16.0,1H), 5.58 (s lH), 6.62-6.57 (m, lH), 7.37-7.36 (d, J =4.0,1H), 7.54-7.51 (dd, J=12.0, 4.0,lH), 7.72-7.70 (d, J =8.0,lH), 7.78-7.76 (d, J =8.0,21-I ), 8.43-8.41 (d, J=8.0,2H) 34h 1H-NMR (400 MHz, MeOH -d4): 8 ppm 1.29 (m,2H), 1.58 (m,4H), 2.07-2.02 (m,lH), 2.33-2.28(m,1H), 3.11-3.08 (d, J=12.0,1H), 3.24-3.21 (d, J=12.0, IH), 3.48-3.41(m,2H), .55(m,2H) , .04 (t, J=16.0, lH), 5.39 (d, J =2.0,lH), 6.66-6.63 (m,lH), ), 6.86-6.84 (d, J =8.02H), 7.19-7.17 (d, J =8.0,2H) , 7.25-7.24 (d, J H), 7.37-7.35 (dd, J =8.0, 6.0,lH), 7.63-7.6l(d, J=8.0,IH) 34i 1H NMR (400 MHz, 4): 8 7.88 (t, J=7.68 Hz,1 H), 7.70 (d, J=8.52 Hz,1 H), 7.50 (m, 3 H), 7.35 (d, J=7.76 Hz,1 H), 6.99 (q, J=6.96 Hz, lH), 5.69 (s, I H), 4.06 (t, J=7.48 Hz,2 I-I), 3.62 (m, 2 H), 3.48 (m, 2 H), 3.22 (d,J=l 1.64 Hz, IH),3.09 (d, J=l 1.44 Hz,1 H), 2.61 (s, 3 H), 2.30 (m, l H), 2.03 , 1.57 (m, 4 H). 34j 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.25 (t, J = 7.4 Hz, 3H), 1.63 (m, 4H), .06 (m, lH), 2.38-2.31 (m, IH), 3.16-3.13 (m, lH), 3.26 (m, lH), 3.31 (m, 2H), 3.55-3.50 (m, 2H), 3.71-3.64 (m, 2H) , 4.11 (M, lH), 5.61 (s, lH), 6.63 (m, lH), 7.36 (s, II-I), 7.52- 7.50 (m, lH) , 7.71-7.68 (m, HI), 7.76-7.75 (m, lH), 7.83 (t, J = 7.8 Hz, lH), 8.04 (d, J = 7.2 Hz, lH) 8.43 (s, lH) 34k 1H NMR (400 MHz, MeOH -d4): s ppm 0.96 (t, J=l2.0, 4H), 1.70-1.62 (m, 8H) , 2.06 (s, lH), 2.32 (s, lH),3.24 (d, J = 12.0, lH), 3.50(s, 2H), , 2H), 4.07 (s, I H), 4.63 (s, lH), 5.61 (s, lH), 6.62 (q, J=8.0, lH), 7.37(s,1H), 7.50 (d,1H,J=8.0),7.79-7.69 (m,2H), 7.83(t,1H,1=8.0), ,1H,J=8.0), 8.45 (s, lH) 341 1HNMR (400 MHz, MeOH-d4): s ppm 8.47 (s, 1 H), 8.03 (d, 1 I-I ), 7.74 (t, 1 H), 7.67 (m, 2 H), 7.51-7.49 (d, 1 H), 7.37 (s, 1 H), 6.64-6.59 (q, 1 H), 5.62 (s, 1 H), 4.12-4.08 (t, 1 H), 3.67 (m, 2 H), 3.50 (m, 2 I-I) , 3.26 (d, 1 H), 3.13 (d, 1 H), 2.35-2.32 (m, 1 I-I), 2.05 (m, I H), 1.63 (m, 6 H), 1.34 (q, 2 H), 0.84-0.80 (t, 3 H) 34m 1H NMR (400 MHz, MeOH -d4): 8 ppm 7.74-7.66 (m, 2H), 7.48-7.39 (m, 3H), 7.27 (m, 2H), 6.73-6.71 (m, lH), 5.53 (s, HI), 4.73 (s, 2H), 4.08 (t, J = 7.1 Hz, lH) , 3.63 (m, 2H), 3.47 (m, 2H), 3.27-3.24 (m, lH), 3.14-3.11 (m, IH), 2.36-2.30 (m, IH), 2.08-2.03 (m, lH), 1.60 (m, 4H) 34n 1H NMR (400 MHz, MeOH -d4)o ppm 7.66 (d, 1 H,J=8.6 Hz), 7.50 (m, 3 H), 7.31 (m, 2 H), 7.24 (d, 1 H,J=8.2 Hz), 6.61 (m, 1 H), 4.21 (m, 1 H), 3.63 (m, 2 H), 3.48 (m, 2 H), 3.21 (m, 1 H), 3.18 (m, 1 H), 3.01 (s, 3 H), 2.37 (m, 1 H),2.07 (m, 1 H), 1.62 (m, 4 H) 340 1H-NMR (400 MHz, MeOH-d4): s ppm 7.97 (s,lH) ,7.60-7.67 (m,2H) ,7.52-7.54 (m,lH),7.40 -7.46 (m, lH),7.31 - 7.31 (m, lH), 7.22 - 7.24 (m,lH),6.61 -6.66 (m, lH), .51 (s, lH), 4.39-4.04 (m, 4H), 3.52-3.60 (m,2H), 3.42-3.50 (m, 2H), 3.15 -3.18 (d, 1 H), 2.96 -2.99 (d, l H), 2.60 -2.64 (m, 2H), 2.18 -2.28 (m, 3H), 1.96 -2.00 (m, I H), 1.58 -1.59 (m, 4H) 34p 1H-NMR (400 MHz, DMSO-d6): s ppm 8.00 (s,lH), 7.56 -7.58 , 7.43 -7.49 (m,2H), 7.26 -7.27 (m, 2H), 6.97 -7.97 (rn, lH), 6.59 -6.55 (m,lH), 5.48 (s, lH), 3.78 - 3.82 (m, lH), 3.70 -3.74 (m,2H), 3.39-3.44 (m, 6H), 2.98 -3.02 (d,IH), 2.82 -2.85 (d,lH), 2.70 (s, 3H), 2.04 -2.11 (m, IH), 1.69 -1.75 (m, lH), 1.36 -1.40 (m, 4H) 34q 1H NMR (400 MHz, MeOH-d4): s ppm 1.64 (t, J = 5.8 Hz, 4H), 2.08 (dd, J = 13.5, 7.6 Hz, IH), 2.40 (dd, J = 13.5, 9.0 Hz, lH), 3.19 (d, J = 11.8 Hz, IH), 3.28 (d, J = 12.2 Hz, 1H), 3.51 (m, 2H), 3.66 (rn, 2H), 4.28 (t, J = 8.4 Hz, lH), 4.87 (s, 16H), 6.53 (q, J = 6.7 Hz, lH), 7.34 (d, J = 2.3 Hz, lH), 7.51 (dd, J = 8.6, 2.3 Hz, lH), 7.75 (m, SH) 34r 1H NMR (400 MHz, MeOH-d) o ppm 1.62 (d, 1=4.88 Hz, 4 H) 2.08 (dd, 1=13.47, 7.22 Hz, 1 H) 2.34 (dd, J=13.37, 9.27 Hz, 1 H) 3.08 - 3.19 (m, lJ-1) 3.28 (d, 1=11.71 Hz, 1 H) 3.38 - 3.56 (m, 2 H) 3.63 (d, 1=5.66 Hz, 2 H) 4.11 (dd, 1=8.98, 7.22 Hz, 1 l-1) 5.51 (s, 1 H) 6.66 (d, J=6.83 Hz, 1 H) 7.30 (d, J=2.15 Hz, 1 H) 7.41 - 7.52 (m, 4 I-1) 7.52 - 7.61 (m, 2 H) 7.69 (d, J=8.59 Hz, l H) 34s 11-1 NMR (400 MHz, Me0H-d4): s ppm 1.60 (d, J=5.47 Hz, 4 H) 1.98 - 2.12 (m, 1 H) 2.26 - 2.39 (m, 1 H) 3.07 - 3.17 (m, 1 H) 3.20 - 3.29 (m, 1 H) 3.38 - 3.55 (m, 2 H) 3.56 - 3.71 (m, 2 H) 4.01 - 4.15 (m, 1 H) 5.51 (s, I H) 6.74 - 6.89 (m, l H) 7 . 11 (s, 1 H) 7.14 (s, 1 H) 7.42 (d, J=2.15 Hz, 11 H) 7.44 - 7.53 (m, 1 H) 7.61 - 7.73 (m, 1 H) 34t 1H NMR (400 MHz, MeOH-d4): o ppm 1.51 (d, J:=4.69 Hz, 4 H) 1.84 - 2.00 (m, l H) 2.09 - 2.31 (m, 1 H) 2.82 - 3.00 (m, 1 H) 3.02 - 3.20 (m, 1 H) 3.32 - 3.64 (m, 4 H) 3.84 - 3.94 (m, 1 H) 3.98 (s, 3 H), 5.50 (s, 1 H) 6.63 (d, J=l.95 Hz, 1 H) 7.13 - 7.27 (m, 1 H) 7.39 (d, J=l.56 Hz, 1 H) 7.55 (d, J=l.76 Hz, 1 H) 7.64 (d, J=8.59 Hz, 1 H) 7.71 (d, J=l.76 Hz, 1 H) 34u 1H NMR (400 MHz, MeOH-d4): o ppm 1.52 - 1.75 (rn, 4 H) 2.07 (dd, J=13.40, 7.30 Hz, 1 H) 2.34 (dd, J=13.42, 9 .18 Hz, 1 H) 3.07 - 3.29 (m, 2 H) 3.40- 3.78 (rn, 4 H) 4.10 (dd, J=9.10, 7.25 Hz, 1 H) 5.59 (s, I H) 6.61 (q, J=6.59 Hz, 1 H) 7.31 (d, 1=2.20 Hz, 1 H) 7.49 (dd, J=8.52, 2.22 Hz, 1 H) 7.61 (d, J=7.03 Hz, 1 H) 7.65 - 7.80 (m, 2 H) 7.97 - 8.10 (m, I H) 8.32 (br. s., 1 H) 34v 1H NMR (400 MHz, MeOH-d4): o ppm 1.52 - 1.71 (m, 4 H) 2.07 (dd, J=13.42, 7.27 Hz, 1 H) 2.33 (dd, 7, 9.27 Hz, 1 H) 3.08 - 3.29 (m, 2 H) 3.36 - 3.76 (m, 4 H) 4.09 (dd, , 7.20 Hz, 1 H) 5.48 (s, 1 H) 6.74 (q, J=7.00 Hz, I H) 6.87 (d, J=7.47 Hz, 1 H) 6.91 (ddd, J=8.19, 2.48, 0.85 Hz, 1 H) 7.05 (d, J=0.73 Hz, 1 H) 7.28 (d, J=2.20 Hz, I H) 7.32 (t, J=7.88 Hz, 1 H) 7.43 (dd, J=8.49, 2.25 Hz, 1 I-1) 7.67 (d, J=8.49 Hz, 1 H) 34w 1H NMR (400 MHz, 4): <> ppm 1.43 - 1.76 (m, 4 H) 2.08 (dd, J:=13.45, 7.15 Hz, 1 H) 2.34 (dd, J=13.42, 9.22 Hz, 1 H) 3.13 - 3.29 (m, 5 H) 3.41 - 3.77 (m, 4 H) 4.10 (dd, J-9.18, 7.17 Hz, 1 H) 5.60 (s, 1 H) 6.57 (q, J=6.57 Hz, 1 H) 7.35 (d, J=2.15 Hz, I H) 7.51 (dd, J=8.52, 2.17 Hz, 1 H) 7.70 (d, J=8.54 Hz, 1 H) 7.72 -7.78 (m, 1 H) 7.78 - 7.87 (m, 1 H) 8.04 - 8.15 (m, 1 H) 8.41 (d, J=0.39 Hz,1 H) 34x 1H NMR (400 MHz, DMSO-d6): s ppm 1.46 - 1.69 (m, 4 H) 1.90 (dd, J=13.25, 9.20 Hz, 1 H) 2.35 (dd, J=13.35, 8.66 Hz, 1 H) 3.14 (br. s., 2 H) 3.64 (br. s., 4 H) 4.45 (t, 1=6.49 Hz, 1 H) 5.84 (br. s., l H), 6.56 (q, J=6.77 Hz, 1 H) 7.48 (d, J=l.07 Hz, l H) 7.62 - 7.69 (m, 2 H) 7.75 - 7.82 (rn, 1 H) 7.83 - 7.91 (m, I H) 7.92 - 8.00 (m, 2 H) 8.97 (br. s., 1 H) .23 (br. s., 1 H) 34y 1HNMR (400 MHz, DMSO-d6): o ppm 1.46 - 1.71 (m, 4 H) 1.91 (dd, J=13.32, 9.27 Hz, 1 H) 2.27 - 2.40 (m, 1 H) 3.14 (br. s., 2 H) 3.63 (d, J=5.37 Hz, 4 H) 3.81 (s, 3 H) 4.36 - 4.53 (m, 1 H) 5.85 (br. s.,1 H) 6.72 (q, J=6.62 Hz, 1 H) 6.94 - 7.10 (m, 3 H) 7.40 (d, J=2.05 Hz, 1 H) 7.49 (t, J=7.96 Hz, I I-I) 7.57 - 7.70 (m, 2 H) 8.96 (d, J=5.71 Hz, 1 H) .27 (br. s., 1 H) 34z 1HNMR (400 MHz, DMSO-d6): o ppm 1.43 - 1.76 (m, 4 H) 1.92 (dd, 8, 9.32 Hz, 1 H) 2.35 (dd, J=13.30, 8.57 Hz, I H) 3.14 (br. s., 2 H) 3.67 (br. s., 4 H) 3.97 - 4.18 (m, 2 H) 4.44 (t, J=6.88 Hz, lH) 5.93 (br. s., 1 H) 6.75 (q, J=6.57 Hz, 1 H) 7.39 (d, J=l.66 Hz, 1 H) 7.53 (br. s., 1 H) 7.57 - 7.71 (m, 5 H) 8.58 (br. s., 3 H) 9.01 (br . s., 1 H) 10.55 (br. s., l H) 34aa 1H NMR (400 MHz, MeOH-d4): o ppm 1.68 - 1.86 (m, 5 H) 2.13 (dd, J=13.69, 8.66 Hz, I H) 2.54 (dd, J=13.72, 8.98 Hz, 1 H) 3.56 (br. s., 1 H) 3.67 (br. s., 3 H) 4.44 - 4.63 (m, 3 H) 5.70 (dd, J=9.42,2.54 Hz, 1 H) 6.19 - 6.35 (m, 2 H) 6.58 (br. s., 1 H) 7.28 (d, J=7.57 Hz, 1 H) 7.34 - 7.40 (m, 2 H) 7.43 (d, J=7.86 Hz, 1 H) 7.47 - 7.56 (m, 2 H) 7.71 (d, J=S.64 Hz, 1 H) 34ab 1H NMR (400 MHz, DMSO-d6): 8 ppm 1.44 - 1.69 (m, 4 H) 1.91 (dd, J=I3.28, 9.18 Hz, 1 H) 2.35 (dd, J=I3.15, 8.61 Hz, 1 H) 3.14 (br. s., 2 H) 3.64 (br. s., 4 H) 4.37 - 4.53 (m, l H) 5.87 (br. s., 1 H) 6.62 (q, J=6.78 Hz, I H) 7.43 (t, J=l.22 Hz, 1 H) 7.65 (s, 2 H) 7.70 (d, J=4.78 Hz, 2 H) 7.99 - 8.12 (m, 1 H) 8.26 (br. s., 1 H) 8.96 (d, J=S.03 Hz, 1 H) 10.25 (br, s., 1 H) 34ac 1H NMR (400 MHz, MeOH-d4): s ppm 1.62 (d, J=4.15 Hz, 4 H) 2.02 - 2.14 (m, I H) 2.26 - 2.43 (m, 1 H) 3.08 - 3.29 (m, 2 H) 3.40 - 3.77 (m, 4 H) 4.09 (dd, , 7.27 Hz, 1 H) 5.55 (s, l H) 6.55 - 6.70 (m, 1 H) 7.30 (d, J=2.05 Hz, 1 H) 7.47 (dd, J=8.47, 2.07 Hz, 1 H) 7.51 - 7.59 (m, 1 H) 7.59 - 7.65 (m, 1 H) 7.67 (d, J=8.30 Hz, 1 H) 7.96 (dd, J=8.52, 1.00 Hz, 1 H) 8.32 - 8.50 (m, 1 H) 34ad 1H NMR (400 MHz, 4): o ppm 1.50 - 1.76 (m, 4 H) 2.07 (dd, J=13.20, 7.15 Hz, I H) 2.34 (dd, J=l3.47, 9.27 Hz, 1 H) 3.14 (d, J=ll.71 Hz, 1 H) 3.23 (s, 3 H) 3.27 (d, J=l 1.86 Hz, 1 H) 3.40 - 3.76 (m, 4 H) 4.09 (dd, J=9.03, 7.27 Hz, I H) 5.54 (s, 1 H) 6.60 (q, J=6.64 Hz, 1 H) 7.34 (d, J=2.15 Hz, 1 H) 7.52 (dd, J=S.49, 2.20 Hz, 1 H) 7.72 (d, J=8.54 Hz, 1 H) 7.78 (d, J=7.76 Hz, 2 H) 8.14 (d, J=8.64 Hz, 2 H) 34ae 1H NMR (400 MHz, MeOH-d4): s ppm 1.61 (q, J=4.88 Hz, 4 H) 2.07 (dd, J=l3.37, 7.13 Hz, 1 H) 2.33 (dd, J=l3.42, 9.22 Hz, 1 H) 3.08 - 3.30 (m, 2 H) 3.38 -3.74 (m, 4 H) 4.10 (dd, J=8.91, 7.35 Hz, 1 H), 5.52 (s, 1 H) 6.53 - 6.69 (m, 1 H) 7.33 (d, J=2.20 Hz, 1 H) 7.50 (dd, J=8.52, 2.22 Hz, 1 H) 7.67 (d, J=7.96 Hz, 2 H) 7.71 (d, J=8.54 Hz, 1 H) 8.08 (d, J=8.64 Hz, 2 H) 34af 1H NMR (400 MHz, Me0H-d4): s ppm 1.62 (q, J = 6.0, 5.0 Hz, 17H), 2.07 (dd, J = 13.4, 7.2 Hz, SH), 2.33 (dd, J = 13.4, 9.2 Hz, SH) , 3.15 (d, J = 1 1 .8 Hz, SH), 3.27 (d, J = 11.8 Hz, 13H) , 3.49 (m, 9H), 3.64 (ddt, J = 15.7, 10.7, 5.2 Hz, 91-1 ), 4. 1 1 (dd, J = 9.2, 7.1 Hz, SH), 6.61 (q, J = 6.7 Hz, 4H), 7.33 (m, 7H), 7.47 (m, 8H), 7.66 (m, 8H) 34ag 1H NMR (400 MHz, MeOH-d4): s ppm 0.86 (m, lH), 1.34 (dd, J = 9.4, 6.0 Hz, 7H), 1.58 (t, J = 5.7 Hz, 4H), 1.98 (dd, J = 13.3, 7.0 Hz, Ill), 2.26 (dd, J = 13 .3 , 9.0 Hz, IH), 3.00 (d, J = 11.5 Hz, l H), 3.16 (d, J = 11.5 Hz, lH), 3.46 (ddt, J = 19.2, 12.6, 5.9 Hz, 2H), 3.62 (dt, J = 12.8, 7.1 Hz, 2H), 3.96 (t, J = 8.1 Hz, lH), 4.69 (p, J = 6.0 Hz, lH), 5.50 (s, IB\ 6.73 (q, J = 6.9 Hz, lH), 6.95 (m, lH), 7.04 (dd, J = 8.5, 2.4 Hz, HI), 7.20 (s, lH), 7.28 (d, J = 2.3 Hz, lH), 7.42 (m, 2H), 7.66 (d, J = 8.5 Hz, lH) 34ah 1HNMR (400 MHz, MeOH-d4): s ppm 1.29 (d, J = 7.3 Hz, lH), 1.41 (t, J = 7.0 Hz, 3H), 1.61 (q, J= 6.2, 5.4 Hz, 4H), 2.07 (dd, J = 13.5, 7.3 Hz, lH), 2.35 (dd, J = 13.5, 9.1 Hz, lH), 3.14 (d, J = 11.8 Hz, lH), 3.26 (d, J = 11.7 Hz, lH), 3.33 (s, lH), 3.48 (m, 2H), 3.66 (dd, J = 14.5, 6.2 Hz, 2H), 4.13 (tt, J = 9.7, 7.2 Hz, 3H), 4.87 (s, 17H), 6.74 (q, J = 6.9 Hz, lH), 6.97 (d, J = 7.6 Hz, lH), 7.04 (dd, J = 8.3, 2.5 Hz, lH), 7.19 (s, lH), 7.29 (d, J = 2.2 Hz, IH), 7.44 (m, 2H), 7.67 (d, J = 8.5 Hz, lH) 34ai 1H NMR (400 MHz, 4): o ppm 1.48 (t, J = 7.0 Hz, 3H), 1.60 (m, 4H), 2.06 (dd, J = 13.4, 6.9 Hz, IH), 2.33 (dd, J = 13.4, 8.9 Hz, lH), 3 .13 (d, J = 11.6 Hz, lH), 3.25 (d, J = 11.4 Hz, lH), 3.48 (ddd, J = 21.0, 14.2, 7.2 Hz, 2H), 3.64 (q, J = 8.9, 8.1 Hz, 2H), 4.09 (t, J = 8.3 Hz, lH), 4.20 (q, J = 6.9 Hz, 2H), 4.88 (s, 15H), 5.52 (s, lH), 6.63 (q, J = 6.7 Hz, lI-I), 7.24 (m, 2H), 7.34 (d, J = 8.3 Hz, HI), 7.43 (dd, J = 8.5, 2.3 Hz, 2H), 7.57 (s, lH), 7.65 (d, J = 8.4 Hz, lH) 34aj 1HNMR (400 MHz, MeOH-d4): s ppm 1.28 (s, 1H), 1.58 (dd, J= 7.1, 4 .1 Hz, 4H), 1.99 (dd, J = 13.4, 7.1 Hz, lH), 2.29 (m, lH), 2.46 (s, 3H), 3.02 (d, J = 11.6 Hz, lH), 3 .18 (d, J = 1 1 .6 Hz, lH) , 3.46 (ddt, J = 21.0, 13.5, 6.0 Hz, 2H) , 3.63 (m, 2H), 3.98 (dd, J = 9.2, 7.1 Hz, lH), 5.52 (s, II-I), 6.60 (q, J = 6.6 Hz, lH), 7.28 (m, 2H), 7.45 (dd, J = 8.3, 2.4 Hz, 2H), 7.56 (rn, lH), 7.66 (d, J = 8.5 Hz, lH) 34ak 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.29 (d, J = 6.2 Hz, lH), 1.40 (d, J = 6.0 Hz, 6H), 1.60 (d, J = 5.2 Hz, 4H), 2.03 (dd, J:::, 13.4, 6.8 Hz, 1 H), 2.30 (dd, J = 13.3, 8.9 Hz, lH), 2.81 (s, lH), 3.07 (d, J = 11.6 Hz, lH), 3.22 (d, J = 11.8 Hz, lH), 3.48 (m, 2H) , 3.64 (d, J :::,9.7 Hz, 2H), 4.03 (t, J = 7.9 Hz, 11-l ), 4.75 (m, IH), 5.53 (s, lH), 6.63 (q, J = 6.8 Hz, lH), 7.29 (m, 3H), 7.43 (dd, J = 8.6, 2.3 Hz, lH), 7.58 (s, IH), 7.65 (d, J = 8.5 Hz, 34a1 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.39 (d, J = 6.0 Hz, 6H), 1.60 (m, 4H), 2.06 (dd, J = 13.5, 7.2 Hz, l H), 2.33 (dd, J = 13.4, 9.2 Hz, II-I), 3 .13 (d, J = 11.7 Hz, 11-I), 3.26 (d, J = 1 1 .7 Hz, IH), 3.48 (m, 2H), 3.64 (q, J = 12.4, 10.4 Hz, 2H), 4.10 (dd, J = 9.2, 7.2 Hz, lH), 4.70 (hept, J = 5.9 Hz, lH), 5.53 (s, lH), 6.67 (q, J = 6.8 Hz, IH), 7.25 (m, 4H), 7.43 (dd, J = 8.5, 2.3 Hz, 1H), 7.65 (d, J = 8.4 Hz, lH) 34am 1H NMR (400 MHz, Me0H-d4): s ppm 1.28 (s, 1H), 1.61 (q, J = 5.7 Hz, 4H), 2.06 (dd, J = 13.4, 7.1 Hz, lH), 2.33 (dd, J = 13.4, 9.2 Hz, lH), 3.12 (d, J = 11.7 Hz, lH), 3.26 (d, J = 11.6 Hz, lH), 3.48 (ddt, J = 18.1, 13.6, 6.0 Hz, 2H), 3.65 (tt, J = 11.7, 4.8 Hz, 2H), 4.08 (dd, J = 9.2, 7.1 Hz, l H), 5.54 (s, lH), 6.49 (q, J = 6.6 Hz, lH), 7.35 (d, J = 2.2 Hz, lH), 7.51 (dd, J = 8.5, 2.3 Hz, lH), 7.69 (d, J = 8.5 Hz, lH), 7.82 (td, J = 17.6, 16.6, 4.9 Hz, 34an 1H NMR (400 MHz, MeOH-d4): s ppm 0.88 (d, J = 7.8 Hz, 11-I), 1.29 (d, J = 6.7 Hz, 2H), 1.62 (q, J = 5.9, 5.4 Hz, 41-I ), 2.07 (dd, J = 13.4, 7.2 Hz, lH), 2.33 (dd, J:::, 13.4, 9.2 Hz, IR), 3 .13 (d, J = 1 1. 7 Hz, lH), 3.26 (d, J = 11.7 Hz, lH), 3.49 (ddd, J = 21.4, 12.5, .9 Hz, 2H), 3.65 (td, J = 12.3, 10.3, 5.5 Hz, 2H), 4.10 (dd, J = 9.2, 7.1 Hz, II- I), 5.55 (s, lH), 6.59 (q, J = 6.7 Hz, IH), 7.25 (d, J = 14.9 Hz, l H), 7.35 (m, 2H), 7.44 {s, lH), 7.51 (dd, J = 8.5, 2.2 Hz, IH), 7.69 (d, J = 8.5 Hz, IH) 34ao 1H NMR (400 MHz, Me0H-d4): s ppm 0.89 (m, 2H), 1. 30 (d, J = 1 1.8Hz, 3H), 1.36 (s, lOH), 1 .60 (m, SH), 2.34 (s, lH), 2.81 (s, lH), 3.14 (d, J = 1 1 .6 Hz, 11- 1), 3.28 (m, 4H), 3.45 (s, 2H), 3.62 (s, 3H), 4.15 (t, J = 8.1 Hz, lH), 4.85 (s, 38H), 6.62 (t, J = 6.7 Hz, IH), 7.28 (m, 2H), 7.46 (m, SH), 7.66 (d, J = 8.5 Hz, 1H) 34ap 1HNMR (400 MHz, Me0H-d4): 8 ppm 1.29 (d, J = 7.5 Hz, 2H), 1.65 (s, 3H), 2.08 (dd, J = 13.5, 7.9 Hz, lH), 2.44 (t, J = 11.2 Hz, l H), 3.24 (dd, J = 14.0, 11.6 Hz, lH), 3.61 (m, 4H), 4.41 (t, J = 8.4 Hz, lI-1), 6.48 (q, J = 6.6 Hz, l H), 7.38 (d, J = 2.2 Hz, IH), 7.54 (dd, J = 8.5, 2.2 Hz, lH), 7.71 (d, J = 8.6 Hz, IH), 7.86 (t, J = 1.5 Hz, 2H) 34aq 1H NMR (400 MHz, 4): 8 ppm 1.28 (d, J = 2.2 Hz, lH), 1.60 (s, 4H), 2.03 (d, J = 13.1 Hz, 1 H), 2.30 (t, J = 1 1 . 1 Hz, lH), 3.08 (d, J = 11.6 Hz, lH), 3.23 (d, J = 12.3 Hz, lH), 3.50 (dt, J = 24.2, 8.0 Hz, 2H), 3.64 (d, J = 10.2 Hz, 2H), 4.03 (t, J = 7.8 Hz, lH), 4.58 (s, lH), 5.55 (s, lH), 6.52 (q, J = 6.7 Hz, lH), 7.37 (d, J = 2.2 Hz, lH), 7.53 (dd, J = 8.5, 2.3 Hz, lH), 7.66 (m, 4H) 34ar 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.57 (q, J = 7.9, 6.6 Hz, 4H), 1.92 (dd, J = 13.2, 7.0 Hz, 1H), 2.19 (dd, J :=: 13.2, 9.0 Hz, lH), 2.88 (d, J = 11.4 Hz, lH), 3.10 (d, J = 11.4 Hz, lH), 3.45 (ddt, J = 20.3, 13.1, 6.1 Hz, 2H), 3.61 (m, 2H), 3.87 (s, 4H), 5.48 (s, IH), 6.70 (q, J = 6.9 Hz, lH), 7.04 (m, 2H), 7 .16 (s, lH), 7.29 (d, J = 2.2 Hz, l H), 7.45 (m, 2H), 7.67 (d, J = 8.5 Hz, 1H) 34as 1H NMR (400 MHz, Me0H-d4): o ppm 1.29 (d, J :=: 10.0 Hz, 2H), 1.61 (d, J = 5.6 Hz, SH),2.06 {dd, J :=: 13.4, 7.2 Hz, ll- 1), 2.33 (dd, J = 13.4, 9.2 Hz, lH), 3 .13 (d, J = 11 . 7 Hz, 11-I), 3.26 (d, J = 11.7 Hz, lH), 3.49 (dt, J = 21.9, 7.2 Hz, 3H), 3.65 (ddt, J = 15.1 , 10.1, .2 Hz, 3H), 4.09 (dd, J = 9.2, 7.1 Hz, lH), 4.86 (s, 26H), 5.53 (s, lH), 6.64 (q, J = 6.8 Hz, lH), 7.28 (m, SH), 7.47 (dd, J = 8.5, 2.3 Hz, 1H), 7.55 (m, 1H), 7.68 (d, J:=: 8.5 Hz, 34at 1H NMR (400 MHz, Me0H-d4): 8 ppm 1.28 (s, lH), 1.35 (s, lH), 1.60 (q, J = 5. 1 Hz, 4H), 2.03 (dd, J = 13.3, 7.1 Hz, IH), 2.30 (dd, J = 13.4, 9.1 Hz, lH), 2.45 (s, 3H), 3.08 (cl, J = 1 1 . 6 Hz, IH), 3.23 (d, J = 1 1 . 7 Hz, lH), 3.31 (s, 3H), 3.47 (ddt, J = 19.8, 12.7, 5.7 Hz, 2H), 3.63 (dt, J = 12.9, 7.5 Hz, 21-l ), 4.04 (dd, J = 9.0, 7.3 Hz, IH), 5.51 (s, lH), 6.62 (q, J = 6.8 Hz, IH), 7.30 (m, 3H), 7.45 (dd, J :=: 8.5, 2.3 Hz, lH), 7.52 (d, J = 8.1 Hz, HI), 7.66 (d, J = 8.5 Hz, IH) 34au 1H NMR (400 MHz, MeOH-d4): o ppm 1.29 (d, J = 6.2 Hz, lH), 1.62 (q, J = 5.5 Hz, 4H), 2.07 (dd, J = 13.5, 7.3 Hz, lH), 2.35 (dd, J = 13.5, 9.2 Hz, lH), 3.15 (d, J = 1 1 . 8 Hz, lH), 3.27 (d, J = 11 . 7 Hz, lH), 3.49 (ddt, J = 21.6, 1 3.6, 6.3 Hz, 2H), 3.66 (ddt, J = 15.6, .1, 4.9 Hz, 2H), 4.14 (dd, J = 9.1 , 7.3 Hz, IH), 4.85 (d, J = 3.1 Hz, 16H), 6.63 (q, J = 6.8 Hz, lH), 7. 12 (m, 3H), 7.34 (d, J = 2.2 Hz, lH), 7.50 (dd, J = 8.5, 2.2 Hz, lH), 7.69 (d, J = 8.5 Hz, IH) 34av 1H NMR (400 MHz, Me0H-d4): o ppm 0.88 (m, IH), 1 .28 (s, 3H), 1.61 (q, J = 6.1 Hz, 4H), 2.07 (dd, J :=: 13.4, 7.1 Hz, IH), 2.33 (dd, J = 13.5, 9.0 Hz, lH) , 3.13 (d, J = 1 1. 6 Hz, lH), 3.26 (d, J = 1 1 . 8 Hz, 2H), 3.48 (ddt, J = 20.7, 12.7, 5.7 Hz, 2H), 3.65 (q, J = 8.9, 6.2 Hz, 2H), 4.10 (m, IH), 4.90 (s, IH), 5.55 (s, IH), 6.57 (q, J = 6.8 Hz, lH), 7.42 (m, SH), 7.67 (d, J = 8.3 Hz, 2H) 34aw 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.29 (t, J = 7.7 Hz, 2H), 1.60 (q, J :=: 6. 1, 4.9 Hz, 4H), 2.03 (dd, J = 13. 3, 7.1 Hz, lH) , 2.30 (dd, J = 13.4, 9.0 Hz, HI), 3.07 (d, J = 11.6 Hz, lH), 3.22 (d, J = 11 . 6 Hz, IH), 3.48 (ddt, J = 20.9, 13.3, 5.7 Hz, 2H), 3.64 (tt, J = 10.8, .3 Hz, 2H), 4.03 (t, J = 8.1 Hz, 1 H), 4.87 (s, l 7H), 5.54 (s, lH), 6.61 (q, J = 6.7 Hz, 1 H), 7.32(t, J = 5.0 Hz, 2H), 7.46 (m, 3H), 7.54 (s, lH), 7.67 (d, J = 8.5 Hz, lH) 34ax 1H NMR (400 MHz, MeOH-d4): 8 ppm 1 .3 0 (dd, J = 17.9, 6.7 Hz, 2H), 1.54 (m, 4H), 1 . 79 (dd, J = 12.9, 7.0 Hz, lH), 2.06 (td, J = 16.5, 14.8, 7.8 Hz, lH), 2.66 (d, J = 1 1 . 0 Hz, lH), 2.97 (d, J = 1 1 . 1 Hz, lH), 3.45 (ddt, J = 20.1, 13.2, 6.0 Hz, 2H), 3.62 (m, 3H), 5.50 (d, J = 16.5 Hz, l H), 6.54 (q, J = 6.7 Hz, lH), 7.34 (d, J = 2.3 Hz, lH), 7.52 (dd, J = 8.5, 2.3 Hz, lH), 7.68 (dd, J = 24.2, 8.1 Hz, 2H), 7.84 (m, 1H), 7.97 (d, J = 8.1 Hz, lH) 34ay 1H NMR (400 MHz, MeOH-d4): 8 ppm 0.89 (m, 2H), 1.28 (s, 2H), 1.40 (s, IOH), 1.60 (q, J = 5.5 Hz, 4H), 2.06 (dd, J = 13.5, 7.1 Hz, 1H), 2.35 (d, J = 3.7 Hz, 7H), 3.13 (d, J = 11.6 Hz, lH), 3.25 (d, J = 11.6 Hz, l H), 3.47 (dq, J = 22.4, 7.8, 6.8 Hz, 2H), 3.63 (dd, J = 13.9, 7.3 Hz, 21-I), 4.11 (t, J = 8.3 Hz, lH), 6.66 (q, J = 6.8 Hz, lH), 7.17 (d, J = 7.1 Hz, 2H), 7.26 (m, 2H), 7.41 (dd, J = 8.5, 2.2 Hz, lH), 7.65 (d, J = 8.5 Hz, lH) 34az 1 H NMR (400 MHz, MeOH-d4): o ppm 0.88 (q, J = 10.5, 8.0 Hz, lH), 1.30 (d, J = 12.4 Hz, 4H), 1.46 (t, J = 7.0 Hz, SH), 1.61 (d, J = 5.7 Hz, 8H), 2.06 (dd, J = 13.4, 7.1 Hz, 2H), 2.33 (dd, J = 13.3, 8.8 Hz, 2H), 3.13 (d, J = 11.5 Hz, 2H), 3.26 (d, J = 11.8 Hz, 2H), 3.48 (m, 4H), 3.62 (d, J = 12.9 Hz, 3H), 4.19 (m, SH), 4.84 (s, 2H), 6.67 (q, J = 6.7 Hz, 2H), 7.27 (m, 7H), 7.43 (dd, J = 8.6, 2.2 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H) 34ba lHNMR (400 MHz, MeOH-d4): o ppm 1.5 9 (m, 4H), 2.04 (dd, J= 13.4, 7.2 Hz, lH), 2.38 (s, 7H), 3.08 (d, J = 1 1 . 7 Hz, lH), 3.23 (d, J = 11.7 Hz, lH), 3.46 (m, 2H), 3.64 (dt, J = 14.7, 5.8 Hz, 2H), 4.04 (dd, J = 9.2, 7.1 Hz, 1H), 5.48 (s, IH), 6.67 (q, J = 6.9 Hz, II-I), 7.03 (s, 2H), 7.12 (s, lH), 7.25 (d, J = 2.3 Hz, lH), 7.42 (dd, J = 8.5, 2.3 Hz, lH), 7.66 (d, J = 8.5 Hz, lH) 34bb 1HNMR (400 MHz, 4): o ppml.28 (s, 3H), 1.58 (m, 4H), 1.98 (dd, J = 13.2, 7.1 Hz, 11-I ), 2.25 (dd, J = 13.3, 9.1 Hz, 11-I ), 2.40 (s, 3H) , 2.98 (d, J = 1 1 . 5 Hz, 1H), 3.17 (d, J = 11.5 Hz, IH), 3.46 (ddt, J = 20.0, 13.0, 6.1 Hz, 2H), 3.63 (dq, J = 12.7, 6.3 Hz, 2H), 3.95 (dd, J = 9 .1 , 7.0 Hz, lH), 4.89 (s, 17H), 5.52 (s, lH), 6. 61 (q, J = 6.7 Hz, lH), 7.30 (d, J = 2.3 Hz, lH), 7.46 (m, 4H) , 7.67 (d, J = 8.4 Hz, lH) 34bc 1H NMR (400 MHz, MeOH-d4): 8 ppm0.88 (d, J = 7.5 Hz, lH), 1.28 (s, 3H), 1.60 (q, J ::: .5 Hz, 4H), 2.05 (dd, J = 13.6, 7.3 Hz, 1H), 2.30 (m, lH), 2.44 (d, J = 2.6 Hz, 6H), 3.10 (d, J = 11.7 Hz, IH), 3.26 (m, 2H), 3.47 (ddd, J = 16.0, 12.4, 6.6 Hz, 21-I ), 3.62 (d, J = 12.7 Hz, 2H), 4.06 (dd, J = 9.2, 7.2 Hz, IH), 5.50 (d, J = 2.5 Hz, lH), 6.64 (q, J = 6.7 Hz, HI), 7.21 (s, 2H), 7.27 (d, J = 2.3 Hz, lH), 7.44 (dd, J = 8.5, 2.3 Hz, lH), 7.66 (d, J = 8.5 Hz, lH) 34bd 1H NMR (400 MHz, MeOH-d4): o ppm 0.89 (t, J = 7.7 Hz, lH), 1.29 (d, J = 5.9 Hz, SH), 1.61 (q, J = 5.6 Hz, 4H), 2.06 (dd, J = 13.5, 7.2 Hz, lH), 2.33 (m, 4H), 2.84 (s, lH), 3.12 (d, J = 11.7 Hz, lH), 3.25 (d, J = 11.7 Hz, lH), 3.48 (m, 2H), 3.64 (ddt, J = 15 .0, 10.2, .1 Hz, 2H), 4.08 (dd, J = 9.2, 7. 1 Hz, lH), 5.52 (s, lH), 6.63 (q, J = 6.8 Hz, lH), 7.26 (m, 4H), 7.43 (dd, J = 8.5, 2.3 Hz, lH), 7.66 (d, J = 8.5 Hz, IH) 34be 1H NM R (400 MHz, MeOH-d4): s ppm 1.28 (s, 1 H), 1.58 (m, 4H), 1.99 (dd, J = 1 3.3, 7.1 Hz, l H), 2.27 (dd, J = 13.3, 9.1 Hz, lH), 2.42 (s, 3H), 3.01 (d, J = 11.6 Hz, IH), 3.19 (d, J = 11 .5 Hz, lH), 3.47 (ddt, J = 21.2, 13.6, 6.9 Hz, 2H), 3.64 (dq, J = 12.3, 5.8 Hz, 2H), 3.98 (dd, J = 9 .1, 7.1 Hz, lH), 5.52 (s, lH), 6.61 (q, J = 6.8 Hz, lH) , 7.18 (s, JH), 7.31 (m, 31-I ), 7.46 (dd, J = 8.5, 2.3 Hz, lH), 7.68 (d, J = 8.3 Hz, lH) 34bf 1H NMR (400 MH z, MeOH-d4): o ppm 0.89 (t, J = 6.6 Hz, lH), 1.29 (d, J = 7.9 Hz, 4H), 1.62 (s, 8H), 2.09 (d, J = 6.9 Hz, lH), 2.34 (t, J = 10.9 Hz, 2H), 3.1 5 (d, J = 8.2 Hz, 2H), 3.25 (m, HI), 3.32 (s, 2H), 3.48 (s, 4H), 3.54 (s, 1 H), 3.66 (s, SH) , 4.12 (s, 2H), 5.56 (s, II-I), 6.60 (q, J = 6.7 Hz, 21-I ), 7.34 (m, SH), 7.50 (dd, J = 8.6, 2.2 Hz, 21-1), 7.68 (d, J = 8.5 Hz, 2H) 34bg 1H NMR (400 MHz, MeOH-d4): s ppm 0.89 (m, 2H), 1.30 (d, J = 14.2 Hz, 7H), 1.61 (s, 12H), 2.07 (m, 3H), 2.36 (dd, J = 13.3, 8.3 Hz, 3H), 2.80 (s, IH), 3.15 (cl, J = 11.8 Hz, 3H), 3.26 (d, J = 11.5 Hz, 3H), 3.46 (d, J = 16.1 Hz, 5H), 3.52 (d, J = 7.0 Hz, 2H), 3.64 (s, 7H), 4.18 (s, 3H), 4.92 (s, IH), 4.98 (s, lH), 6.58 (q, J = 6.7 Hz, 3H), 7.33 (d, J = 2.0 Hz, 3H), 7.47 (m, 12H), 7.67 (m, 6H) 34bh 1H NMR (400 MHz, Me0H-d4): o ppm 0.89 (t, J = 6.4 Hz, lH), 1.29 (d, J = 4.7 Hz, 2H), 1.62 (q, J = 6.3, 5.4 Hz, 4H), 2.07 (dd, J = 13.4, 7.3 Hz, lH), 2.36 (dd, J = 13.5, 9.1 Hz, II-I), 3.15 (d, J = 11.8 Hz, lH), 3.26 (m, lH), 3.50 (ddd, J = 20.3, 10.5, 6.5 Hz, 2H), 3.65 (m, 2H), 4.16 (t, J = 8.2 Hz, lH), 4.68 (s, lH), 4.95 (t, J = 11.4 Hz, IH), 6.40 (q, J = 6.5 Hz, lH), 7.41 (d, J = 2.2 Hz, lH), 7.56 (dd, J = 8.5, 2.3 Hz, lH), 7.71 (d, J = 8.6 Hz, lH), 8.12 (s, 3H) 34bi 1H NMR 400 MHz, MeOH-d4): s ppm 0.89 (d, J = 6.7 Hz, lH), 1.15 (s, lH), 1.28 (m, 9H), 1.57 (d, J = 6.4 Hz, 5H), 1.92 (dt, J = 13.9, 6.8 Hz, lH), 2.21 (dd, J = 13.2, 9.1 Hz, lH), 2.95 (m, 2H), 3.11 (d, J = 11.4 Hz, IH), 3.44 (ddt, J = 20.6, 13.0, 6.2 Hz, 2H), 3.60 (dd, J = 13.8, 6.6 Hz, 2H), 3.87 (dd, J = 9.0, 7.0 Hz, lH), 5.46 (s, lH), 6.61 (q, J = 6.8 Hz, lH), 7.39 (m, 6H) , 7.66 (d, J = 8.5 Hz, lH) 34bj 1H NMR400 MHz, MeOH-d4): s ppm 1.29 (d, J = 5.0 Hz, 3H), 1.55 (m, 6H), 1.82 (dd, J = 12.9, 6.9 Hz, 1 H), 2.10 (dd, J = 13.0, 9.0 Hz, lH), 2.71 (d, J = 11. l Hz, lH), 3.00 (d, J = 1 1.1 Hz, l H), 3.32 (s, 3H), 3.45 (tt, J= 13.0, 6.3 Hz, 3H), 3.65 (ddd, J = 18.3 , 10.9, 7.1 Hz, 4H), 4.88 (s, l 7H), 5.53 (s, 2H), 6.54 (q, J = 6.6 Hz, 1H), 7.32 (d, J = 2.3 Hz, lH), 7.51 (m, SH), 7.59 (t, J = 1.9 Hz, lH), 7.70 (d, J = 8.5 Hz, lH) 34bk 1H NMR (400 MHz, Me0H-d4): s ppml.28 (s, lH), 1.62 (q, J = 5.5 Hz, 4H), 2.07 (dd, J = 13.5, 7.3 Hz, IH), 2.35 (dd, J= 13.6, 9.1 Hz, HI), 3.15 (d, J= 11 . 8 Hz, 11- 1), 3.26 (d, J = 11.7 Hz, 1 H), 3.49 (ddt, J = 21.5, 14.0, 6.1 Hz, 2H), 3.65 (m, 2H), 4.15 (dd, J = 9.1 , 7.4 Hz, lH), 6.49 (q, J = 6.6 Hz, 1 H), 7.34 (d, J = 2.2 Hz, lH), 7.52 (m, 2H), 7.68 (d, J = 8.5 Hz, lH), 7.81 (s, 2H) 34bl 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.33 (m, 8H), 1.56 (q, J = 5.9, 5.2 Hz, 4H), 1.89 (dd, J = 13.1, 7.0 Hz, 1H), 2.18 (dd, J = 13.1 , 9.0 Hz, lH), 2.86 (d, J = 11 .3 Hz, lH), 3.08 (d, J = 11.4 Hz, 1H), 3.46 (ddd, J = 15.1, 12.2, 6.6 Hz, 2H), 3.61 (dd, J = 13.4, 6.0 Hz, 2H), 3.82 (dd, J = 9.0, 7.0 Hz, IH), 4.68 (hept, J = 6.0 Hz, IH) , 5.51 (s, lH), 6.72 (q, J = 8.2, 7.0 Hz, 2H), 6.82 (dt, J = 11.1 , 2.3 Hz, lH), 7.02 (s, lH), 7.28 (d, J = 2.2 Hz, lH), 7.44 (dd, J = 8.5, 2.3 Hz, IH), 7.67 (d, J = 8.6 Hz, lH) 34bm 1H NMR (400 MHz, MeOH-d4): o 2 (d, J = 18.8 Hz, 1 lH), 1.60 (q, J = 5.8 Hz, 4H), 2.05 (dd, J = 13.5, 7.2 Hz, lH), 2.33 (m, 2H), 2.43 (s, 3H), 3.12 (d, J = 11.7 Hz, lH), 3.25 (d, J = 11.7 Hz, lH), 3.45 (ddt, J = 21.7, 13.4, 6.5 Hz, 2H), 3.62 (dq, J = 11.4, .5 Hz, 2H), 4.09 (dd, J = 9.2, 7.2 Hz, lH), 6.64 (q, J = 6.8 Hz, lH), 7.05 (s, lH), 7.26 (m, 2H), 7.34 (d, J = 1.8 Hz, lH), 7.42 (dd, J = 8.5, 2.3 Hz, 1H), 7.66 (d, J = 8.5 Hz, lH) 34bm 1H NMR (400 MHz, Me0H-d4): o ppm 1.28 (s, 2H), 1.53 (t, J = 6.1 Hz, 4H), 1.80 (dd, J = 13.0, 6.9 Hz, lH), 2.09 (dd, J = 13.0, 8.9 Hz, lH), 2.36 (d, J = 2.0 Hz, 3H), 2.68 (d, J = .8 Hz, lH), 2.98 (d, J = 11.1 Hz, lH), 3.42 (m, 2H), 3.63 (m, 3H), 5.49 (s, lH), 6.64 (q, J = 6.8 Hz, lH), 7.24 (m, 3H) , 7.43 (m, 2H) , 7.67 (d, J = 8.5 Hz, lH) 34bo lHNMR (400 MHz, MeOH-d4): o ppm 1.30 (d, J = 13.0 Hz, lH), 1.53 (m, 4H), 1.79 (dd, J = 12.9, 6.9 Hz, lH), 2.08 (dd, J = 12.9, 8.9 Hz, lH), 2.66 (d, J = 11.1 Hz, lH), 2.97 (d, J = 1 1 .0 Hz, l H), 3.42 (m, 3H), 3.62 (m, 3H), 5.50 (d, J = 15.0 Hz, lH), 6.53 (q, J= 6.9 Hz, lH), 7.36 (d, J = 2.3 Hz, lH), 7.53 (dd, J = 8.4, 2.2 Hz, lH), 7.63 (dd, J = 8.0, 5.0 Hz, lH), 7.72 (d, J = 8.5 Hz, lH) , 7.98 (m, lH) , 8.67 (m, lH), 8.74 (s, II-I ) 34bp 11-1 NMR (400 MHz, MeOH-d4): s ppm 1.41 (t, J = 6.9 Hz, 3H), 1.65 (dt, J = 10.9, 5.8 Hz, 4H), 2.08 (dd, J = 13.6, 8.2 Hz, lH), 2.44 (dd, J = 13.6, 8.9 Hz, lH), 3.24 (m, 2H), 3.57 (m, 4H), 4.13 (qd, J = 7.0, 4. 1 Hz, 2H), 4.42 (t, J = 8.5 Hz, II-I), 6.66 (q, J = 6.7 Hz, lH), 7.00 (s, lll), 7.16 (d,J= 8.0 Hz, lH), 7.28 (m, 2H), 7.46 (dd, J = 8.5, 2.3 Hz, lH), 7.67 (d, J = 8.5 Hz, lH) 34bq 1H NMR (400 MHz, MeOH-d4): s ppm 1.36 (s, 1H), 1.59 (q, J = 5.8, 4.7 Hz, OH), 2.05 (dd, J = 13.4, 7.2 Hz, OH), 2.31 (m, OH), 3.12 (d, J = 11.6 Hz, OH), 3.24 (d, J = 11.7 Hz, OH), 3.42 (d, J = 9.4 Hz, OH), 3.49 (m, OH), 3.59 (d, J = 12.4 Hz, OH), 4.09 (dd, J = 9.1, 7.1 Hz, OH), 4.90 (s, 2H), 5.44 (s, OH), 6.65 (q, J = 7.0 Hz, OH), 7.27 (m, OH), 7.45 (m, OH), 7.54 (s, OH), 7.69 (rn, OH) 34br 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.29 (d, J = 7.7 Hz, 3H), 1.59 (m, 6H), 2.04 (dd, J = 13.5, 7.0 Hz, lH), 2.19 (s, 2H), 2.31 (dd, J = 13.5, 9.2 Hz, lH), 3.11 (d, J = 11.5 Hz, f H), 3.24 (d, J = 11.8 Hz, IH), 3.34 (s, IH), 3.47 (dt, J = 24.1, 8.0 Hz, 2H), 3.63 (m, 2H), 4.07 (t, J = 7.9 Hz, lH), 4.73 (s, lH), 5.16 (m, lH), 5.47 (d, J = 10.8 Hz, 2H), 6.62 (q, J = 6.8 Hz, lH), 7.33 (m, lH), 7.51 (m, 3H), 7.68 (d, J = 8.6 Hz, IH) 34bs 1H NMR (400 MHz, MeOH-d4): o ppm 1.28 (s, l H), 1.60 (q, J = 5.9, 5.4 Hz, 4H), 2.04 (m, HI), 2.31 (dd, J = 13.5, 9.2 Hz, lH), 3.11 (s,7H), 3.24 (d, J = 11.6 Hz, lH), 3.47 (m, 2H), 3.63 (s,2H), 4.06 (t, J = 8.1 Hz, lH), 5.50 (s, lH), 6.69 (m, 3H), 7.34 (d, J = 2.2 Hz, IH), 7.48 (dd, J = 8.6, 2.3 Hz, lH), 7.69 (d, J = 8.4 Hz, lH), 8 .18 (d, J = 5.2 Hz, I H) 34bt 1H NMR (400 MHz, MeOH-d4): s ppm 1.56 (t, J = 5.4 Hz, 4H), 1.99 (dd, J = 13.3, 7.0 Hz, lH), 2.26 (dd, J = 13.3, 9.1 Hz, lH), 3.01 (d, J = 11.5 Hz, lH), 3.18 (d, J = 11.5 Hz, lH), 3.43 (ddt, J = 20.5, 13.2, 6.0 Hz, 2H), 3.60 (dd, J = 13.4, 5.7 Hz, 2H), 3.98 (dd, J = 9.1, 7.0 Hz, lH), 4.85 (m, HI), 5.47 (s, HI), 6.68 (q, J = 6.7 Hz, lll), 7.39 (d, J = 2.3 Hz, lH), 7.54 (m, 41-I), 7.72 (d, J = 8.5 Hz, lH), 7.97 (m, 4H) 34bu 1H NMR (400 MHz, CDCb): s ppm 1.36 (dd, J = 6.9, 3.7 Hz, 6H), 1.73 (dd, J = 13.1 , 6.7 Hz, JH), 2.05 (dd, J = 1 3.1 , 8.8 Hz, IH), 2.81 (d, J = 10.5 Hz, ll-I ), 2.94 (d, J= 10.5 Hz, Hi), 3.14 (p , J = 6.9 Hz, l H), 3.47 (dt, J = 12.2, 5.6 Hz, 4H), 3.85 (dd, J = 8.8, 6.7 Hz, lH), 4.19 (q, J= 7.1 Hz, 2H), 4.34 (s, 2H), 5.42 (s, lH), 6.53 (q, J = 6.7 Hz, lH), 7.25 (m, 3H), 7.42 (dd, J = 8.5, 2.2 Hz, lH), 7.68 (d, J = 8.5 Hz, lH), 8.65 (dd, J = 5.0, 0.8 Hz, 34bv 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.30 (d, J = 13.8 Hz, lH), 1.54 (q, J = 6.0, 5.4 Hz, 4H), 1.80 (dd, J = 13.0, 6.9 Hz, 1 I-1), 2.08 (dd, J = 12.8, 8.9 Hz, IH), 2.66 (d, J = 11.2 Hz, 1H), 2.97 (d, J = 11.1 Hz, HI), 3.38 (m, 3H), 3.61 (dt, J = 13.8, 7.1 Hz, 3H), 5.49 (d, J = 1.5 Hz, lH), 6.60 (q, J = 6.7 Hz, lH), 7.28 (m, 3H), 7.47 (m, 3H), 7.66 (d, J = 8.4 Hz, 34bw 1H NMR (400 MHz , 4): o ppm 1.63 (d, J = 7.6 Hz , 4H), 2.07 (dd, J = 13.4, 7.6 Hz, lH), 2.39 (dd, J = 13.6, 9.0 Hz, IH), 3.17 (d, J = 1 1.9 Hz, II-I), 3.28 (m, 2H) , 3.51 (dt, J = 23.6, 8.6 Hz, 2H), 3.62 (d, J = 14.5 Hz, 2H), 4.25 «, J = 8.4 Hz, lH), 6.60 (q, J = 6.6 Hz, lH), 7.29 (d, J = 2.3 Hz, lH), 7.51 (m, 6H), 7.66 (d, J = 8.7 Hz, lH) 34bx 1H NMR (400 MHz, MeOH-d4): o ppm 1.61 (m, 4H), 2.06 (dd, J = 13.5, 7.5 Hz, lH), 2.39 (m, 4H), 3.15 (d, J = 1 1. 8 Hz, 1H), 3.26 (d, J = 11.7 Hz, lH), 3.47 (m, 2H) , 3.62 (ddd, J = 15.6, 9.4, 5.2 Hz, 2H), 4 .18 (dd, J = 9.1, 7.4 Hz, lH), 6.64 (q, J = 6.7 Hz, lH), 7.26 (d, J = 2.3 Hz, lH), 7.38 (m, 4H) , 7.65 (d, J = 8.5 Hz, lH) 34by 1H NMR (400 MHz, MeOH-d4): s ppm: 1.30 (d, J = 17.9 Hz, lH), 1.58 (q, J = 4.3, 2.7 Hz, 4H), 1.78 (m, 4H), 1.98 (dd, J = 13.3, 7.1 Hz, lH), 2.24 (m, 4H), 2.41 (m, IH), 3.02 (d, J = 11.6 Hz, lH), 3.18 (d, J = 11.6 Hz, lH), 3.47 (m, 2H), 3.62 (dq, J = 12.8, 5.9 Hz, 2H), 3.98 (dd, J = 9.1, 7.0 Hz, l H), 5.49 (s, IH), 5.75 (q, J = 2.6, 1.7 Hz, lH), 6.94 (q, J = 6.9 Hz, lH), 7.15 (d, J = 2.3 Hz, IH), 7.29 (dd, J = 8.5, 2.3 Hz, lH), 7.58 (d, J = 8.5 Hz, 34bz 1H NMR (400 MHz, Me0H-d4): 8 ppm 1.02 (m, 7H), 1.28 (d, J = 5.2 Hz, IH), 1.60 (q, J = 6.1 , 5.6 Hz, 4H), 2.06 (ddt, J = 14.1, 11.3, 6.7 Hz, 2H), 2.33 (dd, J = 13.4, 9.2 Hz, 1H), 3.12 (d, J = 11.7 Hz, IH), 3.27 (d, J = 25.3 Hz, 3H), 3.47 (ddt, J = 20.4, 13.1, 5.7 Hz, 2H), 3.65 (m, 2H), 3.81 (m, 2H), 4.08 (dd, J = 9.1, 7.3 Hz, IH), 5.51 (s, lH), 6.71 (q, J = 6.8 Hz, I H), 7.01 (m, 2H), 7.18 (s, lH), 7.29 (d, J = 2.1 Hz, UI), 7.43 (m, 2H), 7.66 (d, J = 8.6 Hz, 11-I) 34ca 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.00 (t, J = 7.3 Hz, 1 H), 1.28 (m, I H), 1.60 (m, SH), 1.97 (m, SH), 2.30 (t, J = 11.2 Hz, IH), 2.83 (t, J = 7.4 Hz, JH), 3.07 (d, J = 11.5 Hz, 11-l), 3.22 (d, J = 11.4 Hz, lH), 3.54 (m, 8H), 4.04 (d, J = 8.7 Hz, lH), 5.08 (s, lH), .56 (s, UI), 6.69 (q, J = 6.6 Hz, lH), 7.31 (d, J = 2.1 Hz, lH), 7.48 (m, 2H), 7.65 (m, 3H), 7.93 (s, IH) 34cb 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.29 (m, lH), 1.62 (m, 6H), 1.90 (m, 8H), 2.32 (dd, J = 13.4, 9.1 Hz, 1 H), 3.11 (d, J = 11.7 Hz, lH), 3.25 (d, J = 11 .6 Hz, lH), 3.47 (ddt, J = 21.4, 13.3, 6.4 Hz, 21-I) , 3.65 (dq, J = 13.0, 6.2 Hz, 2H), 4.08 (dd, J = 9.1, 7.1 Hz, lH), 5.51 (s, IH), 6.72 (q, J = 6.9 Hz, lH), 6.94 (d, J = 7.7 Hz, lH), 7.02 (dd, J = 8.2, 2.6 Hz, H-I), 7.18 (s, lH), 7.28 (d, J = 2.3 Hz, 1H), 7.42 (m, 2H), 7.66 (d, I= 8.5 Hz, lH) 34cc 1H NMR (400 MHz, Me0H-d4): 8 ppm 1.29 (m, 11-I ), 1.49 (m, 8H), 2.02 (m, SH), 2.33 (dd, J = 13.3, 9.0 Hz, l H), 3.13 (d, J = 11.6 Hz, lH), 3.25 (d, J = 12.3 Hz, lH) , 3.58 (ddd, J = 32.1, 26.0, 15.3 Hz, SH), 3.88 (td, J = 10.6, 10.2, 3.9 Hz, lH), 4.08 (t, J = 8.1 Hz, lH) , 5.56 (s, IH), 6.63 (q, J = 6.7 Hz, 1H), 7.29 (d, J = 2.2 Hz, IH), 7.56 (m, 4H), 7.89 (d, J = 7.7 Hz, 1 H), 8.34 (s, 1H) 34cd 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.28 (q, J = 7.6, 6.7 Hz, 4H), 1.57 (p, J = 3.8 Hz, 4H), 1.99 (dd, J = 13.3, 7.1 Hz, lH), 2.27 (dd, J = 13.3, 9.1 Hz, lH), 2.73 (q, J=7.6 Hz, 2H), 3.01 (d, I= 1 1.5 Hz, lH), 3.18 (d, J = 11.6Hz, lH), 3.45 (ddt, J = 21.2, 13.1, 5.9 Hz, 2H), 3.60 (dt, J = 12.5, 6.8 Hz, 21-l ), 3.98 (dd, J = 9.1, 7.1 Hz, lH), 4.93 (s, 1 lH), .47 (s, IH), 6.64 (q, J = 6.8 Hz, IH), 7.30 (m, 4H), 7.43 (m, 2H), 7.66 (d, J = 8.5 Hz, 34ce 1H NMR (400 MHz, MeOH�d4): 8 ppm 1.28 (m, 9H), 1.52 (ddd, J = 11.5 , 7.0, 4.8 Hz, 4H), 1.74 (dd, J = 13.1 , 7.2 Hz, IH), 2 .10 (dd, J = 13.1 , 8.8 Hz, IH), 2.75 (d, J = 10.9 Hz, 1 H), 2.95 (m, 2H) , 3.50 (m, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, 1H), 4. 18 (qd, J = 7.1, 1.5 Hz, 2H), 4.92 (s, 8H), 5.47 (d, J = 14.2 Hz, IH), 6.61 (q, J = 6.8 Hz, lH), 7.32 (m, 4H), 7.44 (m, 2H), 7.66 (d, J = 8.5 Hz, IH) 34cf 1H NMR (400 MHz, MeOH-d4): 8 ppm 0.09 (s, OH), 0.89 (t, J = 6.5 Hz, OH), 1.31 (d, J = 12.8 Hz, lH), 1.59 (m, OH), 1.84 (s, OH), 2.02 (d, J = 6.4 Hz, OH), 2.19 (t, J = 7.8 Hz, OH), 2.65 (s, OH), 2.76 (t, J = 6.7 Hz, OH), 2.87 (d, I= 14.6 Hz, OH) , 3.06 (s, OH), 3.30 (s, lH), 3.49 (m, OH), 3.61 (m, OH), 3.82 (s, OH), 4.98 (s, OH) , 5.33 (m, OH), 5.55 (s, OH), 7.30 (s, OH), 7.38 (d, J = 7.9 Hz, OH), 7.46 (t, J = 7.3 Hz, OH), 7.54 (t, J = 7.8 Hz, OH), 7.64 (m, OH), 7.81 (t, J = 8.6 Hz, OH), 7.93 (m, OH), 8.40 (s, OH) 34cg 1HNMR (400 MHz, 4): o ppm 1.73 (p, J = 7.2, 6.3 Hz, 4H), 2.10 (dd, J = 13.7, 8.5 Hz, IH), 2.50 (dd, J = 13.6, 8.9 Hz, 1H), 3.26 (rn, 4H), 3.61 (m, 1 lI- 1), 3.78 (d, J = 16.7 Hz, 4H), 4.53 (t, J = 8.7 Hz, IH), 6.61 (m, lH), 7.36 (d, J = 2.2 Hz, lH), 7.58 (m, 34ch 1H NMR (400 MH z, DMSO-d6): o ppm 1.43 (m, 4H), 1.79 (dd, J = 13.3, 7.5 Hz, IH), 2.13 (m, lH), 2.30 (s, 3H), 2.48 (m, 3H) , 2.95 (d, J = 1 1 .8 Hz, lH), 3.09 (m, IH), 3.38 (s, lH), 3.44 (s, 6H), 3.66 (s, 2H), 3.82 (t, J = 8.3 Hz, 1 H), 5.54 (s, lH), 6.57 (q, J = 6.8 Hz, lH), 7.34 (d, J = 2.1 Hz, lH), 7.55 (m, 6H) 34ci 1H NMR (400 MHz, MeOH-d4): s ppm 1.29 (d, J = 4.2 Hz, 2H), 1.59 (m, SH), 1.99 (dd, J = 13.4, 6.9 Hz, lH), 2.27 (dd, J = 13.3, 8.9 Hz, lH), 2.80 (s, 3H), 3.01 (d, J = 11.5 Hz, lH), 3.18 (d, J = 11.4 Hz, 1H), 3.48 (m, 3H), 3.62 (q, J = 6.8, 5.6 Hz, 2H), 3.98 (t, J = 8.0 Hz, lH), 5.52 (s, lH), 6.75 (q, J = 6.7 Hz, 1H), 7.49 (m, 3H), 7.69 (d, J = 8.5 Hz, lH), 7.76 (s, lH) 34cj 1H NMR (400 MHz, 4): s ppm 1.29 (m, lH), 1.58 (s, 8H), 2.06 (dd, J = 10.2, 6.4 Hz, 2H), 2.30 (m, 2H), 3.12 (s, 2H), 3.23 (d, J = 9.6 Hz, 2H), 3.49 (m, 4H), 3.64 (s, 9H), 4.07 (t, J = 7.9 Hz, 2H), 5.64 (s, IH), 6.24 (d, J = 7.2 Hz, 2H), 6.50 (t, J = 6.8 Hz, 2H), 7.31 (d, J = 2.2 Hz, 2H), 7.46 (dd, J = 14.7, 7.7 Hz, 3H), 7.65 (d, J = 8.5 Hz, 2H), 7.78 (dd, J = 12.8, 6.1 Hz, 2H) 34ck 1HNMR (400 MHz, MeOH-d4): s ppm 1.62 (q, J = 6.1, 5.6 Hz, 4H), 2.06 (dd, J = 13.4, 7.2 Hz, lH), 2.34 (dd, J = 13.5, 9.2 Hz, ll-1), 2.58 (s, 3H), 3.13 (d, J = 11.7 Hz, lH), 3.26 (d, J = 11.7 Hz, 2H), 3.51 (m, 2H), 3.68 (td, J = 14.8, 14.3, 7.0 Hz, 2H), 4.08 (dd, J = 9.2, 7.1 Hz, lH), 4.87 (d, J = 7.3 Hz, 1 H), 4.97 (s, 1H), 5.60 (s, lH), 6.65 (q, J = 6.6 Hz, lH), 7.34 (d, J = 2.3 Hz, lH), 7.50 (dd, J = 8.6, 2.2 Hz, lH), 7.67 (dd, J = 12.0, 8.0 Hz, 2H), 7.77 (t, J = 7.8 Hz, l H), 7.94 (dt, J = 7.9, 1.4 Hz, lH), 8.31 (s, IH) 34cl 1HNMR (400 MHz, MeOH-d4): o ppm 1.61 (d, J = 5.5 Hz, SH), 2.04 (dd, J= 13.3, 7.1 Hz, lH), 2.31 (dd, J = 13.4, 9.2 Hz, lH), 2.73 (s, 6H), 3.08 (d, J = 11.6 Hz, lH), 3.23 (d, J = 11.7 Hz, IH), 3.53 (rn, 2H), 3.68 (d, J = 14.2 Hz, 2H), 4.04 (dd, J = 9.1, 7.0 Hz, lH), .62 (s, l H), 6.69 (q, J = 6.6 Hz, lH), 7.36 (d, J = 2.3 Hz, lH), 7.50 (dd, J = 8.\ 2.3 Hz, lH), 7.70 (dd, J = 12.4, 7.7 Hz, 2H), 7.86 (m, 2H), 8.33 (s, lH) 34cm 1H NMR (400 MHz, Me0H-d4): 8 ppm 1.27 (s, 1H), 1.57 (p, J = 7 .6, 6.8 Hz, 4H), 1.86 (dd, J = 13.0, 6.9 Hz, Ill), 2.15 (dd, J = 13.2, 9.0 Hz, lH), 2.81 (d, J = 11.2 Hz, lH), 2.95 (s, 4H), 3.05 (d, J = 11.2 Hz, lH), 3.32 (s, lH), 3.46 (ddt, J = 17.4, 1 3.1 , 5.7 Hz, 2H), 3.62 (dq, J = 11.5, 5.5 Hz, 2H), 3.76 (dd, J = 9.0, 6.9 Hz, lH), 5.54 (s, lH), 6.63 (q, J = 6.7 Hz, lH), 7.29 (d, J = 2.3 Hz, lH), 7.46 (dd, J = 8.5, 2.3 Hz, lH), 7.62 (m, 3H), 7.89 (dt, J = 7.7, 1.5 Hz, lH), 8.36 (s, IH) 34cn 1H NMR (400 MHz, MeOH-d4): <> ppm 1.28 (s, 2H), 1.62 (q, J = 5.7, 5.0 Hz, 12H), 2.07 (dd, J = 13.4, 7. 1 Hz, 3H), 2.35 (dd, J = 13.4, 9.1 Hz, 3H), 3.09 (d, J = 26.8 Hz, 23H), 3.26 (s, 2H), 3.53 (m, 6H), 3.64 (d, J = 13.0 Hz, 7H), 4.15 (s, 3H), 4.88 (d, J = 3.3 Hz, lH), 4.97 (s, lH), 5.56 (s, lH), 6.71 (q, J = 6.7 Hz, 3H), 7.32 (d, J = 2.2 Hz, 3H), 7.56 (m, 151-I), 7.78 (s, 3H) 34co 1H NMR (400 MHz, MeOH-d4): 8 ppm 1 .13 (t, J = 7.1 Hz, 3H), 1.26 (m, 4H), l.61 (q, J = 6.1 , 5.6 Hz, 4H), 2.05 (dd, J = 13.4, 7.2 Hz, lH), 2.33 (dd, J = 13.4, 9.3 Hz, lH), 3.13 (d, J = 11.7 Hz, lH), 3.47 (m, lOH), 4.09 (t, J = 8.3 Hz, IH), 5.55 (s, 1 H), 6.74 (q, J = 6.8 Hz, HI), 7.32 (d, J = 2.2 Hz, lH), 7.48 (m, 3H), 7.65 (m, 3H) 34cp 1HNMR (400 MHz, Me0H-d4): 8 ppm l.28 (m, 7H), 1.58 (d, J = 13.6 Hz, 14H), 2.05 (m, 3H), 2.31 (s, 4H), 2.88 (s, lH), 3.11 (d, J = 12.1 Hz, 3H), 3.25 (d, J= 12.8 Hz, 3H), 3.38 (s, lOH), 3.48 (s, 3H), 3.63 (m, SH), 4.09 (t, J = 8.2 Hz, 3H), 4.48 (s, 21-I), 4.98 (s, 3H), 5.10 (s, lH), 5.42 (s, 2H), 5.54 (s, 2H), 6.50 (d, J = 13.3 Hz, 2H), 6.79 (m, lH), 7.22 (s, 2H), 7.44 (s, SH), 7.53 (d, J = 8.4 Hz, SH), 7.76 (s, 7H), 8.11 (m, 3H) 34cq 11-I NMR (400 MHz, Me0H-d4): s ppm 1.31 (s, 3H), 1.62 (s, 8H), 2.08 (dd, J = 13.3, 7.1 Hz, 2H), 2.35 (t, J = 1 1.4 Hz, 2H), 3.16 (d, J = 11.8 Hz, 2H), 3.32' (m, 23H), 3.49 (s, 4H), 3.63 (d, J =19.6 Hz, 3H), 3.83 (s, 4H), 3.90 (s, 2H), 3.97 (s, 2H), 4.05 (s, lH), 4.13 (t, J = 7.7 Hz, 2H), 6.67 (m, 2H), 7.35 (s, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.66 (dq, J = 31.2, 9.5, 9.1 Hz, 7H), 7.84 (s, 2H) 34cr 1H NMR (400 MHz, Me0H-d4): 3 ppm 0.46 (m, 4H), 1.28 (s, IH), 1.58 (s, 4H), 1.69 (d, J = 7.3 Hz, IH), 1.97 (d, J = 9.1 Hz, lH), 2.24 (dd, J = 13.1, 9.0 Hz, lH), 2.58 (s, 2H), 2.73 (s, 2H), 2.96 (d, J = 11.3 Hz, lH), 3.15 (d, J = 11.6 Hz, lH), 3.32 (m, IH), 3.48 (t, J = 12.1 Hz, 4H), 3.63 (s, 2H), 3.76 (s, 2H), 3.92 (t, J= 8.1 Hz, lH), 5.55 (s, lH), 6.71 (q, J = 6.7 Hz, lH), 7.33 (d, J = 2.2 Hz, lH), 7.50 (m, 3H), 7.66 (m, 2H), 7.80 (s, lH) 34cl 1H NMR (400 MHz, MeOH-d4): 3 ppm 8.71 (d, J = 4.7 Hz, lH), 8.02 (t, J = 7.9 Hz, lH), 7.72 (t, J = 7.3 Hz, 2H), 7.52 (d, J = 10.9 Hz, 3H), 6.92 (d, J = 6.7 Hz, lH), 5.87 (s, lH), 4.80 (s, 7H), 4.10 (d, J = 8.7 Hz, IH), 3.66 (s, 2H), 3.50 (s, 2H), 3.30 (s, SH), 3.25 (d, J = 11.8 Hz, lH), 3.12 (d, J = 11.7 Hz, 1H), 2.35 -2.27 (m, lH), 2.06 (dd, J = 13.3, 7.1 Hz, lH), 1.59 (s, 3H), 1.59 (d, J = 11.4 Hz, 1 H) 34cm 1H NMR (400 MHz, MeOH-d4): 8 ppm 8.99 (d, J = 4.9 Hz, 2H), 8.03 (s, 1 H), 7.75 (d, J = 9.4 Hz, 2H), 7.60-7.49 (m, 2H), 5.71 (s, lH), 4.10 (s, lH), 3.59 (d, J = 18.5 Hz, 2H), 3.30 (d, J = 3.1 Hz, 9H), 3.11 (d, J = 12.0 Hz, lH) , 2.31 (t, J = 11.6 Hz, lH), 2.06 (s, lH), 1.57 (s, SH), 1.28 (s, 1H) 34cu 1H NMR (400 MHz, MeOH-d4): 8 ppm 8.96 (d, J = 1.5 Hz , lH), 8.83 - 8.77 (m, lH), 8.71 (d, J = 2.6 Hz, II-I ), 7.77 (d, J = 8.4 Hz, lH), 7.64 - 7.55 (m, 2H) , 6.87 (q, J = 6.7 Hz, IH), 5.64 (s, 1H), 3.99 (t, J = 8.2 Hz, IH), 3.46 (s, IH), 3.19 (d, J = 11.6 Hz, lH), 3.03 (d, J = 11.6 Hz, lH), 2.27 (dd, J = 13.3, 9.2 Hz, lH), 2.00 (dd, J = 13.4, 7.0 Hz, IH), 1.57 (s, 3H), 1.29 (s, lH). 34cv 1H NMR (400 MHz, Me0H-d4): 8 ppm 7.67 (d, J = 8.5 Hz, 2H), 7.44 (ddd, J = 8.0, 4.8, 2.6 Hz, 3H), 7.32- 7.23 (m, 3H), 7.07 (dd, J = 8.4, 2.6 Hz, 2H), 6.98 (d, J = 7.6 Hz, lH), 6.76 (d, J = 7.0 Hz, 2H), 4.26 -4.05 (m, SH), 3.75 (t, J = 4.7 Hz, 3H), 3.42 (s, 4H), 3.36 (s, lH), 3.26 (d, J = 11.7 Hz, 3H), 3. 1 3 (d, J = 11.7 Hz, 2H), 2.33 (dd, J = 13.5, 9.1 Hz, 2H) , 2.06 (dd, J = 13.4, 7.1 Hz, 2H), 1.61 (d, J = 5.6 Hz, SH).
Example 35: (S)(2-amino((R)(5-chloro-3 '-(ethoxycarbonyl)-[1,1'-biphcnyl]yl)- 2,2,2-trifluoro ethoxy)pyrimidiny1)-2,8-diazaspiro [4.5]dccanecarboxylie acid The title compound was prepared as described for (S)(2-amino((R)(2'-(ethoxycarbonyl)- ethyl-1H-pyrazolyl)-[l, henyl]yl)-2,2,2-triflu oroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid (Example 20) starting with (S)(2-amino((R)(2- brom ochlorophenyl)-2,2,2-trifluor oethoxy)pyrimidinyl)((benzyloxy)carbonyl)-2,8- diazaspiro[4.5]decanecarboxylic acid. lHNMR (400 MHz, DMSO-d6): o 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., I H) 7.44 (t, J=I.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=S.61 Hz, 1 H) 10.36 (d, J=5.08 Hz, 1 H). LCMS (MH +): 634.
Example 36: (S)(2-amino((R)(4-chloro(2-methoxyethoxy)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]dccanecarboxylic acid CIY)yYayy�N�>:OH o1 CF3 NyN l._ NH2 I The title compound was prepared as described for (S)(2-amino((R)(4-chloro(3- methyl1-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid (Example lOd) starting with (R)(4-brom o(2- methoxyethoxy)phenyl)-2,2,2-triflu oroethanol and obtained as a white solid.
IH NMR (400 MHz, DMSO-d6): o 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 (hr. 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, I H) 8.93 (d, J=S.42 Hz, 1 H) 9.81 (br. s., 1 H). LCMS (MH+): 560. e 36b: (6-((R)(2-(lH-benzo[d]imiclazolyl)chlorophcnyl)-2,2,2- trlfluoroethoxy)aminopyrimidinyl)-2,8-cliazaspiro [4,51decane-J-carboxylie acid Step 1: To a solution of (R)-l-(2-bromoA-chlorophenyl)-2,2,2-trifluoroethanol (1 g, 3.5 mmol) and zo[d]imidazole (408 mg, 3.5 mmol) in toluene (24 mL) was added sequentially, Cul (131 mg, 0.69 mmol), K2C03 (1.19 g, 8.63 mmol), and (1R,2R)-Nl,N2-dimethylcyclohexane- 1,2-diamine (196 mg, 1.38 mmol). The reaction mixture was purged with N2 and then heated at 130 °Cina sealed tube for 12 h. Afterward, the reaction was cooled to RT. The solid was removed by filtration and the filtrate was concentrated and purified by flash column (EtOAc in hexane= 0 to 50 %) to afford-(R)-l-(2-(lH-benzo[d]imidazol-l-yl)chlorophenyl)-2,2,2- trifl uoroethanol as a white solid.
Steps 2-5: The title compound was made as described for e lOd (Steps 1-4) to prov ide a white solid. lHNMR (400 MHz, DMSO-d6): o ppm 1.59 (m, 4H), 2.05 (dt, J = 13.7, 6.9 Hz, lH), 2.33 (dt, J = 14.5, 8.5 Hz, lH), 3 .13 (dd, J = 11 .7 , 7.6 Hz, lH), 3.26 (m, 2H), 3.49 (m, 3H), 3.63 (m, 2H), 4.10 (q, J = 7.0, 5.2 Hz, 1 H), 5.48 (d, J = 3.9 Hz, IH), 6.43 (p, J = 6.4 Hz, lH), 7.22 (dd, J = 7.8, 4.0 Hz, lH), 7.38 (m, 2H), 7.61 (dd, J = 5.3, 2.2 Hz, lH), 7.81 (m, 3H), 8.54 (s, lH). LCMS (MH+): 603.
Example 36c: (S)(2-amino((R)(4-chloro(lH-indazolyl)phenyl)-2,2,2- trifluor oethoxy)pyrimidinyl)-2,8-diazaspiro [4.5]dccanecarboxylie acid The title compound was prepared as bed for (S)(6-((R)(2-(lH-benzo[d]imidazol-lyl )chlorophenyl)-2,2,2-trifluoroethoxy)aminopyrimidinyl)-2,8-dia zaspiro[4.S]decane carboxylic acid (Example 36b) starting withlH-indazole and obtained as a white solid. 1H NMR (400 MHz, DMSO-d6): 8 ppm 1.57 (m, SH), 2.05 (dd, J = 13.4, 7.1 Hz, ll-1), 2.32 (dd, J = 13.5, 9.2 Hz, lH), 3.12 (d, J = 11.7 Hz, 1H), 3.24 (d, J = 11.7 Hz, 1H), 3.52 (dddd, J = 44.5, .8, 14.0, 7.1 Hz, SH), 4.13 (dd, J = 9.1, 7.1 Hz, 1H), 4.92 (s, lH), 6.68 (q, J = 6.5 Hz, lH), 7.31 (t, J = 7.4 Hz, lH), 7.46 (m, 2H), 7.72 (m, SH), 8.39 (s, 1H). LCMS (MH+): 603.
Example 36d: (S)(2-amino((R)(4-bromo(piperazin-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]dccanecarboxylic acid BrY) ):OH �O��Nf CF3 NyN N NH2 Step 1: A mixture of 4-bromofluoro benzoic acid (2 g, 9.1 mmol), benzy] piperazine carboxylate (2.4 g, 10.9 mmol) and K2C03 (2.5 g, 18.26 mmol) in DMF (40 mL) was stirr ed at 150 °C for 36 h. The reaction was then cooled to RT and extra cted with ethyl acetate, 3 N HCI, brine, dried over Na2S04, fi ltered and concentrated in vacuo to prov ide 2-(4-((benzyloxy) carbonyl)piperazinyl)bromobenzoic acid as yellow oil that was used without further purifi cation.
Step 2: To a mixture of 2-(4-((benzyloxy) carbonyl)piperazin-l-yl)bromobenzoic acid (2 g, 9.1 mmol) in THF (20 mL) was added dropwise BH3/THF (1.0 M, 40 mL) at O °C. The mixture was refluxed for 2 h, then cooled to RT, quenched with H20, and extracted with ethyl acetate, 3 N HCl, brine, then dried over Na2S04, filtered and concentrated. Purification by normal phase silica gel (ethyl acetate/hexanes) provided benzyl romo (hydroxymethyl)phenyl)piperazine-l-carboxylate as a white solid.
Steps 3-10: The title compound was prepared as described for (S)(2-amino((R)-2,2,2- trifluoro(5-(methylsulfonyl)-[1, l '-biphenyl]yl)ethoxy)pyrim idinyl)-2,8- diazaspiro[4.5] decanecar boxylic acid (Example 54d) following Steps 4-1 1. 1H NMR (MeOH-d4): o ppm 0.90 (dt, J = 16.0, 8.0 Hz, IH) , 1.31 (s, 2H), 1.62 (t, J = 5.6 Hz, SH), 2.03 (dd, J = 13.6, 6.9 Hz, 1H), 2.30 (dd, J = 13.4, 9.1 Hz, IH), 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, lH), 3.54 (m, IH), 3.65 (dd, J = 13.9, 6.8 Hz, 2H), 4.01 (t, J = 8 .0 Hz, IH), 5.56 (s, IH), 7.31 (q, J = 6.9 Hz, 11-I), 7.41 (dd, J = 8.4, 1.9 Hz, lH), 7.50 (m, 2H). LCMS (MH+): 615.
Example 36e: (2-amino((R)-2,2,2-trifluoro-l-(4'-isopropoxy(piperazinyl)­ biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decaucca1·boxylic acid H The title compound was prepared starting with (S)benz yl 3-ethyl 8-(2-amino((R)(2-(4- ((benzyloxy)carbonyl)pipera ziny1)bro mophenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)- 2,8-diazaspiro[4. 5]decane-2,3-dicarboxylate (intermediate from Step 8, e 36d] via a Suzuki coupling with (4-isopro poxyphenyl)boronic acid as as described for examp le 54b. 1H NMR (Me0H-d4): o ppm 0.90 (m, 11-I), 1.33 (m, 8H), 1.40 (s, 11-I), 1.59 (q, J = 5.7 Hz, 4H), 2.06 (dd, J = 13.7, 7.0 Hz, IH), 2.31 (dd, J = 13.5, 9.2 Hz, 1 H), 3.11 (m, 3H), 3.26 (d, J = 11.7 Hz, lH), 3.51 (m, lOH), 4.09 (dd, J = 9.3, 6.8 Hz, lH), 4.64 (p, J = 6.0 Hz, lH), 5.56 (s, lH), 6.98 (m, 2H), 7.32 (q, J = 7.0 Hz, lH), 7.53 (m, 4H), 7.64 (d, J = 8.2 Hz, IH). LCMS (MH+): 671.
Example 36f: (S)(2-amino((R)-2,2,2-trifluoro( 4'-isopropoxymorpholino-[1,1'­ bi p henyl]yl)ethoxy)pyrimid inyl)-2,8-diazaspil'o [4.5] decanecarboxylic acid IO The title compound was ed as described for (S)(2-amino((R)-2,2,2-trifluoro ­ isopropoxy(piperazinyl)-[1, l '-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro]4.5]decane- 3-carboxylic acid (Exa mple 36e) substituting morpholine for benzyl piperazin ecarboxylate. 1HNMR (MeOH-d4): s 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, lI-I), 2.83 (m, 2H), 2.99 (d, J = 11.5 Hz, lH), 3.19 (m, 3H), 3.32 (s, lH), 3.48 (ddt, J = 18.5, 8.9, 5.0 Hz, 2H), 3.62 (s, 2H) , 3.92 (m, SH), 4.63 (h, J = 6.0 Hz, 1H), 4.88 (m, lH), 5.54 (s, lH), 6.97 (m, 2H), 7.41 (m, 2H), 7.54 (m, 4H). LCMS (MH+): 672 Example 36g: (S)(6-((R)([1,11-biphenyl]yl)-2,2,2-trifl uot·oethoxy)amino pyl'imidinyl)-2,8-diazaspiro[4.S)decanccarboxylic acid ):OH O��N� CF3 NyN I NH2 The title compound was prepared as described for (S)(2-amino((R)(5-chloro-3'­ sulfamoyl-[ 1, l'<biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[ 4.5]decane- 3-carboxylic acid le 34u) starting with 1-(2-bromophenyl)-2,2,2-trifluoroethanone. 1H NMR (MeOH-d4): s ppm 1.58 (d, J = 5.4 Hz, 4H), 2.00 (dd, J = 13.4, 7.1 Hz, ll-I), 2.27 (dd, J = 13.3, 9.2 Hz, 1H), 3.02 (d, J = 11.6 Hz, lH), 3.19 (d, J = 11.5 Hz, IH), 3.30 (q, J = 1.8 Hz, 3H), 3.45 (td, J = 14.5, 6.3 Hz, llI), 3.61 (m, 2H), 3.99 (m, lH), 5.46 (s, IH), 6.67 (q, J = 6.8 Hz, IH), 7.26 (dd, J = 6.2, 2.4 Hz, lH), 7.45 (m, 7H), 7.70 (d, J = 7.3 Hz, lH) . LCMS (MH+): 528.
Example 37: (3S)(6-(1-((1 r,3r,5S,7S)-adamantanyl)ethoxy)aminopyrimidinyl)- 2,8-diazaspiro [4.5] decanecarboxylic acid )-oH �O��NH Step 1: A solution of adamantanyl-methanol (100 mg, 0.60 mmol) in THF (5 mL) was cooled 1 S to O °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 warmed to RT for 1 h, cooled to O °C, and 4,6-dichloropyrimidinylamine (24 7 mg, 1.5 mmol) was added. The reaction was heated to 65 °C for 16 h, cooled to RT, quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over , fi ltered, and tra ted in vacuo. Purifi cation by normal phase chromatography (EtOAc/heptan e) provided 4-(adamantanwl-ylmethoxy)chloropyrimidinylamine as a white solid.
Step 2: mantany1methoxy)chloro-pyrimidiny1amine (89 mg, 0.30 mmol), (S) benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2)-dicarboxy1ate (157 mg, 0.45 mmol) and NaHC03 (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 to RT, quenched with water, and extracted with EtOAc. The organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provides (S)benzyl 3-ethyl 8-(6-(adamantanl-ylmethoxy )aminopyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Step 3: N-CBZ ection was accomplished via Method B to provide (S)-ethyl 8-(6- (adamantanylmethoxy)aminopyrimidinyl)-2,8-diazaspiro[4.5Jdecanecarboxylate as a white solid.
Step 4: Hydrolysis of (S)-ethyl 8-(6-(adamantanylmethoxy)aminopyrimidinyl)-2,8- diazaspiro[ 4.5]decanecarboxylate using the LiOH l method pro vides the title compound as a white solid. 1H NMR(400MHz, DMSO-d6): 8 ppm 1 . 12 (d, J=6.25 Hz, 3 H) 1.42 - 1 . 7 6 (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 (hr. 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)(6-((lr,3r,5S,7S)-adamantanylmethoxy)aminopyrimidinyl)-2,8- diazaspiro]4.5] dccane-J-carboxyltc acid The title compound was made as described above for (3S)(6-(1-((lr,3r,5S,7S)-adamantan oxy)aminopyrimidinyl)-2,8-diazaspiro(4.5]decanecarboxylic acid (Example 3 7) using (1r,3r,5r, ?r)-adamantanylmethanol. 1H NMR (400 MHz, DMSO-d6): o 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 1-1) 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., l H) 8.97 (br. s., 1 H) 10.40 (br. s., 1 H). LCMS (MH+): 442.
Example 39a: 8-(4-Amino((naphthalenyhnethyl)amino)-l,3,5-triazinyl)-2,8- diazaspiro [4.5] carboxylic acid � >,OH ��'r(NY�N� Step 1: To a solution of 4,6-dichloro-1,3,5-triazinamine (1.6 g) in isopropa nol (14 mL) was added 2-benzyl 3-ethyl azaspiro[4.5)decane-2, 3-dicarboxylate (1.28 g, 3.7 mmol) and EbN (7 mL). The solution was heated to refl ux for 72 h, then cooled to RT, and concentrated in vacuo. Purific ation by normal phase chro ap hy (CH2Cb/M eOH =: 50/1) afforded 2-benzyl 3-ethyl 8-(4-aminochloro- 1,3,5-triazinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a colorless oil.
Step 2: To a solution of 2-benzyl 3-ethyl 8-(4-aminochl oro- 1,3,5-triazinyl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate (265 mg, 0.56 mmol) in isopropanol (3 mL) were added naphthalenylmethanamine (105 mg, 0.67 mmol) and EtJN (1.4 mL). The reaction mixture was heated to reflu x for 12 h, then cooled to RT, and concentra ted in vacuo. Purifi cation by normal phase chromatography (CH2Ch/M eOH) provided 2-benzyl 3-ethyl 8-(-l-amlno-c- ( (naphthalenylmethyl)amino)-1,3,5-triazinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Step 3: Hydrolysis of 2-benzyl 3-ethyl 8-(4-amino((naphthalenylmethyl)amino)-1,3,5- triazinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate using the LiOH general method ed 8-(4-amino((naphthalenylmethyl)amino)-1,3,5-triazinyl) ((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decanecarboxylic acid as a white solid.
Step 4: N-CBZ Deprotection was accomplished via Method B to provide the title compound as a white solid.
Using the generic scheme below, the following examples of Table 13a were prepared as described above for 8-(4-amino((naphthalenylmethyl)amino)-1),5-triazinyl)-2,8- r{-i0 (SJ HvN- 0 STEPl STEP2 STEP4 Table 13a. cP�OH Ay�YiNYN R NyN Ex. A-CH(R)-NH- CASName LCMS No. (MH+) 39a 8-(4-amino((naphthalenylmethyl)amino)-1,3,5- 435 ��'Y triazinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid 39b 8-(4-(([l, l1-biphenyl]A-y1methyl)amino)amino- 460 1,3,5-triazinyl)-2,8-diazaspiro[4.5]decane carboxylic acid 39c C(() 8-(4-amino((2-(piperidinyl)benzyl)amino)- 467 1,3,5-triazinyl)-2,8-diazaspiro[4.5]decane carboxylic acid HNr> 39d 8-(4-(([l, l'-biphenyl]ylmethyl)amino)amino- 460 1,3,5-tdazinyl)-2,8-diazaspiro[4.5]decane ���carboxylic acid 39e 8-(4-amino(((R)(naphthalenyl)ethy l)amino)- 448 l ,3,5-triazinyl)-2,8-diazaspiro[4.5]decane carboxylic acid Table 13b.
NMR Data for Compounds of Table 13a Ex. NMR 39a lH NMR (400 MHz, DMSO-d6): 8 ppm .s.41-1), 1 .6-1.8 (m, IH), 2.1-2.2 (m, lH), 3.0-3.1 (br.s. 3H), 3 .5-3.8 (br.s, 5 H), 4.1 (t, J = 4.8 Hz, 1 H), 4.5 (d, J= 5.5 Hz, 2 H), 6.0- 6.3 (br.s. 2 H), 7.1-7 .3 (m, 3H), 7.5-7.9 (m, 4 H). 39b lH NMR (400 MHz, Me0H-d4): 8 ppm 1.54 - 1 .79 (m, 4 H) 2.02 - 2.19 (m, 1 H) 2.44 - 2.60 (m, 1 H) 3.74 - 3.92 (m, 2 H) 3.93 - 4.08 (m, 2 H) 4.49 - 4.62 (m, 1 H) 4.63 - 4.71 (m, 2 H) 7.30 - 7.40 (m, 1 H) 7.40- 7.51 (m, 4 H) 7.55 - 7.68 (rn, 4 H) 39c lH NMR (400 MHz, MeOH-d4): o ppm 1.66 (br. s., 6 H) 1 .86 (br. s., 4 H) 2.03 - 2 . 16 (m, 1 H) 2.40 - 2.54 (m, 1 H) 3.06 - 3.22 (m, 4 H) 3.66 - 3.87 (m, 2 H) 3.87 - 4.02 (m, 2 H) 4.46 - 4.59 (m, 1 H), 4.75 (s, 2 H) 7.12 - 7.27 (m, 1 H) 7.29 - 7.45 (m, 3 H) 39d lH NMR (400 MHz, MeOH-d4): o ppm 1.29 - 1.79 (m, 4 H) 1.88 - 2.15 (m, 1 H) 2.25 - 2.54 (m, 1 I-I) 3.22 (br. s., 2 H) 3.60 - 4.01 (m, 4 H) 4.35 - 4.54 (m, 1 H) 4.62 (s, 2 H) 7.25 - 7.35 (m, 1 H) 7.36- 7.46 (m, 3 H) 7.51 (d, J=7.61 Hz, 1 H) 7.57 (d, J=8.59 Hz, 3 39e lH NMR (400 MHz, MeOH-d4): o ppm 1.63 (d, J=6.83 Hz, 9 H) 3.01 - 3.21 (m, 1 H) 3.50 - 4.07 (m, 5 H) 4.32 - 4.65 (m, 1 H) 5.14- 5.33 (m, 1 H) 7.32- 7.54 (m, 3 H) 7.81 (d, J=5.08 Hz, 4 H) Example 40: 8-(4-amino((R)(4-chloro(3-methyl-lH-pyrazolyl)phenyl)-2,2,2- trlflu oroethoxy)-1,3,5-triazinyl)-2,8-diazaspiro (4. 5)decane-S-carboxylic acid Step 1: To a solution of (R)(4-chloro(3-methyl- lH-pyrazolyl)phenyl)-2,2,2- trifluoroethanol (380 mg, 1.3 mmol) in 10 mL ofTHF was added NaH (60 mg, 1.4 mmol) and the reaction was stirred at RT for 30 min. Afte r this time, 2-benzyl 3-ethyl 8-(4-aminochloro­ l ,3,5-triazinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (p roduct from Step 1, Example 39a) (570 mg, 1.2 mmol) was added and the reaction was heatd to 50 °C for 12 h. Aft er this time, the reaction was cooled to RT, quenched with methanol and concentrated in vacuo.
Normal phase silica gel chromatography (EtOAc/heptane) prov ided 2-benzyl 3-ethyl 8-(4- amino((R)-l-(4-chloro(3-methyl-lH-pyrazol- 1-yl)phenyl)-2,2,2-triflu oroethoxy)-1,3,5- triaziny l)-2,8-diazaspiro[4.5]decane-2,3-dicarboxy1ate as a white solid.
Step 2: N-CBZ Deprotection was accomplished via Method B to provide ethyl 8-(4-mnino -(4-chloro(3-methyl-IH-pyra zolyl)phenyl)-2,2,2-triflu oroethoxy)-l ,3,5-triazinyl)- azaspiro[4 .5]decanecarboxylate as a white solid.
Step 3: Step 3 : Hydrolysis of ethyl mino((R)(4-chloro(3-methyl-lH-pyrazol yl )pheny1)-2,2,2-triflu oroethoxy)-1,3,5-triazinyl)-2,8-diazaspiro[4.5]decane- 3-carboxylate using the LiOH general method provided the title compound as a white solid. 11-I NMR (400 MHz, MeOH-d4): o 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, l H) 2.36 (s, 3 H) 3.10 (d, J=l 1.71 Hz, 1 H) 3.23 - 3.28 (m, I 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)(2-Amino((2-(piperidinyl)benzyl)amino)pyrimidinyl)-2,8- diazaspiro [4.5]decanecarboxylic acid "1 ):OH ��yy�N� ON N'f'N Step 1: To a on of (S)benzyl l 8-(2-aminochloropyrimidinyl)-2,8-diazaspiro ecane-2,3-dicarboxylate (200 mg, 0.6 mmol) and [2-(1-piperidinyl)phenyl]methanamine (CAS#: 727526) (105 mg, 0.8 mmol) in i-PrOH (2 mL) was added diisopropy lethyl amine (0.5 mL). The reaction was heated to 120 °C for 2 h followed by heating to 140 °C for I h under microwave conditions, then cooled to RT and concentrat ed in vacuo. Purifi cation by normal phase silica gel column (EtOAc/h eptane) provided (S)benzyl 3-ethyl 8-(2-amino((2- (piperidin- 1-yl)benzyl)amino) pyrimidinyl)-2,8-diazaspiro[4.5Jdecane-2,3-dicarboxylate as a white solid.
Step 2: N-CBZ Deprotection was accomplished via Method B to provide (S)-ethyl 8-(2-amino ((2-(piperi dinyl)benzyJ)amino)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate as a white solid.
Step 3: ysis of (S)-ethyl 8-(2-amino((2-(piperidin-l-yl)benzyl)amino)pyrimidinyl)- 2,8-diazaspiro[4.5]decanecarboxylate using the LiOH general method prov ided the title compound as a white solid.
Using the generic scheme below, the following examples of Table I 4a were prepared as described above for (S){2-amino((2-(piperidin-l-yl)benzyl)amino)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid (Example 4 I a).
STEP2 Table 14a.
Ex. Ar CASNamc LCMS No. (MH+) 41a cco (S)(2-amino((2-(piperidin 446 yl)benzyl)amino)pyrimidinyl)-2,8- diazaspiro]4.S]decanecarboxylic acid 41b o (S)(2-amino((2-phenoxy(piperidin 558 yI)benzyl)amino)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxy1ic acid 41c (3 S)(6-(((3S,5S)-adamantan-l-ylmethyl)amino) 441 aminopyrimidiny1)-2,8-diazaspiro[4. ne � carboxylic acid 41d (3S)(6-((1-((1R,3S,5S)-adamantan-l- 456 yl)ethyl)amino)aminopyrimidinyl)-2,8- � diazaspiro[4.5]decanecarboxylic acid Table 14b NMR Data for Compounds of Table 14a Ex. NMR 41a 1H NMR (400 MHz, MeOH-d4): o ppm 1.39 - 1.66 (m, 6 H) 1.67 - 1.85 (m, 4 H) 1.95 - 2.11 (m, 1 H) 2.18 -2.35 (m, 1 H) .95 (m, 4 H) 3.09 (s, 1 H) 3.20 (s, 1 H) 3.35 (s, 4 H) 3.94 - 4.14 (m, 1 H) 4.43 (s, 2 H) 6.93 - 7.05 (m, 1 H) 7.11 (s, 1 H) 7.14 - 7.24 (m, 1 H) 7.26 - 7.38 (m, 1 H) 41b 1H NMR (400 MHz, MeOH-d4): o ppm 1.43 - 1.66 (m, 6 H) 1.67 - 1.85 (m, 4H) 1.94 - 2.09 (m, 1 H) 2.18 - 2.34 (m, 1 H) 2.89 (d, 1=4.49 Hz,4 H) 3.07 (s, 1 H) 3.14 - 3.25 (m, 1 H) 3.32 - 3.63 (m, 4 H) 3.95 - 4.08 (m, 1 H) 4.46 (s, 2 H) 6.49 - 6.58 (m, 1 H) 6.84 - 6.97 (m, 3 H) 7.03 - , 1 H) 7.18 (s, 1 H) 7.28 (d, J=7.91 Hz, 2 H) 41c 1H NMR (400 MHz, MeOH-d4): o ppm 0.00 (hr. s., 6 H) 0.03 - 0.26 (m, IO H) 0.27 - 0.44 (m, 9 I-I) 0.48 - 0.58 (m, 1 H) 0.68 - 0.85 (m, 1 H) 1.33 (s, 2 H) 1.50 - 1.64 (m, 1 H) 1.84 - 2.03 (m, 2 H) 2.11(br, s., 2 H) 2.42 - 2.62 (m, 1 H) 41d 1H NMR (400 MHz, MeOH-d4): o ppm 1.08 (d, J=6.83 Hz, 3 H) 1.52 - 1.71 (m, 13 H) 1.73 (br. s., 3 I-1) 1.93 (s, 2 H) 1.97 (br. s., 3 H) 2.04 - 2.19 (m, 1 H) 2.24 - 2.43 (m, 1 H) 3.06 - 3.21 (m, 1 H) 3.22 - 3.28 (m, 1 H) 3.36 - 3 .58 (m, 3 H) 3.59 - 3.75 (m, 2 H) 4.02 - 4.20 (m, 1 H) Example 42a: (S)(2-amino((R)-l-(3'-chloro-[l,1 '-biphenyl]yl)-2,2,2- trifluorocthoxy)pyrimidinyl)-2,8-diazaspiro[4.5)clccanccarboxylic acid The title compound was made as described for (S)(2-amino((R)-l-(5-chloro-3'- (ethoxycarbonyl)-[1, 1 '-biphenyl]yl)-2,2,2-trifluoro ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid (E xample 35) starting with (S)benzyl 3-ethyl 8-(2- 21 1 amino((R)- l omophenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro [4. 5]decane-2,3-dicarboxylate. 1H NMR (400 MHz, DMSO-d6): s ppm 1.43 (h, J = 8.5, 6.5 Hz, 4H), 1.80 (dd, J = 13.3, 7.4 Hz, lH), 2.12 (dd, J = 13.2, 9.0 Hz, IH), 2.48 (d, J = 1.8 Hz, lH), 2.95 (d, J = 11.7 Hz, lH), 3.08 (d, J = 11.7 Hz, lH), 3.37 (d, J = 16.1 Hz, lH), 3.48 (d, J = 11.2 Hz, 3H), 3.79 (m, 2H), 5.57 (s, IH), 6.62 (q, J = 6.9 Hz, 1 H), 7.27 (dd, J = 5.8, 3.3 Hz, lH), 7.51 (m, 7H). LCMS (MH+): 563.
Example 42b: (S){2-amino((R)-2,2,2-trifluoro(3'-fluoro-[1,1'-biphenyl] oxy)pyrimidinyl)-2,8-diazaspiro[4.5] decanecarboxylic acid The title compound was made as described for (S)(2-amino((R)(5-chloro-3'­ (ethoxycarbonyl)-] 1, l'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyr imidiny1)-2,8- diazaspiro[4.5]decanecarboxylic acid(Example 35) starting with (S)benzyl 3-ethyl 8-(2- 6-((R)(2-bromopheny1)-2,2,2-triflu oro ethoxy)pyrim idinyl)-2,8- diazaspiro [4.5]decane-2,3-dicarboxylate. 1HNMR (400 MHz, DMSO-d6): s ppm 0.89 (m, lH), 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, lH), 2.32 (dd, J = 13.4, 9.1 Hz, lH), 3.1 1 (d, J = 11.7 Hz, lH), 3.24 (d, J = 11. 7 Hz, 11-1), 3.47 (ddt, J = 20.6, 13.4, 6.5 Hz, 2H), 3.64 (ddt, J = 15.8, 10.8, .2 Hz, 2H), 4.07 (dd, J = 9.2, 7.1 Hz, lH), 5.51 (s, lH), 6.68 (q, J = 6.9 Hz, lH), 7.25 (m, 4H), 7.48 (m, 3H), 7.71 (m, lH). LCMS (MI-I+): 546.
Example 43: (S)(5-((R)(4-chloro(3-mcthyl-lH-pyrazolyl)phcnyl)-2,2,2- trifluoroethoxy)pyridazinyl)-2,8-diazaspiro[4.S]decanecarboxylic acid )-OH ClyYo��NH )) CF, l!_N,N Step 1: To (R)(4-chloro(3-methyl-lH-pyrazolyl)phenyl)-2,2,2-trifluoroethanol (1.00 g, 3.44 mmol, Intermediate 3) in oxane (100 mL) was added chloropyridazine (512 mg, 3.44 mmol) and Cs2C03 (3.36 g, 10.3 mmo1). The reaction mixture was then heated at 100°C for 182 h. During this time, the reaction was charged with onal 3,5-dichloropyridazine (2.56 g, 17.2 mmol) at t = 86 h. Then the reaction mixture was cooled to RT, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (EtOAc/heptane) provided 3-chloro[(lR)-l-[4-chloro(3-methylpyra zolyl)phenyl]-2,2,2- trifluoroethoxy]pyridazine as a 3:2 mixture of (R)chloro(1-(4-chl oro(3-methyl-lH­ pyrazol-l-yl)phenyl)-2,2,2-triflu oroethoxy)pyridazine and (R)chloro( 1-(4-chloro(3- methyl-IH-pyrazolyl)phenyl)-2,2,2-trifluoro ethoxy)pyridazine tively.
Step 2: To a on of the (R)chl oro (1-(4-chloro(3-methyl-1 Il-pyrazol- l-yl)phenyl)- 2,2,2-trifl uoroethoxy)pyridazine/(R)chloro(1-(4-chloro(3-methyI-l Fl-pyrazol-l­ yl)phenyl)-2,2,2-tritlu oro ethoxy)pyridazine mixture from step 1 in 1,4-dioxane (19 mL) was added 2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxy1ate (980 mg, 2.83 mmol), Cs2C03 (2.30 g, 7.07 mmol), Pd2(dba)3 (432 mg, 0.471 mmol), and NAP (587 mg, 0.940 mmol), and the reaction mixture was heated to 60 °C for 60 h. Then the reaction mixture was cooled to RT, filt ered through , washed with EtOAc, and the fi ltrate concentrat ed in vacuo.
Purifi cation on a 120 g Isco RediSep silica cartri dge (EtOAc/heptane) provided (S)benzyl 3- ethyl 8-(5-((R)(4-chloro(3-methyl-lH-pyrazo1yl)phenyl)-2,2,2- trifl uoroethoxy)pyri dazinyl)-2,8-diazaspiro[ 4.5]decane-2,3-dicarboxylate as a white solid.
Step 3: N-CBZ ection was accomplished via Method B to provide (S)(5-((R)-l-(4- chloro(3-methyl-IH-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyridazinyl) (ethoxycarbonyl)-2,8-diazaspiro[4.5]decanecarboxylic acid as a white solid.
Step 4: ysis of (S)(5-((R)(4-chloro(3-methyl-lH-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyridazin-S-y1)(ethoxycarbonyl)-2,8-diazaspiro [ 4.5]decanecarboxylie acid using the LiOH general method provided the title compound as an off-white solid. 1H NMR (400 MHz, MeOH-d4): s ppm 1.66 - 1.80 (m, 4 H), 2.1 1 (dd, J = 13.45, 7.05 Hz, 1 H), 2.30 - 2.40 (m, I H), 2.36 (s, 3 H), 3. 16 (d, J = 1 1.8 1 Hz, 1 H), 3.25 - 3.35 (m, 1 H), 3.37 - 3.65 (m, 4 H), 4.03 - 4 .1 9 (m, 1 1-1), 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=2.49Hz, 1 H). LCMS(MH+): 551 e 44: (S)(4-((R)-2,2,2-trifluoro(2-(3-methyl-lH-pyrazol yl)pbcnyl)ctboxy)pyridinyl)-2,8-cliazaspiro [4.5] clecanecarboxylie acid Example 45: (S)(4-((R)(4-chloro(3-methyl-lH-pyrazolyl)phcnyl)-2,2,2- trifluoroethoxy)pyridinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid Example 45 X = Cl Example 44: X = H Step 1: To a solution of 2-chloro nitropyl'i dine (200 mg, 1.00 mmol) in oxane (6 mL) was added (R)(4-chloro- 2-(3-methyl-lH-pyrazolyl)phenyl)-2,2,2-triflu oroethanol (368 mg, 1.27 mmol), and Cs2C03 (828 mg, 2.54 mmol). The reaction was heated to 80 °C for 12 h, then cooled to RT, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2S04, fi ltered, and concentrated in vacuo. Purific ation by normal phase silica gel column (EtOAc/heptane) provided (R)chloro( 1-(4-chloro(3-methyl-1 Il-pyrazol-lyl )phenyl)-2,2,2-trifluoroethoxy)pyridine as an off-white solid.
Step 2: To a on of (R)chloro(1-(4-chloro(3-methyl-lH-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyridine (227 mg, 0.57 mmol) in 1,4-dioxane (5 mL) was added 2-benzyl 3-ethyl azaspiro[4.5]decane-2,3-dicarboxylate (237 mg, 0.68 mmol), Cs2C03 (557 mg, 1.71 mmol), BINAP (142 mg, 0.23 mmol), and Pd2(dba)3. The reaction was heated to 60 °C for 3 d, then cooled to RT, and concentrated in vacuo. Purifi cation by normal phase silica gel column (EtOAc/heptane) provided 2-benzyl 3-ethyl 8-(4-((R)(4-chloro(3-methyl-lH-pyrazol yl)phenyl)-2,2,2-triflu oroethoxy)pyridinyl)-2,8-diazaspiro[4.S]decane-2,3-dicarboxylate as a white solid.
Step 3: Hydro lysis of2-benzyl 3-ethyl 8-(4-((R)(4-chloro- 2-(3-methyl-IH-pyra zol y l)phenyl)-2 ,2,2-trifluoro ethoxy)pyridinyl)-2,8-diazaspiro [4.5]decane-2)-dicarb ox ylate using the Li OH general method prov ided 2-((benzyloxy)carbonyl)(4-((R -chloro(3-methyl­ l H-pyrazol- l -yl)phenyl)-2,2,2-trifl uoroethoxy)pyridinyl)-2,8-diazaspiro[4.S]decane carboxylic acid.
Step 4: N-CBZ Deprotection was accomplished via Method A followed by normal phase silica gel purifi cation :heptane) prov iding both of the title compounds as white solids (120 mg and 75 mg for the des-chloro analog). 8-(4-((R)-2,2,2-trifluoro (2-(3-methyl-IH-pyra zolyl)phenyl)ethoxy)pyridinyl)-2,8- piro[4.5]decanecarboxylic acid: 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.52 - 1.76 (m, 4 H) 1.95 - 2.15 (m, I 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) 3.1 9 - 3.27 (m, 1 H) 3.38 - 3.72 (m, 4 H) 3.77-4.13 (m, 1 H) 6.39 (d, 1=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(rn, 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(2-(3-methyl-lH-pyrazolyl)phenyl)ethoxy)pyridinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid: 1H NMR (400 MHz, MeOH-d4): o 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=l 1.52 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)(4-chloro(3-metltyl-lH-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)phenoxypyrimidiny1)-2,8-diazaspiro [4.5] decanecarboxylie acid Step 1: To a solution of 2-benzyl 3-ethyl 8-(4-chloro((R)(4-chloro(3-methyl-lH­ pyrazoly1)pheny1)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3- oxylate (by-product from Step 3, Example 30a) (250 mg, 0.347 mmol) in 1,4-dioxane (9.0 mL) was added phenol (1.00 g, 10.6 mmol) and Cs2C03 (3.65 g, 11 .2 mmol). The on was heated at 80°C for 12 h, then cooled to RT diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2S04, fi ltered, and concentra ted in vacuo.
Purificat ion on a 12 g Isco RediSep silica dge (EtOAc/heptan e) provided 2-benzyl 3-ethyl 8-(4-((R)(4-chloro (3-methyl-lH-pyrnzolyl)phenyl)-2,2,2-triflu oroethoxy) phenoxypyrimidinyl)-2,8-diazas piro[4.5]decane-2,3-dicarboxylate as an ite solid.
Step 2: N-CBZ Deprotection was accomplished via Method A to provide (ethyl 8-(4-((R)-l-(4- chloro(3-methyl-lH-pyrazolyl)phenyl)-2,2,2-triflu oroethoxy)phenoxypyrimidinyl)- 2,8-diazaspiro[4.5Jdecanecarboxylate as a white solid.
Step 3: Hydrolysis of ethyl 8-(4-((R)(4-chloro(3-methyl-lH-pyrazolyl)phenyl)-2,2,2- tri fluoroethoxy)phenoxypyrimidiny 1)-2,8-diazaspiro[4.5]decanecarboxylate using the LiOH general method provided the title compound as an ite solid. 1H NMR (400 MHz, MeOH-d4): o 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), .44 (d, J = 2.29 Hz, 1 H), 6.27 - 6.33 (m, l 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, l 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. e 47: (3S)(2-Amino(1-(2,6-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxy1ic acid q;OJ0(dtOH Br CF3 NyN The title compound was prepared as described for (S)(2-amino((R)(4-chloro- 2-(3- methyl-IH-pyrazolyl)phenyl)-2,2,2-trifluo roethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decanecarboxylic acid (Example 1 Od) starting with 1-(2,6-dibromophenyl)- 2,2,2-triflu oroe thanol. 1H NMR (400 MH z, MeOH-d4): 6 ppm 1.29 (rn, IH), 1.62 (q, J = 5.7 Hz, 41-I), 2.06 (m, IH), 2.33 (dd, J = 13.5, 9.2 Hz, lH), 3.13 (d, J = 11.7 Hz, lH), 3.26 (d, J = 11.7 Hz, lH), 3.49 (m, 2H), 3.65 (dq, J = 10.7, 5.4 Hz, 2H), 4.09 (dd, J = 9.2, 7.2 Hz, lH), 5.56 (s, lH), 7 .15 (t, J = 8.0 Hz, IH), 7.28 (q, J = 8.0 Hz, 1H), 7.69 (m, 2H). LCMS (MH+): 611.
Example 48: (S)(2-Amino((R)-l-(2,S-dibromophenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro [4.5]decanecarboxylic acid A �o� �OyYa-,N� Br CF3 NyN The title compound was prepared as described for (S)(2-amino((R)(4-chloro(3- methyl-I H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid (Example 1 Od) starting with 1-(2,5-dibromophenyl)- 2,2,2-trifluoroethanol. 1H NMR (400 MHz, Me0H-d4): 6 ppm 1.62 (q, J = 5.8, 5.2 Hz, 4H), 2.06 (dd, J " " 13.5, 7.2 Hz, lH), 2.34 (dd, J = 13.4, 9.2 Hz, lH), 3.13 (d, J = 11.7 Hz, 1 H), 3.26 (d, J" " 11.8 Hz, lH), 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, lH), 4.83 (s, lH), 5.58 (s, IH), 6.97 (q, J = 6.6 Hz, lH), 7.47 (dd, J = 8.6, 2.4 Hz, lH), 7.58 (d, J = 8.6 Hz, 1H), 7.69 (d, J = 2.4 Hz, lH). LCMS (MH+): 611.
Example 49: (S)(2-Amino((R)-2,2,2-trifluoro(3'-(methylsulfonyl)propyl-[1,1 '­ biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.S]decanecarboxylic acid /1 \\ 0 0 Step 1: To a solution of tert-butyl l 8-(2-amino((R)(2-brom ochlorophenyl)- 2,2,2-triflu oro ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (660 mg, 0.95 mmol) in dioxane (12 mL) was added (3-(methylsulfonyl)phenyl)boronic acid (285 mg, 1.43 mmol), pt)Ch (70 mg, 0.095 mmol) and Na2C03(6.0 mL, 2.0 M, aq). The reaction was heated to 90 °C for 2 h, then cooled to RT, concentrat ed in vacuo. The residue was taken up in CH2Ch, washed with bri ne, and extra cted with CH2Ch. The combined organic layers were dri ed over Na2S04. Purification by normal phase silica gel column (EtOAc/heptane) provided (S) tert-butyl 3-ethyl 8-(2-amino((R)-l-(4-chloro-3'-(methylsulfonyl)-[1,11-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro [4.SJ decane-2,3-dicarboxylate as a white sol id.
Step 2: To a solution of (S)tert-butyl 3-ethyl mino((R)(4-chloro-3'­ lsulfonyl)-[1, l enyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decane-2,3-dicarboxylate (500 mg, 0.65 mmol) in DMF ( 10 mL) was added tributyl(prop enyl)stannane (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 13 0 °Cin a sealed tube for 3 h, then cooled to RT. The reaction mixture was partitioned between water and CH2Ch, and extra cted. The ed organic layers were washed with brine, dried over Na2S04, fil tered, and concentra ted in vacuo. Purifi cation by normal phase silica gel column (EtOAc/heptane) provided (S)tert­ butyl 3-ethyl 8-(2-amino((R)-2,2,2-trifl uoro-l-(3'-(methylsulfonyl)(pro p-l-enyl)-[l, 1 '­ biphenyl]yl)ethoxy)pyrimidinyl}2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white 1 5 solid.
Step 3: To a solution of (S)tert-butyl 3-ethyl 8-(2-amino((R)-2,2,2-trifl uoro(3'­ (methylsulfonyl)(pr op-1 -en-I-yl)-] 1,1'-biphenyl]yl)ethoxy)pyrimi dinyl)-2,8- diazaspiro [4.5]decane-2,3-dicarboxylate (200 mg, 0.26 mmol) in EtOH (1 0 mL) was added 10% Pd/C (200 mg) and the reaction mixture was stirred under 1 atm H2 for 12 h. The solids were fi ltered and the fi ltrate was concentrated to affor d (S)tert-butyl 3-ethyl 8-(2-amino((R)- tri fl uoro(31-(methylsulfonyl)propyl-[1, l1-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]dccane-2,3-dicarboxylate as a white solid that is used directly without further purifi cation.
Step 4: To a solution of tert-butyl 3-ethyl 8-(2-amino((R)-2,2,2-trifl uoro(31- (methylsulfonyl)propyl-[1, l '-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro [4.5]decane-2,3-dicarboxy1ate in CH2Ch (4 mL) was added TFA (2.0 mL) dropwise at O °C. The reaction mixturewas stirred at RT for 2 h, then trated in vacuo. The pH was adjusted to 7-8 with saturated aqueous NaHC03 solution. The s layer was extracted with CH2Ch.
The combined organic layers were washed with brine, dri ed over Na2S04, filte red, and concentrated in vacuo. Purification by normal phase silica gel column /MeOH) provided the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4): s ppm 8.41 (m, lH), 8.04 (d, J = 7.8 Hz, lH), 7.79 (t, J = 7.8 Hz, lH), 7.73-7.71 (m, lH), 7.53 (s, lH), 7.33 (d, J = 7.8 Hz, lH), 7.20 (d, J = 7.8 Hz, lH), 6.61 (q, J = 6.7 Hz, lH), 5.61 (s, lH), 4.10 (t, J = 8.4 Hz, lH), 3.72-3.63 (m, 2H), 3.55-3.46 (m, 2H), 3.26 (m, lH), 3.21 (s, 3H), 3.16-3.13 (m, lH), 2.66 (t, J = 7.6 Hz, 2H), 2.38-2.32 (m, lH), 2.10- 2.05 (m, 2H), 1.65-1.60 (m, 3H). LCMS (MH+): 649. e 50: (S)(2-Amiuo((R)-2,2,2-trifluoro(3'-(mcthylsulfonyl)((E)-propenl-yl )-[1,1'-bipheny1)yl)ethoxy)pyrimidiuy1)-2,8-cliazaspiro [4.5)decanecarboxylic acid )-oH oliYQvNH CF3 NyN 's,, ,, NH2 The title nd was prepared as described for (S)tert-butyl 3-ethyl 8-(2-amino((R)- l 5 2,2,2-triflu oro(3'-(methylsulfonyl)(prop-l-enyl)-[1,1 '-biphenyl]yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (Ex ample 49) by omitti ng the olefin hydrogenation on of Step 3. 1H NMR (400 MHz, CD30D-d4): s ppm 8.46-8.42 (m, 11-I), 8.06-8.03 (m, ll-1), 7.82-7.71 (m, 2H), 7.64 (s, IH), 7.45 (dd, J1 = 8.2 Hz, 12 = 33.2 Hz, IH), 7.25 (dd, J1 = 7.9 Hz, J2 = 23.9 Hz, lH), 6.64-6.62 (m, lH), 6.49-6.45 (m, lH), 6.39-5.86 (m, IH), 5.62 (d, J = 5.3 Hz, lH), 4.12- 4.08 (m, lH), 3.70-3.62 (m, 2H), 3.54-3.45 (m, 2H), 3.29-3.26 (m, IH), 3.22-3.21 (m, 3H), 3.1 6- 3.13 (m, lH), 2.37-2.31 (rn, II-I), 2.10-2.05 (m, IH), 1 . 91-1.87 (m, 3H), 1.62 (m, 4H). LCMS (MH+): 647.
Example 51a: (S)(6-((R)-l-([1,1' :4',1 ''-terphenyl]-2'-yl)-2,2,2-trifluorocthoxy) yrimidinyl)-2,8-diazaspiro[4.5)decanecarboxylic acid )-oH O��NH CF3 NyN Step 1: To a on of (Sj-z-tcrt-butyl 3-ethyl 8-(2-amino((R)(2,5-dibromophenyl)-2�2,2- trifluoroethoxy)pyrimidinyl)-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)Ch (70 mg, 0.095 mmol), and (6.0 mL, 2.0 M, aq). The reaction mixture was heated to 90 °C for 2 h, then cooled to RT, concentrated in vacuo, and extracted with CH2Ch. The combined organic layers were washed with brine, and dried over Na2S04. Purification by normal phase silica gel column (E epta ne) provided (S)tert-buty l 3-ethyl 8-(6-((R)([l,1':4',111- terphenyl]-2'-yl)-2,2,2-trifluoroethoxy)aminopyrimidinyl)-2, 8-diazaspiro[4.S]decane-2,3- dicarboxylate as a white solid.
Step 2: To a solution of (S)tert-butyl l 8-(6-((R)([1, I':4', l"-terphenyl]-2'-yl)-2,2,2- 1 S trifluo ro ethoxy)aminopyrimidinyl)-2,8-diazaspiro[4. 5]decane-2,3-dicarboxylate (550 mg, 0.75 mmol) in CH2Ch (4 mL) was added TFA (2.0 mL) dropwise at O °C. The reaction mixture was stirred at RT for 2 h, and trated in vacuo. The pH was adjusted to 7-8 with a saturated aqueous NaHC03 solution. The aqueous layer was extracted with CH2Ch. The organic layer is wahed with brine, dried over Na2S04, fi ltered, and concentrated in vacuo. Purifi cation by normal phase silica gel column (CH2Ch/M eOH) provided (S)-ethyl 8-(6-((R)([l,1':4',1"­ terphenyl]y1)-2,2,2-triflu oroethoxy)aminopyrimidinyl)-2,8-diazaspiro[ 4.S]decane carboxylate as a white solid.
Step 3: Hydrolysis of hyl 8-(6-((R)([l,l ':4', l"-terphenyl]-2'-yl)-2,2,2-trifluo roethoxy) aminopyrimidinyl)-2,8-diazaspiro[4.S]decanecarboxylate using the LiOH general method provided the title compound as a white solid. 1H NMR (400 MHz, CD30D-d4): 6 ppm 7.91 (s, IH), 7.70 (dd, J1= 6.08 Hz, J= 1.88 Hz, lH),7.62 (m,2H), 7.56-7.44 (m,7H),7.39-7.35 (m, 2H), 6.72 (q, J = 6.52 Hz, IH), 5.48(s, lH), 4.18 (q, J = 6.96 Hz, 2H), 3.67 (m, lH), 3.58 (m, 2H),3.4l(m,2H), 2.98 (d, J = 10.96 Hz, lH), 2.69 (d,J = 11.24 I-Iz,lH), 2.12-2.06 (m,IH), 1.83-1.78 (m, lH), 1.52 (m, 4H). LCMS (MH+): 604.5 e Slb: (S)(6-((R)-l-([1,1' :3',11 '-terphcnyl]-2'-yl)-2,2,2-trifluorocthoxy) aminopyrimidinyl)-2,8-diazaspiro[4.5]dccanecarboxylic acid : I :tOH O'('y�N� CF3 NyN NH2 The title nd was prepared as described for (S)(6-((R)([1, l ':4',1 "-terphenyl]-2'-yl)- 2,2,2-trifluoroethoxy)aminopyrirnidinyl)-2,8-diazaspiro[4.S]decanecarboxylic acid (Example 5 1 a) starting with (S)tert-butyl 3-ethyl 8-(2-amino((R)(2,6-dibromophenyl)- 2),2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5] decane-2,3-dicarboxylate (p roduct of Step 4, example 63ao). 1H NMR (400 MHz, CD30D-d4): s ppm 1.32 (dd, J = 15.5, 7.9 Hz, lH), 1.70 (dd, J = 7.9, 4.3 Hz, 51-1), 2.12 (m, IH), 2.49 (ddd, J = 12.3, 9.0, 2.6 Hz, IH) , 3.25 (dd, J = 11.9 , 2.2 Hz, lH), 3.60 (s, 9H), 4.48 (t, J = 8.6 Hz, lH), 6.89 (q, J = 7.8 Hz, IH) , 7.21 (d, J = 7.6 Hz, 21-I), 7.42 (m, 14H).
LCMS (fy! H+): 604. e 52a: (S)(2-Amino((R)(3,4-dimethyl-3' '-(metbylsulfonyl)-[1,1' :3',1 "­ terpheny1)-4'-y1)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro [4.5]dccane carboxylic acid ....__,s,, ,, Step 1: To a solution of (S)benzyl 3-ethyl 8-(2-amino((R)(5-chloro(methylsulfonyl)- [ 1, 1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro [ cane-2,3- dicarboxylate (product of Step 1, Example 34w) (273 mg, 0.34 mmol) in 1,4-dioxane (5 mL) was added (3,4-dimethylphenyl)boronic acid (77 mg, 0.51 mmol), KHC03 (341 mg, 3.40 mmol), and Pd(PCy3)2 (34 mg, 0.051 mmol). The reaction was heated to 100 °C for 44 h. The reaction was charged with additional Pd(PCy3)2 (68 mg, 0.10 mmol) at t = 16 and 39 h. Then the reaction was cooled to RT and extracted with EtOAc. The combined organic layers were dried over Na2S04, fil tered, and concentrated in vacuo. Purifi cation on a 12 g Isco RediSep silica cartridge (EtOA c/h eptane) provided (S)benzyl l 8-(2-amino((R)-l-(3,4-dimethyl (methylsulfonyl)-[ 1,l':31, l11-terphenyl]-4'-yl)-2,2,2-tritlu oroethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decane-2,3-dicarboxylate as an white solid.
Step 2: N-CBZ ection was accomplished via Method B to provide (S)-ethyl 8-(2-amino- 6-((R)(3,4-dimethyl(methylsulfonyl)-[l, 1 ':3', l11-terphenyl]-4'-yl)-2,2,2-triflu oroethoxy) pyrimidinyl)-2,8-diazaspiro[4.S]decanecar boxylate as a white solid.
Step 3: Hydrolysis of (S)-ethyl 8-(2-ami no((R )-l-(3,4-dimethyl(methylsulfonyl)- [ 1 , l1 :31, rphenyl]yl)-2,2,2-triflu oroethoxy) pyrim idinyl)-2,8-diazaspiro[4.S]decane carboxylate using the LiOH genera l method provided the title compound as an off-white solid.
Using the generi c scheme below, the following es of Table 16a were prepared as described above for (2-amino((R)(3,4-dimethyl-3°-(methylsulfonyl)-[1, l ':31,l11- terpheny1]y1)-2,2,2-trifl uoroethox y)pyrimidiny l)-2,8-diazaspiro[4.5]decanecarb oxyIic acid (Example 52a).
STEP2 Table 16a.
I;\\ Ex. Cy CASName LCMS No. (MH+) 52a (2-amino((R)(3,4-dimethyl(methylsulfonyl)- 710 [1, 1':3', 1"-terphenyl]-4'-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 52b 9J (S)(2-amino((R)-2,2,2-trifluoro(3'-(methylsulfonyl)- 733 -(quinolinyl)-[ l, l'-biphenyl]yl)ethoxy)pyrimidin yl)-2,8-diazaspiro[ 4.S]decanecarboxylic acid Table 16b NMR Data for Compounds of Table 16a Ex. NMR 52a 1H NMR (400 MHz, MeOH-d4): S nnm 1.46- 1.73 (m, 4 H) 2.07 (dd, J=13.45, 7.15 Hz, 1 H) 2.28 (s, 3 H) 2.30 (s, 3 H) 2.32 - 2.40 (m, I H) 3.14 (d, J=l 1.76 Hz, I H) 3.22 (s, 3 H) 3.27 (d, J=l 1.76 Hz,1 H) 3.40 - 3.77 (m, 4 H) 4.09 (dd, 1=9.08, 7.27 Hz, 1 H) 5.62 (s, 1 H) 6.63 (q, 1=6.64 Hz, 1 H) 7.18 (d, J=7.96 Hz, l H) 7.35 (dd, 1=7.81, 1.81 Hz, 1 H) 7.40 (s, 1 I-1) 7.47 (d, J=l.85 Hz, 1 H) 7.63 -7.72 (m, l H) 7.72 - 7.77 (m, I H) 7.80 - 7.85 (m, 2 H) 8.07 (dt, 1=6.97, 1.96 Hz, 1 H) 8.48 (br. s., 1 H) 52b 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.59 (t, 1=5.54 Hz, 4 H) 1.92 (dd, J=13.13, 7.03 Hz, 1 H) 2.20 (dd, 5, 9.10 Hz, 1 H) 2.81 - 3.17 (m, 2 H) 3.24 (s, 3 I-I) 3.38- 3.74 (m, 4 H) 3.84 (dd, J=8.96, 7.05 Hz, 1 H) 5.64 (s, I H) 6.67 (q, 1=6.64 Hz, I H) 7.55 (dd, J=8.35, 4.34 Hz, l H) 7.67 (d, J=l.61 Hz, I H) 7.78 - 7.92 (m, 4 H) 8.04 - 8.15 (m, 3 H) 8.21 (s, l H) 8.41 (dd, 1=8.40, 1.56 Hz, 1 H) 8.54 (br. s., l H) 8.84 (dd, J=4.32, 1.68 Hz, 1 H) Example 53: (S)(2-Amino((R)-2,2,2-trifluoro-l-(3'-(methylsulfonyl)((E)-propen- 1-y1)-[1,1 '-bip h enyl]yl)ethoxy)pyrim idinyl)-2,8-diazaspiro [4. 5) decanecarboxylie acid It\\ 0 0 Step 1: To a solution of (S)tert-butyl 3-ethyl 8-(2-amino((R)(2-bromochlo rophenyl)- 2,2,2-tri:flu oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (600 mg, 0.89 mmol) in dioxane (12 mL) was added (3-(methylsulfonyl)phenyl)boronic acid (275 mg, 1.3 mmol), Pd2(dppf)Ch (65 mg, 0.095 mmol), and Na2C03 (6.0 mL, 2.0 M, aq). The reaction was heated to 90 °C for 2 h, then cooled to RT, and concentrat ed in vacuo. The residue was taken up in CH2Ch, wahed with brine , and dried over Na2S04. cati on by normal phase silica gel column /heptane) provides (S)tert-butyl 3-ethyl 8-(2-amino((R)(5-chloro- 3 '­ (methylsulfonyl)-[1, 1 '-biphenyl]yl)-2,2,2-tri:fluoro ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Step 2: To a solution (S)tert-butyl 3-ethyl mino((R )(5-chloro(methylsulfonyl)­ [l ,l -biphenylj-z-y1)-2,2,2-trifl uoro )pyrimidinyl)-2,8-diazaspiro[4.S]decane-2,3- dicarboxylate (500 mg, 0.65 mmol) in DMF (10 mL) was added tributyl(pro penyl)stannane (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 °Cina sealed tube for 3 h, then cooled to RT, and partitioned between between water and CH2Ch. The combined organic layers were washed with brine, dried over Na2SO,i, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)tert-butyl 3-ethyl 8-(2-amino((R)-2,2,2-trifluoro- 1-(3'­ (methylsulfonyl)((E)-prop-1 ylj-jl, 1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5Jdecane-2,3-dicarboxyl ate as a white solid.
Step 3: To a solution of (S)tert-butyl 3-ethyl 8-(2-amino((R)-2,2,2-trifl uoro- 1-(3'- (methylsulfonyl)((E)-propenyl)-[l,1 '-biphenyl]yl)ethoxy)pyrimidinA-yl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate in CH2Ch (4 mL) was added TFA (2.0 mL) dropwise at 0 °C. The reaction mixture was stirred at RT for 2 h, then concentrated in vacuo. The pH was adjusted to 7-8 with a ted aqueous NaHC03 solution. The aqueous layer was extra cted with CH2Ch, washed with brine, dried over Na2S04, filte red, and concentrated in vacuo. Purification by normal phase silica gel column (CH2Ch/M eOH) ed (S)-ethyl mino((R)-2,2,2- trifl uoro- (methylsulfonyl)((E)-prop- l-en-l-ylj-jl ,l '-biphenyl]yl)ethoxy)pyrimidin yl)-2,8-diazaspiro[4.5Jdecanecarboxylate as a white solid.
Step 4: Hydrolysis of (S)(2-amino((R)-2,2,2-trifl uoro (3'-(methylsulfonyl)((E)-prop enyl)-[1, 1 '-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diaza spiro[4.S]decanecarboxylic acid using the LiOH general method ed the title compound as an off-white solid. 1H NMR (400 MHz, CD30D-d4): s 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, l H), 4.09 (m, 1 H), 3.55 (m, 2 I-I), 3.48 (m, 2 H), 3.21 (m, 4H), 3 . 1 0 (m, 1 H), 2.59 (m, 2 H), 2.29 (m, 1 H),l.95 (m, 1 H), 1 .86 (m, 3 I-I), 1.30 (m, 4 H). LCMS (MH+): 646.
Example 54a: (S)(2-Amino((R)-2,2,2-trifluoro(3'-(methylsulfonyl)propyl-[1,1'­ biphcnylJyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]dccanecarboxylic acid It\\ Step 1: To a solution of (S)tert-butyl 3-ethyl 8-(2-amino((R)-2,2,2-trifluoro-l-(3'­ (methylsulfonyl)((E)-prop-l-enyl)-[1)'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate (product from Step 2, Example 53) (200 mg, 0.26 mmol) in EtOH (10 mL) is added l0% Pd/C (200 mg), and the reaction e was stirred under l atm H2 for 12 h. The solids were filtered and the filtrate was concentrated in vacuo to provide (S)tert-butyl 3-ethyl 8-(2-amino((R)-2,2,2-trifl uoro(3'-(methylsulfonyl) propy1-[1 ,l1-bipheny1]yl)ethoxy)pyri 4-y1)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solidthat is used directly without further purifi cation.
Step 2: To a solution of (S)te11-butyl 3-ethyl 8-(2-amino((R)-2,2,2-trifluoro (3'­ (methylsulfonyl)propyl-[1, l 1-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[ 4.5] decane-2,3-dicarboxylate in CH2Ch (4 mL) was added TFA (2.0 mL) dropw ise at O °C. The reaction mixture was stirred at RT for 2 h, then concentrat ed in vacuo. The pH was adjusted to 7-8 with saturated aqueous NaHC03 on. The s layer was extracted with CH2Ch, washed with brine, dried over Na2S04, fi ltered, and concentrated in vacuo. Purific ation by normal phase silica gel column (CH2Ch/MeOH) provided (S)-ethyl 8-(2-amino((R)-2,2,2- trifl uoro (31-(methylsulfonyl)-S-pro pyl-[ 1, l'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- piro]4.5]decanecarboxylate as a white solid.
Step 3: Hydrolysis of (S)-ethyl 8-(2-amino((R)-2,2,2-trifl uoro(3 hylsulfonyl) propyl-[1, l '-biphenyl]yl)ethoxy)pyri midiny1)-2,8-diazaspiro[4.5]decanecarboxylate using the LiOH general method provides the title compound as an ite solid. 1H NMR (400 MH z, CD30D-d4): s 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, l H), 5.56 (s, 1 H), 4.00 (rn, 1 H), 3.55 (m, 2 H), 3.48 (m, 2 H), 3.31 (m, 4H), 3.30 (m, I 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)(2-amino((R)-2,2,2-trifluoro(4-isopropoxy-[1,1':3',1"-tcrphenyl]- 4'-yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.S]decanecarboxylic acid )-oH Orr�NH CF3 NyN I NH2 Step I: To a on of (S)-ethyl 8-(2-amino((R)(5-bromo-(1,1 '-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate (350 mg, 0.56 mmol) in CH2Ch (20 mL) was added Boc20 (436 mg, 2.0 mmol) and Et3N (306 mg, 3.03 mmol) at O °C.
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 afford tert-butyl 3-ethyl 8-(2-amino ((R)- l-(5-bromo-[1, heny1]yl)-2,2,2-triflu oro ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate as a yellow solid.
Step 2: A solution of tert-butyl 3-ethyl 8-(2-amino((R)(5-bromo-[1, l '-biphenyl] yl)-2,2,2-triflu oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (150 mg, 0.2 mmol), ropoxyphenyl boronic acid (44 mg, 0.25 mmol) and Pd(dppf) Ch (15 mg, 0.02 mmol) in dioxane (3.0 mL) I aque ous Na2C03 solution (3.0 mL, 2.0 M, aq.) was stirred at 90 °C for 2 h. The aqueous layer was extracted with CH2Cb, washed with brine, dri ed over Na2S04, fi ltered, and concentrated in vacuo. Puri fica tion by normal phase silica gel column (EtOAc/ Hex = 10 to 50 % )to (S)tert-butyl 3-ethyl 8-(2-amino((R )-2,2,2-trifluor o-1 w(4-isopropoxy- [l,1':3', l"-terphenyl]-4'-yl)ethoxy)pyrimidin-4wyl)-2,8-di azaspiro[4.S]decane-2,3-dicarboxylate as a white solid.
Step 3: To a solution of (S)tert-butyl 3-ethyl 8-(2-amino((R)-2,2,2-tritl uoro(4w isopropoxy-] 1,1':3', 1"-terphenyl]-4'-yl)ethoxy)pyrim idinyl)-2,8-diazaspiro[4.S]decane-2,3- dicarboxylate , 0.164 mmol) in CH2Ch (4 mL) was added TFA (1 mL), and the reaction mixture was stirred at 25 °C for 12 h. The mixture was concentrated, and neutralized to pH 7-8 with saturated aqueous NaHCOJ. The aqueous layer was extracted with CH2Ch, washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to provide (S)-ethyl 8-{2-amino ((R)-2,2,2-trifluoro- 1-(4-isopropoxy-[1, l"-terphenyl]-4'-yl)ethoxy)pyrimidinyl)-2,8- diazaspiro]4.5]decanecarboxylate as a light yellow solid that is used without fu rther purification .
Step 4: Hydrolysis of (S)-ethyl 8-(2-amino((R)-2,2,2-trifl uoro- 1-(4-isopropoxy-[1, 1':3',I"- I O terphenyl]-4'-yl)ethoxy)pyri midinyl)-2,8-diazaspiro[4.5Jdecanecarboxylate using the LiOH general method provided the title compound as an off-white solid. 1H NMR (400 MHz, 4): o ppm 1.31 (d, J = 6.0 Hz, 6H), 1.58 (m, 4H), 2.04 (dd, J = 13.4, 7.2 Hz, lH), 2.32 (dd, J = 13.4, 9.2 Hz, lH), 3.11 (d, J = 11. 7Hz, lH), 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, IH), 4.62 (p, J = 6.1 Hz, lH), 6.67 (q, J = 6.8 Hz, lH), 6.95 (m, 2H), 7.54 (m, 9H), 7.72 (d, J= 8.3 Hz, lH). LCMS (MH+): 663.
Example 54c: (S)(2-amino((R) -2,2,2-trifluoro-l-(4-propoxy-[1,1' :3',1"-terphcnyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro [4.5)dccane-S-carboxylic acid The title compound was prepared as described above for (S)(2-amino((R)-2,2,2-trifl uoro (4-isopropoxy-[1, l1:31,1"-terphenyl]-4'-yl)ethoxy)pyrim -yl)-2,8-diazaspiro[4.5]decane carboxylic acid (Example 54b) by tuting 4-pro poxyphenyl boronic acid for 4- isopropoxyphenyl boronic acid in Step 2. 1H NMR (400 MHz, MeOH-d4): o 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, HI), 3.02 (d, J = 11.6 Hz, 1H), 3.18 (d, J = 11.5 Hz, lH), 3.30 (d, J = 3.2 Hz, lH), 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, lH), 5.47 (s, lH), 6.66 (q, J = 6.9 Hz, lH), 6.97 (d, J = 8.3 Hz, 2H), 7.54 (m, 9H), 7.72 (m, lH). LCMS (MH+): 662.
Example 54d: (S)(2-amino((R)-2,2,2-trifluo1·0-l-(S-(methylsulfonyl)-[1,1'-biphenyl] yl)ethoxy)pyrhnidinyl)-2,8-diazaspiro [4.5]clecanecarboxylic acid 0 0 )-oH ,..,.s'"' oyy�NH CF3 NyN I NH2 Step 1: To a mixture of 2-chloro(methylsulfonyl)benzoic acid (5 g, 21.3 mmol) in anhydrous ol (100 mL) was added concentrated sulfuric acid (0.5 mL). The resulting solution was stirred for 18 hat . Upon cooling, the mixtu re was concentrated under reduced pressure, dissolved in CH2Ch and washed with NaHCOJ solution and brine. The organic phase was dried over sodium sulfate and concentrated to afford methyl 2-chloro(methyJsulfonyl)benz oate as a white solid.
Step 2: To a mixture ofmethyl ro(methylsulfonyl)benzoate (2.2 g, 8.9 mmol), PhB (OH)2 ( 1 .31 g, 10.8 mmol), DME (12 mL), and 2M Na2C03 (6 mL) was added Pd(PPh3)4 (515 mg). The mixture was heated for 20 min at 160 °Cinamicrowave reactor, and then extracted with EtOAc, dried over sodium sulfate and concentrated in vacuo. Purifi cation on normal phase silica gel (hexane/EtOAc) provided methyl 5-(methylsulfonyl)-[1,1 '-biphenyl] ylate as a white solid.
Step 3: To a solution of CaCh (1.52 g, 13.78 mmol) in EtOH (SO mL) at RT was added methyl 5- (methylsulfonyl)-(1, 1 '-biphenyl]carboxylate (2 g, 6.9 mmol) in THF (50 mL) followed by the addition ofNaBH4 (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% HCI, and brine. Purification on normal phase silica gel ed (5-(methylsulfonyl)-[1,1 '-biphenyl]yl)methanol as a white solid.
Step 4: To a solution of (5-(methylsulfonyl)-[1,1'-biphenyl]yl)methanol (1 g, 3.8 mmol) in CH2Ch (50 mL) was added artin inane (2.4 g, 5.7lrnrnol). The reaction was stirred for 2 hat RT, then concentrated in vacuo and ed directly on normal phase silica gel to provide hylsulfonyl)-[1) '-biphenyl]carbaldehyde as a white solid.
Step 5: To a solution of 5-(rneth ylsulfonyl)-[1,l'-biphenyl]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 O °C to and TBAF (0.57 ml., 0.57 mrnol) was added dropwise. The reaction mixture was stirr ed for 2 h, then 3 N 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 e, washed with brine, dried over Na2S04, ed, and concentrated in vacuo. Purifi cation on normal phase silica gel provided 2,2,2- triflu oro(5-(methylsulfonyl)-[1, 1 '-biphenyl]yl)ethanol as a white solid.
Step 6: To a mixture of triflu oro(5-(methylsulfonyl)-[l, 1 '-biphenyl]yl)ethanol (720 mg, 2.2 mmol)) in CH2Ch (50 mL) was added Dess-Martin periodinane (1.1 g, 2.6mmol). The reaction was stirr ed for 2 hat RT, then concentra ted in vacuo and purified directly on normal phase silica gel to provide 2,2,2-triflu oro(5-(methylsulfonyl)-[1,1 '-biphenyl]yl)ethanone as a white solid.
Step 7: Chiral reduction of 2,2,2-trifl uoro (5-(methylsulfonyl)-[1,1 '-biphenyl]yl)ethanone using the Iridium complex-catalyzed hydrogenation as described for Intermediate 1 , (R)(4- bromo(3-methyl-l H-pyrazolyl)phenyl)-2,2,2-triflu oro ethanol, prov ided (R)-2,2,2-triflu oro- 1-(5-(methylsulfonyl)-[ 1,1'-biphenyl]yl)ethanol as a white solid.
Steps 8-11: The title compound was prepared as described for (S)(2-amino((R)(4- chloro (3-methyl-IH-pyrazolyl)phenyl)-2,2,2-triflu oroethoxy)pyrimidiny1)-2,8- diazaspiro[4.5]decanecarboxy1ic acid (Examp1e lOd), Steps 1-4. 1HNMR (400 MHz, MeOH-d4): s ppm 1.63 (q, J = 5.7, 4.9 Hz, 4H), 2.10 (m, lH), 2.36 (dd, J = 13.5, 9.2 Hz, 1 H), 3.23 (d, J = 3 l.O Hz, 5Hl 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, lH), 6.78 (q, J = 6.7 Hz, lH), 7.57 (m, 5H), 7.86 (d, J = 1.9 Hz, lH), 8.01 (m, 2H), 8.17 (s, 11-I). LCMS (MH+): 607.
Example 54e: (S)(2-amino((R)-2,2,2-trifluoro-l-(3-fluoropropoxy-[1,1' :31,l11- terphenyl]-4'-yl)ethoxy)pyrimiclinyl)-2,8-diazaspiro[4.S]decanecarboxylic acid /'---../0 )-oH O'l('y�NH CF3 NyN NH2 The title compound was prepared as described above for (S)(2-amino((R)- 2,2,2-trifluoro- 1- (4-isopro poxy-[1, l1:31, rphenyl]-4'-yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid (Example 54b) by replacing the 4-isopropoxyphenyl boronic acid in Step 2 with (3-flu oro- 4-pro poxyphenyl)boronic acid (CAS# -68"4). 1I·I NMR (400 MHz, MeOH-d4): o ppm 0.86 (m, lH), 1.05 (t, J = 7.4 Hz, 3H), 1.26 (s, lH), 1.59 (s, 4H), 1.83 (h, J = 7.1 Hz, 2H), 2.06 (dd, J = 13.4, 7.2 Hz, lH), 2.33 (m, lH), 3 . 10 (d, J = 11.9 Hz, lH), 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, IH), 6.62 (d, J = 6.8 Hz, lH), 7.09 (t, J = 8.7 Hz, lH), 7.34 (s, IH), 7.43 (m, 4H), 7.50 (s, 3H), 7.60 (m, lH), 7.76 (m, 2H). LCMS (MH+): 681.
Example 54f: (S)(2-amino((R)(3,4-dimethyl-[1,1' :3 ',111-terphenyl]-4'-yl)-2,2,2- trlfl hoxy)py rimidin-d-yl)-2,8-diazaspiro [4.5)decanecarboxylie acid � I >:OH "'-- OY"Y�Nt ,::;,- CF3 NyN � I NH2 The title compound was prepared as described above for (2-amino((R)-2,2,2-trifluoro-l­ (4-isopropoxy-[ 1, l 1:31, l11-terphenyl]-4'-yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid (Example 54b) by ing the 4-isopropoxyphenyl boronic acid in Step 2 with 3,4-dimethylphenyl boronic acid. 1H NMR (400 MHz, MeOH-d4): o ppm 1.62 (s, 4H), 2.06 (dd, J = 13.5, 7.6 Hz, lH), 2.29 (d, J = 9.7 Hz, SH), 2.37 (m, l H), 3.17 (d, J = 1 1 . 8 Hz, lH), 3.26 (d, J = 1 1 .7 Hz, lH), 3.63 (d, J = 14.2 Hz, 2H), 4.27 (t, J = 8.3 Hz, lH), 6.66 (q, J = 6.8 Hz, IH), 7 .18 (d, J = 7.9 Hz, lH), 7.36 (m, 2H), 7.49 (m, SH), 7.64 (dd, J = 8.2, 2.0 Hz, lH), 7.74 (d, J = 8.2 Hz, lH). LCMS (MH+): 633.
Example 54g: (S)(6-((R)([1,1' :3',1 ''-terp11enyl]-4'-y1)-2,2,2-trifluorocthoxy)- 2- aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid >:OH OY"Y�Nt CF3 NyN The title compound was prepared as described above for (2-amino((R)-2,2,2-triflu oro (4-isopropoxy-[l, l 1:31,l11-terphenyl]A'-yl)ethoxy)pyri midinyl)-2,8-diazaspiro[4.S)decane carboxylic acid (E xample 54b) by substituting phenyl boronic acid for 4-isopro poxyphenyl boronic acid in Step 2. 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.62 (s, 4H), 2.06 (dd, J = 13.5, 7.7 Hz, lH), 2.38 (dd, J = 13.5, 9.1 Hz, lH), 3.16 (d, J = 11 .8 Hz, lH), 3.26 (d, J = 1 1 . 8 Hz, lH), 3.47 (s, 2H), 3.62 (s, 2H), 4.26 (t, J = 8.4 Hz, lH), 6.68 (q, J = 6.9 Hz, lH), 7.35 (m, lH), 7.47 (m, 4H), 7.53 (s, 3H), 7.66 (m, 3H), 7.77 (d, J = 8.2 Hz, lH). LCMS (MH+): 604.
Example 54h: (R)(2-amino((R)-l-(5-chloro-[1,1 '-biphenylJyl)-2,2,2- trifluorocthoxy)pyrimidiny1)-2,8-diazaspiro [4.5] decanccarboxylic acid oyy����NH CF3 NYN The title compound was prepared as described above for (S)(2-amino((R)(5-chloro- [I, l1-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.S]decane carboxylic acid (Example 34c) by using (R)benzyl l 8-(2-amino((R)(2-brom o chloropheny1)-2,2,2-trifluoro ethoxy)pyrimidinyl)-2,8-diazaspiro [4.5]decane-2,3- oxylate. 1H NMR (400 MHz, MeOH-d4): o ppm 1.59 (d, J = 5.5 Hz, 4H), 2.03 (dd, J = 13.4, 7.1 Hz, IH), 2.31 (dd, J = 13.4, 9.2 Hz, IH), 3.09 (d, J = 1 I .8 Hz, IH), 3.23 (d, J = 11 .6 Hz, lH), 3.46 (dt, J = 15.3, 8.2 Hz, 21-l), 3.62 (s, 2H), 4.06 (dd, J = 9.1, 7.1 Hz, IH), 5.49 (s, lH), 6.64 (q, J = 6.9 Hz, l H), 7.28 (d, J = 2.2 Hz, lH), 7.46 (m, SH), 7.53 (s, lH), 7.67 (d, J = 8.5 Hz, lH). LCMS (MH+): 562.
Example 54i: (R)(2-amino((S)-l-(5-chloro-[l ,1 '-biphenyl]yl)-2,2,2- trifl uorocthoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid �OYY�NH CF3 NlN The title compound was prepared as b ed above for (S)(2-amino((R)(4-chloro(3- methyl-I H-pyrazol-l-yl)phenyl)-2,2,2-tri:fluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5Jdecanecarboxylic acid (Example 34c) by using (R)benzyl 3-ethyl 8-(2- amino((S)(2-bromochlorophenyl)-2,2,2-trifluoroethoxy)pyrimidiny 1)-2,8- diazaspiro]4. 5]decane-2,3-dicarboxylate. 1H NMR (400 MHz, MeOH-d4): o ppm 7.70 (d, J = 8.5 Hz, lH), 7.59- 7.44 (m, 4H), 7.47- 7.40 (m, 2H), 7.32 (d, J = 2.2 Hz, l H), 6.61 (q, J = 6.5 Hz, lH), 4.51 (t, J = 8.7 Hz, 1H), 3.72 - 3.59 (m, lH), 3.56 (s, lH), 3.28 (s, 1H), 2.49 (dd, J = 13.6, 8.9 Hz , IH), 2.10 (dd, J = 13.6, 8.4 Hz, lH), 1.71 (dt, J = 16.0, 6.6 Hz, 4H), 1.28 (s, OH).LCMS (MH+): 562. e 54j: (S)(2-amino((S)(5-chloro-[l,l '-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5] carboxylic acid Cl y I >,OH "'-- =. O'j("y�Nf ,;:;-- CF3 NyN � I NH2 The title compound was prepared as described above for (S)(2-amino((R)(4-chloro(3- 1 5 methyl-IH-pyra zolyl)phenyl)-2,2,2-triflu oroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid (Example 34c) by using (S)benzyl 3-ethyl 8-(2- amino((S)-l-(2-bromochlorophenyl)-2,2,2-triflu oro ethoxy)pyrimidinyl)-2,8- diazaspiro[ cane-2,3-dicarboxylate. 1 H NMR (400 MHz, MeOH-d4): o ppm 7.70 (d, J = 8.5 Hz, lH), 7.61 - 7.42 (m, 6H), 7.32 (d, J = 2.3Hz, lH), 6.66 (q, J = 6.7 Hz, 1H), 4.25 (dd, J = 9.0, 7.6 Hz, IH), 3.72-3.60 (m, IH), 3.29 (d, J = 11. 7 Hz, lH), 3 .18 (d, J = 1 1 . 8 Hz, lH), 2.40 (dd, J = 13.5, 9.2 Hz, IH), 2.09 (dd, J = 13.5, 7.6 Hz, IH), 1.64 (s, 2H).LCMS (MH+): 562.
Example 54k: (S)(2-amino((S)(3',4 '-clhnethyl(3-methyl-lH-pyrazol-l-yl)-[1,1 '­ biphenyI]y1)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro [4.5] carboxylie acid The title compound was prepared as described above for (S)(2-amino((R)(3',4'­ dimethyl(3-methyl-1 Hvpyrazol-l-ylj-]1,l'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro [4.5]decanecarboxylic add (Example lm) by using (S)benzyl l 8- (2-amino((S)(4-chloro(3-methyl-lH-pyrazolyl)phenyl)-2,2,2- trifluoro ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate. 1H NMR (400 MHz, MeOI-I-d4): o ppm 1.58 (s, 6H), 2.04 (dd, J = 13.4, 7.2 Hz, lH), 2.30 (d, J = 1 1.1 Hz, 9H), 2.40 (s, 3H), 3 .10 (d, J = 1 1 .8 Hz, lI-- I), 3.23 (d, J = 11.7 Hz, IH), 3.48 (s, 2H), 3.66 (d, J = 15.7 Hz, 3H), 4.08 (t, J = 8.2 Hz, HI), 6.41 (d, J = 2.4 Hz, lH), 6.77 (q, J = 6.5 Hz, lH), 7.20 (d, J = 7.8 Hz, lH), 7.38 (d, J = 8.0 Hz, 11-I), 7.44 (d, J = 2.0 Hz, llI), 7.60 (d, J = 1.8 Hz, lH), 7.73 (m, 2H), 7.97 (d, J = 2.4 Hz, IH). LCMS (MH+): 635. e 541: (R)(2-amino((S)(3' ,4 '-climethyl(3-mcthyl-lH-pyrazolyl)-[1,11- biphenyl]yl)-2,2,2-trifluor oetboxy)pyrimicli nyl)-2,8-diazaspiro [4.5]decane carboxyllc acid The title compound was prepared as describe d above for (R)(2-amino((R )-l-(3',41- dimethyl(3-methyl-1 zolyl)-[1, 1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro [4.S]decanecarboxylic acid (Example Im) by using (R)benzyl 3-ethyl 8- (2-amino((S)(4-chloro(3-methy1-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidiny 1)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate. 1H NMR (400 MHz, MeOH-d4): 3 ppm 7.97 (d, J = 2.3 Hz, OH), 7.79- 7.69 (m, OH), 7.61 (d, J = 1.6 Hz, OH), 7.45 (s, OH), 7.42- 7.35 (m, OH), 7.21 (d, J = 7.9 Hz, OH), 6.77 (q, J = 6.5 Hz, OH), 6.41 (d, J = 2.3 Hz, OH), 4.10 (t, J = 8.2 Hz, OH), 3.68 (dd, J = 13.9, 6.3 Hz, OH), 3.58 - 3.43 (m, OH), 3.24 (d, J = 1 1 . 7 Hz, OH), 3 . 1 1 (d, J = 1 1 . 8 Hz, OH), 2.42 - 2.27 (m, lH), 2.05 (dd, J= 13.5, 7.2 Hz, OH), 1.59 (d, J = 11 .4 Hz, OH), 1.59 (s, OH) .. LCMS (MH+): 635.
Example 54m: (R)(2-amino((R)(3' ,4'-climethyl(3-methyl-1H-pyrazolyl)-[1,1'­ biphenyl]yl)-2,2,2-trifluorocthoxy)pyrimiclinyl)-2,8-cliazaspiro[4.5]clecane carboxylic acid The title nd was prepared as described above for (R)benzyl l 8-(2-amino -(4-ch1oro(3-methyl-l I-I -pyrazol- l-yl)phenyl)-2,2,2-trifl uoroethoxy)pyrimidinyl)- 2,8-diazaspil'o [4.S]decane-2)-dicarboxylate (Example Im) by using (R)- 2-benzyl 3-ethyl 8-(2- amino((R)-l-(4-chloro(3-methyl-1 H-pyrazolyl)pheny1)-2,2,2-trifl uoroethoxy)pyri midin- 4-yl)-2,8-diazaspiro[ 4.5]decane-2,3-dicarboxylate. 1H NMR (400 MHz, MeOH-d4): 3 ppm 7.97 (d, J = 2.4 Hz, lH), 7.79 -7.68 (m, 2H), 7.60 (d, J = 1.7 Hz, HI), 7.44 (s, 1 H), 7.38 (d, J = 8.0 I-Iz, IH), 7.20 (d, J = 7.8 Hz, lH), 6.76 (q, J = 6.7 Hz, lH), 6.41 (d, J = 2.3 Hz, 1 H), 5.75 (s, 1 H), 3.98 (t, J = 8.1 Hz, lH), 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, IH), 3.01 (d, J = 11.6 Hz, IH), 2.39 (s, 3H), 2.34 - 2 .18 (m, 8H), 1.99 (dd, J = 13.4, 7 .1 Hz, lH), 1.56 (s, SH). LCMS (MH+): 635.
Example SSan: (S)(2-amino((R)-2,2,2-trifluoro(3'-mcthoxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro [4.5] decanecarboxylic acid )-oH O'(Y�NH CF3 NyN NH2 Step 1: To a solution of (R)-l-(4-bromophenyl)-2,2,2-trifluoroethanol (150 mg, 0.60 mmol) in dioxane (10 mL) was added 4,6-dichloropyrimidinamine (120 mg g, 0.71 mmol) and Cs2C03 (290 mg, 0.88 mmol), and the reaction mixture was heated to 80 °C for 30 h. Then the reaction was cooled to RT. EtOAc was added and the organic layer was washed with brine, dried over Na2S04, fil tered, and concentrat ed in vacuo. Purifica tion by normal phase silica gel column (EtOAc/heptane) prov ided (R )(1-(4-bro yl)-2,2,2-trifl uoroethoxy)chloropy rimidin- e as a colorl ess oil.
Step 2: To a solution of (R)(1-(4-bromophenyl)-2,2,2-trifl hoxy)chloro din amine (19 mg, 0.50 mmol) in dioxane (25 ml) was added (S)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 mixtu re was heated to 100 °C for 48 h. Then the reaction mixture was cooled to RT, and extrac ted with EtOAc. The combined organic layers were washed with brine, dried over , fi ltered, and concentrated in vacuo. Purific ation by normal phase silica gel column (EtOAc/h eptane) provided (S)benzyl 3-ethyl 8-(2-amino((R)(4- bromophenyl)-2,2,2-trifl uoroethoxy)-pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3- dicarboxylate as white solid.
Step 3: To a solution of (S)benzyl 3-ethyl 8-(2-amino((R)-l-(4-bromophenyl)-2,2,2- trifl uoroethoxy)-pyrimidinyl)-2,8-diazaspiro[4.S]decane-2,3-dicarboxylate (190 mg, 0.27 mmol) was added NaOH (100 mg, 0.26 mmol) in 15 mL THF/E tOH/H2 0 (2/1/2.5), and the reaction was d for 12 hat RT. Then, the reaction mixture was concentrated in vacuo to remove most of the organic solvents, and the pH was adjusted to 6 with l N HCl. EtOAc was added, and the organic layer was washed with brine, dried over Na2S04, ed, and concentrated In vacuo to provide (S)(2-amino((R)(4-bromophenyl)-2,2,2- trifluoroethoxy) dinyl)(benzyloxycarbonyl)-2,8-diazaspiro[4.5]decanecarboxylic acid as a white solid which was used without further purification.
Step 4: To a solution of (S)(2-amino((R)(4-bromophenyl)-2,2,2-trifl uoroethoxy) dinyl)((benzyloxy)carbonyl)-2,8-diazaspiro[4.5] decanecarboxylic acid (80 mg, 0.12mmol) in e (1 mL)/Na2C03(l.O mL, 2 M, aq) were added (3-methoxyphenyl)boronic acid (22 mg, 0.14 mmol) and Pd(dppf)2 (8 mg, 0.01 mmol). The reaction fl ask was ed and refil led with argon via balloon 3 times, and the reaction mixture was refl uxed for 4 h. Then the reaction was cooled to RT, concentrated in vacuo, and extracted with EtOAc. The combined c layers were are washed with brine, dried over Na2S04, fi ltered, and concentrated in vacuo. Purifi cation by reverse phase silica gel column (H20/NH40H/MeOH) provided (S)(2- amino((S)-2,2,2-trifl uoro- l-(3'-methoxy-[1, 1'-biphenyl]yl)ethoxy)pyrimidinyl) ((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decanecarboxylic acid as a white solid.
Step 5: N-CBZ Deprotection was accomplished via Method A to provide the title compound as an off-white solid isolated as the zwitterionic form.
Using the generic scheme below, the following examples of Table 17a were prepared as bed above for (S)(2-amino((R)-2, 2,2-trifl uoro(3'-methoxy-[I, 1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid (Example 55an)using the appro pri ate boronic acid or boro nate In some cases, the Cy coupling reaction was performed prior to ethyl ester and N-CBz removal (see altern ative Steps 3a and 4a) as noted in the scheme.
In the cases of example 5 Sal and 55am, racemic 1-(4-bromophenyl)-2,2,2-trifl uoroethanol was used as opposed to (R)(4-bromophenyl)-2,2,2-trifl uoroethanol for all other examples.
STEP2 STEP,1 i Table 17a.
Ex. Cy CASName LCMS (MH+) 55a c. (S)(6-((R)-l-([1, 1'-biphenyl]yl)-2,2,2- 529 trifluoroethoxy)aminopyrimidinyl)-2,8- diazaspiro]4.5]decanecarboxylic acid 55b (S)(2-amino((R)-2,2,2-trifluoro(4-(1- 583 __.N I � methyl-I zol .,,,; yl)phenyl)ethoxy)pyrimidinyl)-2,8- � diazaspiro[4.5ldecanecarboxylic acid 55c r=N (S)(2-amino((R)-2,2,2-trifluoro(4-(1"� methyl-lH-benzo[d]imidazol yl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5ldecanecarboxylic acid 55d (S)(6-((R)(4-(l H-benzo[d]imidazol 569 yIjphenyl)-2,2,2-triflu oroethoxy) II�I � h' aminopyrimidinyl)-2,8-diazaspiro [4.5]decane- oxylic acid 55e F (S)(2-amin R)-2,2,2-triflu oro(3 '- 577 fl uoro-4'-methoxy-[l,1 '-biphenyl] /0�l b yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid 55f (S)(2-amino((R)(4-(benzo[djisothiazol- 586 N�'s � 6-yl)phenyl)-2,2,2-triflu oro ethoxy)pyrimidin yl)-2,8-diazaspirof4.51decanecarboxylic acid 55g (S)(2-amino((R)(4-(benzo[d]isoxazol 570 N�0 � yl)phenyl)-2,2,2-tdflu oroethoxy)pyrimidinA-yl)- 2,8-diazaspiro[4.5]decanecarboxylic acid 55h (S)(6-((R )- l-(4-(1H-indazolyl)phenyl)- 569 N� triflu oxy)amin opyri midinyl)- H 2,8-diazaspiro[4.5ldecanecarboxylic acid 55i (2-amino((R)-2,2,2-triflu oro(4-(1- 583 N�N b methyl-lH-indazol I yl)phenyl)ethoxy)pydmidiny1)-2, 8- ·� diazaspiro [4.5]decanecarboxy Iic acid 55j (S)(2-amino((R)(4-(benzo[djisothiazol- 586 -yl)phenyl)-2,2,2-tri fl uoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 55k f� (S)(2-amino((R)(4-(benzo[d]thiazol 586 s � yl)phenyl)-2,2,2-triflu oro ethoxy)pyrimidinyl)- 2,8-diaza spiro[4.5]decanecarboxylic acid 551 f=N (S)( 6-((R)(4-([1,2,4]triazolo [1,5-a[pyridin- 570 6-yl)phenyl)-2,2,2-trifl uoro ethoxy) N�� I aminopyri midinyl)-2,8-diazaspiro [4.5]decane- 3-carboxylic acid 55m (S)(2-amino((R)-2,2,2-trifluoro(4- 579 (naphthalenyl)phenyl)ethoxy)pyrimidiny1)- �I 2,8-diazaspiro[4.5Jdecanecarboxylic acid 55n -o,0/ (S)(2-amino((R)-2,2,2-trifluoro(3'- 573 methoxy-4'-methyl-[1, 1'-biphenyl) yl)ethoxy)pyrimidinA-yl)-2,8- diazaspirof4.5ldecanecarboxylic acid 550 A0/ (S)(2-amino((R)-2,2,2-trifluoro(3'- 573 methoxy-5'-methyl-[l, 1 '-biphenyl] yl)ethoxy)pyrimidinyl)-2,8- diazaspiro]4.5]decanecarboxylic acid 55p o,0/ (2-arnin o((R)-2,2,2-trifl uoro(5'- 573 methoxy-2'-methyl-[ l,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8- diaza spiro [4.5] decanecarboxylie acid 55q 0/ (S)(2-amino((R)(3',4'-dimethoxy-[1 , 1'- 589 biphenyl]yl)-2,2,2-tri fluoroe thoxy)pyrimidin- /0� 4-yl)-2,8-diazas piro[4.S]decanecarboxylic acid 55r o�0 0/ (S)(2-amino((R)-2,2,2-triflu oro- 1-(3'- 656 methoxy-4'-(p yrrolidinecarbonyl)-[1, l 1- biphenyl)yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decanecarboxylic acid 55s 0 (S)(2-amino((R )-2,2,2-tdfl uoro(4-(1- 585 oxo-1,3-dihydroisobenzofu ran 0 � ' yl)phen yl)ethoxy)pyri midinyl)-2,8- � diazaspiro]4.S]decanecarboxylic acid 55t (S)(2-amino((R)-2,2,2-tritlu oro- l -(4-(2- 596 o��N '-:: oxo-1,2-dihydroquinolin nyl)ethoxy)pyrimidinyl)-2,8- ' � diazaspiro[4.5]decanecarboxylic acid 55u ;N '-::: (S)(2-amino((R)-2,2,2-triflu oro(4-( 1- 610 methy1oxo-1 ydroquinolin I � yl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid 55v (S)(2-amino((R)-2,2,2-trifl uoro(4-(2- 598 oxo-1,2,3A-tetrahydroquinolin I � yl)phenyl)ethoxy)pyrimidinyl)-2,8- piro ecan rboxylic acid 55w (S)(6-((R)-l-(4-(lH-indazolyl)phenyl)- 569 HN� 2,2,2-trifl uoroethoxy)am inopyrimidinyl)- 2,8-diazaspiro[4.5]decanecarboxylic acid 55x (S)(2-amino((R)(4-(1,3-dimethyl-lHN indazolyl)phenyl)-2,2,2- -�I---::: trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid 55y (S)(2-arnino((R)(4-(1,3-dimethyl-lH- 596 indolyl)phenyl)-2,2,2- -N� oroethoxy)pyrimidinyl)-2,8- diazaspiro(4.S]decanecarboxylic acid 55z �A0/ (S)(2-amino((R)-2,2,2-trifluoro(3'- 627 methoxy-5'-(trifluoromethyl)-[ 1, 1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid 55aa .A0/ (2-amino((R )(31-cyanomethoxy- 584 [1,1'-biphenyl]yl)-2,2,2- tri fl uoroethoxy)pyrimidinyl)-2,8- diazaspiro[ 4.5]decanecarboxylic acid 55ab H (2-amino((R)-2,2,2-tri fl uoro(4-(2- 586 o::::\ oxo-2,3-dihydrobenzo[d]oxazol N��I yl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxy Iic acid 55ac (S)(2-amino((R)-2,2,2-trifluo ro (4-(3- 1 methyl-lH-indolyl)phenyl)ethoxy)pyrimidin- :: 4-yl)-2,8-diaza spiro[4.5]decanecarboxylic acid 55ad (S)(6-((R)(3'-acetoxy-4'- 645 0 o,lo (methoxycarb onyl)-[1,l'-biphenyl]yl)-2,2,2- trifl uoroethoxy)aminopyrimidinyl)-2,8- 'o� diazaspiro[4.5]decanecarboxy1ic acid 55ae 0 (S)(2-amino((R)-2,2,2-trifl uoro(4-(2- 596 oxo-2H-clu·omenyl)phenyl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 55af I (S)(2-amino((R)-2,2,2-tri fluoro (4-(1- 560 methyloxo-1,6-dihydropyridin o�, I � yl)phenyl)ethoxy)pyrimidinyl)-2,8- diaza spiro [4.5]decanecarboxylic acid 55ag 0 HO (S)(2-amino((R)(4'-carboxy-3'-hydroxy- 588 [ 1,l'-biphenyl]yl)-2,2,2- HO� triflu oroethoxy)pyrimidiny1)-2,8- diazaspiro[4.S]decanecarboxylic acid 55ah I (S)(2-amino((R)-2,2,2-trifluoro(4-(2- 610 o� methoxyquinolinyl)phenyl)ethoxy)pyrimidin- N '?' 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 55ai I (2-amino((R)-2,2,2-trifluoro(4-(2- 626 ylthio)quinolin s�N "-::: yl)phenyl)ethoxy)pyrimidiny l)-2,8- I � diazaspiro[4.5]decanecarboxylic acid 55aj ;� (S)(2-amino((R)-2,2,2-trifluoro(4-(1- 612 methyloxo-1,2,3,4-tetrahydroquinolin I � yl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid 55ak F -(2-amino(2,2,2-trifl uoro(3'-fluor o- 547 [I,l'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diaza spiro[4.5]decanecarboxylic acid 55al 0/ (3S)(2-amino(2,2,2-trifl uoro- 1-(3'-methoxy- 559 [1,l'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro]4.S]decanecarboxylic acid 55am F (S)(2-amino((R )-2,2,2-triflu oro(3 '- 547 flu oro-[l, l '-biphenyl]yl)ethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 55an 0/ (S)(2-amino((R)-2,2,2-triflu oro (31- 559 methoxy-[ 1, 1'-biphenyl]yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspir o[4.S]decanecarboxylic acid 55ao A0/ (S)(2-amino((R 2-triflu oro (3'- 577 fl uoro-5'-methoxy-[1, 1 '-biphenyl] yl)ethoxy)pyrimidinyl)-2,8- F diazaspiro[4.5]decanecarboxylic acid 55ap AF (S)(2-amino((R)(31,5'-difl uoro-[ 1, l1- 565 yl]yl)-2,2,2-trifl uoroethoxy)pyrimi din- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 55aq ,,oVy (S)(2-amino((R)-2,2,2-trifl uoro(41- 559 methoxy-[l,l '<bipbenylj-d-yljethoxyjpyrimidin- cc;:' � 4-yl)-2,8-diazaspirof4.S]decanecarboxylic acid 55ar I (S)(2-amino((R)-2,2,2-trifl uoro(2'- 559 methoxy-[l, 1 '-biphenyl]yl)ethoxy)pydmidin- � 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 55as F (S)(2-amino((R)-2,2,2-trifluoro- l-(3'- 597 (trifluoromethyl)-[1, 1'-biphenyl] I � yl)ethoxy)pyrimidinyl)-2,8- � diazaspiro[4.S]decanecarboxylic acid 55at F (S)(2-amino((R)-2,2,2-trifluoro(3'- 613 o)<: (trifluoromethoxy)-[1, 1 '-biphenyl] yl )ethoxy)pyrimidiny1)-2,8- diazaspiro]4.5]decanecarboxylic acid 55au (S )(2-amino((R)(31-ethoxy-[ 1, 1 ' - 573 oj biphenyl]y1)-2,2,2-trifluoroethoxy)pyri midin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 55av 0,( (S)(2-amino((R)-2,2,2-trifluoro(3 1- 587 isopropoxy-[1, l'-biphenyl] oxy)pyrimidinyl)-2,8- diazas piro[4.5Jdecanecarb oxylic acid 55aw o,N (S)(2-amino((R)-2,2,2-triflu oro-l-(4- 530 inyl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro [4.S]decanecarboxylie acid 55ax u)y (S)(2-amino((R)-2,2 ,2-trifluoro-l-(4- 530 I � (pyridinyl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro I4.SldecanecarboxyHe acid 55ay N (S)(2-amino((R)-2,2,2-trifl uoro-l-(4- 531 N ho, (p yrimidinyl)phenyl)ethoxy)pyrimidinyl)- 2,8-diazaspirof4.Sldecane-Svcarboxylic acid 55az (S)(2-amino((R )-2,2,2-tri fl -(4-(3- 583 methyl-I I-I-indazol N�N :::.-,. nyl)ethoxy)pyrimidinyl)-2,8- H diazaspiro[4.5]decanecarboxylic acid 55ba (S)(2-amino((R)-l-(4-(1,3-dimethyl-lH- 597 indazolyl)phenyl)-2,2,2- N�N ::::,..., trifluo roethoxy)pyri midinyl)-2,8- I diazaspiro[4.5]decanecarboxylie acid 55bb S)(2-amino((R)(4-(2,3-dimethy1-2H- 597 lyl)phenyl)-2,2,2- -N� triflu oroethoxy)pyrimidinyl)-2,8- diazaspiro[4.Sldecanecarboxylic acid 55bc (S)(2-amino((R )-2,2,2-trifluoro (4-(1- 598 oxo-1,2,3,4-tetrahydrnisoquinolin orI�I : yl)phenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.51decanecarboxylic acid 55bd (S)(2-amino((R)-2,2,2-trifluoro(4- 580 I � (isoquinolinyl)phenyl)ethoxy)pyrimidinyl)- .,/,: 2,8-diazaspiro [4.5]decanecarboxylie acid 55be co, (S)(2-amino((R)-2,2,2-trifluoro(4- 580 N (isoquinolinyl)phenyl)ethoxy)pyrimidinyl)- 2,8-diazaspirof4.5]decanecarboxylic acid 55bf (S)(2-amino((R)-l-(41- 586 'N�I ! ,,.,; ((dimethylamino)methyl)-[l, 1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- piro[4.51decanecarboxylic acid 55bg Y)y (S)(2-arnino((R)-2,2,2-triflu oro(4- 580 N (quino I inyl)phenyl)ethoxy)pyrimidinyl)- .,/,: 2,8-diazaspiro[4.5]decanecarboxylic acid 55bh co, (2-arn ino((R)-2,2,2-trifl uoro- l-(4- 580 (quinolinyl)phenyl)ethoxy)pyrimi dinyl)- 2,8-diazasp iro[4.5]decanecarboxylic acid 55bi �N (S)(2-amino((R)-2,2,2-trifl uoro-l-(4- 581 (quinoxalinyl)phenyl)ethoxy)pyrimidinyl)- N�! � 2,8-diazaspiro[4.5]decanecarboxylic acid 55bj (2-amino((R)-2,2,2-triflu oro- 1-(4-(2- 612 methyloxo-1,2,3,4-tetrahydroisoquinolin or I : yl)phenyl)ethoxy)pyrimidinyl)-2,8- � diazaspiro[4. 5Jdecanecarboxylic acid 55bk -. (S)(2-amino((R)-2,2,2-triflu oro-l-(4- 581 (quinazolin-e-yl)phenyl)ethoxy)pyrimidiny1)- N � ! � 2,8-diazaspiro[4.5]decanecarboxylic acid 55bl (S)(2-amino((R)-2,2,2-triflu oro (4'- 577 F�I -: fl uoro-2'-methoxy-[l, 1 '-biphenyl] y1)ethoxy)pyrimidiny1)-2,8- ,..,.o diazaspiro]4.S]decanecarboxylic acid 55bm .o. (S)(2-amino((R)-2,2,2-trifl uoro- l-(2'- 577 fl uoro-3'-methoxy-[l, 1 '-biphenyl] yl)ethoxy)pyrimidinyl)-2,8- I F diazaspiro]4.Sldecane-Svcarboxylic acid 55bn 0/ (S)(2-arn ino((R )-2,2,2-triflu oro - 577 fl uoro-5'-methoxy-[l,1 '-biphenyl] oxy)pyrimidinyl)-2,8- � piro [4.5]decanecarboxylic acid 55bo (S)(2-amino((R)-2,2,2-trifl uoro (4-(6- 544 methylpyridinyl)pheny1)ethoxy)pyrimidin � yl)-2,8-diazaspiro [4.Sldecanecarboxylic acid 55bp o�0 (S)(2-amino((R)-2,2,2-trifluoro(4'- 626 (pyrrolidinecarbonyl)-[ 1, l'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5Jdecanecarboxylic acid 55bq OA (S)(2-amino((R)(3'-carboxy-[1, 1'- 573 biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- OH 4-yl)-2,8-diazaspirn[4.5]decanecarboxylic acid 55br HO�0 (S)(2-amino((R)( 4'-carboxy-[1,11- 573 biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[ 4.5]decanecarboxylic acid 55bs (S)(2-amino((R)-2,2,2-trifl uoro(4'- 571 propyl-[1, 1 enyl]yl)ethoxy)pyrimi din � yl)-2,8-diazaspirof4.51decanecarboxylic acid 55bt (S)(2-amino((R)-2,2,2-trifl uoro- 1-(3 '- 559 (hydro xymethyl)-[1, 1 '-biphenyl] � yl)ethoxy)pyrimidinyl)-2,8- ....-:::: � diazaspiro[4.5]decanecarboxylic acid 55bu c<HO (S)(2-amino((R)-2,2,2-trifl uoro- l-(2'- 559 (hydroxymethyl)-[l, l '-biphenyl] yl)ethoxy)pyrimidin- 4-yl)-2,8- diazaspiro[4.5]decanecarboxylic acid 55bv 'r°Vy (S)(2-amino((R)-2,2,2-trifluoro - l-(4'- 587 isopropoxy-[1, l"-btphenylj-ayl )ethoxy)pyri midinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid 55bw 0 (S)(2-amino((R)(4'- 600 hylcarbamoylj-] I,1'-biphenyl]yl)-2,2,2- 'N�I [ -: trifl uoroethoxy)pyrimidinyl)-2,8- diazaspiro[ 4.S]decanecarboxylic acid 55bx OA (2-amino((R 2-trifl uoro(3'- 640 (pi peridinecarbonyl)-[l, 1 enyl] 0 oxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid 55by o;'-N/ (S)(2-amino((R)(2'- 586 ((dimethylamino)methyl)-[l, 1 '-biphenyl]yl)- 2,2,2-trifl uoroet hoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid 55bz (S)(2-amino((R)(4'-ethyl-[ 1,1'-biphenyl]- 557 4-yl)-2,2,2-triflu oroethoxy)pyrimidinyl)-2,8- � diazaspiro[4.5]decanecarboxylic acid 55ca .c, (S)(2-amino((R)-2,2,2-triflu oro(3 '- 545 hydroxy-[1, l '-biphenyl]yl)ethoxy)pyrimidin yl )-2,8-diazaspiro r4.Sldecanecarboxylie acid 55cb (S)(2-arnino((R)-2,2,2-trifluoro- l-(4'- 545 110�I,,.-;, y-j l , 1 '-biphenyl]yl)ethoxy)pyrimidin yl)-2,8-diazaspiro[4.5ldecanecarboxylic acid 55cc (S)(2-amino((R)(2',4'-dimethoxy-[1,l '- 589 I ,,.-;, bipheny I]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2, 8-diazaspiro[ 4.5[decane-S-carboxylic acid ,.....o 55cd F (S)(2-amino((R)-2,2,2-trifluoro(4'- 597 ;� (trifluorornethyl)-] 1,l1-biphenyl] yl)ethoxy)pyrimidinyl)-2,8- diazaspiro r4. 5]decanecarboxyl ic acid 55ce 9: (S)(2-amino((R)-2,2,2-trifluoro- 1-(2'- 597 (trifluoromethyl)-] 1, 1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8- F F F diazaspiro[4.S]decanecarboxylic acid 55cf (S)(2-amino((R)(2',6'-difl uoro-[1, 1 '- 565 ,,.,.;, biphenyl]yl)-2,2,2-trifl uoroethoxy)pyrim idin- � 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 55cg (2-amino((R)(2',6'-dimethyl-[1, 1'- 557 biphenyl]yl)-2,2,2-trifluo ro ethoxy)pyrimidin- � 4-yl)-2,8-diaza spiro[ 4.5]decanecarboxylic acid 55ch My (S)(2-amino((R )-1 -(3' ,4'-dimethyl-[ 1, 1'- 557 biphenyl]yl)-2,2,2-triflu oroethoxy)pyrimidin- 4-yl)-2,8-diazaspiror4.Sldecanecarboxy Iic acid 55ci (S)(2-amino((R)(4'-(tert-butyl)-[1, l '- 585 biphenyl]yl)-2,2,2-trifl uoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.S]decanecarboxylic acid 55cj (S)(2-am ino((R)-2,2,2-triflu (4'- 571 isopropyl-Il ,1 '-biphenyl]yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 55ck (S)(2-amino((R)-2,2,2-triflu oro-l-(3'- 571 isopropyl-] 1 ,1'-biphenyl]yl)ethoxy)pyrimidin- � 2,8-diazaspiro[4.5]decanecarboxylic acid 55cl (S)(2-amino((R)(3',4'-dichloro-[ 1, 1'- 597 Cl� yl]yl)-2,2,2-trifl uoro )pyri midin- Cl , 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 55cm -». (S)(2-amino((R )-2,2,2-trifl uoro(4'- 613 F I h (triflu oromethoxy)- [1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid 55cn .o, (S)(2-amino((R)(2',3 '-dimethyl-[1, 1 ' - 557 biphenyl]yl)-2,2,2-trit1uoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro [4.5Jdecanecarboxylic acid 55co F (S)(2-amino((R)-2,2,2-trifluoro(3',4',5'- 583 trifluoro-[l, 1'-biphenyl]yl)ethoxy)pyrimidin f�lh yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 55cp Cl� (S)(2-amino((R)(4'-chloro-2'-methyl- 577 I ,,,:, [1, 1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decanecarboxylic acid 55cq A (S)(2-amino((R)-l-(3',5'-dimethyl-[1, l1- 557 biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-y1)-2,8-diazaspiro[4.5]decanecarboxylic acid 55cr ')C\, (S)(2-amino((R)(3',4'-difl uoro-[1,1 '- 565 I ,,,:, biphenyl]yl)-2,2,2-trifl uoroethoxy)pyrimidin- F 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 55cs (S)(2-amino((R)(2',Y-dimethyl-[1, 1'- 557 biphenyl]yl)-2,2,2-tri fluoroe thoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 55ct (S)(2-amino((R)(4'-butyHl, 1'-biphenyl]- 585 4-yl)-2,2,2-trifluo roethoxy)pyrimi dinyl)-2,8- � diazaspiro [4. 5]decanecarboxylic acid 55cu F (S)(2-amino((R)-2,2,2-trifl uoro(3 '- 561 tl uoro-4 '-methyl-[1)'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8- � diazaspiro[4.S]decanecarboxylic acid 55cv <«-o,0 (S)(2-amino((R)-2,2,2-trifl uoro(4'- 607 (methylsulfonyl)-[1,1 '-biphenyl] yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[ canecarboxylic acid 55cw Vy (S)(2-amino((R)-2,2,2-trifluoro [l, 1 '-biphenyl]yl)ethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 55cx (S)(2-amino((R)-2,2,2-trifl uoro (3'- 543 methyl-[1, 1'-biphenyl]yl)ethoxy)pyrimidin 8-diazaspiro [4.5]decanecarboxylic acid 55cy Cl'C\,� (S)(2-amino((R)(41-chloro-] 1, 1'- 563 l -: biphenyl]yl)-2,2,2-trifl hoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.S]decanecarboxylic acid 55cz .s.0 (S)(2-amino((R)(4-(benzofura n 569 yl)phenyl)-2,2,2-trifl uoroe thoxy)pyrimidinyl)- 2,8-diazaspiro[4.5Jdecanecarboxylic acid 55da o,F (S)(2-amino((R)-2,2,2-trifluoro(5 1- 577 fluoro-z-methoxy-]l ,l -biphenylj-t- yl)ethoxy)pyrimidinyl)-2,8- ,,...o diazaspiro]4.S]decanecarboxylic acid 55db co, (S)(2-amino((R)-2,2,2-trifluoro(4-(2- 599 oxochromanyl)phenyl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.S]decanecarboxylic acid 55dc F (S)(2-amino((R)-2,2,2-trifhtoro(4-(3- 597 quinolinyl)phenyl)ethoxy)pyrimidin yl)-2,8-diazaspiro[4.S]decanecarboxylic acid 55dd (S)(2-amino((R)-2,2,2-trifluoro(41- 587 � propoxy-[1,1'-biphenyl]yl)ethoxy)pyrimidin yl)-2,8-diazaspiro[ 4.S]decanecarboxylic acid o�I� 55de 0 (S)(2-amino((R)(4'-(diethylcarbamoyl)- 628 [I, 1'-biphenyl]yl)-2,2,2-trifl uoroethoxy) �N�) �I pyrimidinyl)-2,8-diazaspiro[4.5)decane carboxylic acid 55df H2N (S)(2-amino((R)(41-carbamoyl-[l, l 1- 572 biphenyl]yl)-2,2,2-trifluo roethoxy)pyri midin- o� 2,8-diazaspiro[4.5Jdecanecarboxylic acid 55dg 0 (S)(2-amino((R)-2,2,2-triflu oro(41- 585 (methylcarbamoyl)-]1,1'-biphenyl] 'N�H � I yl)ethoxy)pyrimidinyl)-2,8- diazaspiro [4.5]decanecarboxylic acid 55dh o� o (S)(2-amino((R)-2,2,2-trifl uoro(4'-((2- 685 morpholinoethyl)carbamoyl)-[ 1, l -biphenylj-e- �yl )ethoxy)pyrimidiny1)-2,8- piro[4.S]decanecarboxylic acid 55di 0 (S)(2-amino((R)-2,2,2-triflu oro- 1-(41- 606 (methylsulfonyl)-[1, 1 '-biphenyl] O'� yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decanecarboxylic acid 55dj H2N,5,0 (S)(2-am ((R)-2,2,2-triflu oro(4'- 607 sulfamoyl-] 1,l'-biphenyl]yl)ethoxy)pyrimidin- O'� 4-yl)-2,8-diazaspiro[ 4.5]decanecarboxylic acid 55dk 'N,.... (S)(2-amino((R)- 1-(41- 600 ( dimethylcarbamoyl)-[1, l 1-biphenyl]yl)-2,2,2- o� trifluoroethoxyjpyrimidin-d-ylj-Zfi- diazaspiro[4.5]decanecarboxylic acid 55dl (N)H (S)(2-amino((R)-2,2,2-trifluoro- 1-(41- 641 N (piperazinecarbonyl)-[l, 1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8- diazaspiro [4. 5]decanecarboxylic acid 55dm (S)(2-amino((R)-2,2,2-trifluoro- 1-(3'- 605 � F fluoro-4 1-propoxy-[l, l1-biphenyl] yl)ethoxy)pyrimidinyl)-2,8- o� diazaspiro[4.5]decanecarboxylic acid 55dn l-c,F (S)(2-amino((R)(41-ethoxyfluoro- 591 [l, l'-biphenyl]yl)-2,2,2- I ,,.-:; trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylie acid 55do lOu),, (S)(2-amino((R)(41-ethoxy-[l,1'- 573 biphenyl]yl)-2,2,2-trifluoroethoxy )pyrimidin- I � 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid 55dp (S)(2-amino((R)-1 -(4-(cinn olin 580 ... ::::,.... yl)phenyl)-2,2,2-triflu oxy )pyrimidinyl)- � 2,8-diazaspiro[ 4.5]decanecarboxy1ic acid 55dq a\, (S)(2-amino((R )(4-(chrom an 584 I yl)phenyl)-2,2,2-trifl uoroethoxy)pyrimidinyl)- 2,8-diazaspiro [4.5]decanecarboxylic acid Table 17b.
NMR Data for Compounds of Table 17a Ex. NMR 55a 1H NMR (400 MH z, MeOH-d4): o ppm 7.66-7.58 (m, 6H), 7.45-7.41 (m, 2H), 7.36- 7.32 (m, lH), 6.64 (q, J = 6.8 Hz, lH), 5.56 (s, lH), 4.00 (m, lH), 3.67-3.60 (m, 2H), 3.52-3.44 (m, 2H), 3.20-3.02 (m, 2H), 2.31-2.25 (m, lH), 2.01 (m, lH), 1.58 ( s, 4H) 55b 1HNMR (400 MHz, MeOH-d4): o ppm 8.02 (s, 1 H), 7.92 (s, 1 H), .65 (m, 3 1-1), 7.61-7.55(m,4H ), 6.60 (m, 1 H), 5.47 (s, 1 H), 3.97 (s, 4 H), 3.53 (rn, 2 H), 3.35 (m, 2 H), 3.15-3. 12 (m, 1 H), 3.13-3.00 (m, l H), 2.21 (m, 1 H), 1.95(m, lH), 1.50 (m,4H) 55c 1H NMR (400 MHz, MeOH-d4): s ppm 8 .1 6 (s, 1 H), 7.89 (s, 1 H), 7.71-7.69 (d, 2 H), .60 (m, 4 H) , 6.67-6.66 (q, 1 H) , 5.52 (s, 1 H), 4.00 (m, 1 H), 3.87 (s, 3 H), 3.62 (m, 2 H), 3.44 (m, 2 H), 3.12 (d, 1 H), 3.06 (d, 1 H) , 2.23 (m, 1 H), 1.99 (m, 1 H), l .54(m, 4 H), 1.23 (m, 3 H). 55d 1H NMR (400 MHz, Me0H-d4): o ppm 8.56 (s, ll-I), 7.90 (s, lH), .61 (m, 6H), 6.66 (q, J = 6.6 Hz, lH), 5.59 (s, lH), 4.17-4.13 (m,lH), .57 (m, 2H), 3.52-3.43 (m, 2H), 3.27-3.24 (m, lH), 3 . 16-3 .13 (m, 11-1), 2.37-2.31 (m, ll-1), 2.09-2.04 (m, SH), 1 .61 ( m, 4H) 55e 1H NMR (400 MHz, MeOH -d4): s uom 7.62-7.56 (m, 4 H), 7.40 (m, 2 H), 7. l 5 (m, I H), 6.61 (m, 1 H), 5.56 (rn, I H), 4.07 (m, 1 H), 3.90 (s, 3 I-I), 3.63 (m, 2 H), 3.48 (m, 2 H), 3.25 (m, 1 H),3.13 (m, 1 H), 2.30 (m, 1 H), 2.04 (rn, 1 H), 1.60 (s, 4 H) 55f 11-1 NMR (400 MHz, DMSO-d6): s ppm 9.09 (s, 1 H), 8.45 (s, 1 H), 8.26 (m, 1 H), 7.83-7.77(m, 3 H), 7.64 (m, 2 H), 6.73 (m, 1H), 6.06 (s,IH), 5.57 (s.lH), 3.45 (m, 4H), 2.99 (m, 2 H), 2.10 (m, l H), 1.79 (m, 1 H), 1.42 (m, 4 H). 55g 1H NMR (400 MHz, MeOH-d4): s ppm 7.66-7.56 (m, 6H), 7.19-7.17 (m, 2H), 6.66 (q, J = 6.7 Hz, lH), 5.56-5.55 (m, lH), 4.08 (m,1H), 3.64-3.59 (m, 2H), 3.53-3.43 (m, 2H), 3.23-3.13 (m, lH), 2.98-2.92 (m, lH), 2.35-2.19 (m, lH), 2.08-2.03 (m, IH), 1.59 ( m, 4H). 55h 1H NMR (400 MHz, MeOH-d4): o ppm 8.06 (s, lH), 7.83 (d, 1 = 8.3 Hz, lH), 7.73 (d, 1 = 7.7 Hz, 3H), 7.62 (d, 1 = 7.5 Hz , 2H), 7.44 (d, J = 8.6 Hz, 1H), 6.67 (q, 1 = 7.4 Hz, IH), 5.58 (s, lH), 4.08 (m,IH), 3.69-3.61 (m, 2H), .43 (m, 2H), 3.23-3.10 (m, 2H), 2.35-2.30 (m, lH), 2.08-2.03 (m, lH), 1.60 (s, 4H). 55i 1H NMR (400 MHz, DMSO-d6): o ppm 8.03 (s, 1 I-I), 7.83-7.82 (d, 2 H, J=4.5 Hz), 7.81-7.79 (d, 2 H, J=7.6 Hz), 7.62-7.60 (d, 2 H,J=:: 7.6 Hz), 7.43-7.41 (d, 2 H, J=8.6 Hz), 6.71-6.70 (q, 1 H, J=6.8 Hz), 5.55 (s, 1 H), 4.02 (s, 3 H), 3.71 (m, l H), 3.55-.344 (m, 4 H), 2.85 (m, 1 H), 2.12 (m, 1 H), 1.71 (m, 1 H), 1.40 (m, 4 H). 55j 1H NMR (400 MHz, MeOH-d4): s ppm 8.96 (s, 1 H), 8.33 (s, 1 H) , 8.09-8.07 (d, 1 H, 1=8.8 Hz), 7.81-7.79(dd, 1 H, J=8.0 Hz), 7.71-7.69 (d, 2 H, J=8.0 Hz), 7.60-7.58 (d, 2 H, 1=8.0 Hz), 6.63-6.58 (q, 1 H),5.51 (s.IH), 4.00-3.96 (m, 1 H), 3.57 (m, 2 H), 3.40 (m, 2 H), 3.17-3 .14 (d, 1 H, 1=11.7 Hz), 3.13-3.00 (d, 1 H, J=l 1.7 Hz), 2.23-2.21 (m, 1 H), 1.99-1.94 (m, 1 H), l .53 (m, 5 H). 55k 1HNMR (400 MHz, 4): s ppm 9.26 (S, 1 H), 8.33 (s, 1 H), 8.13-8. 11 (d, 1 H, 1== 8.5 Hz), 7.84-7.82(dd, 1 H, J=8.5 Hz), 7.76-7.74 (d, 2 H, J=8.3 Hz), 7.65-7.63 (d, 2 H, J=8.3 Hz), .65 (q, 1 H, J=7.2 Hz), 4.15-4.1 1 (m, 1 H), 3.53 (m, 2 H), 3.49 (m, 2 H), 3.27-3.24 (d, 1 H, J=l 1 .7 Hz), 3.15-3.12 (d, 1 H, J:==11.7 Hz), .31 (m, 1 H), .03 (m, 1 H), 1.61 (m, 5 H). 551 1H-NMR (400 MHz, Me0H-d4): o ppm 9.08 9(s,1H), 8.44 (s,IH) ,8.02 -8.03 (m,1H),7.83 -7.86 (m, 21-I ), 7.66 -7.75 (m, 2H),6.66 -6.69 ,5.50 (s,lH),4.07 - 4.07 (m, lH),3.64-3.66 (m, 2H), 3.44 -3.48 (m, 2H), 3.19 -3.24 (m,lH), 3.16 -3.46 (m,lH), 2.29 -2.55 (m,lH), 2.03 -2.08 (m,lH), 1.60 - 1.61 (m,4H) 55111 1H-NMR (400 MHz, DMSO-d6): o ppm 8.19 (s,lH), 7.84 -7.97 (m,6H), 7.63 -7.82 (m, 2H), 7.50 -7.61 (rn, 2H), 6.70 -6.76 (m,1H), 5.58 (s,lH), 3.38 -3.47 (S, lH), 3.00 - 3.00 (m, lH),2.91 -2.94 (m,lH), 2.06-2.13 (m,lH), 1.74 -1.78 (m,IH), 1 .37 -1.44 (m,4H) 55n 1H-NMR(400 MHz, MeOH-d4): s ppm 7.63-7.65 (m,2H), 7.56-7.58 (m, 2H), 7 . 15 - 7.20 (m, lH), 7.07-7.09 (m, 2H), 6.60- 6.65 (m,lH), 4.1 1 - 4 .16 (m,lH), 3.87 (s, 3H), 3.48 -3.66 (m, 4H), 3.23 -3.26 (m, IH), 3.11 -3.16 (m,lH), 2.31 -3.41 , 2.20 (s,3H), 2.02-2.10 (m,lH), 1.59-1.61 , 1.27 -1.31 (m,ll-fl 550 1H NMR (400 MHz, Me0H-d4): o ppm 7.62-7.56 (m,4H), 7.00 (s,lH), 6.93 , ,1H), 6.64 (q, lH, J=8.0), 5.56 (d, lH, J=4.0), 4.08-4.04 (m, lH), 3.80 (s, 3H), 3.63 (s, 21-I), 3.47 (s, 2H) 3.23 (d, IH, J = 16.0), 3 .10 (d, lH, J = 12.0 Hz), 2.36 (s, 3H), 2.04 (s, lH), 1 .59 (s, lH), 1.28 (s, lH) 55p 1H NMR (400 MHz, MeOH-d4): o ppm 0.89 (m, lH), 1.30 (d, J = 15.5 Hz, 3H) , 1.62 (d, J = 5.7 Hz, SH), 2.06 (m, lH), 2.14 (s, 3H), 2.33 (dd, J = 13.5, 9.2 Hz, lH), 3.13 (d, J = 11.7 Hz, IH), 3.25 (d, J = 11 . 3 Hz, lH), 3.51 (dt, J = 20.9, 6.7 Hz, 2H), 3.66 (d, J = 13.3 Hz, 2H), 3.76 (s, 31-1), 4.09 (t, J = 8.2 Hz, IH), 5.57 (s, IH), 6.69 (m, 2H), 6.81 (dd, J = 8.4, 2.8 Hz, lH), 7.15 (d, J= 8.4 Hz, lH), 7.35 (m, 2H), 7.57 (d, J= 7.9 Hz, 55q 1HNMR (400 MHz, MeOH-d4): 8 ppm 7.62 (d,2H,J=8.0), 7.56(d,2H,J=8.0), 7.18(m,2H), 7.02(d,1H,J=8.0), 6.62 (q, 1H,J=8.0), 5.55 (s, lH), 4.01-3.97 (m, lH), .23 (m, lH), 3.89 (s, 3H), 3.86 (s, 3H), 3.67-3.60 (m, 2H),3.49-3.43(m, 2H) 3.19 (d, lH, J = 12.0), 3.02 (d, lH, J = 12.0 27(dd, lH, J = 12.0,8.0), 2.00 (dd, lH, J = 14.0,4.0), 1.58 (s, lH),1.28 (s, lH) 55r 1H NMR (400 MHz, MeOH-d4): s ppm 7.70-7.61 (m, 4H), 7.28 (m, 3H), 6.67 (q, J = 7.6 Hz, lH), 5.56 (s, lH), 4.08 (m,lH), 3.91 (s, 3H), 3.63-3.46 (m, 8H), 3 . 1 3 (m, lH) , 2.35-2.29 (m, IH), 2 .01-1.99 (m, lH), 1.97-1.87 (m, SH), 1.59 (m, 4H). 55s 1H-NMR (400 MHz , MeOH-d4): s ppm 1.74-1.73 (m,4H), .07 (m,lH), 2.52- 2.46 (m,lH), 3.60-3.55 (m, lH), 3.70-3.66 (m,2H), 4.55-4.50 (m,lH) , 5.44 (s,2H), .63 (m,11-I), 7.74-7.69 (m,2H), 7.88-7.80 (m,4H); 7.96-7.92 (m,lH) 55t 1H NMR (400 MHz, MeOH-d4): s ppm 8.03 -8.05 (m,IH) ,7.95 (s, lI-l), 7.84 -7.86 (m,lH), 7.71 -7.73 (m, 2H) , 7.60-7.62 (m, 2H),7.43 -7.45 (m, lH), 6.62 -6.65 (m, 2H), .57 (s, lH), 4.05 -4.10 (m,lH), 3.61-3.70 (m,3H), 3.42-3.52 (m, 3H), 3.09-3.12 (m, lH), 2.29 -2.36 (m,lH), 2.02 -2.07 (m, IH), 1.60 (m, 4H) 55u 1H NMR (400 MHz, DlVJSO-d6): o ppm 8.02 (s,IH), 7.93 -7.98 (m, 2H), 7.76 -7.78 (m, 2H), 7.59 -7.63 (m, 3H), 6.63 -6.73 (rn, 2H), 5.55 (s, 1H), 3.74 -3.79 (m,lH), 3.61 (s,3H), 3.32 -3.47 (m, SH), 2.89 -3.07 (m,2H), 2.08 -2.14 (m,lH), 1.73 -1.80 (m, lH) , 1.41 (m, 41-l). 55v 1H NMR (400 MHz, MeOH-d4): o ppm 7.62(d,2H,J=8.0), 7.56 (d,2H,J=8.0), 7.45 (m,2H), 6.93 (d,1H,J=8.0), 6.62 {q, IH,J=8.0), 5.56 (s, IH), 4.07 (t, lH, , .58 (m, 2H) , 3.52-3.45(m, 2H), 3.24 (d, lH, J = 12.0),3.11 (d, lH, J = 8.0 Hz), 3.01 (t, 2H, J = 8.0 ), 2.59-2.57 (m, 2H), 2.32(dd, IH, J = 12.0,8.0),2.05(dd, lH, J = 12.0,8.0), 1.58 (s, 4H),l.28 (s, lH) 55w 1H NMR (400 MHz, DMSO-d6): o 1.59 (m, 4 H), 2.05-2.01 (m, 1 H, J=l 1.6 Hz), 2.32- 2.28 (m, 1 H, J=ll.6 Hz), 3.11-3.08 (d, 1 H), 3.25-3.22 (d, 1 H), 3.50-3.47 (m, 2 H), 3.68-3.65 (m, 2 H), 4.08-4.04 (q,1 H), 5.57 (s, 1 H), 6.66-6.65 (q, 1 H), 8.10 (s, 1 H), .60 (m, 3 H, J=8.6 Hz), 7.71-7.69 (m, 3 H, J=8.6 Hz), 8.01 (s, 1 H) 55x 1HNMR (400 MHz, MeOH-d4): 8 ppm 1.61 (d, J = 5.7 Hz, 4H), 2.06 (dd, J = 13.5, 7.3 Hz, IH), 2.35 (dd, J = 13.5, 9.2 Hz, lH), 2.56 (s, 3H), 3.15 (d, J = 11.8 Hz, lH), 3.25 (d, J = 11.7 Hz, lH), 3.54 (m, SH), 3.99 (s, 3H), 4.17 (t, J = 8.3 Hz, lH), 5.00 (s, ll-l), 6.66 (q, J = 7. 1 Hz, lH), 7.53 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.70 (m, 3H), 7.91 (s, 1H) 55y 1H NMR (400 MHz, Me0H-d4): o ppm 1.54 (rn, 4 H), 2.10 (m, 1 H), 2.26 (m, 4 H), 3.04 (m, 1 H), 3.1 7 (rn, 1 H), 3.40 (m, 2 H), 3.56 (m, 2 H), 3.69 (s, 3 H), 4.07-4.03 (m, 1 H), 6.65-6.59 (m, 1 H), 6.93 (s, 1 H), 7.37-7.34(m, 1 H), .42 (m, 1 H), 7.57- 7.55 (m, 2 H), 7.72-7.68 (m, 3 H) 55z 1H NMR (400 MHz, Me0H-d4): o ppm 7.72-7.63(m,4H), 7.45(s,1H), 7.40 (s,lH) , 7.18 (s, lH\ 6.66 (q, lH, J=8.0), 4.30 (d, lH, J=8.0), 3.91 (s, 3H), 3.66 (s, 2H),3.55(s, 2H), 3.26 (s, IH), 3.19(d, IH, J = 12.0 Hz), 2.43-2.37 (m, lH), 2.10-2.05 (m, lH), 1.65 (s, SH), 1.28 (s, lH) 55aa 1H NMR (400 MHz, 4): 8 ppm 7.94 (d,1H,J=4.0), 7.71 (d,1H,J=4.0), 7.53- 7.50 (m,2H), 6.82 (q,1H,J=8.0), 6.41 (d, 1H,J=4.0), 5.68 (d, 1H,J=4.0), 4.41 (s, ll-1), 3.09 (s, lH), 2.75(t, 2H, J=8.0 ), 2.46 (d, lH, J=16.0), 2.38 (s, 3H),2.22(dd, lH, J = 16.0,8.0), 1.23-1.19 (m, 3H) 55ab 1H NMR (400 MHz, Me0H-d4): 8 ppm 1.60 (m, 4 H), 2.03-2.05 (m, 1 H), 2.33-2.32 (m, 1 H), 3.14-3.11 (d, 1 H, J=l 1.9 Hz), 3.26-3.23 (d, 1 H, J=ll.9 Hz), 3.52-3.47 (m, 2 H), 3.65-3.54 (m, 2 H), 4.10-4.06 (m, lH), 5.57 (s, 1 H), 6.65-6.64 (q, 1 H), 7.16-7.14 (d, 2 H, J=8.2 Hz), .44 (dd, 2 H, J=8.2 Hz), 7.51 (s, 1 H), 7.60-7.57 (d, 2 H, J=8.3 Hz), 7.65-7.63 (d, 2 H, J=8.3 Hz) 55ac 1H NMR (400 MHz, MeOH-d4): o ppm 7.72-7.69 (m, 3 H), 7.58-7.56 (m, 2 H), 7.38 (s, 2 H), 7.02(m, 1 H), 6.61 (m, 1 H), 4.23(m, 1 H), 3.65 (m, 2 H), 3.48 (m, 2 H), 3.30 (m, 1 H), 3.14 (m, 1 H), 2. 31 (m, 4H), 2.06 (m, 1 H), 1.62 (s, 4 H). 55ad 1HNMR (400 MHz, Me0H-d4): o ppm 8.08 (d, J = 8.2 Hz, lH), 7.77 (d, J = 8.2 Hz, 2H), 7.67-7.65 (m, 3H), 7.46 (m, lH), .61 (rn, lH), 4.47 (m, l H), 3.87 (s, 3H), 3.73-3.52 (m, 4H), 3.27-3.22 (m, 2H),2.50-2.44 (m, lH), 2.33 (s, 3H), 2.12-2.06 (m, 1 H), 1.68 (m, 4H). 55ae 1H NMR (400 MHz, DMSO-d6): 8 ppm 1.22 (d, J = 5.3 Hz, 2H), 1.42 (m, 4H), 1.82 (d, J = 13.2 Hz, l H), 1.98 (dd, J = 17.4, 8.5 Hz, lH), 2.91 (m, lH) , 3.03 (d, J = 1 1.0 Hz, lH), 3.55 (s, lH), 3.68 (s, nn, 3.80 (s, IH), 5.62 (s, lH), 6 .13 (s, 2H), 6.49 (d, J = 9.6 Hz, lH), 6.75 (q, J = 7.3 Hz, lH), 7.67 (m, 4H), 7.83 (dd, J = 22.1, 8.1 Hz, 3H), 8.09 (d, J = 9.5 Hz, lH) 55af 1H NMR ( 400 MHz, Me0H-d4): o ppm 8.01(d,J=2.6Hz)H) ,7.89(dd, J=2.72, 6.8 Hz,lH), ,4H) , 6.64(m, 2H),5.56(s, 1H),4.08(m,1H) s,3H),3.53(m, 4H),3. l2(m, 21-I ), 2.33(m,1H),2.06(m, 1H), l .60(m,4H) . 55ag 1H NMR (400 MHz, Me0H-d4): 8 ppm 7.92 (d, J = 8.8 Hz, II-I), 7.65 (dd, J I =8.4 Hz, J2 = 31.9Hz, 4H), 7.17-7 .14 (m, 2H), 6.66-6.63 (m, lH), 4.14-4.10 (m, lH), 3.66-3.59 (m, 2H) , 3.54-3.43 (m, 2H), 3.26-3.24 (m, lH), 3.15-3.12 (m, HI), 2.37-2.32 (m, lH), 2.08-2.03 (m, lH), 1.61 (m, 4H) 55ah 1H NMR (400 MHz, 4): 8 ppm 8.16 (d,J = 8.92 Hz,lH), 8.02 (d.f= l .56 Hz, lH),7.93-7.86 (m,2H), 7.76 (d,J=8.16 Hz, 2H), 7.64(d,J=8.08 Hz,2H),6.96 (d,J = 8.88 Hz,lH), 6.66 (q, J = 7.12 Hz)H), 5.57(s,1H), 4.06(s,3H), 3.97 (m, lH), 3.64(m, 2H), 3.47(m,2H), 3.17 (d, J=l0.92 Hz,IH), 3.00 (d, J=l2.04 Hz,lH), 2.26 (m, lH), 2.0l(m, lH), 1.58 (s, 4H) 55ai 1H NMR (400 MHz, MeOH-d4): <3 ppm 8.06 (d, J = 8.76 J-Iz,lH), 8.01 (s, lH),7.93 (s ,2H),7.76 (d, J = 8.04 Hz, 2H),7.64 (d, J = 8.16 Hz, 2H), 7.31 (d, J = 8.76 Hz, lH), 6.68 (q, J = 8.48 Hz, 1H), 5.58 (s, lH) , 4.08 (m, l H), 3.63-3.50 (m, 4H), 3.24 (d, J = 11.64 Hz, lH), 3.12 (d,J = 11.64 Hz,lH) , 2.68(s, 3H), 2.3 1 (m, 1 H), 2.05 (m, lH), 1.59 (m, 4H). 55aj 1H NMR (400 MHz, 4): 8 ppm o7.67(d,2H,J=8.0), 7.61-7.57(m,4H), 7.51(s,1H), 7.20(d,1H,J=8.0), 6.63 (q, 1H,J=8.0), 4.29 (t, lH, J=12.0), .58 (m, 2H), 3.53-3.48(m, 2H), 3.38(s,3H), 3.27 (cl, lH, J = 12.0),3.19 (d, IH, J = 8.0 Hz), 2.99-2.95 (m, 2H), 2.65-2.63 (m, 2H), 2.40(dd, lH, J = 12.0,8.0),2.09(dd, lH, J = .0), 1.66 (s, 5H),l.31 (s, 2H) 55ak 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.52 - 1.67 (m, 4 H) 2.05 (dd, J=13.42, 7.13 Hz, 1 1-1 ) 2.32 (dd, 4, 9.30 Hz, 1 H) 3.07 - 3.16 (m, 1 H) 3.24 (d, J=l 1.76 Hz, 1 H) 3.38 - 3.55 (rn, 2 H) 3 .56 - 3.76 (m, 2 H) 4. 10 (t, J=8.18 Hz, 1 H) 5.56 (s, 1 H) 6.63 (q, J=6.96 Hz, 1 H) 7.06 (qd, J=5.74, 3.29 Hz, 1 H) 7.35 (dd, J=9.30, 1.44 Hz, 1 H) 7.38 - 7.48 (m, 2 H) 7.55 - 7.69 (m, 4 H) 55al 1H NMR (400 MHz, MeOH-d4): s ppm 1.59 (d, J=4.59 Hz, 4 H) 2.04 (dd, J=13.50, 7.30 Hz, 1 H) 2.31 (dd, J=13.30, 9.01 Hz, 1 H) 3.05 - 3.25 (m, 2 H) 3.37 - 3.53 (m, 2 H) 3.54 - 3.69 (m, 2 H) 3.81 (s, 3 H) 4.05 (dd, J=9.18, 7.32 Hz, 1 H) 5.54 (s, 1 H) 6.61 (q, J=7.29 Hz, 1 H) 6.89 (dd, J=7.83, 2.12 Hz, 1 H) 7.05 - 7.21 (m, 2 H) 7.26 - 7.38 (m, I H) 7.46 - 7.68 (rn, 4 H) 55am 11-I NMR (400 MHz, MeOH-d4): o ppm 1.63 (d, J=5.08 Hz, 4 H) 2.08 (dd, J=13.32, 7.18 Hz, 1 H) 2.35 (dd, J=13.32, 9.22 Hz, 1 H) 3.07 - 3.20 (m, 1 H) 3.27 (d, J=l 1.71 Hz, 1 H) 3.40 - 3.58 (m, 2 H) 3.59- 3.80 (m, 2 H) 4.11 (t, 1=7.96 Hz, I H) 5.58 (s, 1 H) 6.68 (d, J=7.13 Hz, 1 H) 7.10 (dt, J=6.00, 2.95 Hz, 1 H) 7.38 (d, J=l0.35 Hz, 1 H) 7.42 - 7.52 (m, 2 H) 7.56 - 7.79 (m, 4 H) 55an 1H NMR (400 MHz, MeOH-d4): o ppm 1.48 - 1.66 (m, 4 H) 2.01 (dd, J=13.37, 7.17 Hz, 1 H) 2.28 (dd, J=l3.35, 9.20 Hz, 1 H) 3.06 (d, J=l 1.71 Hz, 1 H) 3.20 (d, J=l 1.67 Hz, 1 H) 3.35 - 3.52 (m, 2 H) 3.53 - 3.69 (m, 2 H) 3.81 (s, 3 H) 4.02 (dd, J=9.15, 7.20 Hz, 1 H) 5.53 (s, 1 H) 6.61 (q, J=7.21 Hz, 1 H) 6.89 (dd, J=8.20, 2.49 Hz, 1 H) 7.06 - 7.21 (m, 2 H) 7.26 - 7.38 (m, I H) 7.47 - 7.68 (m, 4 H) 55ao 1H NMR (400 MH z, MeOH-d4): o ppm 1.63 - 1.87 (m, 4 H) 2.10 (dd, J=13.72, 8.69 Hz, 1 H) 2.48 - 2.62 (m, 1 H) 3.33 (s, 0 H) 3.52 - 3.81 (m, 4 H) 3.84 (s, 3 H) 4.55 (t, J=8.81 Hz, 1 H) 5.93 (s, 0 H) 6.59 (d, J=6.25 Hz, 1 H) .71 (dt, J=l0.75, 2.26 Hz, 1 H) 6.90 - 7.02 (m, 2 I-I) 7.51 - 7.80 (m, 4 H). 55ap 1H NMR (400 MHz, MeOH-d4): o ppm 1.63 - 1.85 (m, 4 H) 2.10 (dd, J=13.64, 8.66 Hz, 1 H) 2.50 (dd, J=13.64, 8.81 Hz, 1 H) 3.51 - 3.88 (m, 5 H) 4.55 (t, J=8.71 Hz, 1 H) .93 (s, 1 H) 6.63 (q, J=6.61 Hz, 1 H) 6.96 (tt, 1=9.06, 2.31 Hz, 1 H) 7.20 - 7.33 (m, 2 H) 7.62 - 7.80 (m, 4 H). 55aq 1H NMR (400 MHz, MeOH-d4): o ppm 1.60 - 1.87 (m, 4 H) 2.09 (dd, J=B.64, 8.76 Hz, 1 H) 2.50 (dd, 9, 8.86 Hz, 1 H) 3.51 - 3.79 (m, 4 H) 3.81 (s, 3 H) 4.56 (t, J=8.74 Hz, 1 H) 5.88 - 5.99 (m, 1 H) 5.93 (s, 1 H) 6.57 (d, J=6.39 Hz, 1 H) 6.94 - 7.04 (m, 2 H) 7.50 - 7.70 (m, 6 H) 55ar 1H NMR (400 MHz, MeOH-d4): s ppm 1.67 - 1.87 (m, 4 H) 2.10 (dd, J=13.64, 8.71 Hz, 1 H) 2.51 (dd, J=13.59, 8.86 Hz, 1 H) 3.54 - 3.77 (m, 4 H) 3.78 (s, 4 H) 4.57 (t, J=8.76 Hz, 1 H) 5.95 (s, I H) 6.59 (q, J=6.22 Hz, 1 H) 7.00 (td, J=7.46, 0.95 Hz, I H) 7.06 (d, J=8.10 Hz, 1 H) 7.19 -7.38 (m, 2 H) 7.48 - 7.66 (m, 4 H) 55as 1H NMR (400 MH z, MeOH-d4): o ppm 1.60 - 1.86 (m, 4 H) 2.10 (dd, J=13.64, 8.66 Hz, 1 H) 2.50 (dd, J=13.62, 8.83 Hz, 1 H) 3.53 - 3.87 (m, 4 H) 4.54 (t, J=8.71 Hz, 1 H) .93 (s, 0 H) 6.64 (q, J=6.65 Hz, 1 H) 7.61 - 7.72 (m, 4 I-I ) 7.73 - 7.80 (m, 2 H) 7.84 - 7.94 (m, 2 H) 55at 1H NMR (400 MHz, MeOH-d4): s ppm 1.67 - 1.84 (m, 4 H) 2.10 (dd, J=13.67, 8.69 Hz, 1 H) 2.51 (dd, J=l3.69, 8.81 Hz, 1 H) 3.55 - 3.82 (m, 4 H) 4.56 (t, J=8.76 Hz, 1 H) .95 (s, I H) 6.63 (q, J=6.56 Hz, 1 H) 7.29 (dt, J=8.19, 1.15 Hz, 1 H) 7.48 - 7.58 {m, 2 H) 7.61 - 7.76 (m, 5 H) 55au 1H NMR (400 MHz, Me0H-d4): s ppm 1.39 (t, J=7.00 Hz, 3 H) 1.65 - 1.86 (m, 4 H) 2.09 (dd, J=l3.64, 8.76 Hz, I H) 2.50 (dd, 2, 8.79 Hz, 1 H) 3.51 - 3.84 (m, 4 H) 4.07 (q, J=6.98 Hz, 2 H) 4.57 (t, J=8.74 Hz, 1 H) 5.94 (s, l H) 6.61 (q, J=6.57 Hz, 1 H) 6.82 - 6.95 (m, 1 H) 7.06 - 7.20 (m, 2 H) 7.28 - 7.43 (m, 1 H) 7.55 - 7.73 (m, 4 H) 55av 1H NMR (400 MHz, Me0H-d4): o ppm 1.32 (d, 1=6.05 Hz, 6 H) 1.65 - 1.86 (m, 4 I-I ) 2.09 (dd, 7, 8.69 Hz, 1 I-1) 2.50 (dd, J=13.64, 8.86 Hz, 1 H) 3.48 - 3.85 (m, 4 H) 4.55 (t, J=8.71 Hz, 1 H) 4.65 (dt, J=l2.08, 6.06 Hz, 1 H) 5.92 (s, 1 H) 6.59 (q, J=6.43 Hz, 1 H) 6.91 (dd, J=8.22, 1.93 Hz, I H) 7.11 (t, J=2.03 Hz, 1 H) 7.15 (d, J=7.71 Hz, 1 H) 7.29 - 7.39 (m, 1 H) 7.56 - 7.73 (m, 4 H) 55aw 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.62 - 1.93 (m, 4 H) 2.11 (dd, J=13.69, 8.76 Hz, 1 H) 2.54 (dd, J=13.69, 8.86 Hz, 1 H) 3.46 - 4.00 (m, 4 H) 4.59 (t, J=8.74 Hz, 1 H) 6.01 (s, 1 H) 6.74 (q, J=6.65 Hz, 1 H) 7.75 - 8.02 (m, 4 H) 8.20 (dd, J=8.22, 5.78 Hz, 1 H) 8.87 (d, J=5.71 Hz, 1 H)8.97 (dt, , 1.72 Hz, 1 H) 9.24 (d, J=2.00 Hz, 1 I-I) 55ax 1H NMR (400 MHz, MeOI-I-d4): s ppm 1.64 - 1.90 (m, 4 H) 2.11 (dd, J=13.67, 8.79 Hz, 1 H) 2.52 (dd, J=13.64, 8.86 Hz, 1 H) 3.49 - 4.02 (m, 4 H) 4.57 (t, J=8.71 Hz, 1 H) 6.01 (s, 1 H) 6.76 (d, J=6.54 Hz, 1 H) 7.85 (d, J=8.35 Hz, 2 H) 8.09 (d, J=8.49 Hz, 2 H) 8.33 - 8.54 (m, 2 H) 8.80 - 8.99 (m, 2 H) 55ay 1H NMR (400 MHz, MeOH-d4): o ppm 1.56 - 1.91 (m, 4 H) 2.10 (dd, J=13.69, 8.66 Hz, 1 H) 2.51 (dd, J=13.81, 8.83 Hz, 1 H) 3.53 - 3.94 (m, 5 H) 4.56 (dt, J=8.48, 4.37 Hz, 1 H) 5.89 - 6.14 (m, 1 H) 6.51 - 6.82 (m, 1 H) 7.48 - 8.01 (m, 4 H) 9.19 (s, 1 H) 9.24 (s, 1 H) 55az 1H NMR (400 MHz, MeOH-d4): s ppm 1.60 (t, J=5.08 Hz, 4 H) 2.00 (s, 2 H) 2.03 - 2.13 (m, 1 I-I) 2.26 - 2.39 (m, 1 H) 2.52 - 2.64 (m, 4 H) 3.07 - 3.18 (m, 1 H) 3.26 (d, J=l 1.71 Hz, 1 H) 3.39 - 3.57 (m, 2 H) 3.57 - 3.77 (m, 2 H) 4.01 - 4.20 (m, 1 H) 5.58 (s, 1 H) 6.67 (s, 1 H) 7.40 (dd, J=8.49, 1.07 Hz, 1 H) 7.59 - 7.68 (m, 3 H) 7.69 - 7.79 (m, 3 55ba 1H NMR (400 MHz, Me0H-d4): 8 ppm 1.4 7 - 1.74 (m, 4 H) 1.99 - 2.13 (m, 1 H) 2.26 - 2.40 (m, 1 H) 2.55 (s, 3 H) 3.07 - 3.19 (rn, 1 H) 3.21 3.29 (m, lH) 3.48 (d, J=4.88 Hz, 2 H) 3.65 (d, J=3.32 Hz, 2 H) 4.01 (s, 3 H) 4.10 (dd, J=8.98, 7.22 Hz, 1 H) 5.59 (s, 1 H) 6.69 (d, J=7.03 Hz, 1 H) 7.41 (dd, J=8.49, 1.07 Hz, 1 H) 7.58 - 7.70 (m, 3 H) 7.70 - 7.84 (m, 3 H) 55bb 1H NMR (400 MHz, MeOH-d4): o ppm 1.58 (br, s., 4 H) 1.95 - 2.09 (m, 1 H) 2.24 - 2.38 (m, 1 H) 2.63 (s, 3 H) 3.01 - 3.14 (m, 1 H) 3.17 3.25 (m, 1 H) 3.38-3.54 (m, 2 H) 3.55-3.74 (m, 2H) 55bc 1H NMR (400 MHz, MeOH-d4): o ppm 1.62 (hr. s., 4 H) 1.97 - 2.09 (m, I H) 2.24 - 2.36 (m, 1 H) 3.07 (s, 3 H) 3.18 - 3.27 (m, 1 H) 3.55 (s, 4 H) 3.60 - 3.75 (m, 2 H) 3.96 - 4.07 (m, 1 H) 5.59 (s, 1 H), 6.61 - 6.75 (m, 1 H) 7.54 - 7.61 (m, 1 H) 7.66 (s, 3 H) 7.72 (s, 2 H) 7.95 - 8.08 (m, 1 H) 55bd 1H NMR (400 MHz, MeOH-d4): o ppm 1.50 - 1.68 (m, 4 H) 1.86 - 2.01 (m, I H) 2.11 - 2.28 (m, 1 H) 2.77 - 2.91 (m, I H) 3.04 - 3.13 (m, 1 H) 3.40 - 3.57 (m, 2 H) 3.59 - 3.74 (m, 2 H) 3.76 - 3.88 (m, 1 H) 5.54 - 5.66 (m, 1 H) 6.61 - 6.79 (m, 1 H) 7.67 - 7.77 (m, 2 H) 7.81 - 7.97 (m, 3 I-1) 7.99 - 8.09 (m, 1 H) 8.16 - 8.27 (m, 2 H) 8.41 - 8.53 (m, l H) 9.21 - 9.33 (m, 1 H) 55be 1H NMR (400 MHz, 4): o ppm 1.50 - 1.65 (m, 4 H) 1.92 - 2.00 (m, l H) 2.14 - 2.28 (m, 1 H) 2.84- 2.94 (m, 1 H) 3.04 - 3.16 (m, 1 H) 3.40 - 3.57 (m, 2 H) 3 .58- 3.73 (m, 2 H) 3.79 - 3.91 (m, 1 H) 5.59 (s, 1 H) 6.62 - 6.78 (m, 1 H) 7.64 - 7.75 (m, 2 H) 7.86 (d, J=8.59 Hz, 3 H) 8.01 - 8.09 (m, l H) 8 .10 - 8.20 (m, I H) 8.35 - 8.42 (m, 1 H) 8.43 - 8.48 (m, 1 H) 9.25 - 9.37 (m, 1 H) 55bf 1H NMR (400 MHz, MeOH-d4): o ppm 1.61 (br. s., 4 H) 1.94 - 2.04 (m, 1 H) 2.28 (s, 7 H) 2.92 - 3.06 (m, I H) 3.11 -3.23 (m, l H) 3.53 (s, 4 H) 3.59 - 3.75 (m, 2 H) 3.89 - 4.02 (m, 1 H) 5.58 (s, 1 H) 6.60 - 6.70 (m, 1 H) 7.43 (s, 2 H) 7.57 - 7.74 (m, 6 H) 55bg 1H NMR (400 MHz, MeOH-d4): o ppm 1.56 (d, J=4.69 Hz, 4 H) 1.78 - 1.95 (m, 1 I-1) 2.07 - 2.22 (m, 1 H) 2.69 - 2.83 (m, 1 H) 2.96 - 3.09 (rn, 1 H) 3.38 - 3.54 (m, 2 H) 3.56 - 3.69 (m, 2 H) 3.70- 3.79 (m, l H) 5.57 (s, 1 H) 6.59 - 6.77 (m, I H) 7.51 - 7.61 (m, 1 H) 7.68 (d, J=8.00 Hz, 2 H) 7.83 (d, J=8.20 Hz, 2 H) 8.11 (s, 2 H) 8.20 (s, 1 H) 8.38 - 8.50 (m, I H) 8.77 - 8.92 (m, 1 H) 55bh 1HNMR (400 MHz, MeOH-d4): o ppm 1.57 (br. s., 4 H) 1.84 - 2.03 (m, 1 H) 2.12 - 2.29 (m, I H) 2.91 (s, 1 H) 3.04 - 3.16 (m, 1 H) 3.38 - 3.55 (m, 2 H) 3.56 - 3.73 (m, 2 H) 3.78 - 3.96 (m, 1 H) 5.58 (s, 1 H) 6.60 - 6.80 (m, 1 H) 7.47 - 7.58 (m, 1 H) 7.69 (d, J=8.20 Hz, 2 H) 7.83 (d, J=8.20 Hz, 2 H) 7.93 (d, J=l.17 Hz, 1 H) 8.02 (d, J=8.59 Hz, 1 H) 8.25 (s, I H) 8.37 (s, 1 H) 8.87 (d, J=2.93 Hz, I H) 55bi 1H NMR (400 MHz, MeOH-d 4): s ppm 1.56 (d, J=5.08 Hz, 4 H) 1.76 - 1.88 (m, 1 H) 2.05 - 2.20 (m, I H) 2.63 - 2.81 (m, 1 H) 2.94 - 3.07 (m, 1 H) 3.37 - 3.54 (m, 2 H) 3.55 - 3.79 (m, 3 H) 5.58 (s, lI-I) 6.61 - 6.78 (m, 1 H) 7.71 (d, J=8.20 Hz, 2 H) 7.86 (d, J=8.40 Hz, 2 H) 8 .17 (s, 2 H) 8.32 (s, I H) 8.89 (dd, J=12.98, 1.66 Hz, 2 H) 55bj 11-I NMR (400 MHz, 4): 8 ppm 1.54 - 1.72 (m, 4 H) 2.01 - 2. 13 (m, 1 H) 2.27 - 2.41 (m, 1 H) 3.06 - 3 .16 (m, 3 H) 3.18 (s, 3 H) 3.22 - 3.30 (m, 1 H) 3.41 - 3.59 (m, 2 H) 3.67 (s, 4 H) 4.02 - 4 .16 (m, 1 H) 5.53 - 5.66 (m, 1 H) 6.61 - 6.74 (m, I H) 7.54 - 7.57 (m, 1 H) 7.61 - 7.67 (m, 3 H) 7.70 - 7.80 (m, 2 H) 7.96 - 8.06 (m, 1 H) 55bk 1HNMR (400 MHz, Me0H-d4): 6 ppm 1.54- 1.72 (m, 4 H) 2.05 - 2.18 (m, 1 H) 2.29 - 2.43 (m, 1 H) 3.08 - 3.20 (m, 1 H) 3.24 - 3.29 (m, 1 H) 3.43 - 3.76 (m, 4 H) 4.05 - 4.17 (m, 1 H) 5.57 - 5.67 (m, 1 H) 6.64 - 6.79 (m, 1 H) 7.65 - 7.76 (m, 2 H) 7.83 - 7.94 (m, 2 H) 8.08 - 8.19 (m, 1 H) 8.32 - 8.48 (m, 2 H) 9.21 - 9.33 (m, 1 H) 9.56 - 9.67 (m, I H) 55bp 1H NMR (400 MHz, MeOH-d4): o ppm 1.60 (q, J = 5.9, 5.2 Hz, 4H), 1.98 (m, SH), 2.32 (dd, J = 13.4, 9.3 Hz, lH), 3.12 (d, J = 11.8 Hz, lH), 3.25 (d, J = 11 .7 Hz, lH), 3.50 (m, 4H), 3.61 (m, 4H), 4.08 (dd, J = 9.2, 7.2 Hz, lH), 5.57 (s, IH), 6.67 (q, J = 7.1 Hz, lH), 7.61 (ddd, J = 356.8, 7.9, 5.7 Hz, 4H), 7.71 (m, 4H) 55cc 1H NMR (400 MHz, MeOH-d4): s ppm 0.09 (d, J = 1.2 Hz, OH), 1.28 (s, OH), 1.61 (q, J = 5.3 Hz, OH), 1.92 (m, OH), 2.05 (dd, J = 13.3, 7.3 Hz, OH), 2.32 (m, OH), 3 .10 (s, OH), 3.29 (s, 2H), 3.53 (s, OH), 3.65 (s, lH), 3.80 (dd, J = 16.8, 1.2 Hz, OH), 4.07 (t, J = 8.2 Hz, OH), 4.89 (d, J = 3.8 Hz, OH), 5.56 (d, J = 1.2 Hz, OH), 5.99 (m, OH), 6.60 (m, OH), 7.21 (dd, J = 8.4, 1.2 Hz, OH), 7.48 (d, J = 1.2 Hz, IH) 55ce 1H NMR (400 MHz, DMSO-d6): s ppm 1.58 (q, J = 6.7, 6.1 Hz, 4H), 1.94 (dd, J = 13.2, 9.1 Hz, IH), 2.39(dd, J = 13.3, 8.6 Hz, 11- I), 3.20 (s, 2H), 3.80 (m, 3H), 4.54 (t, J = 8.4 Hz, lH), 5.74 (s, lH), 6.31 (s, 2H), 6.90 (q, J = 7.2 Hz, lH), 7.49 (t, J = 6.5 Hz, 3H), 7.76(m, 6H), 9.01 (dt, J = 21.8 , 11.9 Hz, IH), 9.74 (d, J = 11. 9 Hz, lH) 55cg 1H NMR (400 MHz, DMSO-d6): s ppm 1.59 (m, 4H), 2.00 (s, 7H), 2.41 (m, lH), 3.20 (s, 2H), 3.60 (m, 4H), 3.83 (m, lH), 4.53 (d, J = 8.7 Hz, 1H), 5.74 (s, lH), 6.34 (dd, J = 28. l , 14.7 Hz, 2H), 6.91 (q, J = 7.4 Hz, lH), 7.24 (m, SH), 7.67(d, J = 7.8 Hz, 2H), 8.99(s, IH), 9.77 (d, J = 8.4 Hz, ll-I) 55cj 1H NMR (400 MHz, DMSO-d6): s ppm 1.29 (d, J = 6.8 Hz, 6H), 1.58 (m, 4H), 1.94 (dd,J = 13.2 , 9.2 Hz, lH), 2.39 (dd, J = 13.4, 8.6 Hz, lH), 2.99 (hept, J = 7.1 Hz, 1H), 3.19 (s, 2H), 3.59 (m, 4H), 4.55 (d,J = 9.2 Hz, IH), 5.73 (s, lH), 6.28 (m, 2H), 6.81 (q, J = 7.4 Hz, lH), 7.41 (d, J = 7.9 Hz, 2H), 7.65(m, 4H), 7.78 (d, J = 8.0 Hz, 2H), 8.97 (d, J= 13.6 Hz, lH), 9.76 (s, IH) 55ck 1H NMR (400 MHz, DMSO-d6): 8 ppm 0.99 (s, ll- 1), 1.31 (d, J = 6.9 Hz, 7H), 1.58 (m, 4H), 1.94(dd, J = 13.2, 9.2 Hz, lH), 2.39 (dd, J = 13.4, 8.6 Hz, IH), 3.02 (hept, J = 7.2 Hz, lH),3.19 (s, 2H), 3.55 (ddd, J= 19.7, 12.2, 5.9 Hz, 2H), 3.86 (s, 2H), 4.05 (s, IH), 4.54 (q, J = 8.9, 6.7 Hz, lH), 5.73(s, lH), 6.31 (m, 2H), 6.81 (q, J = 7.3 Hz, lH), 7.46 (m, SH), 7.65 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 21-I), 8.96 (dt, J = 20.8, 8.6 Hz, lH), 9.77 (d, J = 8.5 Hz, lH) 55cp 1H NMR (400 MHz, DMSO-d6): s ppm 1.29 (s, lH), 1.57 (dd, J = 9.4, 5.0 Hz, 12H), 1.94 (dd, J = 13.3, 9.1 Hz, 3H), 2.28 (s, 9H), 2.41 (m, 4H), 2.61 (d, J = 7.4 Hz, IH), 3.19 (s, 7H), 3.59 (m, 13H), 4.15 (s, lH), 4.55 (d, J = 8.4 Hz, 4H), 5.75 (s, 3H), 6.38 (m, SH), 6.87 (q, J = 7.4 Hz, 3H), 7.46 (m, 22H), 8.98 (m, 3H), 9.76 (m, 3H) 55cq 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.60 (m, 4H), 2.05 (m, lH), 2.34 (s, 71-I), 3.12 (d, J = 11.5 Hz, IH), 3.24 (d, J = 11.5 Hz, lH), 3.49 (m, 2H), 3.64 (dq, J = 12.6, 6.5, 4.7 Hz, 2H), 4.08 (t, J = 8.2 Hz, lH), 5.56 (s, lH), 6.64 (q, J = 7.1 Hz, IH), 6.99 (s, un, 7.21 (s, 2H), 7.59 (m, SH) 55cr 1H NMR (400 MHz, DMSO-d6): s ppm 1.29 (s, 1 H), 1.58 (dq, J = 11.6, 7.5, 7.1 Hz, l lH), 1.94 (dd, J = 13.3, 9.1 Hz, 3H), 2.15 (s, OH), 2.39 (dd, J = 13.3, 8.6 Hz, 3H), 2.61 (d, J = 8.8 Hz, 3H), 3.05 (s, OH), 3.19 (s, 6H), 3.40 (s, l H), 3.54 (h, J = 6.4 Hz, 3H), 3.81 (m, 4H), 4.01 (dd, J = 19.9, 11.7 Hz, lH), 4.16 (s, lH), 4.54 (t, J = 8.6 Hz, 3H), .73 (s, 3H), 6.28 (d, J = 15 . 5 Hz, SH), 6.81 (q, J = 7.3 Hz, 3H), 7.63 (m, 1 lH), 7.86 (dd, J = 17.4, 7.8 Hz, 81-l), 8.99 (dq, J = 23.7, 15.7, 12.4 Hz, 2H), 9.72 (s, 3H) 55cs 1H NMR (400 MHz, DMSO-d6): o ppm 1.57 (rn, J = 8.0, 6.2 Hz, 8H), 1.94 (dd, J = 13.2, 9.2 Hz, 2H), 2.23 (s, 6H), 2.34 (s, SH), 3.20 (s, SH), 3.57 (dp, J = 22.0, 7.4, 6.0 Hz, 9H), 4.54 (t, J = 8.4 Hz, 3H), 5.76 (s, 2H), 6.34 (d, J = 14.9 Hz, lH), 6.45 (s, l H), 6.86 (q, J = 7.4 Hz, 2H), 7.18 (m, 6H), 7.56 (dd, J = 46. 1 , 7.8 Hz, 8H), 8.99 (m, 2H), 9.77 (d, J = 15.0 Hz, 2H) 55ct 1H NMR (400 MHz, DMSO-d6): 8 ppm 0.97 (t, J = 7.3 Hz, 3H), 1.50 (m, 9H), 1.94 (dd, J = 13.3, 9.2 Hz, IH), 2.39 (dd, J = 13.3, 8.6 Hz, lH), 2.67 (q, J = 6.9, 6.2 Hz, 2H), 3.19 (s, 2H), 3.57 (m, SH), 3.85 (m, IH), 4.06 (d, J = 16.1 Hz, lH), 4.54 (m, lH), 5.74 (s, IH), 6.31 (s, 2H), 6.81 (q, J = 7.3 Hz, lH), 7.35 (d, J = 7.8 Hz, 2H), 7.64 (d, J = 7.8 Hz, 4H), 7.78 (d, J = 8.0 Hz, 21-1), 8.96 (m, lH), 9.73 (d, J = 8.2 Hz, lH) 55cv 1HNMR (400 MHz, 6): s ppm 1.29 (s, lH), 1 .38 (s, lH), 1.58 (qd, J = 12.6, 8.1, 7.6 Hz, l lH), 1.95 (m, 8H), 2.43 (m, SH), 2.94 (t, J = 10.0 Hz, 1 H), 3 .08 (dd, J = 16.3, 7.0 Hz, lH), 3.19 (s, 6H), 3.33 (s, 8H), 3.52 (m, 4H), 3.82 (m, SH), 4.11 (m, 4H), 4.53 (dt, J = 12.6, 6.0 Hz, 3H), 5.75 (s, 2H), 6.20 (s, lH), 6.28 (d, J = 9.3 Hz, 2H), 6.48 (s, 3H), 6.84 (q, J = 7.3 Hz, 2H), 7.56 (s, lH), 7.93 (m, 21H), 8.98 (dd, J = 13.6, 8.0 Hz, 2H), 9.71 (m, 2H) 55cw 1H NMR (400 MHz, DMSO-d6): 3 ppm 1.29 (s, lH), 1.5 8 (dd, J = 7.3, 4.2 Hz, 8H), 1.94 (dd, J = 13.2, 9.1 Hz, 2H), 2.14 (d, J = 1.4 Hz, OH), 2.40 (s, 8H), 2.49 (d, J = 9.3 Hz, OH), 3.03 (m, II-I), 3.19 (s, SH), 3.55 (rn, 3H), 3.81 (t, J = 8.1 Hz, OH), 4.00 (m, 8H), 4.24 (rn, OH), 4.35 (m, lH), 4.54 (m, 2H), 5.74 (s, 2H), 6.31 (m, 3H), 6.80 (q, J = 7.3 Hz, 2H), 7.34 (d, J = 7.8 Hz, 4H), 7.64 (d, J = 8.1 Hz, 8H), 7.78(m, 4H), 8.99 (q, J = 8.5, 7.4 Hz, 2J-l), 9.74 (s, 2H) 55cx 1H NMR (400 MHz, DMSO-d6): 8 ppm 1.29 (s, lH), 1.59 (m, 1 lH), 1.94 (dd, J = 13.3 , 9 . 1 Hz, 3H), 2.43 (s, l ll-I), 2.61 (d, J = 9.0 Hz, ll-I), 3.19 (s, 6H), 3.58 (m, 11H ) , 4.13 (s, lH), 4.54 (m, 6H), 5.75 (s, 2H), 6.26 (s, 1H), 6.34 (s, lH), 6.42 (s, 21-I ), 6. 8 1 (q, J = 7.3 Hz, 3H), 7.27 (d, J = 7.5 Hz, 3H), 7.58 (m, 20H), 8.98 (s, 3H), 9.77 (d, J = 9.9 Hz, 55db 1H NMR (400 MHz, MeOH-d4): s ppm 1.24 (m, 8H), 1 .76 (dd, J = 12.6, 6.8 Hz, 9H), 2.01 (s, 3H), 2 . 12 (m, 4H), 2.51 (dd, J = 13.6, 8.8 Hz, 3H) , 2.63 (td, J = 7.6, 5.4 Hz, 4H), 2.90 (m, 6H), 3.36 (d, J = 12.8 Hz, 7H), 3.63 (dt, J = 11.5 , 5.0 Hz, 4H), 3.76 (m, 4H), 4.11 (qd, J = 7.1, 3.6 Hz, 4H), 4.56 (t, J = 8.7 Hz, 3H), 4.94 (s, 2H), 6.62 (dq, J = 19.2, 6.7 Hz, 3H), 7.02 (dt, J = 6.2, 2.0 Hz, 3H), 7.16 (m, 2H), 7.38 (m, 2H), 7.65 (m, 9H), 7.84 (m, lH) 55dc 1H NMR (400 MHz, Me0H-d4): 8 ppm 1.58 (t, J = 5.4 Hz, 4H), 2.02 (dd, J = 13.4, 7.0 Hz, 1 H), 2.29 (dd, J = 13.4, 9.1 Hz, lH), 3.08 (d, J = 11.6 Hz, lH), 3.21 (d, J = 11.5 Hz, lH), 3.46 (ddt, J = 20.6, 13.2, 5.7 Hz, 2H), 3.61 (d, J = 16.6 Hz, 2H), 4.05 (t, J = 8.1 Hz, lH), 4.94 (s, lOH), 5.58 (s, lH), 6.69 (q, J = 7.2 Hz, lH), 7.66 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 7.9 Hz, 2H), 8.00 (dd, J = 8.9, 1.9 Hz, lH), 8.12 (m, 3H), 8.79 (d, J = 2.7 Hz, lH) 55dd 1I-I NMR (400 MHz, Me0H-d4): 8 ppm 1.05 (t, J = 7.4 Hz, 3H), 1.29 (d, J = 5.8 Hz, lH), 1.59 (q, J = 5.8, 5.0 Hz, 4H), 1.80 (h, J = 6.9 Hz, 2H), 2.04 (dd, J = 13.5, 7.1 Hz, lH), 2.32 (dd, J = 13.4, 9.2 Hz, lH), 3.11 (d, J = 11.8 Hz, lH), 3.23 (d, J = 12.0 Hz, lH), 3.47 (ddt, J = 20.6, 13. 1 , 6.1 Hz, 2H), 3.64 (m, 2H), 3.96 (t, J = 6.4 Hz, 2H), 4.07 (dd, J = 9 .1, 7.3 Hz, lH), 5.55 (s, lH) , 6.62 (q, J = 7.1 Hz, lH), 6.97 (m, 2H), 7.56 (m, 55dc 1H NMR (400 MHz, 4): 8 ppm 1. 15 (t, J = 7.0 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.61 (q, J = 5.9, 5.1 Hz, 4H), 2.05 (dd, J = 13.4, 7.2 Hz, lH), 2.32 (dd, J = 13.4, 9.2 Hz, I H), 3.11 (d, J = 11.8 Hz, HI), 3.24 (d, J = 11.6 Hz, lH), 3.35 (m, 3H), 3.56 (dddd, J = 47.5, 27.9, 14.5, 7.8 Hz, 61-I), 4.07 (dd, J = 9.2, 7.1 Hz, lH), 4.92 (s, 17H), .57 (s, lH), 6.66 (q, J = 7.1 Hz, lH), 7.46 (m, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.71 (m, 55df 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.28 (s, 1H), 1.64 (m, 4H), 2.07 (dd, J = 13.5, 7.6 Hz, IH), 2.39 (dd, J = 13.5, 9.0 Hz, lH), 3.17 (d, J = 11.7 Hz, lH), 3.27 (d, J = 12.0 Hz, 2H), 3.53 (dt, J = 22.9, 7.5 Hz, 2H), 3.67 (td, J = 13.8, 13.2, 6.4 Hz, 2H), 4.26 (t, J = 8.3 Hz, lH), 4.87 (m, 31-I ), 6.66 (q, J = 7.0 Hz, lH), 7.63 (d, J = 8.1 Hz, 2H), 7.74 (m, 4H), 7.96 (m, 2H) 55dg 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.3 1 (dd, J = 17.3, 3.8 Hz, 2H), 1.62 (m, 4H), 2.06 (dd, J = 13.5, 7.4 Hz, lH), 2.36 (dd, J = 13.5, 9.1 Hz, lH), 2.93 (s, 3H), 3. 15 (d, J = 1 1 .9 Hz, lH), 3.26 (d, J = 11.6 Hz, 11-I), 3.51 (m, 2H), 3.64 (dq, J = 12.1, 6.4, 5.1 Hz, 2H), 4.18 (dd, J = 9.1, 7.5 Hz, lH), 4.93 (d, J = 1.7 Hz, 19H), 6.66 (q, J = 7.1 Hz, lH) , 7.63 (d, J = 8.1 Hz, 2H), 7.72 (dd, J = 8.3, 5.9 Hz, 4H), 7.89 (m, 2H) 55dh 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.60 (q, J = 6.0, 5.0 Hz, 4H), 2.03 (dd, J = 13.4, 7.2 Hz, IH), 2.31 (dd, J = 13.4, 9.2 Hz, IH), 2.59 (dt, J=24.2, 5.7 Hz, 6H), 3 .10 (d, J = 11.7 Hz, lH), 3.23 (d, J = 1 1 .9 Hz, lH), 3.62 (m, lOH), 4.06 (dd, J = 9.2, 7.2 Hz, lH), 4.87 (s, lH), 5.57 (s, lH), 6.66 (q, J = 7.1 Hz, lH), 7.62 (d, J = 8.1 Hz, 2H), 7.72 (m, 4H), 7.91 (m, 2H) 55di 1I-I NMR (400 MHz, MeOH-d4): 8 ppm 1.61 (d, J = 5.5 Hz, 4H), 2.05 (dd, J = 13.4, 7.1 Hz, lH), 2.32 (dd, J = 13.4, 9.3 Hz, lH), 3.15 (s, 4H), 3.25 (d, J = 11.6 Hz, lH), 3.50 (dt, J = 20.2, 7.0 Hz, 2H), 3.64 (m, 2H), 4.09 (dd, J = 9.2, 7.1 Hz, 11-1), 5.58 (s, lH), 6.68 (q, J = 7.2 Hz, lH), 7.65 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 8.01 (m, 2H) 55dj 1HNMR (400 MHz, MeOH-d4): s ppm 1.28 (s, lH), 1.60 (q, J = 6.4, 5.0 Hz, 4H), 2.03 (dd, J = 13.4, 7.1 Hz, lH) , 2.31 (dd, J = 13.4, 9.2 Hz, 1H), 3.10 (d, J = 11.7 Hz, lH) , 3.23 (d, J = 11.8 Hz, UI) , 3.48 (m, 2H), 3.63 (m, 2H), 4.06 (dd, J = 9.2, 7.1 Hz, lH) , .57 (s, lH), 6.67 (q, J = 7.1 Hz, lH), 7.68 (m, 4H), 7.79 (m, 2H), 7.96 (m, 2H) 55dk 1H NMR (400 MHz, MeOH-d4): s ppm 1.29 (d, J = 3.6 Hz, lH), 1.63 (q, J = 5.8 Hz, SH), 2.07 (dd, J = 13.5, 7.5 Hz, lH), 2.37 (dd, J = 13.5, 9.0 Hz, lH), 3.04 (s, 3H), 3.15 (d, J = 24.6 Hz, 6H), 3.27 (m, lH), 3.52 (dt, J = 24.6, 8.3 Hz, 2H), 3.65 (m, 2H), 4.23 (t, J = 8.1 Hz, lH), 6.66 (q, J = 7.0 Hz, lH), 7.51 (d, J = 8.1 Hz, 2H), 7.68 (m, 6H) 55dl 1H NMR (400 MHz, MeOH-d4): s ppm 1.29 (m, 3H), 1.60 (q, J = 6.1, 4.7 Hz, 4H), 2.05 (dd, J = 13.2, 7.0 Hz, lH), 2.32 (dd, J = 13.5, 9.2 Hz, HI), 3.13 (d, J = 11.6 Hz, lH), 3.26 (m, SH), 3.48 (ddd, J = 26.8, 12.6, 5.3 Hz, 2H), 3.64 (td, J = 19.2, 16.1, 9.2 Hz, 2H), 3.78 (s, lH), 3.90 (m, 3H), 4.10 (dd, J = 9.2, 7.1 Hz, lH), 4.95 (s, 13H), 5.56 (s, lH), 6.67 (q, J = 7.0 Hz, lH), 7.67 (m, 7H) 55dm 1H NMR (400 MHz, MeOH-d4): s ppm 1.06 (t, J = 7.4 Hz, 4H), 1.59 (d, J = 6.1 Hz, 51-I), 1.82 (dq, J = 14.1, 6.6 Hz, 2H), 2.02 (dd, J = 13.4, 7.2 Hz, lH), 2.30 (dd, J = 13.5, 9.2 Hz, lH), 3.07 (d, J = 11.6 Hz, lH), 3.21 (m, 2H), 3.48 (dt, J = 20.5, 6.6 Hz, 2H), 3.65 (d, J = 15.7 Hz, 2H), 4.03 (td, J = 7.7, 6.5, 5.1 Hz, 3H), 4.91 (m, 1H), 5.55 (s, lH), 6.63 (q, J = 7.2 Hz, lH), 7.13 (t, J = 8.7 Hz, 1H), 7.38 (m, 2H), 7.59 (q, J = 8.4 Hz, 4H) 55dn 1H NMR (400 MH z, Me0H-d4): o ppm 1.28 (d, J = 2.6 Hz, lH), 1.43 (t, J = 6.9 Hz, 3H), 1.60 (q, J = 5.8 Hz, 4H), 2.05 (dd, J = 13.1, 7.0 Hz, lH), 2.33 (dd, J = 13.4, 9.0 Hz, lH), 3 . 12 (d, J = 11 . 4 Hz, lH), 3.25 (d, J = 11.4 Hz, lH), 3.48 (m, 2H), 3.65 (q, J = 12.5, 10.8 Hz, 2H), 4.11 (dq, J = 16.7, 8.5, 7.7 Hz, 3H), 5.56 (s, lH), 6.63 (q, J = 7.0 Hz, lH), 7.13 (t, J = 8.6 Hz, lH), 7.38 (m, 2H), 7.59 (q, J = 8.1 Hz, 4H) 55do 1HNMR (400 MHz, MeOH-d4): s ppm 1.40 (t, J = 7.0 Hz, 3H), 1.60 (q, J = 5.9, 5.1 Hz, 4H), 2.05 (dd, J = 13.4, 7.2 Hz, lH), 2.33 (dd, J = 13.4, 9.2 Hz, lH), 3.12 (d, J = 1 1.7 Hz , II-I ), 3.24 (d, J = 11 . 7 Hz, lH), 3.47 (ddt, J = 20.2, 12.7, 5.6 Hz, 2H), 3.64 (m, 2H), 4.07 (p , J = 7.1 Hz, 3H), 5.56 (s, lH), 6.62 (q, J = 7.1 Hz, lH), 6.97 (m, 2H), 7.57 (m, 6H) 55dp 1H NMR (400 MHz, MeOH-d4): s ppm 1.28 (s, lH), 1.64 (d, J = 6.8 Hz, SH), 2.07 (dd, J = 13.5, 7.6 Hz, 11-l), 2.38 (dd, J = 13.5, 9.1 Hz, lH), 3 .17 (d, J = 11.8 Hz, lH), 3.27 (d, J = 11.8 Hz, lH), 3.52 (m, lH), 3.66 (m, l H), 4.24 (t, J = 8.3 Hz, 1H), 6.70 (p, J = 7.2 Hz, 1 H), 7.72 (d, J = 8.1 Hz, 3H), 7.90 (m, 3H), 8.28 (m, 3H), 8.53 (m, lH) , 9.31 (d, J = 5.9 Hz, lH) 55dq 1H NMR (400 MHz, Me0H-d4): s ppm 7.62- 7.49 (m, 4H), 7.33 -7.24 (m, 21-l ), 6.76 (d, J = 8.3 Hz, IH), 6.62 (q, J = 7.2 Hz, IH), 5.53 (s, lH), 4.19 -4.12 (m, 2H), 4.08 (dd, J = 9.1, 7.3 Hz, lH), 3.61 (s, 2H), 3.44 (ddt, J = 20.8, 13.4, 6.0 Hz, 2H), 3.22 (d, J = 11.7 Hz, lH) , 3.10 (d, J = 11.7 Hz, IH), 2.80 (t, J = 6.5 Hz, 2H), 2.30 (dd, J = 13.5, 9.2 Hz, 1!-1), 2.00 (ddd, J = 17.2, 12.5, 6.7 Hz, 3H), 1.57 (q, J = 5.9, 4.6 Hz, 4H), 1.27 (s, lH) Example 56: (S)(2-amino((R)-2,2,2-trifluoro-1 ,2,3,4-tetrahydroquinoxalin yl) phonyI) ethoxy)pyrimidinyl)-2,8-diazaspiroI4.5]decanecarboxylie acid Hydrolysis of (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro-l-(1,2,3,4-tetrahydroquinoxalin yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate (a by-product from the NCBZ ection of Example 55bi) using the LiOH l method provided the title compound as an off-white solid. 1H NMR (400 MHz, MeOH-d4): o 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 (rn , 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)(2-amino((R)-l-(3,4-clihydroquinazolinyl)-2,2,2- oroethoxy)pyrim idinyl)-2,8-diazaspiro[4.5]clecanecarboxylic acid fl�� �OOH N � NH ""- I OY'YN CF3 NyN Hydrolysis of (S)-ethyl 8-(2-amino((R)(3,4-dihydroquinazolinyl)-2,2,2- trifl uoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate (a by-product from the N-CBZ deprotection ofExample 55bk) using the LiOH genera l method provided the title compound as an off- white solid. 1H NMR (400 MHz, Me0H-d4) o 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, l H) 7.51 - 7.57 (m, 2 H) 7.57 - 7.64 (m, 2 H). LCMS (MH+): 583 Example 58: (S)(2-amino((R)-2,2,2-triflu oro(1,2,3,4-tetrahydroquinazolin yl)ethoxy) pyrimidinyl)-2,8-diazaspiro[4.5] clecanecarboxylie acid (�� (PO OH HN �e-: I OYYN NH CF3 NyN Hydrolysis of (S)-ethyl 8-(2-amino((R)-l-(3,4-dihydroquinazolinyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxy1ate (a by-product from the N-CBZ deprotection of Example 55bk) using the Li OH general method provided the title compound as an off-white solid. 1H NMR ( 400 MHz, 4) 8 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 (rn, 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)(2-amino((R)(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin y1)-2,8-diazaspiro [4.5]decane-S-carboxylic acid N-CBZ Deprotection was carried out using Method B with (S)(2-am ino((R)(4- bromopheny1)-2,2,2-triflu oroethoxy) pyrimidinyl)(benzyloxycarbony1)-2,8- diazaspiro [4.5]decanecarboxylic acid (75 mg, product of Step 3, Example 55an) providing the title compound as a white solid. 1HNMR (400 MHz, MeOH-d4): s ppm 1.5 0- 1.68 (m, 4 H) 1.96 (s, 2 H) 2.04 (dd, 5, 7.20 Hz, 1 H) 2.31 (dd, J=l3.35, 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, 1=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)(2-amino((R)-2,2,2-trifluoro(naphthalenyl)ethoxy)pyrimidin yl)-2,8-cliazaspiro[4.5]decanecarboxylic acid (Yn >,OH �O��N� CF3 N'fN The title compound was made as described for Example 1 Oe, starting with (R)-2,2,2-trifluoro (naphthalenyl)ethanol. 1H NMR (400 MHz, DMSO-d6): s ppm 1.20 (dt, J = 12.5, 5.3 Hz, 2H), 1.47 (m, 3H), 1.88 (dd, J = 12.4, 8.0 Hz, IH), 2.57 (s, HI), 2.69 (s, lH), 2.80 (d, J = 12.4 Hz, IH), 3.36 (m, 3H), 3.97 (dt, J = 12.3, 5.2 Hz, 2H), 6.05 (s, lH), 6.37 (m, 3H), 7.53 (m, 2H), 7.77 (dd, J = 7.5, 1.5 Hz, lI-1), 7.93 (m, 4H); LCMS (MH+): 562.
Example 59c: (S)(2-amino((R)-2,2,2-trifluoro(4-(3-fluoroquinoliuyl) methylphcnyl)ethoxy)pyrhnidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid >,OH F o�()-vN� CF3 NyN Step 1: To a on of omethylbenzoic acid (5.0 g, 23.2 mmol) in DMF (50 mL) was added potassium carbonate (6.4 g,46.4 mm ol) and iodomethane (6.6 g, 46.479 mmol). The mixture was stirr ed at RT for 12 h then diluted with water and extra cted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo.
Purification by normal phase silica gel column provided methyl 4-bromomethylbenzoate as a colorless oil.
Step 2: To a solution of methyl 4-bromomethylbenzoate (2 g, 8.7 mmol) in THF (20 mL) was added LAH (663 mg, 17.5 mmol) at 0°C. The mixture was stirred at RT for 1 h, then diluted with NaOH (I .OM, 10 mL) and extracted with ethyl acetate. The ed organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. Purification by normal phase silica gel column provided (4-bromomethylphenyl)methanol as a ess oil.
Step 3: To the solution of (4-bromomethylphenyl)methanol (1.8 g, 8.1 mmol) in CH2Ch (20 mL) was added Dess-Martin Periodinane (5.1 g, 12.1 mmol) at 0°C. The mixture was stirred at RT for 1 h, then diluted with water, and the solid was removed by fi ltra tion. The fi ltrate was extra cted with CH2Ch. The combined organic layer was washed with brine, dried over Na2S04 and concentra ted in vacuo. Purifi cation by normal phase silica gel column provided 4-bro mo benzaldehyde as a yellow oil.
Step 4: To a solution of 4-bromomethylbenzaldehyde (1.5 g, 7.5 mmol) in THF (20 mL) was added TMSCF3 (2.2 g, 15.5 mmol) at O'C and then TBAF (1.1 ml., THF). The mixture was stirred at RT for lh, then diluted with HCI (3.0 M, 10 mL), stirred at RT for 1 hand extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04 and concentra ted in vacuo. Purification by normal phase silica gel column pro vided 1-(4- bromomethylphenyl)-2,2,2-triflu oro ethanol as an off -white solid.
Step 5: To a solution of 1-(4-bromomethylphenyl)-2,2,2-triflu oro l (1.8 g, 6. 7 mmol) in CH2Ch (20 mL) was added Dess-Martin Periodinane (3.4 g, 8.1 mmol) at 0°C. The mixture was stirred at RT for 2 h, then diluted with water (IOmL) an d fil tered. The filt ra te was ted with CH2Ch. The combined organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. Purifi cation by normal phase silica gel column prov ided 1-(4-bromo methylphenyl)-2,2,2-trifl uoroethanone as a yellow oil.
Step 6: Chiral reduction of 1-(4-bromomethylphenyl)-2,2,2-tri:fl uoroethanone using the Iridium complex-catalyzed hydrogenation as described for ediate 1, (R)(4-bromo(3- methyl-I H-pyrazolyl)phenyl)-2,2,2-trifluoroethanol provides (R)(4-bromo methylphenyl)-2,2,2-trifluoroethanol.
Steps 7: The title compound was ed as described for (S)(2-amino((R)-2,2,2-trifluoro- 1-(31-methoxy-[l, 1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5Jdecane ylic acid (Example 55an) Steps 4-5. 3-Fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)quinolone was used as the Suzuki coupling partner (CAS# 12517313). 1HNMR(400MHz,MeOH-d4): oppm 1.28(s, lH), 1 .59(s,4H), 2.04(dd,J= 13.5, 7.0Hz, lH), 2.31 (dd, J = 13.3, 9.3 Hz, lH), 2.65 (s, 3H), 3. 10 (d, J = 1 1.7 Hz, lH), 3.23 (d, J = 11 .5 Hz, lH), 3.47 (t, J = 14.3 Hz, 2H), 3.63 (t, J = 13.8 Hz, 2H), 4.07 (t, J = 8.1 Hz, IH), 5.56 (s, lH), 6.87 (q, J = 7.0 Hz, IH), 7.63 (d, J = 4.6 Hz, 3H), 8.01 (d, J = 8.9 Hz, lH), 8.12 (m, 3H), 8.80 (m, IH). LCMS (MH+): 611 .
Example 59d: (S)(2-amino((R)(2-ethyl(3-fluoroquinolinyl)pbenyl)-2,2,2- trifluoroethoxy)pyrimiclinyl)-2,8-diazaspiro[4.S]decanecarboxylic acid /" )-oH F � O"j('y�NH CF3 N'fN Step 1: To a O °C solution of LDA (10.7 mL, 21.39 mmol) in THF (20 mL) was added mo- 2-methylbenzoic acid (2 g, 9.3 mmol) in THF (5 mL). The mixtu re was stirred at O °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 up to O °C, stirr ed for 3 h, then quenched with H20, and the pH was adjusted to 1-2 with 3 N HCL The mixture was then diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo.
Purific ation by normal phase silica gel column ed 4-bromoethylbenzoic acid as a white solid.
Step 2: The title compound was prepared as described above for (2-amino((R)-2,2,2- tri fluoro-l-I4-(3-fluoroquinoliny 1)methy lphenyl)ethoxy)pyrim idinyl)-2,8- diazaspiro ecanecarboxylie acid (Example 59c) starting with 4-bromoethylbenzoic acid in place of 4-bromomethylbenzoic acid. 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.29 (m, 1 H), 1.41 (t, J = 7.5 Hz, 3H), 1.59 (q, J = 6.1, .6Hz,4H),2.04(dd,J= 13.5, 7.1 Hz, lH),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, lH), 3.48 (dt, J = 21.5, 6.9 Hz, 2H), 3.62 (m, 2H) , 4.08 (dd, J = 9.1, 7.0 Hz, IH), 4.94 (s, 15H), 5.56 (s, ll-1), 7.00 (q, J = 6.9 Hz, lH), 7.67 (m, 3H), 8. 11 (m, SH), 8.80 (d, J = 2.8 Hz, lH). LCMS (M H+): 626.
Example 60: 9-(2-Amino((R)(4-chloi·o(3-methyl-lH-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrhnidinyl)-3,9-diazaspiro[5.5]undecanecarboxylic acid Step 1: To a solution of methyl 3,9-diazaspiro[5 .S]undecanecarboxylate (30 mg, 0.14 mmol) in dioxane (2 mL) I i-PrOH (2 mL) was added 4-chloro[(lR)[4-chloro{3-methylpyrazoll-yl )phenyl]-2,2,2-triflu oro-ethoxy]pyrimidinamine (92 mg, 0.22mmol), and the reaction was heated at 100 °C under ave for 3 h. The reaction was cooled to RT, and trated in vacuo. The residue was purifi ed by reversed phase HPLC (MeOH/H20/ 0.5% TFA) to provide methyl 9-(2-amino((R )(4-chloro(3-methyl-lHMpyra zolyl)phenyl)-2,2,2- trifluoro ethoxy)pyrimidinyl)-3 ,9-diazaspiro[5.5]undecanecarboxylate as an off-white solid.
Step 2: Hydrolysis of methyl 9-(2-amino((R)-lw(4-chlorow2-(3-methyl-1H-pyrazol-l- y1)phenyl)-2,2,2-trifluoroethoxy)pyrimidiny1)-3 ,9-diazaspiro [5.5]undecane-2Mcarboxylate using the LiOH general method es the title compound as an off-white solid. 1H NMR (400 MHz, MeOH-d4): 8 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=l2.59, 6.83 Hz, 1 H) 2.37 (d, J=l.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)(2-Amino((4-(3-methyl-lH-indazolyl)phenoxy)methyl)pyrimidin y1)-2,8-cliazaspiro [4.5] decanecarboxylic acid )-oH O��NH N'f'N NH2 Step 1: A mixture of 4-bromophenol (173 mg, 1.00 mmol), 4-chloro(chloromethyl)pyrimid in- 2-amine (CAS#: 923118) (178 mg, 1.16mmol) an d K2C03 ( 175 mg, 1.00 mmol) inDMF (5 mL) was heated to 100°C for 12 h. The on was cooled to RT, concentrated in vacuo, and the e taken up in and EtOAc. The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. Purifica tion on normal phase silica gel /petroleum ether) provided 4-((4-bromophenoxy)methyl)chloropyrimidinamine as a white solid.
Step 2: A mixture of 4-((4-Bromophenoxy)methyl)chloropyr imidinamine (454 mg, 1.4 mmol), (S)benzy l 3-ethyl 2,8-diazaspiro[4.5Jdecane-2,3-dicarboxylate (500 mg, 1.44 mmol) and NaHCOJ( 605 mg,7 mmol) in dioxane (5 mL) was heated to 100°C for 12 h. The reaction was cooled to RT, concentra ted in vacuo, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, and concentrated in vacuo. Purifi cation on normal phase silica gel (EtOAc/petro leum ether) ed (S)benzyl 3-ethyl 8-(2-amino ((4-bromophenoxy)methyl)pyrimidinyl)-2,8-diazaspiro[4.S]decane-2,3-dicarboxylate as a white solid.
Step 3: To a solution of (S)benzyl 3-ethyl 8-(2-amino((4-bromophenoxy)methyl)pyrimidin- 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 O °C. The mixture was stirred at O °C for 2 h, then concentrated in vacuo. The residue was dissolved in CH2Ch (20 mL) followed by the sequential addition of'EtsN (267 mg, 2.6 mmol), and (BOC)20 (285 mg, 1.3 mmol). The reaction mixture was stirred at RT for 16 h then trated in vacuo. Purification on normal phase silica gel (CH2Cb/MeOH) provides (S)tert-butyl 3-ethyl 8-(2-amino((4-bromop henoxy) methyl)pyrimidinyl)-2,8-diazaspiro[4. 5]decane-2,3-dicarboxylate as a light yellow solid.
Step 4: A mixture of (S)tert-butyl 3-ethyl 8-(2-amino((4-bro mophenoxy) methyl)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (350 mg, 0.56 mmol), 3- (4,4,5,5-tetramethyl-l,3,2-dioxaboro lanyl)-lH-indazole (285 mg, 1. 1 mmol) and Pd(dppf) Ch (62 mg, 0.09 mmol) in dioxane (5 mL)/aq. Na2C03 solution (2.0 M, 5 mL) was heated to 90 °C for 4 h. The reaction was cooled to RT, the solids fi ltered away, and the solution trated in vacuo. Purifi cation on normal phase silica gel (CI-hCh/MeOH) provided (S) tert-buty1 3-ethyI 8-(2-amino( methy1-1H-indazo1yl)phenoxy)methyl)pyrim idinyl)- 2,8-diazaspiro [4.5]decane-2,3-dicarboxylate as a brown solid.
Step 5: To a solution of (S)tert-butyl 3-ethyl mino((4-(3-methyl-lH-indazol yl)phenoxy)methyl)pyrim idinyl)-2,8-diazaspiro[4.S]decane-2,3-dicarboxylate (150 mg, 0.19 mmol) in CH2Cb (5 mL) was added TFA (3 mL), and the resulting mixture was stirred at RT for 1 h. The reaction mixture was concentra ted in vacuo, and the resulting material ioned bewt een CH2Cb and saturated NaHC03, and extrac ted. The combined organic layers were dried over Na2S04, fi ltered, and trated in vacuo. Purifi cation by prep-TLC (CH2Ch/MeOH) provided (S)-ethyl 8-(2-amino((4-(3-methyl-lH-indazolyl)phenoxy)methyl)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylate as a brown solid.
Step 6: To a solution of (S)-ethyl 8-(2-ami no((4-(3-methyl-lH-indazolyl)phenoxy)methyl) pyri 4-yl)-2,8-diazaspiro[4.5]decanecarboxylate (70 mg, 0.11 mmol) in MeOH (3 mL) is added 4 N 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 precipitated solid was collected by filtration, and the filter cake was washed with cold water, then dried to afford the title compound as an off-white solid. 1HNMR (400 MHz, DMSO-d6): o 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, l H), .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, I H), 1.82-1.80 (m, 1 H), 1.44 (m, 4 H). LCMS (MH+): 514.
Example 62: (S)(2-amino((5-chloro(metl1ylsulfonyl)-[1,1'-biphenyl] yl)methoxy)pyrimidinyl)-2,8-diazaspiro[4.5Jdecanecarboxylic"�o acid p (Po OH Cl I h NH OYYN Step 1: A mixture of (2-bromochlorophenyl)methanol (173 mg, 1. mmol), 4-chloro (chloromethyl)pyrimidinamine (178 mg, 1 .1 6 mmol) and K2C03 ( 175 mg, 1.00 mm ol) in DMF (5 mL) was heated to 100 °C for 12 h. The reaction was cooled to RT, concentrated in vacuo, and extra cted with EtOAc. The ed c layers were washed with bri ne, dried over Na2S04, and concentra ted in vacuo. Purific ation on normal phase silica gel (EtOAc/petrolemn ether) prov ided 4-((2-bromochlorobenzyl)oxy)chloropyrimidinamine as a white solid.
Step 2: A e of 4-((2-bromo-4"chlorobenzyl)oxy)chloropyrimidinamine (300 mg, 1.1 mmol), (S)benzyl 3-ethyl 2,8-diazaspiro[ 4.5]decane-2,3-dicarboxylate (400 mg, 1.2 mmol), and NaHC03( 550 mg,7 mmol) in dioxane (5 mL) was heated to 100 °C for 12 h. The reaction was cooled to RT, concentra ted in vacuo, and extra cted with EtOAc. The combined organic layers were washed with brine, water, dried over Na2S04, and concentra ted in vacuo.
Purifi cation on normal phase silica gel (EtOAc/petroleum ether) provided (S)benzyl 3-ethyl 8- (2-amino((2-bromochlorobenzyl)oxy)pyrimidinyl)-2,8-diazaspiro ecane-2,3- dicarboxylate as a white solid.
Step 3: To a on of (S)benzyl 3-ethyl 8-(2-amino((2-bromo chlorobenzyl)oxy)pyrimidinyl)-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 O °C. The reaction mixture was stirred at O °C for 2 h, then concentrated in vacuo. The residue was dissolved in CH2Ch (20 mL), followed by the sequential addition of Et3N (267 mg, 2.6 mmol), and (BOC)20 (285 mg, 1.3 mmol). The reaction mixture was stirred at RT for 16 h, then concentrated in vacuo. Purifi cation on normal phase silica gel h/M eOH) provided (S) utyl 3-ethyl mino((2-bromochlorobenzy l)oxy)pyrimidinyl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate as a light yellow solid.
Step 4: A mixture of (S)tert-butyl 3-ethyl 8-(2-amino((2-bromochlorob enzyl) oxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (300 mg, 0.4 mmol), (3- (methylsulfonyl)phenyl)boronic acid (280 mg, 1 mrnol), and Pd(dppf) Ch (62 mg, 0.09 mmol) in dioxane (5 mL)/aq. Na2C03 solution (2.0 M, 5 mL) was heated to 90 °C for 4 h. The reaction was then cooled to RT, the solids fi ltered away, and the fi ltrat e concentrated in vacuo.
Purifi cation on normal phase silica gel (CH2Ch/MeOH) provided (S)tert-butyl 3-ethyl 8-(2- amino((5-chloro-3 '-(methylsulfonyl)-[1 , l1-biphenyl]yl)methoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Step 5: To a solution of (S)tert-butyl l 8-(2-amino((5-chloro- 3'-(methylsulfonyl)- [l,1'-biphenyl]yl)methoxy)pyrimidinyl)-2,8-diazaspiro[4.S]decane-2,3-dicarboxylate (200 mg, 0.25 mmol) in CH2Ch (5 ml) was added TF A (3 mL), and the resulting mixture was stirred at RT for l h. The reaction e was concentrated in vacuo, and the residue was partitioned between CH2Ch and saturated NaHC03. The organic layer was dried over Na2S04, fi ltered, and concentra ted in vacuo. Purifi cation by LC (CI-12Ch/M eOH) provided (S)-ethyl 8-(2- amino((5-chloro-3 1-(methylsulfonyl)-[l, 1 '-biphenyl]yl)methoxy)pyrimidinyl)-2,8- diazaspiro [4.5]decanecarboxylate as an off-white solid.
Step 6: To a solution (S)-ethyl 8-(2-amino((5-chloro(methylsulfonyl)-[l)1-biphenyl] yl)methoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate (100 mg, 0.13 mmol) in MeOH (3 ml.) was added 4 N NaOH (3 mL), and the mixture was stirred at RT for 4 h. The reaction e was then concentrated in vacuo. The residue was diluted with water (5 mL) and the pH adjusted to 6-7. The precipitated solid was collected by filtration, the filter cake was washed with cold water, then dried to afford the title compound as an off-white solid isolated as the zwitterionic form. 1HNMR (400 MHz, MeOH-d4): s 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.
The following esters were isolated as either a TF A or HCl salt formed during the HPLC purification pro cedure used to isolate the fi nal compounds.
Example 63bd: (S)-ethyl 8-(2-amino((R)(3',4'-climethyl(3-methyl-lH-pyrazolyl)­ [1,1 '-bipltenyl]yl)-2,2,2-trifluoroethoxy)pyrimiclinyl)-2,8-diazaspiro[4.5]decanc carboxylate A solution of (S)benzyl 3-ethyl 8-(2-amino((R)(3',4'-dimethyl(3-methyl-lH-pyraz ol­ l-yl)-[l, l 1-biphenyl]yl)-2,2,2-trifluo roethoxy)pyrimidinyl)-2,8-diazaspiro [ 4.5]decane-2,3- dicarboxylate (from Step 3, Example lm, 220 mg, 0.3 mmol,) in EtOAc (5 mL) was enated using Method A by using an H-Cube apparatus and a 10% (w/w) Pd/C cartridge with a fl ow rate of 1 . 0 mL/min at RT. Purifi cation on l phase silica gel (EtOAc/heptane) ed (S)-ethyl 8-(2-amino((R)-l-(3',4'-dimethyl(3-methyl-lH-pyrazolyl)-[1, l 1- biphenyl]yl)-2,2,2-triflu oro ethoxy) pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate.
Example 63kp: (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro-l-(3'-(hydroxymethyl)-4'­ methyl(3-methyl-IH-pyrazolyl)-[1,1'-biphenyl]yl)etl10xy)pyrimidinyl)-2,8- diazaspiro [4.S]decanccarboxylate The title compound was ed as described for (S)-ethyl 8-(2-amino((R)(31,4'-dimethyl- 3-(3-methyl-1H-pyrazolyl)-[1, l1-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylate (Example 63bd) using Method A to remove the N-CBz group. e 63i: (Sj-ethyl mino((R)-l-(5-chloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro [4.5]clccanecarboxylate o I Cl YY�o CF3 NyN I NH2 A solution of (S)benzyl 3-ethyl 8-(2-amino((R)(5-chloro-[1, henyl]yl)-2,2,2- tri:fluoroethoxy)pyrimidinyl)-2,8-diazaspi ro[4.5)decane-2,3-dicarboxylate (from Step 3, Example 34c, 315 mg, 0.43 mmol) in acetonitrile (300 mL) was added TMSI (0.13 mL, 0.9 mmol) [Method B]. The reaction mixture was then warmed to RT for an additional 30-40 min, then cooled to 0-5 °C, and 2 M HCl in diethyl ether (0.5 mL) was added. The reaction mixture was the allowed to warm RT and then concentrated in vacuo. Normal phase silica gel chromatography provide the title compound as an off-white solid.
Ethyl ester prodrugs in Table 18a were prepared by removing the N-CBZ group by either method A or method B, as shown below.
Table 18a.
Ex. LCMS Ar Method CASName No. AorB MH+ 63a (S)-ethyl 8-(2-amino((R)(4- (benzo[d]thiazolyl)phenyl)- A 2,2,2-trifluoroethoxy)pyrimidin 613 yl)-2,8-diazaspiro[4.5]decane carbox late 63b (S)-ethyl 8-(6-((R)(4-(lH­ indazolyl)phenyl)-2,2,2- trifluoroethoxy) aminopyrimidinyl)-2,8- A diazaspiro[4.S]decane 596 carboxylate 63c hyl 8-(2-amino((R)-2,2,2- trifluoro(3'-methoxy-4 '­ (pyrrolid carbony1)-[ 1, 1 '­ A 683 biphenyl]yl)ethoxy)pyrimidi n- 4-yl)-2,8-diazaspiro[ 4.S]decane carbox late 63d o� yo (S)-ethyl 8-(2-amino((R)(5- chloro-4'-nitro-fl, 1 enyl] yl)-2,2,2- A trifluoroethoxy)pyrimidiny1)- 631 2,8-diazaspiro[4.5]decane carboxylate 63e (S)-ethyI 8-(2-amino((R)(4- (benzo[d]isothiazo1yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro[ 4.5]decane B carboxylate 613 63f (S)-ethyl 8-(2-amino((R)(4- (benzo[d] isothiazolyl)phenyl)- trifluoroethoxy)pyrimidin A yl)-2,8-diazaspiro[4.5]decane 616 carboxylate 63g (S)-ethyl 8-(2-amino((R) ,,,,o (3',4'-dimethoxy-[ 1,1'-biphenyl] yl)-2,2,2- A 616 "o� trifl uoroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane ylate 63h (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro-I -(4-(1-methyloxo- l ,2-dihydroq uinolin A 637 yl)phenyl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane carbox late 63i (S)-ethyl 8-(2-amino((R)(5- chloro- [1, 1 '-biphenyl]yl)-2,2,2- B trifl uoro ethoxy)pyrimidinyl)- 591 2,8-diazaspiro[4.S]decane Cl carboxylate 63j (S)-ethyl 8-(2-amino((R)(3'- aminochloro- [ 1 phenyl] 2,2- B 606 tri fluoroethoxy)pyrimidinyI)- 2,8-diazaspiro[4.S]decane carbox late 63k (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(3'-(methylsulfonyl) propyl-[1,l'-biphenyl] A 676 oxy)pyri midiny1)-2,8- diazaspiro [4. 5]decane carbox rlate 631 (S)-ethy I 8-(2-amino((R)(4- (1,3-dimethyl-1 H-indol yl)phenyl)-2,2,2- A 622 trifluoroethoxy)pyrimidinyl)- 2,8-diazaspiro[ 4.5]decane carbox -late 63m H (S)-ethyl 8-(6-((R)(3'- �N acrylamidochloro-[1, 1 '- 0 biphenyl]yl)-2,2,2- A trifluoroethoxy) 659.1 aminopyrimidinyl)-2,8- diazaspiro [4.S]decane carbox -late 63n (S)-ethyl 8-(2-amino((R)-2,2,2- oro (3'-flu oro-4'-methoxy- [ iphenyl] A 604 yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decane carbox late 630 if (S)-ethyl 8-(2-amino((R)-2,2,2- triflu oro(4-(l-methyl-e-oxo- <, 1,6-dihydropyridin A 587 Q:,,' nyl)ethoxy)pyrimidinyl)- 2,8-diazaspiroI4.5]decane carbox late 63p (S)-ethyl 8-(2-amino((R)-2,2,2- o ro(4-(2-oxo-1,2,3,4- · tetrahydroquinolin A 626 yl)phenyl)ethoxy)pyrimidinyl)- 2,8-diazasp iro[4.S]decane carbox late 63q (S)-ethyl 8-(2-amino((R)-2,2,2- triflu oro(4-(2-oxo- l,2- dihydroquinolin A 623 yl)phenyl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane carbox late 63r hyl 8-(2-amino((R)-2,2,2- trifluoro(3'-(methylsulfonyl) ((E)-propenyl)-[1,1'- B 674 yl]yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.S]decane � carbox late 63s h (Sj-ethyl 8-(2-amino((R)-2,2,2- trifluoro(4-(3-methyl-lH- pyrazolyl)-[1,1'-biphenyl] A yl)ethoxy)pyrimidinyl)-2,8- 583 diazaspiro[4.5Jdecane carboxylate 63t (S)-ethyl 8-(2-amino((R)(41- Cl�� I chloro(3-methyl-JH-pyrazol , � yl)-[ l,1'-biphenyl]yl)-2,2,2- "' %� B 671 trifluoroetho x y)pyrimid iny1)- 2,8-diazaspiro[4.5]decane carboxylate 63u (S)-ethyl 8-(2-amino((R)-2,2,2- triflu oro(3 '-(methylsulfonyl) propyl-[1, 1 '-biphenyl) yl)ethoxy)pyrimidinyl)-2,8- A 677 diazaspiro[4.5]decane carboxylate 63v hyl 8-(2-amino((R)-2,2,2- trifl uoro(3'-(methylsulfonyl) ((E)-prop-l-eny1)-[l,1'- biphenyl]yl)ethoxy)pyrim idin- B 675 4-yl)-2,8-diazaspiro[4.5]decane carboxylate 63w (S)-ethyl 8-(2-amino((R)(5- chloro-3'-(ethylsulfonyl)-[1, t 1- biphenyl]yl)-2,2,2- B trifl hoxy)pyrimidinyl)- 683 2,8-diazaspiro[4.S]decane carboxylate 63x (S)-ethyl 8-(2-amino((R)(5- chloro-3'-(propylsulfonyl)-[1, l '- biphenyl]yl)-2,2,2- B trifluoroethoxy)pyrimidinyl)- 697 2,8-diazaspiro[4.5]decane carboxylate 63y (S)-ethyl 8-(2-amino((R)(5- chloro-3'-(butylsulfonyl)-[1, I' - Cl biphenyl]yl)-2,2,2- � A oroethoxy)pyrimidinyl)- 711 JO=S=O 2,8-diazaspiro[4.S]decane carboxylate 63z (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(4-(1-oxo-1 ,3- dihydroisobenzofuran A 612 o_ yl )phenyl)ethoxy)pyrimidinyI)- 2,8-diazaspiro[4.5]decane carbox late 63aa (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro (4-(2-methoxyquinolin- 6-yl)phenyl)ethoxy)pyrimidin yl)-2,8-diazaspiro[ 4.S]decane 638 carboxyJate 63ab HO (S)-ethyl 8-(2-amino((R)(5- chloro-3'-(hydroxymethyI)-[ l , 1 '- biphenyl]yl)-2,2,2- A trifluoroetho xy)pyrimidinyl)- 621 2,8-diazaspiro[4.5]decane carboxylate 63ac YN (S)-ethyl 8-(2-amino((R)(5- -3'-(2-oxopyrrolidinyl)- 0 [1,1'-biphenyl]yl)-2,2,2- o xy)pyrimidiny1)- 673 2,8-diazaspiro[ cane carboxylate 63ad (ti\ 0 (S)-ethyl 8-(2-amino((R)(5- chloro-3'-(3-methyl oxoimidazolidinyl)-[l, 1 '- ' � B biphenyl]yl)-2,2,2- 688 triflu oroethoxy)pyrimidinyJ)- � I 2,8-diazaspiro[4.S]decane Cl c.:-.. carbox late 63ae (S)-ethyl 8-(2-amino((R)-l-(4- chloro-3'-(methylsulfonyl)-[l ,1 '- biphenyl]yl)-2,2,2- B trifluoroethoxy)pyrimidinyl)- 668 2,8-diazaspiro[4.5]decane carboxylate 63af I (S)-ethyl 8-(2-amino((R)(5- 0=S=0 HN -3 '-(methy]sulfonamido)- [1, 1'-biphenyl]yl)-2,2,2- B trifluoroethoxy)pyrimidinyl)- 683 azaspiro[4.5]decane carboxylate 63ag ¢fBr hyl 8-(2-amino((R)(2- bromoch]orophenyl)-2,2,2- B tri fluoroethoxy)pyri midiny1)- 593 2,8-diazaspiro[4.5]decane carbox -late 63ah (S)-ethyl 8-(2-amino((R)-2,2,2- trifl uoro(4-(1-methyloxo- 1,2,3,4-tetra hydroquinolin A 595 yl)phenyl)ethoxy)pyrim idinyl)- 2,8-diazaspiro[4.5]decane carbox late ( 63ai hyl mino((R)-2,2,2- trifl uoro(4-(2- (methylthio)quinolin A yl)phenyl)ethoxy)pyrimidinyl)- 554 2,8-diazaspiro[4.5]decane carboxylate 63aj ¢fBr (S)-ethyl 8-(2-amino((R) (2,5-dibromophenyl)-2,2,2- B trifl uoroethoxy)pyrimidiny1)- 638 2,8-diazaspiro [4.5]decane Br carbox late 63ak (S)-ethyl 8-(6-((R)([1, 1':4',1"- terphenyl]-2'-yl)-2,2,2- triflu oroethoxy) A 633 aminopyrimidinyl)-2,8- diazaspiro[4.5]decane carbox late 63al (S)-ethyl 8-(2-amino((R)(2'- (ethoxycarbonyl)(3-methyl- lH- A pyrazolyl)-[1,1 '-biphenyl] 708 yl)-2,2,2- trifluoroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane carbox late 63am (S)-ethyl 8-(2-amino((R)(3'- (ethoxycarbonyl)(3-methyl-1 H- 0 pyrazolyl)-[1,l'-biphenyl] ) A yl)-2,2,2- 708 trifl uoroethoxy)pyri midiny1)- 2,8-diazaspiro[4.5]decane carboxylate 63an (S)-ethyl 8-(2-amino((R)-l-(4'- (ethoxycarbonyl)(3-methyl-1 H- lyl)-[1,1'-biphenyl] 0 A yl)-2,2,2- 708 (0 trifluoroethoxy)pyrimidiny1)- 2,8-diazaspiro[ 4.S]decane carbox late 63ao 0(Br hyl 8-(2-amino((R) (2,6-dibromophenyl)-2,2,2- triflu oro ethoxy)pyrimidinyl)- Br B 638 azas piro[4.S]decane carboxylate 63ap (S)-ethyl 8-(2-amino((R) (3',5-dichloro-[1,1 '-biphenyl] yl)-2,2,2- B 625 triflu oro ethoxy)pyrimidiny1)- 2,8-diazaspiro[4.5]decane carbox late 63aq (S)-ethyl 8-(2-amino((R)(5- chloro-3 '-methyl-[1 ,1'-biphenyl]- 2-yl)-2,2,2- B 605 tri flu oroe thoxy)pyrimidiny1)- Cl 2,8-diazaspiro[4.5]decane carbox late 63ar F F (S)-ethyl 8-(2-amino((R)(5- chloro-3'-(trifl uoromethyl)-( 1,1'- biphenyl]yl)-2,2,2- B trifl hoxy)pyrimidinyl)- 659 2,8-diazaspiro[4.S]decane carboxylate 63as h (S)-ethyl 8-(2-amino((R)-2,2,2- oro(3-(3-methyl-lH- N lyl)-4'-(methylthio)- A [1,l'-biphenyl] 583 yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5Jdecane carbox late 63at (S)-ethyl 8-(2-amino((R)(4- chloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)- B 591 2,8-diazaspiro[4.S]decane carboxylate 63au h (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(41-methyl(3- N methyl-lH-pyrazolyl)-[1, 1 '- A biphenyl]yl)ethoxy)pyrimidin- 651 4-yl)-2,8-diazaspiro[ 4.S]decane ylate 63av (S)-ethyl 8-(2-am ino((R)-2,2,2- trifl uoro(3'-methyl(3- methyl-IH-pyrazolyl)-[1, 1'- A 651 biphenyl]y1) ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane carboxylate 63aw h (S)-ethyI 8-(2-amino((R) (3',4'-dichloro(3-methyl-lH- N pyrazolyl)-[1,1 '-biphenyl] B yl)-2,2,2- 705 tri fluoroeth oxy)pyrimi yl)- 2,8-diazaspiro[ 4.5]decane carbox late 63ax of:) (S)-ethyl 8-(2-amino((R)(4- chloro (2-oxopyrro lidin (J( yl)phenyl)-2,2,2- B 598 trifl hoxy)pyrimidinyl)- Cl 2,8-diazaspiro[4.5]decane carbox late 63ay Q ethyl 8-(2-amino((R)(4- chloro(3-methyl-1 Il-pyrazol-l- ,ei yl)phenyl)-2,2,2- B 594 tl'itlu oroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane Cl carbox late 63az Q (S)-ethyl mino((R)(4- chloro(3-methyl-lH-pyrazol yl)phenyl)-2,2,2- B oroethoxy)pyrimidinyl)- 594 2,8-diazaspiro[4.S]decane Cl� carboxylate 63ba /oif (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(3'-methoxy-[ 1, l'- A biphenyl]yl)ethoxy)pyrimidin- 587 4-yl)-2,8-diazaspiro[4.5]decane ylate 63bb Q (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(4-methoxy(3- 'oiY methyl-Ill-pyrazol-l- A 591 nyl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane carboxylate 63bc ,if (S)-ethy1 8-(2-amino((R)-2,2,2- tdfl uoro (3'-flu oro-[1, 1 '- 7' I biphenyl]yl)ethox y)pyrimidin- ::::.-... A 575 4-yl)-2,8-diazaspiro[4.S]decane carboxylate 63bd Q (S)-ethyl 8-(2-amino((R)-l- (3',4'-dimet (3-methyl-lH- pyra zolyl)-(1, 1'-biphenyl] yl)-2,2,2- � , A 665 :::::,.... trifluoroethoxy)pyrimidiny1)- , � 2,8-diazaspiro[4.S]decane � carboxylate 63be Q (S)-ethyl 8-(2-amino((R)(4- ethyl(3-methyl-lH-pyrazol yl)phenyl)-2,2,2- A triflu oroetho xy)pyrimidinyl)- 589 2,8-diazaspiro [4.S]decane � carboxylate 63bf Q (S)-ethyl 8-(2-amino((R)-2,2,2- trifl uoro(2-(3-methyl-UI- ..o' pyrazol-l-yl) A pro pylphenyl)ethoxy)pyl'imidin 603 yl)-2,8-diazaspiro[ 4.S]decane carboxylate 63bg h (S)-ethy 1 8-(2-amino((R)(4- butyl(3-methyl-lH-pyrnzol N yl)phenyl)-2,2,2- A oroethoxy)pyrimidinyl)- 617 2,8-diazaspiro[4.5]decane � carboxylate 63bh A' (S)-ethyl mino((R)(5- ycarbonyl)(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2- '-.....,-0 A trifluoroethoxy)pyrimidinyl)- 633 0 2,8-diazaspiro[4.5]decane carboxylate 63bi h (S)-ethyl 8-(2-amino((R)(4- (ethoxycarbonyl)(3-methyl-lH- N pyrazolyl)phenyl)-2,2,2- A trifluoroethoxy)pyrimidinyl)- 632 2,8-diazaspiro[4.5]decane '-.....-- Io� carboxylate 63bj 0 (S)-ethyl 8-(2-amino((R)(5- /'o� ((E)ethoxyoxoprop -l-en (3-methyl-1H-pyrazol �� A yl)phenyl)-2,2,2- 559 trifluoroethoxy)pyrimidinyl)- 2,8-diazaspiro[ 4.5]decane carboxylate 63bk 0 (S)-ethyl 8-(2-amino((R)(5- /'o� (3-ethoxyoxopropyl)(3- � w·N methyl-I H-pyrazolyl)phenyl)- A 588 � 2,2,2-trifl uoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decane carboxylate 63bl h (S)-ethyl 8-(2-amino((R)-2,2,2- trifl uoro(6-methyl(3-methyl- N 1H-pyrazolyl)pyri din A 618 y])ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decane � carboxylate 63bm h (S)-ethyl 8-(2-amino((R)-2,2,2- oro(2-(3-methyl-lH- 'N pyrazolyl)((E)-propen yl)phenyl)ethoxy)pyrimidinyl)- I --.:::: B 600 »: 2,8-diazaspiro[4.S]decane r carboxylate 63bn (S)-ethyl 8-(2-amino((R) (3',41-dimethyl(3-methyl-1 H- .. ,::;;� ' pyrazol-l-yl)-[l ,l enyl] � A yl)-2,2,2- 664 trifluo roethoxy)pyrimid iny1)- ��N- 2,8-diazaspiro[4.5]decane carboxylate 63bo h (S)-ethyl 8-(2-amino((R)-2,2,2- trifluo ro(2-(3-methyl-1 H- 'N l-l-yl) I --.:::: A propylphenyl)ethoxy)pyrimidin 602 -: yl)-2,8-diazaspiro[4.S]decane carboxylate 63bp )) (S)-ethyl 8-(2-amino((R)(5- ethyl(3-methyl-lH-pyrazol r yl )phenyl)-2,2,2- A trifl uoroethoxy)pyrimidi nyl)- 588 2,8-diazaspiro[4.S]decane carboxylate 63bq h (S)-ethyl 8-(2-amino((R)(5- butyl(3-methyl-IH-pyrazol N yl)phenyl)-2,2 ,2- tri:fl uoroethoxy)pyrimidinyl)- I � A 2,8-diazaspiro[4.S]decane 616 carboxylate 63br h (S)-ethyl 8-(2-amino((R)-2,2,2- trifl uoro(2-(3-methyl-1 H- rN pyraz l) B vinylphenyl)ethoxy)pyrimidin 586 yl)-2,8-diazaspiro[ 4.5Jdecane carboxylate 63bs � (S)-ethyl 8-(2-amino((R)(5- N(N» ((E)-butenyl)(3-methyl- 1H-pyra zolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)- B 614 2,8-diazaspiro[4.5]decane ylate 63bt (S)-ethyl 8-(2-amino((R)- l-(4- I chloro(1-methyl-lH-pyrazol yl)phenyl)-2,2,2- B 594 Cl�I� oroethoxy)pyrimidinyl)- ,,..,; 2,8-diazaspiro(4.S]decane carbox late 63bu cc:I (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(2-(1-methy)-lH- '-:::: pyrazol A 560 � yl)phenyl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.S]decane carbox late 63bv (S)-ethy1 8-(2-amino((R)(4- (1,3-dimethyl-1 Il-indazol-eyl )phenyl)-2,2,2- A 624 trifl uoro )pyrimidinyl)- 2,8-diazaspiro[4.5]decane carboxylate 63bw (S)-ethyl 8-(2-amino((R)(4- (2,3-dimethyl-2H-indazol yl)phenyl)-2,2,2- A 624 trifl uoroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane carbox late 63bx (S)-ethyl 8-(2-amino((R)-2,2,2- triflu oro (4-(1-oxo-1,2,3,4- tetrahydroiso quinolin 0 A 625 yl)pheny I)ethoxy)pyrimidinyI)- azaspiro[4. 5]decane carbox late 63by (S)-ethyl 8-(2-amino((R)-2,2,2- triflu oro(4-(isoquinolin A yl)phenyl)ethoxy)pyrimidinyl)- 607 2,8-diazaspiro[4.S]decane carboxylate 63bz (S)-ethyl 8-(2-amino((R)-l-(4- (3-ethoxyoxopropyl)(3- methyl-IH-pyrazolyl)phenyl)- A 660 2,2,2-trifluoroethoxy)pyrimidin 8-diazaspiro[4.5]decane carbox late 63ca (S)-ethy1 mino((R)-2,2,2- trifluoro(4-(isoquinolin A yl)phenyl)ethoxy)pyrimidinyl)- 607 2,8-diazaspiro[4.5Jdecane carbox late 63cb (S)-ethyl 8-(2-amino((R)(5- 'b (4-ethoxyoxobutyl)(3- ��N1,...N methyl-I H-pyrazolyl)phenyl)- � A 674 2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro[ 4.S]decane carboxy late 63cc (S)-ethyl 8-(2-amino((R)-l-(4- (4-ethoxyoxobutyl)phenyl)- 2,2,2-tr ifl uoroethoxy)pyrimidin A yl)-2,8-diazaspiro[4.5Jdecane 594 carboxylate 63cd (S)-ethyl 8-(2-amino((R)-l-(4- (4-ethoxyoxobutyl)(3- methyl- lH-pyrazol-l-yl)phenyl)- A 674 2,2,2-triflu oroethoxy)pyrimidin yl)-2,8-diazas piro[4.S]decane carboxylate 63ce hyl 8-(2-amino((R)(3 '­ cyano(3-methyl-lIf-pyrazol-l­ yl)-[l ,1 '-biphenyl]yl)-2,2,2- A tritl uoro ethoxy)pyrimidinyl)- 661 2,8-diazaspiro[4.S)decane carboxylate 63cf (S)-ethyl 8-(2-amino((R)(5- chloro-St-cyano-Il phenyl] yl)-2,2,2- B 615 tri fluoro ethoxy)pyrimidin- 4-y1)- 2,8-diazaspi ro[4.5)decane carbox late 63cg I (S)-ethyl 8-(2-amino((R)(5- chloro-3'-methoxy-[1, l '-biphenyl]- 2-yl)-2,2,2- B 620 trifluoroethoxy)pyrimidiny1)- 2,8-diazaspiro[4.S]decane carbox late 63ch (S)-ethyl 8-(2-amino((R)(5- chloro-3'-sulfamoyl-[1,1 '- biphenyl]yl)-2,2,2- HOi B trifluoroethoxy)pyrimidiny1)- 669 2,8-diazaspiro[4.5]decane carboxylate 63ci (S)-ethyl 8-(2-amino((R)(5- I � chloro-3'-hydroxy-[1, 1 enyl]- 2-yl)-2,2,2- B 606 I "" trifluoroethoxy)pyrimidinyl)- Cl ,,-:. 2,8-diazas piro[4.5]decane carboxylate 63cj (S)-ethyl 8-(2-amino((R)(5- -3'-(methylsulfonyl)-[1, 1'- biphenyl]yl)-2,2,2- B trifl uoro ethoxy)pyrimidinyl)- 668 azaspiro[4.5]decane carboxylate 63ck H,N (S)-ethyl 8-(2-amino((R)(3'- (aminomethyl)chloro-(1,1 '- biphenyl]yl)-2,2,2- B trifluoroetho xy)pyrimidinyl)- 619 2,8-diazaspiro[4.5]decane carboxylate 63c1 hyl 8-(2-amino((R)-2,2,2- trifluoro-l-I4-(quinolin-o- A yl)phenyl)ethoxy)pyrimidinyl)- 608 azaspiro[4.S]decane carboxylate 63cm (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro (4-(quinolin A yl)phenyl)ethoxy)pyrimidiny 1)- 608 2,8-diazasp iro[4.5]decane carbox late 63cn h (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(4'-isopropoxy(3- N methyl-lH-pyrazolyl)-[ l,l1- A biphenyl]yl)ethoxy)pyrimidin- 694 4-yl)-2,8-diazaspiro[4.S]decane ylate 63co (S)-ethyl 8-(2-amino((R)-2,2,2- oro-l-I4-(quinoxalin A yl)phenyl)ethoxy)pyrimidinyl)- 608 2,8-diazaspiro[4 .5]decane carboxylate 63cp h (S)-ethyl 8-(6-((R)(41- (acetamidomethyl)(3-methyl- N IH-pyrazolyl)-[1, 1 '-biphenyl]- 4-y1)-2,2,2-triflu oroethoxy) A 707 aminopyrimidinyl)-2,8- H diazaspiro[4.5]decane YiN carboxylate 63cq (S)-ethyl 8-(6-((R)(4'-(2- acetamid oethyl)(3-methyl-1 H- 0 pyrazolyl)-[l,1 '-biphenyl] )(N A 2,2-tri fl uoroethoxy) 721 H aminopyrimidinyl)-2,8- diazaspiro[4.S]decane carboxylate 63cr hyl 8-(2-amino((R)-2,2,2- trifl uoro(2-(3-methyl-1H- pyrazol-l-yl)(quinolin A 687 yl)phenyl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane carbox late 63cs h (S)-ethyl 8-(2-amino((R)-2,2,2- triflu oro(4-(2-methoxypyridin- N 4-yl)(3-methyl-1H-pyra zol A yl)phenyl)ethoxy)pyrimidinyl)- 666 2,8-diazaspiro[4.5]decane carboxylate 63ct (S)-ethyl 8-(6-((R)-l-(4-(1H- indolyl)(3-methyl-1 H- l-l-yl)phenyl)-2,2,2- A 595 triflu oroethoxy) aminopyrimidinyl)-2,8- diazaspiro 4.5 decane carbox late 63cu (S)-ethyl 8-(2-amino((R)(5- ,/""-0 chloro-3'-(ethoxycarbonyl)-[1,1 '- biphenyl]yl)-2,2,2- B trifluoroethoxy)pyrimidinyI)- 662 2,8-diazaspiro[4.5]decane carboxylate 63cv 2'-((R)((2-amino((S) ycarbonyl)-2,8- diazaspiro[4.S]decan B yl)pyrimidinyl)oxy)-2,2,2- 634 trifluoroethyl)-5'-chloro-[ 1, l1- biphenyl]carboxylic acid 63cw (S)-ethyl 8-(6-((R)(31- (acrylamidomethyl)chloro- Cl [1,1'-biphenyl]yl)-2,2,2- B trifluoroethoxy) 673 aminopyrimidinyl)-2,8- piro[4.5]decane carboxylate 63cx (S)-ethyl 8-(2-amino((R)-l-(3'- H2N carbamoylchloro-[1, l'- biphenyl]yl)-2,2,2- B triflu oroethoxy)pyrimidinyl)- 633 azaspiro[4.S]decane carboxylate 63cy I (S)-ethyl 8-(2-amino((R)(5- O:S:=O chloro(methylsulfonyl)-[l ,l1- biphenyl]yl)-2,2,2- B triflu oro ethoxy)pyrimid inyl)- 668 2,8-diazaspiro(4.5]decane carboxylate 63cz hyl 8-(2-amino((R)(5- chlorosulfamoyl-[l, l 1- biphenyl]yl)-2,2,2- B trifluoroethoxy)pyrimidiny1)- 669 2,8-diazaspiro[4.5]decane carboxylate o=s-NH2 63da w (S)-ethyl 8-(2-amino((R)(21- � (ethoxycarbonyl)(3-methyl-lH- A pyrazolyl)-[ l, l'-biphenyl] 708 /0 'SQ ·�i-r- 2,2- trifluoroethoxy)pyrimidiny1)- 2,8-diazaspiro[4.5]decane carbox late 63db (S)-ethy 1 8-(2-amino((R)(3'­ (ethoxycarbony1)(3-methyl-1 H­ pyrazo)yl)-[1, 1'-biphenyl] yl)-2,2,2- A 708 trifluoroethoxy)pyrimidinyl)- 2,8-diazaspiro[4. 5]decane carboxylate 63dc (S)-ethyl mino((R)-l-(4'­ (ethoxycarbonyl)(3-methyl-lH­ 0 pyrazolyl)-[1, 1'-biphenyl] A yl)-2,2,2- 708 trifluoroethoxy)pyrimidinyl)- 2,8-diazaspiro[4. S]decane carboxylate 63dd thyl 8-(2-amino((1 R) (4-( 1,2-dihydroxyethy1)(3- methy1-1 H-pyrazolyl)phenyl)- A 2,2,2-triflu oro ethoxy)pyrimidin 620 yl)-2,8-diazaspiro[4.5]decane carboxylate 63de (S)-ethyl mino((R)(4'­ (aminomethyl)(3-methyl-IH­ pyra zolyl)-(1, l '-biphenyl] A yl)-2,2,2- 666 trifluoro ethoxy)pyrimidiny1)- 2, 8-diazaspiro[4.S]decane carbox late 63df (S)-ethyl8-(2-amino((R)(31- �0-r� �u�N ... N -"'- .......D /,-.._ _A ((E)ethoxyoxoprop-l-en yl)(3-methyl-l H-pyrazolyl)­ � A [1,1'-biphenyl]yl)-2,2,2- 734 triflu oroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.S]decane carboxylate 63dg 0 (S)-ethyl8-(2-amino((R)-l-(4'­ ,.,,........0 I /;, -ethoxyoxopropen yl)(3-methyl-1H-pyrazolyl)­ A [1, 1'-biphenyl]yl)-2,2,2- 734 trifl uoroethoxy)pyrimidiny1)- azaspiro [4.S]decane carboxylate 63dh (S)-ethyl mino((R)(3'- �?- (3-ethoxyoxopropyl)(3- �o I methyl-1 H-pyrazolyl)-[1, 1'- ......:: biphenyl]yl)-2,2,2- A 736 trifluoroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane carboxylate 63di 0 (S)-ethyl mino((R)(4'- (3-ethoxyoxopropyl)(3- �o�� ::;," methyl-lH-pyrazolyl)-[1,1 '- :::,... I N"'Nv- A biphenyl]yl)-2,2,2- 736 trifluoroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane carboxylate 63dj JO (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(3'-fluoro(3-methyllH-pyrazolyl )-[1, 1'-biphenyl]- A 4-yl)ethoxy)pyrimidinyl)-2,8- 654 diazaspiro[4.5]decane F -;:::"'�I� carboxylate :::,.... 63dk it (S)-ethyl 8-(2-amino((R)-2,2,2- o- trifluoro(2-(3-methyl-1 H- .-,,,::. N.,..N -;:::"' � , pyrazol-l-yl)(quinolin " :::,.... A 687 N yl)phenyl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane carboxylate 63dl h (3S)-ethyl 8-(2-amino((IR)- ofr 2,2,2-trifl uoro- 1-(2-(3-methyl-1H- N lyl)(2-oxo-1,3- A an 646 yl)phenyl)ethoxy)pyrimidinyl)- O==( 2,8-diazaspiro[4.S]decane 0 carboxylate 63dm ,y (S)-ethyl 8-(2-amino((R)-2,2,2- tri fl uoro(4-(2-methyloxo- I � 1,2,3,4-tetra hydroisoquinolin 0 h A 639 '.;; nyljethoxyjpyrimidin-t-yl)- /N 2,8-diazaspiro [4.5]decane carboxylate 63dn (S)-ethyl (R)(4- (acetamidomethyl)(3-methyl- 1 zol-l-yl)phenyl)-2,2,2- A trifluoroethoxy) 631 aminopyrimidinyl)-2,8- diazaspiro] 4.S]decane carboxylate 63do (3S)-ethyl 8-(2-amino((lR)- 2,2,2-trifluoro(3-(3-methyl-lH­ pyrazolyl)-4'-((2-((2- oxotetrahydrofuran A 823 yl)thio)ethyl)carbamoyl)-[ 1, l1- biphenyl]yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.S]decane carbox late 63dp (S)-ethyl 8-(2-amino((R) (3,4-dimethyl-3"­ (methylsulfonyl)-(1,1':3',J 11- A terphenyl]-4'-yl)-2,2,2- 738 triflu oroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane carboxylate 63dq (S)-ethyl 8-(2-amino((R)-2,2,2- triflu oro(3 '-(methylsulfonyl) (quinolinyl)-[ 1, henyl] A 761 yl )ethox y)pyrimidinyl)-2,8- diazasp iro[4.5]decane carbox late 63dr (S)-ethyl 8-(2-amino((R)-2,2,2- trifl uoro(41-(hydroxymethyl) methyl(3-methyl-1H-pyrnzol A yl)-[ 1,l1-biphenyl] 680 yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decane carbox late 63ds (S)-ethyl mino((R)-2,2,2- tri flu oro- 1-(31-(hydroxymethyl) methyl(3-methyl-1 H-pyrazol A yl)-[1,l'-biphenyl] 680 yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decane carbox late 63dt 'o (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(4'-(methoxycarbonyl)- 4-(3-methyl-lH-pyrazolyl)- A [1,1'-biphenyl] 694 yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decane carbox late 63du HO 3'-((S)((2-amino((R) (ethoxycarbonyl)-2,8- diazaspiro[4.5]decan A yl)pyrimidinyl)oxy)-2,2,2- 680 trifluoroethyl)-4'-(3-methyl- lH- pyrazolyl)-[1, l'-biphenyl] carbox lie acid 63dv (S)-ethyl mino((R)-2,2,2- triflu (2-(3-methyl-1 H- 0 pyra zol-l-yl)(1-oxo-1,3- A oisobenzofuran 693 yl)phenyl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.S]decane carboxylate 63dw (S)-ethyl 8-(2-amino((R)-2,2,2- triflu oro (4-(quinazolin A yl)pheny1)ethoxy)pyrimidiny1)- 608 2,8-diazaspiro[4.5]decane carboxylate 63dx -0 (S)-ethyl 8-(2-amino((R)-2,2,2- trifluo ro(2-(3-rn ethyl-1 H- pyrazolyl)(pyrimidin A yl)phenyl)ethoxy)pyrimidinyl)- 638 2,8-diazaspiro(4.5]decane carboxylate 63dy (S)-ethyl 8-(2-amino((R) N� (31,41-diflu oro(3-methyl-lH- pyraz olyl)-[l,l'-biphenyl] A 2,2- 672 triflu oroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane carboxylate 63dz (S)-ethyl 8-(2-amino((R)(4'­ N� chloro(3-methyl-l H-pyrazol yl)-[l,l'-biphenyl]yl)-2,2,2- B tr i fluoroethoxy)pyrim idinyJ)- 671 2, 8-diazasp iro [4. 5]decane carboxylate 63ea (S)-ethyl 8-(2-amino((R)(5- chloro-[1, l'-biphenyl]yl)-2,2,2- B tri fluoroethoxy)pyri midinyl)- 591 � 2,8-diazaspiro [4.5)decane CJ carbox late 63eb (S)-ethyl 8-(2-amino((R)(4'­ chloro(3-methyl-lH-pyrazol-lyl )-[1, 1 '-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidiny1)- 671 Cl 2,8-diazaspiro[4. S]decane carbox late 63ec (S)-ethyl 8-(2-amino((R)-l­ N� (3',4'-difl uoro(3-methyl-lH­ pyrazolyl)-[l,l'-biphenyl] A yl)-2,2,2- 672 F trifl hoxy)pyrimidinyl)- F azaspiro[4.5]decane carbox late 63ed (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro-l-]4-(3-methyl-lH­ pyrazol-l-yl)-[l, l 1-biphenyl] A 636 yl)ethoxy)pyrim idinyl)-2,8- diazaspiro[4.5]decane carbox late 63ec (S)-ethyl 8-(2-amino((R)-l­ (3',4'-dichloro(3-methyl-1H­ l-l-yl)-] 1, 1'-biphenyl] B yl)-2,2,2- 705 trifl hoxy)pyrimidinyl)- azaspiro[4.5Jdecane carboxylate 63ef (S)-ethyl 8-(2-amino((R)-2,2,2- triflu oro(3'-flu oro-[1, I '­ A biphenyl]yl)ethoxy)pyrimidi n- 574 4-yl)-2,8-diazaspiro[4.S]decane carbox late 63eg - (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(2-(3-methyl-1H- pyrazol-l-yl)(pyrimidin A 638 yl)phenyl)ethox y)pyrimidiny1)- ll_ 2, 8-diazaspiro [4.S]decane N carboxylate 63eh ¢f°CIF (S)-ethyl 8-(2-amino((R) (4',5-dichlorofluoro-[l, l '- biphenyl]yl)-2,2,2- B 643 oroethoxy)pyrimidiny1)- I 2,8-diazaspiro[4.S]decane Cl carboxylate 63ei 0 ............... (S)-ethyl 8-(2-amino((R)(5- chloro-3'-ethoxy-[1,1'-biphenyl]- 2-yl)-2,2,2- B 635 trifluoroethoxy)pyrirnidinyl)- � 2,8-diazaspiro[4.5]decane Cl carbox ylate 63ej Cl (S)-ethyl 8-(2-amino((R)- I- (3',5-dichloroethoxy-[1, l1- �o� biphenyl]yl)-2,2,2- B 669 trifluo ro ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane Cl&O, carboxylate 63ek Cl (S)-ethyl 8-(2-amino((R) (31,5-dichloro-5'-fl uoro-[ 1, l'- biphenyl]yl)-2,2,2- B 643 trifl uoro ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane Cl ylate 63el 6 (S)-ethyl 8-(2-amino((R)(3'- (tert-butyl)chloro -[1, l '- biphenyl]yl)-2,2,2- B trifl uoroethoxy)pyrimidinyl)- 647 ?" I ::::::.--. 2,8-diazaspiro[4.5]decane Cl ylate 63em Cl (S)-ethyl 8-(2-amino((R) ,::;,-- I (3 ',5-dichloro-5'-(trifl thyl)- F [1,1'-biphenyl]yl)-2,2,2- ,::;,-- I � B 693 F F trifluoroethoxy)pyrimidiny1)- ::::::.--. 2,8-diazaspiro[4.S]decane Cl carboxylate 63en (S)-ethyl 8-(2-amino((R)(5- �, �F chloro-3 '-fluoro-5'- � I (trifluoromethyl)-[1, 1'-biphenyl]- F B 2-yl)-2,2,2- 677 F F � trifluoroethoxy)pyrimidinyl)- Cl 2,8-diazaspiro[4.S]decane ylate 63eo &OCl (S)-ethyl 8-(2-amino((R)-l-(3'- -[1, 1'-biphenyl]yl)-2,2,2- B trifluoroethoxy)pyrimidinyl)- 591 2,8-diazaspiro[4.S]decane carboxylate 63ep &00/ (S)-ethyl 8-(2-amino((R)(5- chloro-3'-methoxy-[1, 1 '-biphenyl]- 2-yl)-2,2,2- B 621 trifluoroethoxy)pyrimidinyl)- Cl 2,8-diazaspiro[4.5]decane carboxylate 63eq (S)-ethyl 8-(2-amino((R)(5- &Co� chloro-3'-isopropoxy-[1, 1 '- biphenyl]yl)-2,2,2- B trifluoroethoxy)pyrimidiny1)- 649 2,8-diazaspiro[4.5]decane car boxylate 63er Cl (S)-ethyl 8-(2-amino((R) (3',5-dichloro-4'-methyl-[1, l '- biphenyl]yl)-2,2,2- B 639 trifl uoro ethoxy)pyrimidiny1)- � 2,8-diazaspiro[4.5]decane Cl carboxylate 63es Cl hyl 8-(2-amino((R) �oy (3',5-dichloro-4'-isopropoxy-[1,1 '- biphenyl]yl)-2,2,2- B 683 oroethoxy)pyrimidinyl)- I azaspiro[4.S]decane Cl carboxylate 63et F (S)-ethyl 8-(2-amino((R)(5- �oy chloro-P-fluoro-d-isopropoxy- [l,l '-biphenyl]yl)-2,2,2- B 667 trifluoro ethoxy)pyrimidinyl)- I 2,8-diazaspiro[4.5]decane Cl carboxylate 63eu hyl 8-(2-amino((R) ( 4' ,5-dichloro-3'-(trifluoromethyl} [1, 1'-biphenyl]yl)-2,2,2- �' B 693 trifluo roethoxy)pyrimidinyl)- 2,8-diazaspiro[4.S]decane carboxylate 63ev &DF (S)-ethy 1 8-(2-amino((R)(5- chloro-3 '-fluoro-[1, l'-biphenyl] yl)-2,2,2- B 609 trifluoroetho imidiny1)- 2,8-diazaspiro[4.5]decane Cl ylate 63ew (S)-ethyl 8-(2-amino((R) (4',5-dichloro-3'-methyl-[l ,1'- �Cl yl]yl)-2,2,2- B 639 trifluoroethoxy)pyrim id iny1)- 2,8-diazaspiro[4.S]decane Ci carboxylate 63ex F (S)-ethyl 8-(2-amino((R) e-: (3 ', 5-dichloro-4'-(trifl uoromethyJ)- I F (1,1'-biphenyl]yl)-2,2,2- ::::.... Cl B 693 ?" I tri fluo roethoxy)pyrimidinyl)- ::::.... 2,8-diazaspiro[4.S]decane Cl carboxylate 63ey &O,F (S)-ethyl 8-(2-amino((R)(5- chloro-3',5'-difl uoro-[1,1 '- biphenyl]yl)-2,2,2- trifl uoroethoxy)pyrimidin-t-y1)- 2,8-diazaspiro[4.S]decane Cl carboxylate 63ez Cl (S)-ethyl 8-(2-mnino((R) (3 ',5-dichloro-4'-fl uoro-[ 1, l '- �' biphenyl]yl)-2,2,2- tri flu oroethoxy)pyrimidiny1)- 2,8-diazaspiro[ 4.S]decane Cl carboxylate 63fa F (S)-ethyl rni no((R)(5- chlo 4'-diflu oro-[1,l '- biphenyl]yl)-2,2,2- �F B triflu oroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.S]decane Cl carboxylate 63fb (S)-ethyl 8-(2-amino((R)(5- chloro-3',4'-dimethyl-(1, 1'­ biphenyl]yl)-2,2,2- B 619 trifluoroethoxy)pyrimidiny1)- 2,8-diazaspiro [4. 5]decane Cl carboxylate 63fc (S)-ethyl 8-(2-amino((R) (4',5-dichloro-3',5'-dimethyl-(1, 1 '­ biphenyl]yl)-2,2,2- B 653 trifluoroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.S]decane Cl carbox late 63fd F (S)-ethyl 8-(2-amino((R)(5- y�r t'lJ 0'/ chloro-4'-ethoxy-3'-fluoro-[1, 1 '­ biphenyl]yl)-2,2,2- B 653 oroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.S]decane Cl carbox late 63fe (S)-ethyl mino((R)(5- chloro-3',5'-dimethyl-[1,1'­ yl]yl)-2,2,2- B 619 oroe thoxy)pyrimidinyl)- 2,8-diazas piro[4.S]decane Cl carboxylate 63ff &°'Cl (S)-ethy1 8-(2-amino((R) (3 ',5-dichloro-5'-methyl-[ 1, 1 '­ biphenyl]yl)-2,2,2- B 639 trifl uoro ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]dccane Cl carbox -late 63fg &6' (S)-ethyl 8-(2-amino((R)(5- chloro-4'-:fl '-methyl-[1, l '­ biphenyl]yl)-2,2,2- trifluoroet hoxy)pyrimidinyl)- 2,8-diazaspiro[4.5Jdecane Cl carboxylate 63fh (S)-ethyl 8-(2-amino((R)(5- O F chloro-3'-methyl-4'­ ')(_F F (trifluoro methoxy)-[l, 1 '­ B biphenyl]yl)-2,2,2- 689 trifluoroethoxy)pyrimid inyl)- Cl 2, 8-diazaspiro [4.5]decan e carboxylate 63fi F F (S)-ethyl 8-(2-amino((R)(5- chloro-3'-(trifluoromethoxy)-[1, 1 '- biphenyl]yl)-2,2,2- B trifluoroethoxy)pyrimidiny1)- 675 2,8-diazaspiro[4.5]decane carboxylate 63fj (S)-ethyl 8-(2-amino((R)(5- ?" I -3'-isopropyl-[l, 1 '- � biphenyl]yl)-2,2,2- , � B 633 ....-::. tri fluoroethoxy)pyrimidi ny1)- Cl 2,8-diazaspiro[4.5]decane carboxylate 63fk F (S)-ethyl 8-(2-amino((R)(5- F F -31,S'-bis(trifluoromethyl)- � l [1, henyl]yl)-2,2,2- F B trifluoroethoxy)pyrim idinyI)- 727 7' I � F F 2,8-diazaspiro[4.S]decane � carboxylate 63fl F (S)-ethyl 8-(2-amino((R)(5- chloro-3'-fluoro-4 '-methyl-[l, 11- biphenyl]yl)-2,2,2- B 623 triflu oroethoxy)pyrimid iny1)- � 2,8-diazaspiro[4.S]decane Cl carboxylate 63fm QPc,Cl (S)-ethyl 8-(2-amino((R)-2,2,2- triflu oro- 5,S1-trichloro-[l ,l '- B biphenyl]yl)ethoxy)pyrimid in- 659 4-yl)-2,8-diazaspiro[4.5]decane carboxylate 63fn F (S)-ethyl 8-(2-amino((R)(5- F F fluoro- 31- � I F (trifl uoromethyl)-[1,1 '-biphenyl]- � B 2-yl)-2,2,2- 677 7' I trifl uoroethoxy)pyrimidinyl)- � 2,8-diaza spiro[4.5]decane &°Cl carboxylate 63fo (S)-ethyl 8-(2-amino((R)- l-(4- chloro(p yridinyl)phenyl)- B 2,2,2-tri fl uoroethoxy)pyrimidin 592 yl)-2,8-diazaspiro[4.S]decane Cl carboxylate 63fp F (S)-ethyl 8-(2-amino((R)(5- chloro-Jvfluoro-S'dsopropoxy- [ 1, l1-biphenyl]yl)-2,2,2- B 667 �o� trifluoroethoxy)pyrimidinyl)- azaspiro[4.5]decane Cl carboxylate 63fq F (S)-ethyl 8-(2-amino((R)(5- -J'cethoxy-S'dluoro-l l , 1'- biphenyl]yl)-2,2,2- B 653 �o� trifluoroethoxy)pyrimidinyl)- 2,8-diazaspiro(4.5]decane Cl carboxylate 63fr (S)-ethyl 8-(2-amino((R)(31- ?' I butyl)chloro-5'-methyl- � ( 1, 1'-biphenyl]y 1)-2,2,2- e-: B 661 I trifl uoroethoxy)pyrimidinyl)- ::.:::.... 2,8-diazaspiro[4.S]decane Cl carboxylate 63fs (S)-ethyl 8-(2-amino((R)(5- cyano-[l, l '-biphenyl] yl)-2,2,2- B 616 �N trifluoroethoxy)pyrimidiny1)- Cl 2,8-diazaspiro[4.S]decane carboxylate 63ft l_o (S)-ethyl 8-(2-amino((R)(31- ethoxy-5'-fl uoro(3-methyl-1H- � I pyrazolyl)-[1, 1 '-biphenyl] F ::.:::..., 2,2- I � A trifluoroetho xy)pydmidinyl)- 698 2,8-diazaspiro[4.5]decane "µ carboxylate 63fv F (S)-ethyl 8-(2-amino((R)(41- ?' chloro -3 '-fl uoro(3-methyl-lH- ::::-... pyra zolyl)-[l,1'-biphenyl] ?' I B yl)-2,2,2- � 689 trifl uoroethoxy)pyrimidinyl)- "µ 2,8-diazaspiro[4.S]decane carboxylate 63fw (S)-ethyl 8-(2-amino((R)(3'- chloro-4'-ethoxy(3-methyl-1H- pyrazol-l-ylj-] 1,I1-biphenyl] B yl)-2,2,2- 715 "µ trifluoroethoxy)pyrimidiny1)- I 2,8-diazaspiro[4.5]decane carbox late 63fx (S)-ethyl 8-(2-amino((R)(3'- ethoxy(3-methyl-1 Hvpyrazol-lyl )-[1, 1'-biphenyl]yl)-2,2,2- A tri:fluoroethoxy)pyrimidinyl)- 680 "µ 2,8-diazaspiro[4.S]decane I carboxylate 63fy F (S)-ethyl mino((R)-l- (3',5'-difluoro(3-methy l-IH- pyraz olyl)-[1,1'-biphenyl] A yl)-2,2,2- 672 tri:flu oroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.S]decane carboxylate 63fz (S)-ethyl 8-(2-am ino((R)-2,2,2- F triflu oro (3-(3-methyl-lH- F F pyraz l)-3'-(trifl uoromethy])- A [1,1'-biphenyl] 704 "µ yl y)pydmidinyl)-2,8- /, diazaspiro[4.S]decane carbox late 63ga Cl (S)-ethyl 8-(2-amino((R)(5- chloro-Svethoxy-a-fluoro-]1 ,l'- biphenyl]yl)-2,2,2- B triflu oroethoxy)pyrim idinyl)- 653 azaspiro[4.5]decane carboxylate 63gb lo (S)-ethyl mino((R)-2,2,2- trifl uoro(3'-fluoro-4'- isopropoxy(3-methyl-lH- A pyrazol-l-yl)-[1,1 '-biphenyl] 712 "µ yI)ethoxy)pyrimidiny1)-2,8- Ii diazaspiro[4.S]decane carbox late 63gc hyl 8-(2-amino((R) (31,51-dimethyl(3-methyl-1H- pyrazolyl)-[1, 1'-biphenyl] A yl)-2,2,2- 664 "µ trifl uoroethoxy)pyrimidinyl)- Ii 2,8-diazaspiro[4.5]decane carboxylate 63gd (S)-ethyl 8-(2-amino((R)-l-(3 '- chloro-5 1-methyl(3-methyl-lH- pyrazolyl)-[l,l'-biphenyl] B yl)-2,2,2- 685 "µ trifluoroethoxy)pyrimidinyl)- I. 2,8-diazaspiro[4.5]decane ylate 63ge (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(3 ro-4 1-methyl (3-methyl-1H-pyrazolyl)-[1,1 '- A 678 biphenyl]yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.S]decane carbo x late 63gf (S)-ethyl 8-(2-amino((R)(3 '- (tert-butyl)(3-methyl-lH- pyraz olyl)-[1, 1'-biphenyl) A yl)-2,2,2- 692 trifluoroethoxy)pyri midinyl)- 2,8-diazaspiro[4.5]decane carbox late 63gg (S)-ethyl 8-(2-amino((R)-l-(3'- (3-methyl-IH-pyra zol-l- yl)-[1, 1 '-biphenyl]yl)-2,2,2- B tri fluo roethoxy)pyrimidiny1)- 671 "µ 2,8-diazaspiro[ 4.5]decane Ii carboxylate 63gh Cl (S)-ethyl 8-(2-amino((R)(3 '- F chloro-4'-flu oro(3-methyl-lH- pyrazolyl)-[l, 1'-biphenyl] B yl)-2,2,2- 689 triflu oroethoxy)pyrimidinyl)- "µ azaspiro[4.S]decan e /, carboxylate 63gi F (S)-ethyl 8-(2-amino((R) (3',4'-difluoro(3-methyl-lH- F pyrazol-l-yl)-]1, 1'-biphenyl] A yl)-2,2,2- 672 "µ trifluoroethoxy)pyrimidinyl)- /, 2,8-diazaspiro[4.S]decane carbox -late 63gj (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(4'-fluoro(3-methyllH-pyrazolyl )-3'- A uoromethyl)-[1, l '<biphenyl]- 722 "µ 4-yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.S]decane carbox late 63gk F (S)-ethyl 8-(2-amino((R)-l-(3 '- chloro(3-methyl-lH-pyrazol- lyl )(tri fluo romethyl)-[1, 1'- biphenyl]yl)-2,2,2- B triflu oroethoxy)pyrimidinyl)- 739 azaspiro[4.5]decane carboxylate 63gl hyl 8-(2-am ino((R)-2,2,2- F('oF trifl uoro(3-(3-methyl-1H- pyra zol-l-yl)-3'- µ A (tritlu oromethoxy)-[l ,l1- 720 biphenyl]yl)ethoxy)pyrimi din- N 4-yl)-2,8-diazaspiro[4.5]decane carb oxylate 63gm (S)-ethyl mino((R)-l-(3 '- (tett-butyl)-5'-methyl(3-methyl- 1H-pyrazolyl)-[ 1, l1-biphenyl]- 4-yl)-2,2,2- A trifl uoroethoxy)pyrimidinyl)- 706 "µ 2, 8-diazas piro [4.5]decane !. carboxylate 63gn (S)-ethyl 8-(2-amino((R)(4'- chloro- 3'-methyl(3-methyl-lH- l-l-yl)-[1,l '-biphenyl] yl)-2,2,2- B 685 "µ tritl uoroeth oxy)pyrimidinyl)- I. 2,8-diazaspiro[4.5]decane carboxylate 63go (S)-ethyl 8-(2-amino((R)-l-(4'- chloro-3',5'-dimethyl(3-methyllH-pyrazolyl )-[1, l1-biphenyl)- B 4-yl)-2,2,2- 699 "µ trifluoroethoxy)pyrimidinyl)- N 2,8-diazaspiro[4.5]decane carboxylate 63gp (S)-ethy1 8-(2-amino((R)-2,2,2- trifluoro(4'-fluoro-3'-methy! (3-methyl-lH-pyrazolyl)-[1, l '- A 668 biphenyl]yl)ethoxy)pyrimidin- 2,8-diazaspiro[4.5]decane carbox late 63gq (S)-ethyl 8-(2-amino((R)(4'- l F ethoxy-3'-fluoro (3-methyl-lH- 0 pyrazol-l-yl)-]1 ,1'-biphenyl] A yl)-2,2,2- 698 triflu oxy)pyrimidinyl)- 2,8-diazaspiro[4.S]decane carboxylate 63gr Cl hyl 8-(2-amino((R) (3',5'-dichloro(3-methyl-lH- pyrazolyl)-[l, l '-biphenyl] B yl)-2,2,2- 705 oroethoxy)pyrimidinyl )- 2,8-diazaspiro(4.5]decane carboxylate 63gs (S)-ethyl 8-(2-amino((R )-2,2,2- trifl uoro-l-(3'-isopropyl(3- methyl-lH-pyrazolyl)-(1, 1 '- A biphenyl]yl)ethoxy)pyrimidin- 678 "µ 4-yl)-2,8-diazaspiro[4.5]decane I. carboxylate 63gt (S)-ethyl 8-(2-amino((R)(41- chloro(3-methyl-lH-pyrazol yl)(tri fl uoromethyl)-[l .l'- B yl]yl)-2,2,2- 739 "µ tri fluoroe th oxy)pyrimi dinyl)- I. 2,8-diazaspiro[4.S]decane carbox late 63gu (S)-ethyl 8-(2-amino((R)-l-(3'- chloro(3-methyl-1 H-pyrazol -(trifluoromethyl)-[ 1, 1'- B biphenyl]yI)-2,2,2- 738 "µ trifluoroethoxy)pyrimidiny1)- azaspiro[4.S)decane Ii carboxylate 63gv (S)-ethyl 8-(2-amino((R)(3'- H2N carbamoyl(3-methyl-1 H- pyrazolyl)-[l, henyl] A yl)-2,2,2- 679 "µ trifluoroethox y)pyrimidiny1)- Ii 2,8-diazaspiro[4.S]decane carboxylate 63gw F (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(3-(3-methyl-1H- pyrazolyl)-3',5'- bis(trifluoromethyl)-[1, 1 '- A biphenyl]y 1)ethoxy)pyrimid in- 772 4-yl)-2,8-diazaspiro[ 4.S]decane "µ carboxylate 63gx Ao (S)-ethyl 8-(2-amino((R)-2,2,2- trifl uoro-l-(3'-isopro poxy(3- methylI-pyrazolyl)-[l, 1 '- A biphenyl]yl)ethoxy)pyrimidin- 694 "µ 4-y1)-2,8-diazaspiro[4.5]decane /, carboxylate 63gy F (S)-ethyl 8-(2-amino((R)(3'- ethoxy-4'-flu oro(3-methyl-1H- ,,,..........0 lyl)-[l ,1'-biphenyl] A yl)-2,2,2- 698 "µ trifl uoroethoxy)pyrimidinyl)- /, azaspiro[4.5]decane carbox -late 63gz F (S)-ethyl 8-(2-arn ino((R)-2,2,2- trifl uoro(3'-fl uoro-5'- Ao isopro poxy(3-methyl-1 H- A pyra zolyl)-[l, 1 '-biphenyl] 712 yl)ethoxy)pyrimidinyl)-2,8- "µ diazaspiro[4.5]decane /. carboxylate 63ha (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(4'-methoxy(3- methyl-lH-pyrazolyl)-[1, l1- A biphenyl]yl)ethoxy)pyrimidin- 666 "µ 4-yl)-2,8-diazaspiro [4.S]decane Ii carboxylate 63hb '-../0 (S)-ethyl 8-(2-amino((R)(4'- ethoxy(3-methyl-1 Il-pyrazol-I- yl)-[1, l'-biphenyl]yl)-2,2,2- A tri fluoroethoxy)pyrimidinyl)- 680 "µ 2,8-diazaspiro[4.S]decane I. carboxy]ate 63hc (S)-ethyl 8-(2-amino((R)-2,2,2- F trifluoro(3', 4',5'-triflu oro(3- methyl-lH-pyrazolyl)-[1,1 '- A 690 F biphenyl]yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.S]decane carbox rlate 63hd Cl (S)-ethyl 8-(2-amino((R)(4- (1-methyloxo-1,2- dih ydropyridinyl)phenyl)-2,2,2- B 622 triflu oroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane carbox late 63he (S)-ethyl 8-(2-amino((R)-2,2,2- trifl -(3'-methyl(3- -lH-pyrazolyl)-4'- A (trifl uoromethoxy)-[1,1 '- 734 "/) biphenyl)yl)ethoxy)pyri midin- I. 4-yl)-2,8-diazaspiro[4.5]decane carboxylate 63hf (S)-ethyl 8-(2-amino((R)(3'- chl oro- 4'-methyl(3-methyl-lH- pyrazolyl)-[1, henyl] B yl)-2,2,2-triflu oroethoxy) 685 "µ pyrimidinyl)-2,8- diazaspiro[4.5]decan e carboxylate 63hg F (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(3'-:fluoro(3-methyllH-pyrazol-l-yl )-5'- A (trifluoromethyl)-[1, I'-biphenyl]- 722 4-yl)ethoxy)pyrimidinyl)-2,8- "µ diazaspiro[ 4.S]decane !. carboxylate 63hh F (S)-ethyl 8-(2-amino((R)-l-(3'- chloro-5'-fluoro(3-methyl-IH- pyrazol-l-yl)-[1,1'-biphenyl] A yl)-2,2,2- 689 "µ trifluoroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.S]decane I carboxylate 63hi (S)-ethyl 8-(2-amino((R)(5- chloro-3'-cyclopropyl-[1,1 '- biphenyl]yl)-2,2,2- B 631 trifluoroethoxy)pyrimidiny1)- azaspiro[4.5Jdecane carbox ,late 63hj (S)-ethyl 8-(2-amino((R)-l-(3'- -4'-isopropoxy(3-methyl- 1 azol-l-yl)-] 1, I'-biphenyl]- B 4-yl)-2,2,2-trifl uoroethoxy) 729 "µ pyrimidinyl)-2,8- diazaspiro[4.5]decane carbox late 63hk (S)-ethyl 8-(2-amino((R)(2- (benzo[d]thiazolyl) chlorophenyl)-2,2,2- B trifl hoxy)pyrimidinyl)- 648 2,8-diazaspiro[4.5]decane carboxylate 63hl (S)-ethyl 8-(2-amino((R)(4- chloro(2- (dimethylamino)pyridin B yl)phenyl)-2,2,2- 635 trifl uoroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane carbox late 63hm (S)-ethyl 8-(2-amino((R)(4- chloro(naphthalen nyl)-2,2,2- B trifluoroethoxy)pyrimidiny1)- 641 2,8-diazaspiro[4.5]decane carboxylate 63hn (S)-ethyl 8-(2-amino((R)-l-(3'- (tert-butyl)chloro-[ 1, 1'- biphenyl]yl)-2,2,2- B 647 trifluoroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.S]decane carbox late 63ho -o, (S)-ethyl 8-(6-((R)(2-(lH- benzo[d]imidazolyl) :::-.._ I pheny l)-2,2,2- N B trifluoroetho xy) 631 (5-j aminopyrim idinyl)-2,8- diazaspiro[4.S]decane carbox ,fate 63hp (S)-ethyl 8-(2-amino((R)(4- Cl�:::-.._ I chloro(lH-indazol OJN yl)phenyl)-2,2,2- N, 631 trifluoroethoxy)pyrimid iny1)- azaspiro[4.S]decane carbox late 63hq (S)-ethyl mino((R)- l-(4- chloro(2-isopropylpyridin yl)phenyl)-2,2,2- B triflu oroethoxy)pyrimidinyl)- 634 2,8-diazaspiro[4.S]decane carboxylate 63hr (S)-ethyl 8-(2-amino((R)(5- chloro-4'-flu oro-[1, 1 '-biphenyl] yl)-2,2,2- B trifl uoroethoxy)pyri midinyl)- 609 2,8-diazaspiro[4.S]decane carboxylate 63hs o?CI (S)-ethyl 8-(2-amino((R) (4' ,5-dichloro-[1, 1 '-biphenyl] Cl yl)-2,2,2- B 625 trifl hoxy)pyrimidinyl)- .....:. 2,8-diazaspiro[4 .5]decane carbox late 63ht (Sj-ethyl 8-(2-amino((R)(5- chloro-4'-methyl-[1 , 1 '-biphenyl]- 2-yl)-2,2,2- B 605 trifluoroethoxy)pyrimidinyI)- 2,8-diazaspiro[4.S]decane carbox late 63hu (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(2-(3-methyl-1H- p pyrazolyl)A-(naphthalen A yl)phenyl)ethoxy)pyrimidinyl)- 687 !. 2,8-diazaspiro[4.5Jdecane carboxylate 63hv Cl (S)-ethyl 8-(2-amino((R)(5- chloro-2''3' 4' 5'-tetrahydro-[1 1 '- ) ., ' yl]yl)-2,2,2- B 595 trifluoroetho xy)pyrimidiny1)- 2,8-diazaspiro ecane carboxylate 63hw hyl 8-(2-amino((R)-l-(41- (benzyloxy)-3'-fluoro(3- methyl-lH-pyra zolyl)-[ 1, l1- biphenyl]yl)-2,2,2- p A 761 trifluoroethoxyjpyrimidin-d-yl)- 2,8-diazaspiro[4.5]decane !. carboxylate 63hx (S)-ethyl 8-(2-ami no((R)-2,2,2- trifl uoro(4'-isopropoxy-3'- methyl(3-methyl-lH-pyra zol A , 1 '-biphenyl] 709 "µ yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decane carbox late 63hy (S)-ethyl 8-(2-amino((R)(5- Cl�Oy -3'-isobutoxy-[l, l '- biphenyl]yl)-2,2,2- B 663 l h triflu oroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane carbox late 63hz (S)-ethyl 8-(2-amino((R)-2,2,2- trifl uoro- 1-(4-isopropoxy- [1 ,1':3',111-terphenyl]-4'- A yl)ethoxy)pyrimidinyl)-2,8- 690 diazaspiro[4.5]decane carboxylate 63ia (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(4-(3-:fluoroquinolin F A ny 1)ethox y)pyrimidinyl)- 626 2,8-diazaspiro[ 4.S]decane carbox late 63ib �o (S)-ethyl mino((R)-2,2,2- trifluoro(3'-fluoro(3-methyl- F lH-pyrazolyl)-4'-propoxy-[l, l '- A biphenyl ]y 1)ethoxy)pyrimidin- 713 "µ 2,8-diazaspiro[4.S]decane /, carboxylate 63ic �o (S)-ethyl 8-(2-amino((R)(4'- butoxy-3'-fluoro(3-methyl-1 H- pyrazolyl)-[l, 1 '-biphenyl] A 2,2- 727 "µ trifluoroethoxyjpyrimidin-d-yl)- /, 2,8-diazaspi ro[4.S]decane carbo x late 63id N-N (S)-ethyl 8-(2-amino((R)-2,2,2- -I( I tdfl uoro- 1-(3'-fluo ro-4'-(5-methyl- 1,3,4-oxadiazolyl)(3-methyl- IH-pyra zolyl)-[ 1, l'-biphenyl]- A 734 4-yl)ethoxy)pyrimidinyl)-2,8- "µ piro[4.5]decane carboxylate 63ie (S)-ethyl 8-(2-ami no((R )(5- chloro-3 '-(p yrrolidine-l-carbonyl)- [1,1'-biphenyl]yl)-2,2,2- B triflu oroethoxy)pyrimidinyl)- 688 0 2,8-diazaspiro[ 4.5]decane 0 carboxylate 63if (S)-ethyl 8-(2-amino((R)(5- chloro-3 '-(cyclopentyloxy)-[ 1, 1'- biphenyl]yl)-2,2,2- B trifluoroethox y)p yrimid iny1)- 675 2,8-diazaspiro[4.5]decane carboxylate 63ig hyl 8-(2-amino((R)(5- chloro-3'-(morpholine carbonyl)-[1, 1 '-biphenyl]yl)- trifluoroethoxy)pyrimidin 704 yl)-2,8-diazaspiro[ cane CN) carboxylate 63ih (S)-ethyl 8-(2-amino((R)(5- chloro-3'-(((1R,4R) hydroxycyclohexyljcarbamoyl)- [1, l'-biphenyl]yl)-2,2,2- B 732 trifluoroethoxy)pyri midiny1)- 2,8-diazaspiro[4.5]decane carboxylate 63ii (S)-ethyl 8-(2-amino((R)(5- chloro-3'-ethyl-[1, 1 '-biphenyl] yl)-2,2,2- 619 trifluoroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decane carbox late 63ij Cl (S)-ethyl 8-(2-amino((R)-l-(5- chloro -3'-isoprop yl-[ 1,1'- biphenyl]yl)-2,2,2- B 633 tri fluoroethox y)pyrimidiny1)- 2,8-diazaspiro[4.5]decane carbox late 63ik (S)-ethyl mino((R)-2,2,2- � trifluoro(41-propoxy-[l, l'- 0 biphenyl]yl)ethoxyjpyrimidin- A 4-yl)-2,8-diazaspiro[4.S]decane 614 carboxylate 63il (S)-ethyl 8-(2-amino((R)(2- ethy1(3-fl uoroquinolin F yl)phenyl)-2,2,2- A 654 tritluoroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.S]decane carbox late 63im hyl 8-(2-amino((R)(5- chloro-3 '-(4-methylpiperazine carbonyl)-[1, l1-biphenyl]yl)- 2,2,2-trifluoroethoxy) pyrimidin- B 4-yl)-2,8-diazaspiro[4.5)decane 717 CN) carboxylate 63in (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(4-(3-fluoroquinolin F yl) A 640 rnethylphenyl)e pyrimidin yl)-2,8-diazaspiro[ 4.5]decane carbox late 63io hyl mino((R)(4'- I (diethylcarbamoyl)-[1, 1 '- ) biphenyl]yl)-2,2,2- A 656 trifl uoroethoxy)pyrimidiny1)- 2,8-diazaspiro[4.5]decane carbox late 63ip (S)-ethyl 8-(2-amino((R)(4'- H2N carbamoyl-{1,1 '-biphenyl]yl)- Cl� A 2,2,2-tritluoroethoxy)pyrimidin 600 yl)-2,8-diazaspiro[4.S]decane carboxylate 63iq (S)-ethyl 8-(2-amino((R )(4- � 1 chloro(2-methylthiazol yl)phenyl)-2,2,2- B 612 s '-:::: trifl hoxy)pyrirni diny1)- )=N 2,8-diazaspiro[4.5]decane carbox late 63ir (S)-ethyl 8-(2-amino((R)-2,2,2- trifl uoro(4-propoxy-[1,1 ':3', l "- terphenyl]yl)ethoxy)pyrimidin- A 4-yl)-2,8-diazaspir o[4.5Jdecane 691 carboxylate 63is Cit (S)-ethy1 8-(2-arnino ((R)(4- l h chloro- 2-(5-chlorothi ophen yl)phenyl )-2,2,2- B 631 7" s trifl uoroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5)decane Cl carbox late 63it (S)-ethy 1 8-(2-amino((R)-2,2,2- trifluoro( 4'-(methylsulfonyl)- [l,1'-biphenyl) A 635 yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[ 4.5]decane carboxylate 63iu (S)-ethy l 8-(2-amino((R)-2,2,2- trifluoro(3-(3-methyl-IH- lyl)-4'-(methylsulfonyl)- A [l,11-biphenyl] 715 yl)ethoxy)pyrimidiny1)-2,8- diazaspiro[4.S]decane carbox late 63iv (Sj-ethyl 8-(2-amino((R)-2,2,2- trifluoro(3-(3-methyl-1H- pyrazolyl)-4'-p ropoxy-(1, 1 '- A bipheny 1)y1) ethoxy)pyrimidin- 695 "µ 4-yl)-2,8-diazaspiro[4.5]decane /, carboxylate 63ix (S)-ethyl 8-(2-amino((R)-l-(4'- /"'-.N (diethylcarbamoyl)(3-methyt- ) 1H-pyrazolyl)-(l,I-biphenyl]- A 4-yl)-2,2,2- 736 o xy)pyrimidinyl)- "µ 2,8-diazaspiro[4.5]decane !. carboxylate 63iy (S)-ethyl 8-(2-amino((R)-2,2,2- oro-l-]4'-(methylcarbamoyl)- H (l,l'-biphenyl] A 613 yl)ethoxy)pyrimidinyl)-2,8- piro]4.S]decane carbox late 63iz (S)-ethyl 8-(2-amino((R)-2,2,2- trifluo ro(3-(3-methy l-1 H- pyra zolyl)sulfamoyl-[1, 1 '- A biphenyl]yl)ethoxy)pyrimidin- 715 q 4-yl)-2,8-diazaspiro[4.5]decane carboxylate 63ja (S)-ethyl 8-(2-amino((R)-2,2,2- triflu oro(4'-sulfamoyl-[1,1 '- A bipheny1]yl)ethoxy)pyrimidin- 635 4-yl)-2,8-diazaspiro[4.5]decane carboxylate 63jb 01 (S)-ethyl 8-(2-amino((R)-2,2,2- I trifluoro(4'-((2- �N�N morpholinoethyl)carbamoyl)-[1, l 1- H A 712 biphenyl]yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane ylate 63jc 01 (S)-ethyl 8-(2-amino((R)-2,2,2- �N�N trifluoro-1 -(3-(3-methyl-1H- H pyrazolyl)-4'-((2- A morpholinoethyl)carbamoyl)-[1, l 1- p bipheny I]yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.S]decane carboxylate 63jd 'w .... hyl 8-(2-amino((R)-l-(4'- (dimethylcarbamoyl)-[1, l'- biphenyl]yl)-2,2,2- A 628 trifluoro ethoxyjpyrimidin-q-yl)- 2,8-diazasp 5]decane carbox late 63je (S)-ethyl 8-(2-amino((R)-2,2,2- ['N I tri fl uoro- 1-(4'-(pipera zine carbonyl)-[l,1'-biphenyl] HN� A 669 yljethoxyjpyrimidin-q-ylj-Zfi- diazas piro[4.5]decane carbox late 63jf 0 (S)-ethyl 8-(2-amino((R)-2,2,2- ['N trifluoro- 1-(3-(3-methyl-1 I-I- HN� pyrazol-l-ylj-t'{pipera zine-l- A carbonyl)-[ 1 ,1 '-biphenyl] 749 p yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4. 5Jdecane /, carboxylate 63jg (S)-ethyI 8-(2-amino((R)(4- chloro(1-methyloxo-1,2- 0 dihydro pyrid inyl)phenyl)-2,2,2- B 622 trifluoroethoxyjpyrimidin-a-yl)- azaspiro ecane carboxylate 63jh 0 (S)-ethyl 8-(2-amino((R)( 4'- 'N (dimethylcarbamoyl)(3-methyl- I 1 H-pyrazolyl)-[1,1 '-biphenyl]- A 4-yl)-2,2,2- 708 trifluoroethoxy)pyrimidinyl)- "µ 2,8-diazaspiro[4.5]decan e I. car boxylate 63ji ,..,o hyl 8-(2-amino((R)-2,2,2- trifluoro(3'-fluoro-4'-methoxy- 3-(3-methyl-lH-pyrazolyl)- A [l,l'-biphenyl] 685 "µ yl)ethoxy)pyrimidinyl)-2,8- /, diazaspiro [4. S]decane carbox ,)ate 63jj (S)-ethyl 8-(2-amino((R)-2,2,2- /'-.../0 trifluoro(3' -fluoro-4'-p ropoxy- [1 , 1 '-biphenyl] A 633 yl)ethox y)pyrimidiny 1)-2, 8- diazaspiro[ 4.5Jdecane carbox -late 63jk (S )-ethy1 8-(2-amino((R)- 2,2, 2- 'N trifl uoro(3-(3-methyl-1H- H pyrazol-l-yl)-4'- A (methylcarbamoyl)-[1, 1 '- 694 biphenyl)yl)ethoxy)pyrimidin- "µ 2,8-diazaspiro[4.5]decane I. carboxylate 63jl HN/ hyl 8-(2-amino((R)(5- 0=S=0 chloro-3'-(N-m ethylsulfamoyI)- [1, henyl]yl)-2,2,2- B 684 tritlu oroethoxy)pyrimidi )- Cl�� ! 2,8-diazaspiro[4.S]decane carboxylate 63jm '-N/ (S)-ethyl 8-(2-amino((R)-l-(S- I chloro-3'-(N,N- 0:::S:::O dimethylsulfa moyl)-(1,1 '- B biphenyl]yl)-2,2,2- 698 Cl�s-: trifluo roethoxy)pyrimidiny1)- � I 2,8-diazaspiro[4.S]decane carboxylate 63jn y (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(4'-isopropoxy morpholino-[l, henyl] o�� ,:;,,' � I A yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4 .5]decane CN) carboxylate 63jo I (S)-ethyl 8-(2-amino((R)(5- 0 NH " chloro-3'-(methylcarbamoyl)-[l, l 1- biphenyl]yl)-2,2,2- B 648 Cl tri fluo roethoxy)pyri midiny1)- ,:;,,'o{I� 2,8-diazaspiro[4.5]decane carboxylate 63jp Cl (S)-ethyl mino((R)(5- s, I -J'{dimethylcarbamoyl)- [l .i 1-biphenyl]yl)-2,2,2- l � B trifluoroethoxy)pyrimidiny l)- 662 o� h 2,8-diazaspiro[4.5]decane /N"-. carboxylate 63jq (S)-ethyl 8-(2-amino((R)(41- ethoxy-3'-fluo ro- [1, 1 '-biphenyl] �o� yl)-2,2,2- F � � A 618 trifl uoroe thoxy)pyrim idinyl)- 2,8-diazaspiro[4.5]decane carboxylate 63jr "l (S)-ethyl 8-(2-amino((R)(41- ethoxy-[1, l '-biphenyl]yl)-2,2,2- l h A tri:fl uoro ethoxy)pyrim idinyl)- 601 o�I � 2,8-diazaspiro[4.5]decane »: carboxylate 63js 'sW (S)-ethyl 8-(2-amino((R)-2,2,2- trifl uoro(5-(methylsulfonyl)- [l,1'-biphenyl] O' I � A 635 yl)ethoxy)pyrimidinyl)-2,8- diazaspiro]4.S]decane carboxylate 63jt Cl l � (S)-ethyl 8-(2-amino((R)(5- . chloro-3'-(diethylcarbamoyl)-[l, 11- biphenyl]yl)-2,2,2- � I B tri fluoroethoxy) pyrimidinyl)- 690 s, ,,0 2,8-diazaspiro[4.5]decane carboxylate 63ju �o (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(4'-isobutoxy(3- -I H-pyrazolyl)-[l,1 '- A biphenyl]yl)ethoxy)pyrimidin- 709 "µ 4-yl)-2,8-diazaspiro [4.S]decane I. carboxylate 63jv (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(3-(3-methyl-1 H- pyrazolyl)-4'-(neopentyloxy)- A [I, 1'-biphenyl] 723 "µ yl)ethoxy)pyrimidinyl)-2,8- Ii diazaspiro[4.S]decane ylate 63jw (S)-ethyl 8-(6-((R)(2-(lH- 'lNH benzo[d]imidazolyl) chlorophenyl)-2,2,2- B triflu oroethoxy) 631 Cl��l aminopyrimidinyl)-2,8- diazaspiro[4.S]decane carbox late 63jx (S)-ethyl 8-(2-amino((R)(4- anyl)(3-methyl-lH- pyrazolyl)phenyl)-2,2,2- A tri fl uoroethoxy)pyrimidinyl)- 693 "µ 2,8-diazaspiro[4.S]decane I. carboxylate 63jy fNH hyl 8-(2-amino((R )(5- 0 N.__) chloro- 3'-(p iperazinecarbonyl)- ' [l,l1-biphenyl)yl)-2,2,2- B triflu oroethoxy)pyrimidinyl)- 703 2,8-diazaspiro[4.5]decane carboxylate 63jz ("w'l� (S)-ethyl 8-(2-amino((R)(5- chloro -3'-(4- N.__) cyclopropylpiperazine-l- A carbonyl)-[1, l 1-biphenyl)yl)- 743 2,2,2-trifl uoroethoxy) pyrimidin- 4-yl)-2,8-diazas piro[4.S]decane carboxylate 63ka N.,..,.N (S)-ethyl mino((R)-l-(4- ?"' I :::::--.. :::::--.. (cinnolinyl)(3-rnethyl-lH- , � pyrazol-l-yl)phenyl)-2,2,2- � A trifluoroethoxy)pyrimidinyl)- 689 2;8-diazaspiro[4.5]decane I. ylate 63kb Cltyy (S)-ethyl 8-(2-amino((R)-l-(4- � I chloro(3-(trifluoromethyl)-1 H- pyrazolyl)phenyl)-2,2,2- B trifluoroethoxy)pyrimidinyl) - 649 Fp 2;8-diazaspiro[4.5]decane F F carboxy)ate 63kc Cltyy� ' (S)-ethyl 8-(2-amino((R)(2- p (3-(tert-butyl)- lH-pyraz olyl) chl orophenyl)-2,2,2- B trifl uoroethoxy)pyrim idiny1)- 637 2,8-diazaspiro[4.S]decane carboxylate 63kd Cltyy (S)-ethyl 8-(2-amino((R)(4- _p:::::--.. I chloro(3-isopropy1-1If-pyrazol- 1-yl)phenyl)-2,2,2- B trifl uoroethoxy)pyrimidiny1)- 624 I. 2,8-diazaspiro[4.S]decane ylate 63ke ClyY (S)-ethyl 8-(2-amino((R)(4- :::::--.. I chloro(3-cyclopropy1-1H- ;? pyrazol-l-yl)phenyl)-2,2,2- I trifluoroethoxy)pyrimidiny1)- 622 2,8-diazaspiro[4.S]decane carboxylate 63kf hyl 8-(2-amino((R)-l- (3',4'-dimethyl(3- � ?"' (trifluoromethylj-I Il-pyrazol-l- �:::::--.. Ip yl)-[l ,1 '-biphenyl]yl)-2,2,2- A triflu oroethoxy)pyrimidinyl)- 719 azaspir o[4.S]decane F carboxylate F F 63kg (S)-ethyl 8-(2-amino((R)- � F f 2,2,2-triflu oro(3-flu oro 0 I � pro poxy-[ 1,1':3',1"-terphenyl]-4'- A 660 � ' �"-::: ,,r; yl)ethoxy)pyrimidinyl)-2,8- piro[4.5]decane carboxylate 3 17 63kh (S)-ethyl 8-(2-amino((R)-1 - (3,4-dimethyl-[ 1, l':3', 1"- terphenyl]-4'-yl)-2,2,2- A tri fluoroethoxy)pyri midiny1)- 708 2,8-diazaspiro[4.5]decane ylate 63ki (S)-ethyl (R)-l -([ 1, 1'- biphenyl]yl)-2,2,2- tri fluoroethoxy) A 556 aminopyrimidinyl)-2,8- diazaspiro[4.5]decane carbox -late 63kj (S)-ethyl 8-(6-((R)-l-([1, 1':3', 1"- nyl]-4'-yl)-2,2,2- trifluoroethoxy) A aminopyrimidinyl)-2,8- 633 diazaspiro[4.5]decane carboxylate 63kl (S)-ethyl 8-(2-amino((R)-2,2,2- tri fl uoro(4'-(hydro xymethyl) (3-methyl-1H-pyrazolyl)-[1, 1 '- biphenyl]yl)ethoxy) pyrimidin- A 4-y1)-2,8-diazaspiro[4.S]decane 667 carboxylate 63km (S)-ethyl 8-(2-amino((R)-l-(4- (chromanyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)- A 2,8-diazaspiro[4.S]decane 612 carboxylate 63kn (S)-ethyl 8-(2-amino((R)-l -(4- chloro(p yridinyl)phenyl)- c,o:) B 2,2,2-trifl uoroethoxy)pyrimidin 592 yl)-2,8-diazas piro[4.5]decane carbox late 63ko hyl 8-(2-amino((R)(4- chloro(pyri midinyl)phenyl)- e-: I N B 2,2 ,2-tri ethoxy)pyrimid in 593 � yl)-2,8-diazaspiro[4.S]decane carboxylate 63kp (S)-ethyl 8-(2-amino((R)-2,2,2- trifluoro(3'-(hydroxymethyl)-4 ' - methyl(3-methyl-1 H-pyrazol A yl)-[l ,l -biphenylj-t- 681 yl)ethoxy)pyrimidinyl)-2,8 - diazasp iro[4.5]decane carbox late 63kq (S)-ethyl 8-(2-amino((R)-2,2,2- HO trifluo ro(4'-(hydroxymethyl)-3'- methyl(3-methyl-1 H-pyrazol A ,11-biphenyl] 681 yl)ethoxy)pyrimidinyl)-2,8- I. diazaspiro[4.5 ]decane � carbo x late 63kr l (S)-ethyl mino((R)(4- 0 (6-ethoxypyridinyl)(3- methyl-lH-pyrazolyl)phenyl)- A 2,2,2-trifl uoroethoxy)pyrimidin 681 yl)-2,8-diazaspiro[ 4.5]decane carboxylate 63ks I (S)-ethyl 8-(2-amino((R)-2,2,2- 0 trifluoro-1 -(4-(6-methoxypyridin- 3-yl)(3-methyl-lH-pyrazol A 668 nyl)ethoxy)pyri midinA-yl)- 2,8-diazaspiro[4.5]decane carboxylate 63kt (S)-ethyl 8-(2-amino((R)(5- chloro-3 '-(2-methoxyethoxy)- [1 ,1'-biphenyl]yl)-2,2,2- 665 trifltto roethoxy)pyrimidinyl)- A 2,8-diazaspiro[4.5]decane carboxylate .,....o 63ku hyl 8-(2-amino((R)(4- Cl�I � chloro(pyraziny})phenyl)- B 2,2,2-tri:fl hoxy)pyrimidin 594 NV,:::,,- N yl)-2,8-diazaspiro[4.5]decane carboxylate 63kv (S)-ethyl 8-(2-amino((S) (3 ',4'-bis(hydroxymethyl)(3- methyl-lH-pyrazolyl)-[1, l'­ B biphenyl]yl)-2,2,2- 697 trifl uoroethox y)pyrimidiny1)- 2,8-diazaspiro [4. 5]decane carbox late Table 18b.
NMR Data for Compounds of Table 18a Ex. NMR 63a 1H NMR (400 MHz, Me0H-d4): s PPM 1.26 (t, J = 7.1 Hz, 3H), 1.50 (m, SH), 1.63 (s, lH), 1.73 (dd, J = 13.0, 7.2 Hz, lH), 2.07 (dd, J = 13.0, 8.7 Hz, lH), 2.74 (d, J == 11.0 Hz, lH), 2.88 (d, J = 11.0Hz, 1 H), 3.50 (pd, J = 13.6, 5.4 Hz, SH), 3.81 (t, J = 8.0 Hz, lH), 4.17 (qd, J= 7.0, 1.6 Hz, 2H), 4.92 (s, 6H), 5.55 (s, lH), 6.66 (q, J = 7.2 Hz, 11-1), 7.63 (d, J = 8.0 Hz, 2H), 7.77 (m, 4H), 8.10 (d, J = 8.6 Hz, lH), 8.29 (d, J = 1.8 Hz, lH), 9.24 (s, lH) 63b 1H NMR (400 MHz, CDC13): o ppm 1.28 (m, SH), 1.59 (t, J = 5.6 Hz, 2H), 1.77 (dd, J = 13.1, 6.8 Hz, 1H), 2.09 (m, 11-I) , 2.87 (d, J = 10.6 Hz, 11-I ), 2.98 (d, J = 10.6 Hz, lH), 3.51 (dt, J = 14.9, 5.0 Hz, 4H) , 3.92 (m, lH), 4.21 (q, J = 7.1 Hz, 2H), 4.62 (s, 2H), .54 (s, lH), 6.63 (q, J = 7.0 Hz, lH), 7.40 (dd, J = 8.5, 1.4 Hz, lH), 7.62 (q, J = 8.3 Hz, 6H), 7.81 (d, J = 8.5 Hz, lH), 8 . 11 (s, lH) 63c 1H NMR (400 MHz, CDC13): s ppm 0.87 (dd, J = 7.5, 3.2 Hz, lH), 1.28 (dd, J = 14.0, 6.9 Hz, 7H), 1.57 (dt, J = 17.4, 5.6 Hz, 4H), 1.87 (m, SH), 2.11 (dd, J = 13 .1, 8.8 Hz, lH), 2.89 (d, J = 10.6 Hz, lH), 2.99 (d, J = 10.6 Hz, lH), 3.28 (t, J = 6.7 Hz, 21-I), 3.51 (m, 4H) , 3.67 (t, J = 6.9 Hz, 2H) , 3.89 (s, 4H), 4.21 (q, J = 7.1 Hz, 2H) , 4.59 (s, 2H), .53 (s, lH), 6.61 (q, J = 7.1 Hz, lH), 7.07 (d, J = 1.5 Hz, IH), 7.17 (dd, J = 7.7, 1.5 Hz, HI), 7.33 (d, J = 7.8 Hz, lH), 7.58 (s, 4H) 63d 1H-NMR (400 MHz, MeOH-d4): s ppm 1.62(m,4H), 2.09-2.04(m,1H), 2.40- 2.35(m,1H), , 1H), 3.25(m,lH), 3.47(m,2H), 3.31-3.30(m,2H), 4.22- 4.20(m,1H), 5.49(s,1H), .80(m,1H), 6.52-6.38(m,2H), 6.65(m,1H), ,J=2.0,1H), 7.45-7.43 (d, J=8.0, 3H), 7.68-7.66(d, J=8.0, IH), 7.80-7.78(d, J=8.0, 21-I) 63e 1H Ntv1R (400 MHz, CDC13): 8 ppm 0.07 (s, lH), 0.87 (dd, J = l 7.8, 8.8 Hz, 2H), 1 .12 (s, 3H), 1.29 (m, 18H), 1.51 (s, lH), 1.63 (dq, J = 29.6, 7.7, 6.6 Hz, lOH), 1.89 (dd, J = 13.2, 7.4 Hz, 2H), 2.23 (dd, J = 13.2, 8.6 Hz, 2H), 3.13 (m, 4H), 3.53 (h, J= 6.6 Hz, 16H), 4.04 (s, II-I ), 4.20 (dq, J = 33.0, 7.5 Hz, 8H), 4.35 (s, lH), 4.60 (m, SH), 5.52 (d, J = 16.0 Hz, 2H), 6.64 (q, J = 7.0 Hz, 2H), 7.39 (m, 2H), 7.50 (d, J = 7.6 Hz, HI), 7.65 (q, J = 7.9 Hz, 9H), 7.79 (dd, J = 24.7, 8.0 Hz, 3H), 8.03 (d, J = 8.5 Hz, 2H), 8.23 (s, 2H), 8.97 (s, 2H) 63f 1H NMR (400 MHz, CDCl3): o ppm 0.87 (dd, J = 16.5, 9.8 Hz, 2H), 1.28 (m, 12H), 1 .58 (m, 4H), 1.79 (dd, J = 13.1, 6.9 Hz, lH), 2.12 (dd, J = 13 .1 , 8.9 Hz, lH), 2.90 (d, J = I 0.7 Hz, IH), 3.00 (d, J = 10.6 Hz, lH), 3.52 (dt, J = 11.4, 5.4 Hz, 7H), 3.96 (t, J = 7.8 Hz, lH), 4.21 (q, J = 7.2 Hz, 2H), 4.61 (s, 2I-I), 5.54 (s, lH), 6.64 (q, J = 7.1 Hz, lH), 7.66 (q, J = 8.4 Hz, SH), 8.12 (t, J = 4.2 Hz, 2H), 8.94 (s, II-I) 63g 1H NMR (400 MHz, MeOH-d4): s ppm 1.32 (m, 4H), 1.64 (dq, J = 14.1, 8.9, 7.2 Hz, 4H), 2.03 (td, J = 13.3, 8.9 Hz, lH), 2.49 (dd, J = 13.6, 8.7 Hz, lH), 3.27 (s, 2H), 3.58 (m, 4H), 3.88 (d, J = 11.8 Hz, 6H), 4.32 (qd, J = 7.2, 2.5 Hz, 2H), 4.58 (t, J = 8.8 Hz, lH), 6.62 (q, J= 7.1 Hz, lH), 7.03 (m, lH), 7.19 (m, 2H), 7.57 (d, J= 8.2 Hz, 2H), 7.64 (m, 2H) 63h 1H NMR (400 MHz, CDCl3): s ppm 7.769-7.796 (m,lH), 7.707-7.740(m,2H), 7.585- 7.636(111, 4H), 7.422-7.444(m, lH), 6.738-6.762(m,1H), 6.579-6.658-6.537 (m, 521 (s, IH), 4.612 (s)H), 4.200-4.253 (q,2H), 4.114-4.154 (t, lH) , 3.747(s,3H), 3.475-3.523 (m, 4H), 3.047-3.160 (m,2H), 2.171-2.726 (m, II-I ), 1.840-1.891 (m, lH) , 1.543-1.649 (m, 4H), 1.209-1.305 (t, 31-1 ) 63i 1H NMR (400 MHz, DMSO-d6): s ppm 1.25 (t, J=7.10 Hz , 3 I-I ) 1.42 - 1.69 (m, 4 H) 1.92 (dd, J=l3.25, 9.35 Hz, 1 H) 2.35 (dd, J=13.25, 8.47 Hz, 1 H) 3.14 (br. s., 2 H) 3.60 (br. s., 4 H) 4.24 (qd, J=7.09, 2.10 Hz, 2 H) 4.54 (br. s., 1 H) 5.77 (br. s., 1 H) 6.70 (q, J=6.65 Hz, 1 H) 7.37 (d, 1=2.10 Hz, 1 H) 7.43 - 7.52 (rn, 3 H) 7.53 - 7.69 (m, 4 H) 9.23 (br. s., 1 H) 10.44 (br, s., 1 H) 63j 1H NMR (400 MHz, : s ppm 7.66-7.64 (d, 1 H, J=8.6 Hz), 7.43-7.41 (d, 1 H, J=8.6 Hz), 7.26-7.20 (m, 2 H), .68 (m, 4 H), 5.42 (s, 1 H), 4.19-4.16 (q, 1 H, J=7.0 Hz), 3.83-3.81 (t, 1 H), 3.49-3.47 (m, 4 H), 2.91-2.89 (d, 1 H, J=l0.9 Hz), 2.77- 2.75(d, 1 H,J=10.9Hz),2.ll-2.07(m, 1 H),2.12-2.lO(m, 1 H), .51 (m,4H) , 1.28-1.25 (t, 3 H, J=:7.0 Hz Hz) 63k 1H NMR (400 MHz, Me0H-d4): 8 ppm 8.42 (s, 1 H), 8.30 (d, 1 H), 7.61 (m, 2 H), 7.31 (m, 1 H), 7.10 (s, 1 H), 6.58 (m, 1 H), 5.57 (s, 1 H), 4.20 (m, 2 H), 3.84 (m, 1 H), 3.48 (m, 4 H),3.16 (s, 3 H), 2.77 (m, l H), 2.70 (m, 1 H), 2.61 (m, 1 H), 2.14 (m, 1 H), 1.77 (m, 1 H), 1.65 (m, 2 H), 1.54 (m, 4 H), 1.20 (m, 3 H), 0.98 (rn , 3 H) 631 1H NMR (400 MHz, CD30D-d4): o ppm 1.28-1.24 (m, 4 H), 7.72-7.68 (m, 3 H), 1.52 (m, 4 H), 1.71 (m, 1 H), 2.10 (m, 1 H), 2.32 (s, 3 H), 2.76-2.73 (m, 1 H), 2.90-2.87 (m, 1 H), 3.49 (m, 4 H), 3.75 (s, 3 H), 3.81 (m, 2 H), 4.20-4.15 (m, 2 H), 5.54(s.1H), 6.65- 6.59 (m, I H), 6.93 (s, 1 H), .34(m, 1 H), 7.45-7.42 (m, 1 H), 7.57-7.55 (m, 2 H) 63m 1H NMR (400 MHz, MeOH-d4): s ppm 8.19 (s, 1 H), 7.64 (cl, 1 H), 7.53-7.42 (m, 5 H), 7.29 (s, 1 H), 7.16 (s, 2 H), 6.63 (q, 1 H), 6.52-6.35 (m, 3 H), .77 (d, l H), .50 (s, 1 H), 4.21-4.18 (m, 2 H), 3.97 (t, 1 I-I), 3.49 (m, 4 H), 2.98-2.95 (d, 1 H), 2.86- 2.83 (d, 1 H), 2.16w2.14 (m, 1 H), 1.80-1.76 (m, 1 H), 1.54 (m, 4 ID, .16 (t, 3 H) 63n 1H NMR (400 MH z, MeOH-d4): o ppm 1.27 (q, J = 7.1, 6.1 Hz, 4H), 1.52 (dt, J = .4, 5.7 Hz, 4H), 1.74 (dd, 1 = 13.0, 7.2 Hz, lH), 2.09 (dd, J = 13.1 , 8.8 Hz, lH), 2.75 (d, J = 1 1.0 Hz, lH), 2.89 (d, J = 11.0 Hz, lH), 3.52 (tq, J = 14.5, 8.2 Hz, 4H), 3.82 (dd, J = 8.8, 7.2 Hz, lH), 3.90 (s, 3H), 4.18 (qd, J = 7.1 , 1.6 Hz, 2H), 4.89 (d, J = 1.5 Hz, 13H), 5.51 (d, 1 = 18.8 Hz, 2H), 6.62 (q, 1 = 7.1 Hz, lH), 7.15 (t, J = 8.6 Hz, lH), 7.39 (m, 2I-I), 7.59 (m, 4H) 630 1HwNMR (400 MHz, MeOH-d4): s ppm o8.00(d,J=2.36 Hz,lH) ,7.88(dd, 1=2.6,6.76 Hz, 1 H), 7.5 8(m,4H),6.62(m, 2H),5.55(s, 1H),4.22(m,3H) ,3 .64(s,3H),3 .52(rn, 4H),3 .02(m, 27(m, lH), 1.89(m, 1H), l .59(m,4H),l .29(t, 1=7 .16 Hz,3H). 63p 11-I NMR (400 MHz, MeOH-d4): s ppm 7.62(d,2H,J:==8.0), 7.56(d,2H,J=8.0), 7.45(m,2H), 6.93(d,1H,J=8.0), 6.62 (q, 1H,J=8.0), 5.54 (s, lH), 4.21 (t, 2H, 1=4.0),3.99 (t, 11-1, , 3.5603.49 (m, 41-1), 3.00(dd, 3H,1=20.0,8.0), 2.86 (d, 11-1, 1 = 8.0),2.59-2.57 (m, 2H), 2.18 (dd, 2H, 1 = 12.0,8.0), l.80(dd, 2H, 1 = 8.0,4.0), l.54(m, 5), , 4H, 1 = 8.0) 63q 1H-NMR (400 MHz, CDCI3): 8 ppm 11.76 (m,lH) ,7.84-7.86 (m,IH) ,7.70 -7.73 (m,2H),7.59 (m, 4H),7.43 -7.45 (m, 1H),6.73 -6.75 (m,lH), 6.57 -6.63 (q, lH), 5.53 (s, ll-I), 4.61 (s,2H), 4.17 -4.23 (q,2H), 3.90-3.94 (t, lI-1), 3.48 -3.51 (m, 4H), 2.86- 2.99 (m,2H), 2.07-2.12 (m, 2H), 1.74 -1.79 (m, lH), 1.53 -1.59 (m, 4H),1.24-1.29 (t, 3H). 63r 1H NMR (400 MHz, CD30D-d4): 8 ppm 8.42 (s, 1 H), 8.04 (d, l H), 7.79 (m, 3 H), 7.63 (m, 1 H), 7.46 (m, 1 H), 6.58 (m, 1 H), 6.40 (m, 1 H), 5.56 (m, 1 H), 4.18 (m, 2 I-I), 3.83 (m, 1 H), 3.50 (m, 4 H), 3.21(s, 3 H), 2.90 (m, 1 H), 2.78 (m, 1 4 (m, 1 H), 1.86 (m, 3 H), 1.76(m, 1 H), 1.54 (m, 4 H), 1.26 (m, 3 I-1) 63s 1H NMR (Me0H-d4): 8 ppm 0.90 (t, J = 6.9 Hz, 1 H), 1.17 (p, 1 = 6.3 Hz, 3H), 1.29 (s, 2H), 1.56 (m, 4H), 1.80 (s, lH), 2.29 (s, lH), 2.41 (s, 3H), 2.80 (m, 4H), 3.26 (d, 1 = 11.3 Hz, lH), 3.44 (s, lH), 4.09 (tdd, J = 14.2, 7.9, 4.6 Hz, 2H), 4.48 (s, lH), 4.87 (s, 2H), 5.56 (s, IH), 6.42 (t, J = 2.2 Hz, lH), 6.93 (m, lH), 7.46 (m, 4H), 7.61 (m, 2H), 7.80 (dd, 1 = 8.3, 2.2 Hz, lH), 7.93 (dd, 1 = 5.2, 2.5 Hz, 2H) 63t 1HNMR (MeOH-d4): 8 ppm 0.91 (dd, J = 12.4, 6.3 Hz, 2H), 1 . 17 (q, J = 7.4 Hz, 3H), 1.31 (d, 1 = 16.3 Hz, 3H), 1.65 (m, 4H), 1.83 (s, 1 H), 2.32 (s, 2H) , 2.41 (s, 3H), 2.92 (ddt, J = 18.2, 14.3, 9.1 Hz, SH), 3.28 (s, IH), 4.11 (dtt, 1 = 10.7, 7.1, 3.9 Hz, 21-I ), 4.48 (s, lH), 4.95 (d, 1 = 1 1 .7 Hz, lH), 6.43 (d, 1 = 2.2 Hz, lH), 6.94 (q, J = 6.5 Hz, lH), 7.50 (m, 3H), 7.61 (dd, 1 = 8.6, 2.1 Hz, 2H), 7.79 (dt, J = 8.3, 1.4 Hz, lH), 7.93 (dd, J = 10.2, 3.2 Hz, 2H) 63u 1H NMR (400 MHz, CDCh-d): 8 ppm 8.50 (s, IH), 7.99-7.96 (m, lH) , 7.69-7.63 (m, 2H), 7.51 (s, lH), 7.25-7.23 (m, lH), 7. 11 (d, J = 7.8 Hz, lH), 6.57 (q, 1 = 6.6 Hz, 1H), 5.51 (s, lH), 5 .18 (s, 2H), 4.21 (q, 1 = 7.1 Hz, 2H), 3.93-3.89 (m, lH) , 3.53-3.48 (m, 4H), 3.14 (s, 3H), 2.93 (dd, J I = 10.6 Hz, 12 = 42.0 Hz, 2H), 2.66-2.62 (m, 2H), 2.12-2.07 (m, lH), 1.79-1.74 (m, lH), 1.69-1.63 (m, 2H), 1.61-1.58 (m, 2H), 1.55- 1.52 (m, 21-I), 1 .29 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H) 63v 1H NMR (400 MHz, CDCh): 3 ppm 8.52 (d, 1 = 9.5 Hz, lH), 7.99-7.97 (m, lH), 7.69-7.62 (m, 3H), 7.38 (dd, J1 = 7.9 Hz, J2 = 20.6 Hz, 11-l), 7.15 (dd, J1 = 7.9 Hz, 12 = 17.0 Hz, lH), 6.57 (m, IH), 6.46-6.42 (m, lH), 6.34-5.84 (m, II-I), 5.51-5.50 (m, lH), 5.18 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.87 (t, 1 = 7.6 Hz, lH), 3.52-3.50 (m, 4H), 3.15-3.14 (m, 3H), 2.90 (dd, JI= 10.2 Hz, J2 = 47.8 Hz, 2H), 2.10-2.05 (m, lH), 1.91 (d, 1 = 6.4 Hz, 31-1), 1.78-1.73 (m, lH), 1.58-1.53 (m, 4H), 1.28 (t, J = 7 .1 Hz, 3H) 63w 1H NMR (400 MHz, MeOH-d4): 8 ppm 8.49 (s, 1H), 7.98 (d, J = 7.5 Hz, IH), 7.71 (t, J = 7.8 Hz, lH), 7.65-7.63(m, 2H), .40 (m, lH), 7.23 (d, J = 1.9 Hz, lH), 6.53 (q, J = 6.8 Hz, 11-1 ), 5.48 (s, lH), 5.26 (s, 2H), 4.22 (q, J = 7.1 Hz, 21-1 ), 4.03 (t, J = 8.0 Hz, 1H), 3.52-3.51 (m, 4H), 3.21 (q, J = 7.4 Hz, 2H), 3.02 (dd, J I= 10.9 Hz, J2 = 34.9 Hz, 2H), 2.18-2.12 (m, lH), 1.85-1.80 (m, IH), 1.62-1.61 (m, 2H), 1.56-1.55 (m, 2H), .28 (rn, 6H) 63x lHNMR(400 MHz, MeOH-d4): s ppm 8.45 (s, 1H),8.03(d,1H,J=8.0), 7.83(t,1H,J=8.0), 7.79-7.69(m,2H),7.50(d,1H,J=8.0), 7.37(s,1H), 6.62 (q, 1H,J=8.0), .61 (s, IH), 4.38 (t, 1H,J=8.0),4.32-4.27 (m, 2H), 3.64-3.49(m, 4H),3.16(q, 2H,J=12.0), 2.39 (dd, lH, 1 = .0),1.98 (dd, lH, J = .0), l.70-1.62(m, 7H),1.31(dd, SH, J = 12.0,8.0) 0.96(t, 4H,J=8.0) 63y 1H NMR (400 MHz, MeOH-d4): o ppm 8.50 (s, 1 H), 8.05-8.03 (d, 1 H), 7.82 (t, 1 H), 7.76-7.70 (m, 2 H), 7.52-7.51 (d, 1 H), 7.38-7.37 (d, 1 H), 6.62-6.60 (q, 1 H), 5.60 (s, 1 H), 4.20-4.19 (q, 2 H), 3.85 (t, 1 H), 3.57 (m, 4 H), 2.82 (d, 1 H), 2.77 (d, 1 H), 2.09 (m, 1 H), 1.77 (m, 1 H), 1.57 (m, 6 H), 1.31 (q, 2 H), 1.26 (m, 3 H), .81 (t, 3 H) 63z 1H NMR (400 MHz, MeOH-d4): o ppm 0.09 (dd, J = 4.2, 2.0 Hz, lH), 0.90 (t, J = 6.5 Hz, 3H), 1.28 (m, 14H), 1.54 (dt, J = 10.5, 5.6 Hz, 6H), 1.76 (dd, J = 13.2, 7.3 Hz, lH), 2.03 (s, lH), 2.15 (ddd, J = 29.1, 14.1, 8.4 Hz, 2H), 2.78 (d, J = 10.9 Hz, 1H), 2.92 (d, J = 11.0 Hz, lH), 3.53 (td, J = 13.8, 13.4, 6.0 Hz, 6H), 3.86 (dd, J = 8.8, 7.3 Hz, IR), 4.20 (m, 3H), 5.46 (d, J = 22.4 Hz, 3H), 5.56 (s, IH), 6.67 (q, J = 7.2 Hz, 2H), 7.66 (d, J = 8.1 Hz, 3H), 7.75 (m, 3H), 7.85 (m, 3H), 7.93 (d, J= 7.9 Hz, 2H) 63aa 1H NMR (400 MHz, MeOH-d4): 8 ppm: 8.16 (d,J = 8.84 Hz,lH), 8.03 (d,J =1.84 Hz, 1H),7.94-7.81(m,2H), 7.77 (d,J = 8.32 Hz,2H), ,J = 8.24 Hz,2H), 6.96 (d,J = 8.88 Hz,1H), 6.65 (q, J " " 7.08 Hz,lH), 5.56 (s,lH), 4.18 (m,2H), 4.06(s,3H), 3.82 (m, lH), 3.53{m, 4H), 2.90 (d, J=l 1.0 Hz,lH), 2.76 (d, J=l 1.0 Hz,lH), 2.09 (m, lH), 1.75(m, lH), 1.53 (s, 4H),l.27 (t, J = 7.12 Hz,3H) 63ab 1H NMR (400 MHz, : s ppm 7.76 (s, 1 H), 7 .65 (d, J = 8.5 Hz, 1 H), 7.43 (t, J = 7.6 Hz, lH), 7.37 (dd, J1 = 2.2 Hz, J2 = 8.5 Hz, lH), 7.33 (d, J = 7.6 Hz, lH), 7.28 (d, J = 7.8 Hz, lH), 7.24 (d, J = 2.2 Hz, lH), 6.63 (q, J = 6.7 Hz, lH) , 5.41 (s, lH), .02 (s, 21-I), 4.80 (m, 2H), 4.21 (q, J = 7.1 Hz, 2H), 4.05-4.01 (m, lH), 3.48-3.46 (m, 4H), 3.01 (dd, J1 = 10.9 Hz, J2 = 31.0 Hz, 2H), 2.17-2 .11 (m, lH), 1.83-1.78 (m, lH), 1.59-1.50 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H) 63ac 1H-NMR (400 MHz, Me0H-d4): o ppm 7.97 (s,lH) ,7.60 -7.67 (m,2H), .56 (m,lH),7.43 -7.45 (m, lH), 7.31 -7.31 (m, IH) ,7.22 -7.24 (m,1H),6.621-6.663(m, 1H),5.498(s, IH), 4.16 A.22 (m, 2H), 4.92-4.03 (m, 2H), 3.83 -3.87 (M, th), 3.46 - 3.53 (m,4H), 2.90-2.92 (d,lH), 2.76-2.78 {d,lH), 2.59 -2.63 (m, 2H), 2.10 -2.22 (m, 3H), 1.71 -1.78 (m, 1H),l.52 -1.55 (m, 4H), 1.25 -1.28 (m, 3H) 63ad 1H-NMR (400 MHz, MeOH-d4) o ppm: 7.98 (s,lH), 7.63 -7.65 (m,lH), 7.42 -7.50 (m,3H), 7.30 -7.30 (m, lH), 7.05 -7.07 (m, 1H), 6.62-6.67 (m,lH), 5.49 (s, IH), 4.15 - 4.22 (m, 2H), 3.80 -3.98 (m, 3H), 3.46 -3.56 (m, 6h), 2.73-2.92 (m,4H), 2.73 -2.78 (d,IH), 2.07 -2.13 (d,lH), l.73 -1.78 (m, lH), 1.49 -1.57 (m, 4H), 1.25 -1.29 (m, 3H) 63ae 11-I NMR (400 MHz, DMSO-d6) o ppm: 1.25 (t, J=7.10 Hz, 3 H) 1.42 - 1.69 (m, 4 H) 1.92 (dd, 5, 9.35 Hz, l H) 2.35 (dd, J=l3.25, 8.47 Hz, 1 H) 3.14 (br. s., 2 H) 3.60 (br. s., 4 H) 4.24 (qd, J=7.09, 2.10 Hz, 2 H) 4.54 (br. s., 1 H) 5.77 (br. s., 1 H) 6.70 (q, J=6.65 Hz, 1 H) 7.37 (d, J=2.10 Hz, 1 H) 7.43 - 7.52 (m, 3 H) 7.53 - 7.69 (m, 4 H) 9 .23 (hr. s., 1 H) 10.44 (br. s., 1 H) 63af 1H NMR (400 MHz, MeOH-d4): o ppm 7.66 (d, l 4 Hz), 7.50 (m, 3 H), 7.31 (d, 2 H,J=8.7 Hz), 7.24 (d, l H,J::::7.2 Hz), 6.64 (m, 1 H), 5.50 (m, l H), 4.21 (m, 1 H), 3.87 (m, 1 H), 3.53 (m, 4 H), , 3 H), 3.18 (m, 1 H), 2.90 (m, 3 H), 2.79 (m, 1 H),2.07 (m, l H), 1.74 (m, 1 H), 1.53 (m, 4 H), 1.27 (rn, 3 H) 63ag 1H NMR (400 MHz, CDC13): s ppm 7.54 (d, J = 2.2 Hz, lH), 7.51 (d, J = 8.6 Hz, IH), 7.19 (dd, J1 = 2.6 Hz, 12 = 8.6 Hz, lH) , 6.85 (q, J = 6.6 Hz, lH), 5.49 (s, lH), 4.56 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.90-3.86 (m, lH), 3.53-3.47 (m, 4H), 2.90 (dd, J1 = .4 Hz, J2 = 47.6 Hz, 21-I), 2.13-2.05 (m, lH), 1.78-1.73 (m, IH), 1.59-1.56 (m, 2H), l .54-1 .51 (m, 2H) , 1.28 (t, J = 7.1 Hz, 3H) 63ah 1H NMR (400 MHz, CDC13): 3 nnm 7.54 (d, J = 2.2 Hz, ll-I ), 7.51 (d, J = 8.6 Hz, lH), 7.19 (dd, J1 = 2.6 Hz, 12 = 8.6 Hz, 1H), 6.85 (q, J = 6.6 Hz, lH), 5.49 (s, lH), 4.56 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.90-3.86 (m, lH), 3.53-3.47 (rn, 4H), 2.90 (dd, Jl = .4 Hz, J2 = 47.6 Hz, 2H), 2.13-2.05 (m, lH), 1.78-1.73 (m, lH), 1.59-1.56 (m, 2H), 1.54-1.51 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H) 63ai 1H NMR (400 MHz, MeOH-d4): o ppm 8.06 (d, J = 8.72 Hz,lH), 8.01 (s, 1 H),7.94 (s .76 (d, J = 8.28 Hz, 2H),7.64 (d, J = 8.16 Hz, 2H), 7.31 (d, J = 8.68 Hz, IH), 6.66 (q, J = 7.32 Hz, lH), 5.56 (s, lH), 4.18 (q, J = 7.04 Hz, 2H), 3.84-3.80 (m, lH), 3.51 (rn, 4H), 2.89 (d, J = 10.96 Hz, IH), 2.75 (d,J = 11 Hz,lH), 2.68(s, 3H), 2.10- 2.01 (m, lH), 1.76-1.71 (m, IH), .49 (m, 4H), 1.25 (t, J = 7.12 Hz, 3H) 63aj 1H NMR (400 MHz, Me0H-d4): o ppm 7.69 (d, J = 1.8 Hz,1H), 7.60-7.57 (d, UI), 7.48 (dd, Jl =2.44, J2=8.6 Hz, lH), 6.96 (q, J = 7.32 Hz, IH), 5.56 (s, lI-1), 4.19 (q, J = 7.12 Hz, 2H), 3.86-3.82 (m, lH), 3.54 (m, 4H), 2.91 (d, J = 11 Hz, lH), 2.77 (d,J = 1 1 , 2.14-2.08(m,1H), 1.79-1.73 (m, IH), 1.55 (m, 4H), 1.27 «, J = 7.12 Hz, 63ak 1H NMR (400 MHz, MeOH-d4): o ppm 7.91 (s, lH), 7.71 (dd, JI= 6.12 Hz,J2= 1.96 Hz, lH),7.63 (m,2H), 7.56-7.49 (m,7H) ,7.39-7.35 (m,2H), 6.74 (q, J = 6.88 Hz, lH), .50(s, lH), 4.18 (q, J = 6.96 Hz, 2H) , 3.83 (m, lH), 3.50 (m, 4H), 2.89 (d, J = 11.04 Hz, IR), 2.75 (d,J = 11 Hz,IH), 2.12-2.06 (m,lH), 1.76-1.71 (m, lH), 1.54-1.49 (m, 41-I ), 1.27 (t, J = 7.12 Hz, 3H) 63al 1H NMR (400 MHz, 4): o ppm 0.84 (t, J = 7.1 Hz, 8H), 1.26 (t, J = 7.1 Hz, 81-I), 1.50 (dt, J = 11.1, 5.8 Hz, 4H), 1.73 (dd, J = 13.1, 7.1 Hz, 1H), 2.06 (dd, J = 13.1 , 8.8 Hz, lH), 2.38 (s, 3H), 2.73 (d, J = 11. 0 Hz, lH), 2.88 (d, J = 11.0 Hz, IH), 3.51 (m, 4H), 3.81 (dd, J = 8.7, 7.1 Hz, lH), 4.00 (qd, J = 7.1, 4.5 Hz, 2H), 4.17 (qd, J = 7.1 , 1.5 Hz, 2H), 5.74 (s, IH), 6.39 (d, J = 2.3 Hz, II-I ), 6.85 (q, J = 6.7 Hz, lH), 7.45 (m, SH), 7.80 (m, 2H), 7.90 (d, J = 2.4 Hz, lH) 63am 1H NMR (400 MHz, Me0H-d4): s ppm 0.89 (m, 11-1 ), 1.26 (m, 7H), 1.40 (t, J = 7.1 Hz, 3H), 1.51 (m, 4H), 1.73 (dd, J = 13.1 , 7.2 Hz, II-I ), 2.05 (m, IH), 2.40 (s, 3H), 2.74 (d, J = 11.0 Hz, 1 H), 2.88 (d, J = 11.0 Hz, lH), 3.53 (m, 4H), 3.81 (dd, J = 8.8, 7.l Hz, IH), 4.18 (qd, J = 7.1 , 2.5 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 5.73 (s, lH), 6.43 (d, J = 2.4 Hz, lH), 6.82 (q, J = 6.6 Hz, lH), 7.57 (t, J = 7.8 Hz, lH) , 7.68 (d, J = 1.9 Hz, lH), 7.79 (m, 2H), 7.90 (dt, J = 8.0, 1.4 Hz, lH), 8.02 (m, 2H), 8.28 (d, J = 1.9 Hz, lH) 63an 1H NMR (400 MHz, MeOH-d4): o ppm 1.33 (dt, J = 54.3, 7.1 Hz, 6H), 1.50 (dt, J = .8, 5.8 Hz, 4H), 1.73 (dd, J = 13.1 , 7.2 Hz, IH), 2.07 (dd, J = 13.1, 8.8 Hz, IH), 2.40 (s, 3H), 2.74 (d, J = 11.0Hz, lH), 2.88 (d, J = 11.0 Hz, lH), 3.52 (m, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, lH), 4.18 (qd, J = 7.1, 1.5 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 5.74 (s, lH), 6.43 (d, J = 2.3 Hz, IH), 6.84 (q, J = 6.6 Hz, lH), 7.77 (m, SH), 8.00 (d, J = 2.3 Hz, IH) , 8.09 (m, 2H) 63ao 1H NMR (400 MHz, MeOH-d4): s ppm l.27 (t, J = 7.1 Hz, 3H), 1.54 (m, 4H), 1.76 (dd, J = 13.1, 7.2 Hz, 1 H), 2.11 (dd, J = 13.1, 8.7 Hz, lH), 2.77 (dd, J = 11.0, 1. 1 Hz, lH), 2.91 (d, J = 11.0 Hz, lH), 3.53 (td, J = 11.9, 11.4, 4.9 Hz, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, lH), 4.19 (qd, J = 7.2, 1.6 Hz, 2H), 5.53 (s, IH), 7.15 (t, J= 8.0 Hz, lH), 7.27 (q, J = 8.0 Hz, 11-1) , 7.69 (m, 2H) 63ap 1H NMR (400 MHz, CDC13): o ppm 1.28 (m, 4H), 1.56 (dq, J = 25.2, 5.5, 4.9 Hz, 4H), 1.78 (dd, J = 13.1, 6.9 Hz, lI-1), 2. 12 (m, lH), 2.90 (d, J = 10.7 Hz, lH), 2.99 (d, J = 10.6 Hz, 1 H), 3.49 (dt, J = 11.5 , 5.7 Hz, 41-I ), 3.94 (dd, J = 8.8, 6.9 Hz, IH), 4.21 (q, J=7.1 Hz, 2H), 4.58 (s, 2H), 5.43 (s, lH), 6.55 (q, J= 6.8 Hz, lH), 7.24 (m, 3H), 7.41 (m, 31-I), 7.65 (m, 2H) 63aq IH NMR (400 MHz, CDC13): s ppm 0.84 (m, 2H), 1.14 (s, lH), 1.28 (t, J = 7.1 Hz, 31-I), 1.53 (m, 4H), 1.74 (dd, J = 13.1, 6.8 Hz, lH), 2.05 (m, 11-I), 2.43 (s, 3H), 2.82 (d, J = 10.5 Hz, lH), 2.94 (d, J =10.5 Hz, lH), 3.46 (dt, J = 14.0, 5.8 Hz, 4H), 3.86 (dd, J = 8.8, 6.7 Hz, lH), 4.19 (q, J = 7.1 Hz, 2H), 4.35 (s, 2H), 5.40 (s, lH), 6.61 (q, J = 6.8 Hz, lH), 7.33 (m, SH), 7.65 (d, J = 8.5 Hz, lH) 63ar 1H NMR (400 MHz, Me0H-d4): 8 ppm 1.27 (t, J = 7.1 Hz, 4H), 1.54 (dt, J = 7.9, 4.7 Hz, 4H), 1.76 (dd, J = 13 . 1, 7.2 Hz, lH), 2.12 (m, lH), 2.78 (m, lH), 2.90 (m, lH), 3.52 (m, 4H), 3.85 (td, J = 9.2, 8.8, 7.3 Hz, lH), 4.19 (qd, J = 7.1, 1.6 Hz, 2H), 4.86 (d, J = 0.8 Hz, 1 lH), 5.51 (d, J = 13.8 Hz, lH), 6.52 (q, J = 6.7 Hz, IH), 7.34 (d, J = 2.2 Hz, lH), 7.51 (dd, J = 8.5, 2.2 Hz, 1 H), 7.75 (m,5H) 63as 1H NMR (400 MHz, Me0H-d4): 8 ppm 1.32 (t, J = 7.1 Hz, 3H), 1.67 (m, 4H), 2.05 (dd, J = 13.6, 8.8 Hz, lH), 2.46 (d, J = 45.5 Hz, 7H), 2.66 (s, lH), 3.28 (s, 21-I), 3.69 (m, 4H), 4.32 (qd, J = 7.1 , 2.3 Hz, 2H), 4.58 (t, J = 8.7 Hz, lH), 6.43 (d, J = 2.4 Hz, lH), 6.85 (q, J = 6.3 Hz, lH), 7.37 (m, 2H), 7.66 (m, 3H), 7.79 (m, 2H), 7.97 (d, J = 2.4 Hz, lH) 63at 1H NMR (Me0H-d4): s ppm 1.28 (m, l 5H), 1.53 (m, 13I-I), 1.76 (dd, J = 13.1 , 7.3 Hz, 3H), 1.86 (s, lH), 2.12 (dd, J = 13.1, 8.8 Hz, 3H), 2.79 (d, J = 11 .0 Hz, 3H), 2.92 (d, J = 11. 0 Hz, 3H), 3.51 (qdt, J = 18.0, 13.3, 5.9 Hz, 12H), 3.63 (d, J = 8.6 Hz, lH), 3.87 (m, JH), 4.19 (qd, J = 7.1, 1.6 Hz, SH), 5.51 (s, 3H), 6.68 (q, J = 6.7 Hz, 3H), 7.29 (m, 6H), 7.47 (m, 19H), 7.65 (m, SH) 63au 1H NMR (MeOH-d4): 8 ppm 1.13 (s, 2H), 1.26 (t, J = 7.3 Hz, 4H), 1.49 (rn, 6H), 1.73 (dd, J = 13.1, 7.2 Hz, lH), 2.06 (dd, J = 13 .1 , 8.7 Hz, lH), 2.38 (d, J = 12.1 Hz, 7H), 2.73 (d, J = 11.0 Hz, lH), 2.87 (d, J = 11.0Hz, lH), 3.53 (tt, J = 14.1, 5.1 Hz, SH), 3.81 (m, 11-I), 4.18 (tt, J = 7.8, 3.6 Hz, 2H), 4.81 (s, 2H), 4.97 (d, J = 15 .9 Hz, lH), .74 (s, IH), 6.41 (d, J = 2.1 Hz, IH), 6.78 (q, J = 6.7 Hz, lH), 7.26 (d, J = 7.9 Hz, 2H), 7.57 (m, SH), 7.73 (m, 2H), 7.96 (d, J = 2.3 Hz, lH) 63av 1H NMR (MeOH-d4): 8 ppm 1.26 (m, 3H), 1.51 (dt, J = 10.6, 5.6 Hz, 4H), 1.74 (dd, J = 13 . 1 , 7.2 Hz, lH), 2.07 (dd, J = 1 3 .l , 8.8 Hz, 1H), 2.40 (s, 7H) , 2.74 (d, J = 10.9 Hz, IH), , J = 11.0 Hz, HI), 3.54 (m, 4H), 3.81 (dd, J = 8.8, 7.1 Hz, lH), 4. 18 (qd, J = 7.1 , 1.6 Hz, 2H), 5.74 (s, lH), 6.42 (d, J = 2.4 Hz, lH), 6.79 (q, J = 6.6 Hz, lH), 7.21 (d, J = 7.5 Hz, IH), 7.33 (t, J = 7.6 Hz, lH), 7.46 (m, 2H), 7.62 (d, J = 1.9 Hz, lH), 7.75 (m, 2H), 7.98 (d, J = 2.4 Hz, lH) 63aw 1H NMR (Me0H-d4): o ppm 0.90 (m, lH), 1.27 (rn, SH), 1.5 1 (dt, J = 10.5, 5.6 Hz, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, IH), 2.09 (dd, J = 13.1 , 8.7 Hz, lf- I), 2.40 (s, JH), 2.76 (d, J = 1 1 . 0 Hz, l H), 2.90 (d, J = 11.0Hz, IH), 3.54 (rn, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, lH), 4.1 9 (qd, J = 7.1, 1.7Hz, 2H), 5.73 (s, lH), 6.43 (d, J = 2.4 Hz, lH), 6.84 (q, J = 6.5 Hz, 1I-I), 7.64 (m, 3H), 7.80 (m, 3H), 8.01 (d, J = 2.4 Hz, lH) 63ax 1HNMR (400 MHz, Chloroform-d): s ppm 1.27 (m, 9H), 1.52 (dt, J = 22.3, 5.4 Hz, 4H), 1.72 (d, J = 1 3. 1 Hz, lH), 2.05 (m, lH), 2.25 (ddd, J = 18 . 1 , 13.9, 8.2 Hz, 2H), 2.63 (m, 2H), 2.82 (d, J = 10.5 Hz, IH), 2.94 (d, J = 10.4 Hz, 11- I), 3.48 (dd, J = 13.6, 7.4 Hz, 5H), 3.63 (m, l H), 3 .81 (m, 4H), 4.19 (q, J = 7.1 Hz, 2H), 4.86 (s, 2H), 5.46 (s, lH), 6.46 (m, HI), 7.22 (d, J = 2.2 Hz, lH), 7.34 (dd, J = 8.5, 2.2 Hz, lH), 7.59 (d, J = 8.5 Hz, lH) 63ay 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.35 (d, J=2.64 Hz, 4 H) 1 .61 - 1.86 (m, 5 H) 2.04 - 2.16 (m, 1 H) 2.42 (d, J=l.27 Hz, 3 H) 2.48 - 2.60 (m, 1 H) 3.55 - 4.03 (m, 4 H) 4.25 - 4.44 (m, 2 H) 4.55 - 4.70 (m, l H) 6.45 (s, 1 H) 6.90 - 7.04 (m, 1 I-I) 7.61 (s, 2 H) 7.68 - 7.79 (m, 1 H) 7.88 - 8.00 (m, 1 I-I) 63az 1HNMR (400 MHz, MeOH-d4): o ppm 1.25 (t, J=7.15 Hz, 3 H) 1.43 - 1.60 (m, 4 H) 1.78 (dd, J=13.13, 7.42 Hz, 1 H) 2.13 (dd, J=l3.08, 8.74 Hz, 1 H) 2.35 (s, 3 H) 2.73 - 3.01 (m, 2 H) 3.39- 3.63 (m, 4 H) 3.94 (t, J=7.91 Hz, 1 H) 4.18 (qd, J=7.13, 1.78 Hz, 2 H) 5.65 (s, 1 H) 6.38 (d,J=2.39 Hz, 1 H) 6.79 (q, J=6.74 Hz, 1 I-I) 7.41 - 7.54 (m, 2 H) 7.68 (d, J=8.35 Hz, 1 H) 7.91 (d, J=2.34 Hz, 1 H) 63ba 400 MHz, MeOH-d4): o ppm 1.33 (t, J= 7.13 Hz, 3 H), 1.53 -1.75 (m, 4 H), 2.05 (dd, J = 13.62, 8.88 Hz, 1 H), 2.49 (dd, J = 13.57, 8.74 Hz, 1 H), 3.27 (s, 2 H), 3.42 - 3.74 (m, 4 H), 3.84(s, 3 H), 4.25 - 4.40 (m, 2 H), 4.58 (t, J = 8.79 Hz, l H), .60 (s, 1 H), 6.59 - 6.71 (m, 1 H), 6.92 (ddd, J = 8.22, 2.54, 0.76 Hz, 1 H), 7.11 - 7.16 (m, 1 H), 7.16 - 7.24 (m, 1 H), 7.31 - 7.38 (m, 1 I-I), 7.54 - 7.61 (m, 2 H), 7.62 - 7.70 (m, 2 I-I) 63bb 1H NMR (400 MHz, romethane-d2): 5 ppm 1.29 (t, J=7.15 Hz, 3 H) 1.47 - 1.85 (m, 4 H) 2.01 (dd, 1=13.52, 8.30 Hz, 1 H) 2.30 - 2.36(m, 1 H) 2.38 (s, 3 H) 3.27 - 3.41 (m, 2 H) 3.41 -3.67 (m, 4 H) 3.82 (s, 3 H) 4.26 (qd, J=7.17, 4.00 Hz, 2 H) 4.45 (t, J=8.49 Hz, 1 H) 4.96 (hr. s, 2H) 5.49 (s, I H) 6.31 (d, J=2.25 Hz, I H) 6.62 (q, J=6.90 Hz, 1 H) 6.88 (d, J=2.59 Hz, 1 H) 6.96 (dd, J:=8.81, 2.61 Hz, 1 H) 7.61 (d, J=8.74 Hz, 1 H) 7.66 (d, J=2.25 Hz, 1 H) 63bc 1H NMR (400 MHz, Me0H-d4): o ppm 1.35 (t, J=7.22 Hz, 3 H) 1.67 - 1.89 (m, 4 H) 2.05 - 2.18 (m, 1 H) 2.49 - 2.62 (m, 1 H) 3.56 - 3.90 (m, 4 H) 4.35 (dd, J=7.13, 1.85 Hz, 2 H) 4.65 (s, 1 H) 5.97 (s,1 H) 6.58 - 6.72 (m, 1 H) 7.14 (br, s., 1 H) 7.41 (d, J=9.18 Hz, 1 H) 7.45 - 7.53 (m, 2 H) 7.64 - 7.72 (m, 2 H) 7.73 - 7.82 (m, 2 H) 63bd 1H NMR (400 MHz, MeOH-d4): o ppm 1.28 - 1.39 (m, 4 H) 1.74 (d, J:=18.35 Hz, 4 H) 2.03 - 2.14 (m, 1 H) 2.35 (d, J=l2.89 Hz, 6 H) 2.43 (s, 3 H) 2.46 "2.57 (m, 1 H) 3.62" 3.96 (m, 4 H) 4.34 (dd, J:== 7.13, 1.85 Hz, 2 H) 4.56 - 4.68 (m, 1 H) 6.44 (d, J=2.34 Hz, 1 H) 6.50 - 6.61 (m, 1 H) 6.81 - 6.96 (m, I H) 7.26 (d, J=7.81 Hz, l H) 7.40 - 7.47 (m, 1 H) 7.50 (s, 1 H) 7.68 (d, J=l .37 Hz, 1 H) 7.78 (s, 1 H) 7.82 (d, J=l .37 Hz, 1 H) 7.98; (d, J=2.15 Hz, 1 H) 63be 1H NMR (400 MHz, Me0H-d4): o ppm 1.30 (m, 6 H) 1.59 (rn , 4 H) 2.02 (m, 1 H) 2.38 (s, 3 H) 2.45 (dd, J=13.54, 8.76 Hz, 1 H) 2.72 (q, J=7.60 Hz, 2 H) 3.24 (m, 2 H) 3.58 (m, 4 H) 4.32 (m, 2 H) 4.53 (t,J:== 8.76 Hz, 1 H) 5.72 (s, 1 H) 6.38 (d, 1=2.20 Hz, 1 H) 6.71 (m, 1 H) 7.25 (d, J=l.56 Hz, 1 H) 7.36 (dd, J=8.10, 1.61 Hz, 1 H) 7.63 (d, J=8.10 Hz, 1 H) 7.85 (d, J=2.29 Hz, 1 H) 63bf 11-I NMR (400 MHz, MeOH"d4): s ppm 0.96 (t, J=7.35 Hz, 2 H) 1.32 «, J=7.15 Hz, 4 H) 1.63 (m, 6 H) 2.00 (dd, 1=13.59, 8.61 Hz, 1 H) 2.37 (s, 3 H) 2.42 (m, 1 H) 2.66 (m, 2 I-1) 3.21 (m, 2 H) 3.58 (m, 4 H) 4.31 (m, 2 H) 4.49 (t, J=8.69 Hz, 1 H) 5.72 (s, 1 H) 6.38 (d, J=2.29 Hz, 1 H) 6.7l(q, J=6.67 Hz, 1 H) 7.23 (d, J=l.66 Hz, 1 H) 7.34 (dd, J=8.10, 1.66 Hz, 1 H) 7.63 (d, J=8.10 Hz, I H) 7.85 (d, J:=2. 29 Hz, 1 H) 63bg lI-J NMR (400 MHz, MeOH-d4): s ppm 0.95 (t, J=7.35 Hz, 3 H) 1.32 (t, J=7.15 Hz, 4 H) 1.63 (m, 6 I-I ) 2.02 (rn, 1 H) 2.38 (s, 3 H) 2.45 (dd, J=13.54, 8.76 Hz, 1 H) 2.69 (m, 2 H) 3.24 (m, 2 H) 3.58 (m, 4 H) 4.32 (m, 2 H) 4.53 (t, J=8.74 Hz, 1 I- 1) 5.72 (s, 1 H) 6.38 (d, J=2.29 Hz, 1 H) 6.71 (m, 1 H) 7.23 (d, J=l.61 Hz, 1 H) 7.34 (dd, J=8.15, 1.61 Hz, 1 H) 7.62 (d, J=8.15 Hz, 1 H) 7.85 (d, J=2.34 Hz, I H) 63bh 1H NMR (400 MHz, FORM-d): o ppm 1.18-1.36 (m, 3 H) 1.43 (t, J =6.74 Hz, 3 H) 1.54-2.29 (m, 6 H) 2.39 (br. s., 3 H) 3.78 (br. s., 4 H) 4.26 (br. s., 2 H) 4.42 (d J =6.15 Hz, 2 H) 5.53 (br. s., I H) 6.36 (s, 1 H) 6.59 (br. s., 1 H) 7.48 (d, J =7.96 Hz, 1 I-I)7.61(br. s., 1 H) 8.16 (d, J=8.05Hz, 1 H) 8.34 (hr. s., 1 H) 63hi 1HNMR (400 MHz, MeOH-d4): oppm 1.24-1.30 (m, 5 H) 1.37 (t, J=7.13 Hz, 3 H) 1.45 - 1.62 (m, 4 H) 1.84 (dd, J=13.32, 7.86 Hz, 1 H) 1.95 (s, 4 H) 2.22 (dd, J=13.30, 8.86 Hz, 1 H) 2.38 (s, 3 H) 2.88 - 3.09 (m, 2 H) 3.41 - 3.71 (m, 4 H) 4.10 (t, J=8.25 Hz, 1 H) 4.22 (qd, J=7.13, 2.00 Hz, 2 H) 4.37 (q, J=7.13 Hz, 2 H) 5.66 (s, 1 H) 6.41 (d, J=2.39 Hz, 1 H) 6.84 (q, J=6.54 Hz, 1 H) 7.83 (d, J=8.30 Hz, 1 H) 7.94 (d, J=2.34 Hz, 1 H) 7.99 (d, J=l.61 Hz, 1 H) 8.08 (dd, J=8.27, 1.64 Hz, 1 H) 63bj 1H NMR (400 MHz, MeOH-d4): <> ppm 1.31 (td, J=7.13, 3.22 Hz, 6 H) 1.52 - 1.64 (m, 4 H) 1.97 (s, 1 H) 2.01(dd, J=l3.59, 8.81 Hz, 1 H) 2.37 (s, 3 H) 2.44 (dd, J=13.62, 8.74 Hz, 1 H) 3.18 - 3.26 (m, 2 H) 3.43- 3.68 (m, 4 H) 4.19 - 4.34 (m, 4 H) 4.53 (t, J=8.74 Hz, 1 H)5.75 (s, 1 H) 6.40 (d, J=2.39 Hz, 1 H) 6.55 (d, J=16.06 Hz, 1 H) 6.95 (q, J=6.56 Hz, 1 H) 7.46 (d, J=8.30Hz, 1 H) 7.68 (d, J=16.06 Hz, 1 H) 7.80 (dd, J=8.32, 2.03 Hz, 1 H) 7.87 (s, 1 H) 7.91(d, J=2.39 Hz, I H) 63bk 11-I NMR (400 MHz, MeOH-d4): o ppm 0.92 (t, J=7.37 Hz, 3 H) 1.32 (dq, J=14.94, 7.38 Hz, 2 H) 1.50 - 1.68 (m, 6 H) 2.06 (dd, J=13.37, 7.22 Hz, 1I-I) 2.31 (dd, J=13.45, 9.25 Hz, 1 H) 2.37(s, 3 H) 2.69 (t, J=7.59 Hz, 2 H) 3.06 - 3.29 (m, 2 H) 3.41 - 3.76 (m, 4 H) 4.08 (dd, J=9.20, 7.25 Hz, l H) 5.75 (s, 1 H) 6.36 (d, J=2.15 Hz, 1 H) 6.69 (q,J=6.62 Hz, 1 H) 7.28 - 7.33 (m, 1 H) 7.34 - 7.39 (m, 1 H) 7.53 (s, 1 H) 7.82 (d, J=2.29 Hz, 1 H) 63bl IHNMR ( 400 MHz, DMSO-d6): s ppm 1.50 - 1.73 (m, 4 H) 1.80 (quin, J=7 .52 Hz, 2 H) 1.90 (dd, J=13.23, 9.22 Hz, 1 H) 2.15 - 2.26 (m, 2 H) 2.27- 2.41 (m, 4 H) 2.69 (t, J=7.66 Hz, 2 H) 3.00- 3.20 (m, 2 H) 3.69 (hr. s., 4 H) 4.33 - 4.52 (m, I H) 6 .14 (br. s., 1 H) 6.38 (d, Hz, 1 H) 7.05 (br. s., 1 H) 7.37 - 7.52 (m, 3 H) 7.76 (hr. s., 1 H) 8.02 (d, J=2.29 Hz, 1 H) 8.97 (d, J=S.32 Hz, 1 H) 10.42 (br. s.,l H) 63bm 1HNMR (400 MHz, MeOH-d4): o ppm 1.31 (t, J=7.15 Hz, 3 H) 1.52 - 1.70 (m, 4 H) 1.90 (dd,J=6.30, 1.22 Hz, 3 H) 1.97 (dd, J=13.52, 8.44Hz, 1 H) 2.35 - 2.41 (m, 4 H) 3.06 - 3.24 (m, 2 H) 3.42 - 3.79 (m, 4 H) 4.21 - 4.35 (m, 2 H) 4.40 (t, J=8.57 Hz, I H) .75 (s, 1 I-1) 6.27 - 6.54 (m, 3 H) 6.75 (q, J=6.64 Hz, 1 H) 7.32 (d, J=8.25 Hz, 1 H) 7.52 (dd, J=8.30, 2.00 Hz, 1 H) 7.64 (s, 11-I ) 7.83 (d, J=2.29 Hz, 1 H) 63hn 1H NMR (400 MHz, Me0H-d4): s ppm 1.32 (t, J=7.15 Hz, 3 H) 1.49 - 1.70 (m, 4 H) 2.01 13.59, 8.76 Hz, 1 H) 2.29 (s, 3 H) 2.32 (s, 3 H) 2.40 (s, 3 H) 2.40 - 2.44 (m, 1 H) 3.24 (s, 2 H) 3.43 - 3.71 (m, 4 H) 4.22 - 4.41 (m, 2 H) 4.56 (t, J=8.74 Hz, 1 H) 5.80 (s,1 H) 6.41 (d, J=2.29 Hz, 1 H) 6.81 - 6.92 (m, I H) 7.20 (d, J=7.81 Hz, 1 H) 7.26 - 7.32 (m, 1 H) 7.35 (s, 1 H) 7.45 (d, J=8.30 Hz, 1 H) 7.73 (dd, J=8.27, 2.12 Hz, 1 H)7.88 - 7.90 (m, 2 H) 63bo 1H NMR (400 MHz, MeOH-d4): o ppm 0.92 (t, J=7.35 Hz, 3 H) 1.32 (t, J=7.13 Hz, 3 I-I) 1.49 - 1.76 (m, 6 H) 1.94 - 2.06 (m, I I-I) 2.37 (s, 3 H) 2.43 (dd, J=l3.57, 8.79 Hz, 1 H) 2.66 (t, J=7.52 Hz, 2 H)3.13 - 3.28 (rn, 2 H) 3.43 - 3.76 (m, 4 H) 4.21 - 4.39 (m, 2 H) 4.50 (t, J:=8.66 Hz, 1 H) 5.74 (s, 1 H) 6.37 (d, J=2.29 Hz, 1 H) 6.70 (q, J=6.69 Hz, 1 H) 7.26 - 7.33 (m, 1 H) 7.34 - 7.42 (m, 1 H) 7.53 (s, 1 H) 7.82 (d, J=2.29 Hz, 1 63bp 1H NMR (400 MHz, MeOH-d4): o ppm 1.25 (t, J=7.61 Hz, 3 H) 1.33 (t, J=7.15 Hz, 3 H) 1.57 - 1.71 (m, 4 H) 2.04 (dd, 1'=13.93, 8.52 Hz, I H) 2.37 (s, 3 H) 2.47 (dd, J=l3.62, 8.74 Hz, l H) 2.72 (q, J=7.61 Hz, 2 H) 3.26 (d, J=l.51 Hz, 2 H) 3.44 - 3.77 (m, 4 H) 4.23 - 4.43 (m, 2 H) 4.57 (t, J=8.79 Hz, 1 H) 5.76 (s, 1 H) 6.37 (d, J=2.20 Hz, 1 H) 6.63 - 6.78 (m, 1 H) 7.27 - 7.35 (m, 1 H) 7.36 - 7.46 (m, 1 H) 7.55 (s, I H) 7.81 (d, J=2.29 Hz, 1 H) 63hq 1H NMR (400 MHz, MeOH-d4): 8 ppm 0.92 (t, J:=7.35 Hz, 3 H) 1.22 - 1.42 (m, 5 H) 1.49 - 1.75 (m, 6 H) 1.94 - 2.08 (m, 1 H) 2.37 (s, 3 H) 2.44 (dd, J=I3.57, 8.74 Hz, 1 H) 2.68 (t, J:==7.61 Hz, 2 H) 3.15 - 3.29 (m, 2 H) 3.42 - 3.76 (m, 4 H) 4.23 - 4.40 (m, 2 H) 4.53 (t, J=8.74 Hz, 1 H) 5.75 (s, 1 H) 6.37 (d, J=2.34 Hz, 1 H) 6.70 (q, J:=6.69 Hz, 1 H) 7.27 - 7.33 (m, 1 H) 7.34 - 7.41 (m, 1 H) 7.53 (s, 1 H) 7.82 (d, J=2.34 Hz, 1 H) 63hr 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.33 (t, J=7.13 Hz, 3 H) 1.53 - 1.74 (m, 4 H) 2.05 (dd, J=13.62, 8.83 Hz, 1 H) 2.38 (s, 3 H) 2.48 (dd, , 8.79 Hz, 1 H) 3.28 (s, 2 H) 3.44 - 3.79 (m, 4 H) 4.22 - 4.43 (m, 2 H) 4.59 (t, J=8.79 Hz, 1 H) 5.37 (d, J=l 1.08 Hz, 1 H) 5.73 - 5.96 (m, 2 H) 6.39 (d, J=2.34 Hz, 1 H) 6.68 - 6.95 (m, 2 H) 7.40 (d, J=8.25 Hz, 1 H) 7.65 (dd, J=8.27, 1.98 Hz, 1 H) 7.73 (s, 1 H) 7.87 (d, J:== 2.34 Hz, 1 H) 63hs 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.11 (t, J=7.47 Hz, 3 H) 1.33 (t, J=7.15 Hz, 3 H) 1.51 - 1.72 (m, 4 H) 2.04 (dd, J=13.62, 8.83 Hz, 1 H) 2.18 - 2.33 (m, 2 H) 2.38 (s, 3 H) 2.47 (dd, J=13.59, 8.81 Hz, 1 H) 3.26 (s, 2 H) 3.44 - 3.78 (rn, 4 H) 4.19 - 4.43 (m, 2 H) 4.58 (t, J=8.79 Hz, 1 H) 5.79 (s, 1 H) 6.30 - 6.53 (m, 3 H) 6.69 - 6.84 (m, I H) 7.33 (d, J=8.25 Hz, 1 H) 7.55 (dd, J=8.30, 2.00 Hz, 1 H) 7.65 (s, 1 H) 7.84 (d, 1=2.34 Hz, 1 H) 63ht 1H NMR (400 MHz, MeOH-d4): s ppm 1.30 (t, J=7.13 Hz, 3 H) L45 - 1.65 (m, 4 H) 1.79 - 1.91 (m, 1 H) 2.16 - 2.32 (m, 1 H) 3.03 (s, 2 H) 3.51 (hr . s., 4 H) 3.75 - 3.81 (m, 1 H) 4.07 - 4 .17 (m, 1 H) 4.20 - 4.32 (m, 2 H) 5.55 (s, 1 H) 6.65 (d, J=2.34 Hz, 1 H) 7. 15 - 7.28 (m, 1 H) 7.36 - 7.46 (m, 1 H) 7.57 (d, J=2.15 Hz, 1 H) 7.62 - 7.70 (m, 1 H) 7.73 (d, J=2.15 Hz, 1 H) 63bu 11-I NMR (400 MHz, MeOH-d4): o ppm 1.29 (t, J=7.13 Hz, 3 H) 1.40 - 1.6 1 (m, 4 H) 1.71 - 1 .86 (m, l H) 2.07 - 2.22 (m, 1 H) 2.86 (s, 1 H) 2.94 (s, 1 H) 3.50 (d, J=4.69 Hz, 4 H) 4.00 (s, 4 H) 4.22 (dd, J=7.22, 0.98 Hz, 2 H) 5.57 (s, 1 H) 6.61 (d, J=2.15 Hz, 1 H) 7.13 - 7.28 (m, 1 H) 7.35 -7.50 (m, 2 H) 7.55 (d, J=l.17 Hz, 1 H) 7.72 (d, J=2.34 Hz, 2 H) 63bv 11-I NMR (400 MHz, MeOH-d4): 8 ppm 1.35 (t, J=7.13 Hz, 3 H) 1.57 - 1.83 (m, 4 H) 1.99 - 2.16 (m, 1 H) 2.56 (s, 4 H) 3.31 (s, 2 H) 3.68 (br, s., 4 H) 4.03 (s, 3 H) 4.35 (dd, J=7.03, 2.15 Hz, 2 H) 4.62 (s, 1 H) 5.70 (s, 1 H) 6.70 (d, J=6.83 Hz, 1 H) 7.42 (dd, , 0.88 Hz, 1 H) 7.60 - 7.72 (m, 3 H) 7.73 - 7.86 (m, 3 H) 63bw 1H NMR (400 MHz, MeOH-d4): o ppm 1.35 (t, J=7.13 Hz, 3 H) 1.67 - 1.90 (m, 4 H) 2.03 - 2 . 1 8 (m, 1 H) 2.47 - 2.61 (m, 1 H) 2.72 (s, 3 H) 3.34 (hr. s., 2 H) 3.56 - 3.87 (m, 4 H) 4.17 (s, 3 H) 4.35 (dd, J=7.13, 2.05 Hz, 2 H) 4.64 (s, 1 H) 5.89 - 6.04 (m, 1 H) 6.59 - 6.75 (m, 1 H) 7.45 (d, J=0.98 Hz, 1 H) 7.70 (d, J=8.20 Hz, 2 H) 7.77 (s, 1 H) 7.79 - 7.92 (m, 3 H) 63hx 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.35 (t, J=7. l 3 Hz, 3 H) 1.77 (hr. s., 4 H) 2.04 - 2.15 (m, 1 H) 2.47 - 2.58 (m, 1 H) 3.09 (s, 2 H) 3.57 (t, J=6.74 Hz, 6 H) 4.28 - 4.43 (rn, 2 H) 4.57 - 4.69 (m, lH) 5.80 - 5.92 (m, 1 H) 6.60 - 6 .75 (m, 1 H) 7.62 (s, 1 H) 7.69 (d, J=8.40 Hz, 3 H) 7.74 - 7.85 (m, 2 H) 8.03 (d, J=8.00 Hz, 1 H) 63hy 1H NMR (400 MHz, MeOH-d4): s ppm 1.35 (t, J=7.13 Hz, 3 H) 1.61 - 1.81 (m, 4 H) 2.00 - 2.16 (m, 1 H) 2.44 - 2.59 (m, 1 H) 3.47 - 3.80 (m, 4 H) 4.35 (dd, J=7.03, 2.54 Hz, 2 H) 4.63 (s, 1 H) 5.73 (s,1 H) 6.64 - 6.83 (m, 1 H) 7.76 (d, J=8.20 Hz, 2 H) 7.95 (d, J=8.20 Hz, 2 H) 8.12 - 8.33 (m, 2 H) 8.36 - 8.47 (m, 2 H) 8.48 - 8.68 (m, 1 H) 9.39 - 9.76 (m, 1 H) 63bz 1H NMR (400 MHz, MeOH-d4): o ppm 1.10 - 1.20 (m, 3 H) 1.26 (t, J=7.13 Hz, 3 H) 1.42 - 1.64 (m, 4 H) 1.79 (dd, J=l3.15, 7.44 Hz, 1 H) 1.94 (s, 2 H) 2.15 (dd, J=12.98, 8.69 Hz, 1 H) 2.35 (s, 3 I-I) 2.62 - 2.71 (m, 2 H) 2.81 - 2.87 (m, 1 H) 2.93 - 3.02 (m, 3 H) 3.40- 3.66 (m, 4 H) 3.96 (t, J=8.18 Hz, 1 H) 4.06 (q, J=7.18 Hz, 2 H) 4.16 - 4.25 (m, 2 H) 5.69 (s, 1 H) 6.36 (d, J=2.25 Hz, 1 H) 6.71 (q, J=6.67 Hz, 1 H) 7.27 (d, J=l.56 Hz, 1 H) 7.35 (dd, J=S.13, 1.83 Hz, 1 H) 7.62 (d, J=8.20 Hz, 1 H) 7.83 (d, J=2.29 Hz, 1 H) 63ca 1H NMR (400 MHz, Me0H-d4): o ppm 1.35 (t, J=7.13 Hz, 3 H) 1.63 - 1.82 (m, 4 H) 2.03 - 2.17 (m, 1 H) 2.47 - 2.60 (m, 1 H) 3.51 - 3.83 (m, 4 H) 4.27 - 4.42 (m, 2 H) 4.57 - 4.69 (m, 1 H) 5.69 - 5.88 (m, 1 H) 6.65 - 6.85 (m, 1 H) 7.71 - 7.85 (m, 2 H) 7.89 - 8.01 (m, 2 H) 8.22 - 8.35 (m, 2 H) 8.36 - 8.49 (m, 1 H) 8.52 - 8.60 (m, 1 H) 8.62 - 8.72 (m, 1 H) 9.56 - 9.75 (m, 1 H) 63ch 1H NMR (400 MHz, DMSO-d6): o ppm 1.18 (t, J=7.10 Hz, 3 H) 1.24 (t, J=7.13 Hz, 3 H) 1.37 - 1.63 (m, 4 H) 1.82 (quin, J=7.52 Hz, 2 H) 1.90 (dd, J=l3.28, 9.42 Hz, 1 H) 2.19 - 2.41 (m, 6 H) 2.67 (t, J=7.69 Hz, 2 H) 3.12 (br. s., 2 H) 3. 18 - 3.74 (m, 4 H) 4.05 (q, J=7 .13 Hz, 2 H) 4.15 - 4.30 (m, 2 H) 4.52 (t, 1=8.49 Hz, 1 H) 5.72 (br. s., 1 H) 6.01 (br, s., 2 H) 6.37 (d, J=2.15 Hz, l H) 6.99 (q, J=6.87Hz, 1 H) 7.33 - 7.44 (m, 2 H) 7.47 (s, 1 H) 8.01 (d, 1=2.25 Hz, 1 H) 9.20 (hr. s., 1 H) 10.39 (br. s., 1 H) 63cc 1H NMR ( 400 MHz, DMSO-d6): 8 ppm 1.10 - 1.20 (m, 3 H) 1.25 (t, 1=7.10 Hz, 3 H) 1.44 - 1.63 (m, 4 H) 1.82 (quin, J:=:7.53 Hz, 2 H) 1. 9 1 (dd, 8, 9.37 Hz, 1 H) 2.19 - 2.40 (m, 3 H) 2.60 (t, J=7.71 Hz, 2 H) 3.13 (hr. s., 2 H) 3.40 - 3.68 (m, 4 I-I ) 4.02 (q, 1=7.09 Hz, 2 H) 4.13 - 4.33 (m, 2 H) 4.53 (hr. s., 1 H) 5.70 (hr. s., 1 H) 6.29 (br. s, 2 H) 6.62 - 6.76 (m, 1 H) 7.28 (d, 1=8.20 Hz, 2 H) 7.43 (d, J=8.10 Hz, 2 H) 9.21 (br. s., 1 H) 10.43 (hr. s., 1 H) 63cd 1H NMR (400 MH z, DMSO-d6): o ppm 1.15 (t, J=7.13 Hz, 3 H) 1.24 (t, J=7.10 Hz, 3 H) 1.39 - 1.64 (m, 4 H) 1.78 - 1.97 (m, 3 H) 2.22 - 2.39 (m, 6 H) 2.66 (t, J== 7.71 Hz, 2 H) 3.11 (br. s., 2 H) 3.38 - 3.64 (m, 4 H) 3.93 - 4.07 (m, 2 H) 4. 1 5 - 4.31 (m, 2 H) 4.52 (br. s., 1 H) 5.73 (br. s., 1 H) 6.05 (br. s., 2 H) 6.38 (d, J=2.10 Hz, 1 H) 7.00 (q, J=6.72 Hz, 1 H) 7.30 (d, J=l.51 Hz, 1 H) 7.33 - 7.41 (m.I H) 7.59 (d, J=8.05 Hz, 1 H) 8.04 (d, J=2.29 Hz, I H) 9.20 (br. s., 1 H) 10.38 (br. s., 1 H) 63ce 1H NMR (400 MHz, MeOH-d4): o ppm 1.22 - 1.30 (m, 3 I-1 ) 1.48 - 1.61 (m, 4 H) 1.82 (dd,J=13.30, 7.74 Hz, 1 H) 1.94 (s, 3 H) 2.15 - 2.23 (m, 1 H) 2.38 (s, 3 H) 2.87 - 2.92 (m, 1 H) 2.96 - 3.02 (m, 1 H) 3.42 - 3.64 (m, 4 H) 4.01 - 4.08 (m, 1 H) 4.16 - 4.25 (m, 2 H) 5.72 (s, 1 H) 6.41 (d, 1=2.39 Hz, 1 H) 6.81 - 6.88 (m, 1 H) 7.61 - 7.66 (m, 1 H) 7.71 (d, 1=1.76 Hz, 1 H) 7.73 - 7.86 (m, 3 I-I ) 7.97 - 8.02 (m, 2 I-1 ) 8.08 (s, 1 H) 63cf 1H NMR ( 400 MHz, 6): o ppm 1.25 (t, J=7 .13 Hz, 3 H) 1.45 - 1.66 (m, 4 H) 1.92 (dd, 1=13.18, 9.42 Hz, 1 H) 2.35 (dd, 1=13.28, 8.54 Hz, 1 H) 3.14 (br. s., 2 H) 3.60 (hr. s., 4 H) 4.1 4 - 4.31 (m, 2H) 4.54 (br. s., 1 H) 5.75 (br. s., 1 I-I ) 6.56 {q, J=6.72 Hz, 1 H) 7.47 (t, J=l.27 Hz, 1 H) 7.65 (s, 2 H) 7.75 - 7.84 (m, 1 H) 7.89 (d, 1=7.81 Hz, 1 H) 7.93 - 8.01 (m, 2 H) 9.21 (hr. s., 1 H) 10.36 (br. s., 1 H) 63cg 1H NMR (400 MHz, DMSO-d6): o ppm 1.25 (t, J=7.10 Hz, 3 H) 1.5 7 (d, J=5.37 Hz, 4 H) 1.83 - 1.99 (m, 1 H) 2.28 - 2.40 (m, 1 H) 3.14 (hr. s., 2 H) 3.58(hr. s., 4 H) 3.81 (s, 3 H) 4.24 (dd, J=7.13, 2.25 Hz, 2 H) 4.43 - 4.63 (m, 1 H) 5.62 - 5.85 (m, 1 H) 6.73 (d, J=6.78 Hz, I H) 6.96 - 7.16 (m, 3 H) 7.39 (d, J=2.15 Hz, 1 H) 7.50 (dd, J=8.74, 7.61 Hz, 1 H) 7.55 - 7.69 (m, 2 H) 9.09 - 9.32 (m, 1 H) 10.26 - 10.47 (m, 1 H) 63ch R (400 MHz, MeOH-d4): 8 ppm 1.32 (t, J=7.15 Hz, 3 H) 1.52 - 1.70 (m, 4 H) 1.93 - 2.02 (m, 1 H) 2.40 (dd, J=13.45, 8.71 Hz, 1 H) 3.09 - 3.24 (m, 2 H) 3.43 - 3.74 (m, 4 H) 4.25 - 4.35 (m, 2 H) 4.40 (t, J=8.57 Hz, 1 H) 5.59 (s, 1 H) 6.61 (q, J=6.56 Hz, 1 H) 7.32 (d, J=2.15 Hz, 1 H) 7.49 (dd, J=8.49, 2.25 Hz, 1 H) 7.61 (d, J=8.00 Hz, 1 H) 7.65 - 7.77 (m, 2 H) 7.97 - 8.10 (m, 1 H) 8.32 (br. s., 1 H) 63ci 1HNMR (400 MHz, MeOH-d4): 8 ppm 1.32 (t, J=7.13 Hz, 3 H) 1.50 - 1.70 (m, 4 H) 1.91 - 2.02 (m, 1 H) 2.39 (dd, J=13.50, 8.76 Hz, 1 H) 3.08 - 3.23 (m, 2 H) 3.41 - 3.69 (m, 4 H) 4.24 - 4.34 (m, 2 H) 4.38 (t, J=8.54 Hz, 1 H) 5.50 (s, 1 H) 6.75 (q, J=6.96 Hz, 1 H) 6.87 (d, J=7.66 Hz, 1 H) 6.91 (ddd, J=8.21, 2.50, 0.90 Hz, 1 H) 7.06 (br. s., 1 H) 7.28 (d, J=2.20 Hz, I H) 7.32 (t, J=7.88 Hz, 1 H) 7.43 (dd, J=8.47, 2.27 Hz, 1 H) 7.66 (d, J=8.44 Hz, 1 H) 63cj IH NMR (400 MHz, Me0H-d4): o ppm 1.32 (t, J=7 .13 Hz, 3 H) 1.52 - 1.70 (m, 4 H) 1.93 - 2.06 (m, 1 H) 2.41 (dd, J=l3.42, 8.74 Hz, 1 H) 3.10 - 3.25 (m, 5 H) 3.44 - 3.74 (m, 4 H) 4.21 - 4.37 (m, 2 H) 4.42 (t, J=8.59 Hz, 1 H) 5.61 (s, 1 H) 6.57 (q, J=6.57 Hz, 1 H)7.36 (d, J=2.20 Hz, l H) 7.51 (dd, J=8.54, 2.20 Hz, 1 H) 7.70 (d, J=8.44 Hz, 1 H) 7.72 - 7.78 (m, 1 H) 7.78 - 7.89 (m, 1 H) 8.09 (dt, J=7.85, 1.49 Hz, 1 H) 8.41 (d, J=O.73 Hz, 1 H) 63ck 1HNMR (400 MHz, DMSO-d6): s ppm 1.21 (t, J=7.10 Hz, 3 H) 1.38 - 1.64 (m, 4 H) 1.88 (dd, J=13.20, 9.35 Hz, 1 H) 2.30 (dd, J:=13.20, 8.47 Hz, 1 H) 3.09 (br. s., 2 H) 3.42 - 3.61 (m, 4 H) 3.95 - 4.11 (m,2 H) 4.12 - 4.28 (m, 2 H) 4.48 (br. s., 1 H) 5.71 (br. s., 1 H) 6.32 (br,s., 1 H) 6.71 (q, J=6.74 Hz, 1 H) 7.33 (d, J=2.05 Hz, 1 H) 7.44 - 7.69 (m, 6 H) 8.52 (br,s., 3 H) 9.27 (hr. s., 1 H) 10.62 (hr. s., 1 H) 63cl 1H NMR (400 MHz, MeOH-d4): s ppm 1.35 (t, J=7.13 Hz, 4 H) 1.82 (br. s., 4 H) 2.03 - 2.21 (m, 1 H) 2.47 - 2.64 (m, 1 H) 3.35 (s, 2 H) 3.56 - 3.92 (m, 4 H) 4.27 - 4.43 (m, 2 H) 4.59 - 4.70 (m, 1 H) 6.65 - 6.82 (m, l H) 7.81 (d, J=8.00 Hz, 2 H) 8.00 (d, J=8.20 Hz, 2 H) 8.05 - 8.14 (m, 1 H) 8.29 - 8.40 (m, 1 H) 8.46 - 8.55 (m, 1 H) 8.63 (d, J=l.56 Hz, 1 H) 9.21 (s, 2 H) 63cm 1H NMR (400 MHz, Me0H-d4): s ppm 1.35 (t, J=6.93 Hz, 5 H) 1.83 (hr. s., 4 H) 2.04 - 2.22 (rn, 1 H) 2.47 - 2.65 (m, 1 H) 3.36 (hr. s., 2 H) 4.35 (d, J=6.64 Hz, 2 H) 4.57 - 4.71 (m, 1 H) 6.64 - 6.85 (m, I H) 7.84 (d, J=6.64 Hz, 2 H) 8.03 (d, J=6.83 Hz, 2 H) 8.08 - 8.18 (m, 1 H) 8.27 - 8.41 (m, 1 H) 8.50 (br, s., 2 H) 9.26 (br. s., 2 H) 63cn 1HNMR (400 MHz, Me0H-d4): 8 ppm 1.24 - 1.45 (m, 10 H) 1.75 (d, 5 Hz, 4 H) 2.01- 2 . 18 (m, 1 H) 2.43 (s, 3 H) 2.47 -2.62 (m, 1 H) 3.86 (br. s., 3 H) 4.34 (d, J=S.86 Hz, 2 H) 4.54 - 4.75 (m, 2 H) 6.44 (d, J=l .95 Hz, 1 H) 6.89 (d, J=S.66 Hz, 1 H) 7.03 (d, J=8.59 Hz, 2 H) 7.57 - 7.71 (m, 3 H) 7.72 - 7.87 (m, 2 H) 7.98 (d, J=l.76 Hz, 1 H) 63co 1HNMR (400 MHz, MeOH-d4): 8 ppm 1.35 (s, 3 H) 1.64 - 1.91 (m, 4 H) 2.03 - 2.20 (m, 1 H) 2.47 - 2.64 (m, 1 H) 3.35 (br. s., 2 H) 3.56 - 3.95 (m, 4 H) 4.25 - 4.44 (m, 2 H) 4.57 - 4.71 (m, 1 H) 6.57- 6.84 (m, 1 H) 7.70 - 7.85 (m, 2 H) 7.90 - 8.07 (m, 2 H) 8.23 (s, 2 H) 8.33 - 8.47 (m, 1 H) 8.86 - 9.05 (m, 2 H) 63cp 1H NMR (400 MHz, Me0H-d4): o ppm 1. 18 - 1.31 (m, 3 H) 1.44 - 1.60 (m, 4 H) 1.79 (dd, J=13.28, 7.61 Hz, 1 H) 1.93 (s, 2 H) 1.98 (s, 3 H)2.14 (dd, J=13.18, 8.79 Hz, 1 H) 2.37 (s, 3 H) 2.80 - 2.89 (m, 1 H) 2.91 - 3.00 (m, 1 H) 3.40 - 3.64 (m, 4 I-I) 3.97 (t, J=8.15 Hz, 1 H) 4.19 (qd,J=7.13, 1.81 Hz, 2 H) 4.37 (s, 2 H) 5.72 (s, 1 H) 6.39 (d, 1=2.20 Hz, 1 H) 6.76 (q, J=6.56 Hz, 1 H) 7.36 (d, J=8.30 Hz , 2 H) 7.59 - 7.66 (m, 3 H) 7.69 - 7.81 (m, 2 H) 7.95 (d, 1=2.29 Hz, 1 H) 63cq 1HNMR (400 MHz, 6): s ppm 1.10 - 1.20 (m, 3 H) 1.25 (t, J=7.10 Hz, 3 H) 1.44 - 1.63 (m, 4 I-I) lH NMR (400 MHz, MeOH-d4): o ppm 1.21 - 1.31 (m, 3 H) 1.52 (dt, J=l0.53, 5.35 Hz, 4 H) 1.79 (dd, J=13.15, 7.44 Hz, 1 H) 1.89 (s, 3 H) 1.93 (s, 2 H) 2.14 (dd, J=13.13, 8.79 Hz, 1 H) 2.38 (s, 3 H) 2.78 - 2.88 (m, 3 H) 2.91 - 2.99 (m, 1 H) 3.40 (t, J=7.35 Hz, 2 H) 3.44 - 3.66 (m, 4 H) 3.95 (t, J=8.13 Hz, I H) 4.12 - 4.25 (m, 2 H) 5.72 (s, 1 H) 6.40 (d, J=2.29 Hz, I H) 6.77 (q, J=6.74 Hz, l H) 7.31 (d, J=8.25 Hz, 2 H) 7.58 - 7.64 (m, 3 H) 7.70 - 7.80 (m, 2 H) 7.95 (d, J=2.29 Hz, 1 H) 63cr 1H NMR (400 MHz, Me0H-d4): o ppm 1.25 (t, J=7.13 Hz, 3 H) 1.47 - 1.58 (m, 4 H) 1.79 (dd, J=13.20, 7.44 Hz, 1 H) 1.93 (s, 2 H) 2.15 (dd, J=13.23, 8.74 Hz, 1 H) 2.40 (s, 3 H) 2.81 - 2.87 (m, 1 H) 2.92 - 2.98 (m, 1 H) 3.44 - 3.63 (m, 4 H) 3.97 (dd, 1=8.52, 7.83 Hz, 1 H) 4.14 - 4.24 (m, 2 H) 5.75 (s, 1 H) 6.42 (d, J=2.29 Hz, I H) 6.84 (q, J=6.69 Hz, 1 H) 7.55 (dd, 1=8.30, 4.34 Hz, I H) 7.83 (d, J=l.76 Hz, 1 H) 7.85 - 7.99 (m, 3 H) 8.00 - 8.07 (m, 2 H) 8.30 (d, J=l.51 Hz, 1 I-1 ) 8.37 - 8.42 (m, 1 H) 8.88 (dd, J=4.30, 1.66 Hz, 1 H) 63cs 1H NMR (400 MHz, MeOH-d4): o ppm 1.34 (d, J=6.05 Hz, 6 H) 1.60 (br. s., 4 H) 2.02 - 2.13 (m, 1 H) 2.26 - 2.37 (m, 1 H) 2.42 (s, 3 H) 3.04 - 3.18 (m, 1 H) 3.26 (d, J=l l.71 Hz, 1 H) 3.41 - 3.78 (m, 4 H) 4.02 - 4.17 (m, 1 H) 4.66 (s, 11-I ) 5.78 (s, 1 H) 6.43 (d, J=2.15 Hz, l H) 6.69 - 6.86 (m, 1 H) 6.99 (d, J=8.79 Hz, 2 H) 7.50 - 7.66 (m, 3 H) 7.67 - 7.82 (m, 2 H) 7.97 (d, J=2.34 Hz, 1 H) 63ct 1H NMR (400 MHz, Me0H-d4): 8 ppm 1.35 (t, J=7.13 Hz, 3 H) 1 .58 - 1.78 (m, 4 H) 2.02 - 2.16 (m, 1 H) 2.43 - 2.60 (m, l H) 3.30 (s, 2 H) 3.46 - 3.78 (m, 4 H) 4.27 - 4.41 (m, 2 H) 4.55 - 4.66 (m, I H), 5.61 - 5.77 (m, 1 H) 6.42 - 6.53 (m, 1 H) 6.59 - 6.70 (m, l H) 7.25 - 7.39 (m, 2 H) 7.62 (s, 4 H) 7.72 (s, 2 H) 63cu 1H NMR (400 MHz, DMSO-d6): o ppm 1.25 (t, J=7 .10 Hz, 3 H) 1.33 (t, J=7. l O Hz, 3 H) 1.44 - 1.64 (m, 4 H) 1.92 (dd, 8, 9.27 Hz, 1 H) 2.35 (dd, J=13.28, 8.49 Hz, 1 H) 3.14 (br, s., 2 H) 3.44 - 3.66 (m, 4 H) 4 .14 - 4.29 (m, 2 H) 4.30 - 4.43 (m, 2 H) 4.54 (br. s., 1 H) 5.75 (br. s., 1 H) 6.43 (br, s., 1 H) 6.59 (q, J=6.72 Hz, 1 H) 7.37 - 7.47 (m, 1 H) 7.57 - 7.67 (m, 2 H) 7.68 - 7.81 (m, 2 H) 8.08 (dt, J=6.77, 1.96 Hz, 1 H) 8.24 (br. s., 1 H) 9.22 (br. s., l H) 10.41 (br. s, 1 H) 63cv 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.34 (t, J=7.13 Hz, 3 H) 1.69 - 1.88 (m, 4 H) 2.11 (dd, J=13.64, 8.96 Hz, 1 H) 2.55 (dd, 1=13.62, 8.69 Hz, 1 H) 3.34 (s,2 H) 3.52 - 3.80 (m, 4 H) 4.35 (qd, J=7.13, 1.93 Hz, 2 H) 4.63 (t, J=8.79 Hz, I H) 6.55 - 6.67 (m, I H) 7.37 (d, J=2.20 Hz, 1 H) 7.54 (dd, , 2.22 Hz, 1 H) 7.58 - 7.63 (m, 1 H) 7.65 - 7.70 (m, 1 H) 7.71 (d, J=8.59 Hz, 1 H) 8.17 (dt, J=7.74, 1.43 Hz, 1 H) 8.35 (br. s., 1 H) 63cw 1H NMR (400 MHz, DMSO-d6): o ppm 1.44 - 1.69 (m, 4 H) 1.91 (dd, J=13.28, 9.18 Hz, 1 H) 2.35 (dd, J=13.15, 8.61 Hz, 1 H) 3.14 (br. s., 2 H) 3.64 (br. s., 4 H) 4.37 - 4.53 (m, I H) 5.87 (br . s., 1 H) 6.62 (q, J=6.78 Hz, 1 H) 7.43 (t, J=l.22 Hz, 1 H) 7.65 (s, 2 H) 7.70 (d, J:=4.78 Hz, 2 H) 7.99 - 8.12 (m, 1 H) 8.26 (br, s., 1 H) 8.96 (d, J=5.03 Hz, 1 H) 10.25 (hr. s., 1 H) 63cx 1HNMR (400 MHz, MeOH-d4): o ppm 1.33 (t, J=7.15 Hz, 3 H) 1.55 - 1.74 (m, 4 H) 2.04 (dd, J=13.57, 8.79 Hz, 1 H) 2.48 (dd, J=l3.54, 8.76 Hz, 1 H) 3.26 (s, 2 H) 3.44 - 3.73 (m, 4 H) 4.25 - 4.41 (m, 2 I-1) 4.56 (t, J=8.74 Hz, 1 H) 5.57 (s, 1 H) 6.63 (q, J=6.80 Hz, I H) 7.30 (d, J=2.20 Hz, 1 H) 7.47 (dd, J=8.52, 2.22 Hz, 1 H) 7.52 - 7.59 (m, 1 H) 7.59 - 7.65 (m, 1 H) 7.67 (d, J=8.54 Hz, 1 H) 7.90 - 8.04 (m, 1 H) 8.41 (br, s., 1 I-I) 63cy 1HNMR (400 MHz, MeOH-d4): o ppm 1.33 (t, J=7.15 Hz, 3 H) 1.53 - 1.74 (m, 4 H) 2.05 (dd, J=13.57, 8.79 Hz, 1 H) 2.48 (dd, J=13.54, 8.76 Hz, 1 H) 3.23 (s, 3 H) 3.27 (d, J=l.22 Hz, 2 H) 3.42 - 3.79 (rn, 4 H) 4.22 - 4.42 (m, 2 H) 4.57 «. J=8.79 Hz, 1 H) .54 (s, 1 H) 6.61 (q, J=6.72 Hz, 1 H) 7.35 (d, J=2.20 Hz, 1 H) 7.52 (dd, J=8.54, 2.25 Hz, 1 H) 7.72 (d, J=8.54 Hz, 1 H) 7.77 (d, J=7.86 Hz, 2 H) 8.08 - 8.20 (m, 2 H) 63cz 1HNMR (400 MHz, MeOH-d4): o ppm 1.33 (t, J=7.13 Hz, 3 H) 1.54 - 1.72 (m, 4 H) 1.99 - 2.07 (m, 1 H) 2.46 (dd, J=13.57, 8.74 Hz, 1 H) 3.17 - 3.28 (m, 2 H) 3.42 - 3.72 (m, 4 H) 4.26 - 4.39 (m, 2 H) 4.51 (t, J=8.69 Hz, 1 H) 5.53 (s, 1 H) 6.56 - 6.66 (m, 1 H) 7.34 (d, J=2.20 Hz, 1 H) 7.51 (dd, J=8.52, 2.22 Hz, 1 H) 7.67 (d, J=8.00 Hz, 2 H) 7.71 (d, J=8.49 Hz, 1 H) 8.02 - 8.14 (m, 2 H) 63da IH NMR (400 MHz, MeOH-d4): s ppm 0.99 (t, J=7.15 Hz, 3 H) 1.33 (t, J=7 .13 Hz, 3 H) 1.62 - 1.78 (m, 4 H) 2.07 (dd, 1=13.64, 8.86 Hz, 1 H) 2.41 (s, 3 H) 2.50 (dd, 7, 8.79 Hz, 1 H) 3.29 - 3.31 (m, 2 H) 3.55 - 3.84 (m, 4 H) 3.84 - 4.06 (m, 2 H) 4.23 - 4.42 (m, 2 H) 4.60 (t, J=8.81 Hz, 1 H) 6.23 - 6.36 (m, 1 H) 6.43 (d, J=2.34 Hz, 1 H) 6.89 - 7.01 (m, 1 H) 7.40 (dd, J=7.66, 0.93 Hz, 1 H) 7.48- 7.59 (m, 4 H) 7.60 - 7.69 (m, 1 H) 7.86 (dd, J=7.79, 1.24 Hz, 1 H) 7.93 (d, 1=2.34 Hz, 1 H) 63db 1HNMR (400 MHz, MeOH-d4): o ppm 1.30 (t, J=7.15 Hz, 3 H) 1.40 (t, J=7.13 Hz, 3 H) 1.52 - 1.67 (m, 4 H) 2.00 (dd, J=13.59, 8.81 Hz, 1 H) 2.39 (s, 3 H) 2.44 (dd, J=l3.64, 8.76 Hz, 1 H) 3.17 - 3.27 (m, 2 H) 3.41 - 3.73 (m, 4 H) 4.23 - 4.36 (m, 2 H) 4.40 (q, J=7.13 Hz, 2 H) 4.54 (t, J=8.79 Hz, 1 H) 5.78 (s, 1 H) 6.41 (d, J=2.15 Hz, 1 H) 6.92 (q, 1=6.62 Hz, l H) 7.52 (d, J=8.25 Hz, 1 H) 7.58 (t, J=7.74 Hz, 1 H) 7.77 - 7.87 (m, 2 H) 7.88 - 7.97 (rn, 2 H) 8.03 (dt, J=7.79, 1.33 Hz, 1 H) 8.21 (t, J=l.61 Hz, 1 63dc 1HNMR (400 MHz, MeOH-d4): s ppm 1.32 (t, J=7.13 Hz, 3 H) 1.41 (t, J=7.13 Hz, 3 H) 1.56 - 1.69 (m, 4 H) 2.03 (dd, J=13.62, 8.83 Hz, 1 H) 2.41 (s, 3 H) 2.47 (dd, 7, 8.79 Hz, 1 H) 3.26 (s, 2 H) 3.46 - 3.75 (m, 4 H) 4.32 (qd, J=7.15, 2.37 Hz, 2 H) 4.40 (q, J=7.14 Hz, 2 H) 4.57 (t, J=8.79 Hz, 1 H) 5.87 (s, 1 H) 6.43 (d, J=2.34 Hz, 1 H) 6.89 - 7.03 (m, 1 H) 7.55 (d, J=8.30 Hz, I H) 7.68 - 7.79 (m, 2 H) 7.87 (dd, J=8.30, 2.15 Hz, 1 H) 7.94 (d, J=2.34 Hz , 1 H) 7.98 (d, J=l.51 Hz, 1 H) 8.08 - 8.18 (m, 2 H) 63dd 1H NMR (400 MHz, MeOH-d4): o ppm 1.32 (t, J=7.15 Hz, 3 H) 1.50 - 1.71 (m, 4 H) 2.00 (dd, J:=,]3.54, 8.61 Hz, 1 H) 2.38 (s, 3 H) 2.42 (dd, J=l3.59, 8.81 Hz, 1 H) 3.12 - 3.28 (m, 2 H) 3.42 - 3.77 (m, 6 H) 4.21 - 4.39 (m, 2 H) 4.48 (t, J=8.69 Hz, 1 H) 4.69 - 4.79 (m, 1 H) 5.72 (d, J=2.05 Hz, I H) 6.39 (d, J=2.29 Hz, 1 H) 6.77 (q, J=6.54 Hz, 1 H) 7.45 (d, J=I.56 Hz, 1 H) 7.52 (dd, , 1.56 Hz, lH) 7.70 (d, J:==8.15 Hz, 1 H) 7.88 (dd, J=4.37, 2.37 Hz, 1 H) 63de 1H NMR (400 MHz, MeOH-d4): s ppm 1. 22 - 1.29 (m, 3 H) 1.51 (dt, J=l 1.74, 5.65 Hz, 4 H) 1.75 (dd, J=12.98, 7.32 Hz, 1 H) 1.90 (s, 4 H) 2.09 (dd, J=l 3.13 , 8.74 Hz, 1 H) 2.38 (s, 3 H) 2.73 - 2.93 (m,2 H) 3.43 - 3.63 (m, 4 H) 3.85 (dd, J=8.71, 7.39 Hz, 1 H) 4.10 (s, 2 H) 4.13 -4.23 (m, 2 H) 5.70 (s, 1 H) 6.41 (d, J=2.25 Hz, 1 H) 6.78 (q, J:=:6.88 Hz, 1 H) 7.52 (d, J=8.35 Hz, 2 H) 7.66 (d, J=l.71 Hz, 1 H) 7.72 - 7.84 (m, 4 H) 7.97 (d, J=2.34 Hz, 1 H) 63df 1H NMR (400 MHz, MeOH-d4): o ppm 1.33 (dt, J=I0.30, 7.13 Hz, 6 H) 1.50 - 1.69 (m, 4 H) 2.01 (dd, J=13.57, 8.74 Hz, 1 H) 2.40 - 2.45 (m, 1 H), 2.41 (s, 3 H) 3.22 (d, J=2.00 Hz, 2 I-I) 3.44 - 3.74 (m,4 H) 4.21 - 4.36 (m, 4 I-I) 4.52 (t, J=8.74 Hz, 1 H) 5.80 (s, 1 H) 6.43 (d, J=2.29 Hz, 1 H) 6.61 (d, J=16.06 Hz, 1 H) 6.92 (q, 1=6.65 Hz, 1 H) 7.49 - 7.56 (m, 2 H) 7.61 - 7.70 (m, 2 H) 7.72 - 7.80 (m, 2 H) 7.83 (dd, , 2.17 Hz, 1 H) 7.94 (dd, J=6.39, 1.85 Hz, 2 H) 63dg 1H NMR (400 MHz, MeOH-d4): o ppm 1.26 - 1.39 (m, 6 H) 1.52 - 1.63 (m, 4 H) 1.94 (dd, J=13.50, 8.32 Hz, 1 H) 2.34 (dd, J=13.40, 8.76 Hz, 1 H) 2.40 (s, 3 H) 3.04 - 3.20 (rn, 2 H) 3.44 - 3.69 (m, 4 H)4.21 - 4.31 (m, 4 H) 4.34 (t, J=8.54 Hz, 1 H) 5.78 (s, I H) 6.42 (d, J=2.20 Hz, I I-I) 6.58 (d, J=16.06 Hz, 1 H) 6.92 (q, J=6.67 Hz, 1 H) 7.51 (d, J=8.25 Hz, 1 H) 7.62 - 7.77 (m, 5 H) 7.82 (dd, J=8.30,2.15 Hz, 1 H) 7.93 (d, J=2.34 Hz, 1 H) 7.97 (d, J=l.27 Hz, 1 H) 63dh 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.18 (t, J='7.13 Hz, 3 H) 1.32 (t, J=7.15 Hz, 3 H) 1.54 - 1.68 (m, 4 H) 2.03 (dd, J=l3.62, 8.83 Hz, 1 H) 2.40 (s, 3 H) 2.46 (dd, J=13.59, 8.76 Hz, 1 H) 2.68 (t, J=7.47 Hz, 2 H) 3.01 (t, J=7.49 Hz, 2 H) 3.25 (s, 2 H) 3.45 - 3.75 (m, 4 H) 4.10 (q,J=7.13 Hz, 2 H) 4.25 - 4.40 (m, 2 H) 4.57 (t, J=8.79 Hz, 1 H) 5.82 (s, 1 H) 6.42 (d, J=2.25 Hz, 1 H) 6.88 (q, J=6.70 Hz, 1 H) 7.27 (d, 1=7.42 Hz, 1 H) 7.36 - 7.42 (m, 1 H) 7.42 - 7.47 (m, 2 H) 7.50 (d, J=8.30 Hz, 1 H) 7.79 (dd, J=8.27, 2.12 Hz, 1 H) 7.88 - 7.94 (m, 2 H) 63di 1H NMR (400 MHz, Me0H-d4): 8 ppm 1.22 (t, J=7.13 Hz, 3 H) 1.32 (t, J=7.15 Hz, 3 H) 1.53 - 1.72 (rn , 4 H) 2.03 (dd, J=13.62, 8.83 Hz, 1 H) 2.40 (s, 3 H) 2.47 (dd, 9, 8.76 Hz, 1 H) 2.67 (t, J=7.57 Hz, 2 H) 2.92 - 3.03 (m, 2 H) 3.25 (s, 2 H) 3.45 - 3.80 (m, 4 H) 4.11 (q, J=7.13 Hz, 2 H) 4.32 (qd, J=7.13, 2.32 Hz, 2 H) 4.57 (t, J=8.79 Hz, 1 H) 5.84 (s, 1 H) 6.41 (d, J=2.34 Hz, l H) 6.87 (q, 1=6.57 Hz, 1 H) 7.34 (d, J=8.25 Hz, 2 H) 7.49 (d, J=8.30 Hz, l H) 7.53 (d, J=8.25 Hz, 2 H) 7.78 (dd, J:==8 .30, 2.15 Hz, 1 H) 7.90 (d, J=2.24 Hz, 2 H) 63dj 1H NMR (400 MHz, MeOH-d4): 6 ppm 1.20 - 1.35 (m, 3 H) 1.42 - 1.60 (m, 4 H) 1.68 - 1.83 (m, 1 H) 1.99 - 2 .15 (m, 1 H) 2.42 (s, 3 H) 2.75 (d, J=l0.93 Hz, 1 H) 2.89 (d, J=l0.93 Hz, 1 H) 3.55 (d, 1=5.86 Hz, 4 H) 3.82 (s, I H) 4.20 (dd, J:==7.13, 1.27 Hz, 2 H) 5.74 (s, I H) 6.44 (d, J== 2.15 Hz, 1 H) 6.85 (d, J=6.64 Hz, 1 H) 7.04 - 7.24 (m, I H) 7.39 - 7.53 (m, 3 H) 7.67 (d, J=l.56 Hz, 1 I- 1) 7.76 (d, J=l.76 Hz, 1 H) 7.79 - 7.88 (m, 1 H) 8.01 (d, J=2.15 Hz, I H) 63dk 1H NMR (400 MHz, Me0H-d4): 15 ppm 1.28 (t, J=7.13 Hz, 3 H) 1.42 - 1.63 (m, 4 H) 1.69 - 1.82 (m, 1 H) 2.01 -2.16 (m, 1 H) 2.44 (s, 3 H) 2.77 (s, 1 H) 2.89 (s, 1 H) 3.57 (d, J=5.86 Hz, 4 H) 3.76 - 3.89 (m, 1 H) 4.19 (dd, J=7.22, 1.37 Hz, 2 H) 5.78 (s, 1 H) 6.46 (d, J=2.15 Hz, 1 H) 6.78 - 6.96 (m, 1 H) 7.53 - 7.65 (m, 1 H) 7.79 - 7.98 (m, 3 H) 8.06 (d, J=2.34 Hz, 1 H) 8.14 (s, 2 H) 8.28 (s, 1 I- 1) 8.40 - 8.52 (m, 1 H) 8.80 - 8.96 (m, 1 H) 63dl 1HNMR(400 MHz, MeOH-d4): 8 ppm 1.32 (t, J=7.13 Hz, 3 H) 1.51 - 1.68 (m, 4 H) 1.96 -2.06 (m, 1 H) 2.39 (s, 3 H) 2.43 (dd, J=13.54, 8.81 Hz, I H) 3 . 15 - 3.27 (m, 2 H) 3.43 - 3.72 (m, 4 H) 4.26 - 4.36 (rn , 2 H) 4.39 - 4.45 (m, I H) 4.49 (t, J:== 8.69 Hz, 1 H) 4.90 (t, 1=8.44 Hz, 1 H) 5.70 (d, J=2.83 Hz, I H) 5.87 (td, J=7.86, 1.66 Hz, 1 H) 6.42 (d, J=2.34 Hz, 1 H) 6.79 - 6.91 (m, 1 H) 7.52 (t, J=l.85 Hz, 1 H) 7.58 (dt, 1=8.20, 2.17 Hz, l H) 7.82 (dd, 1=8.27, 1.54 Hz, 1 H) 7.95 (dd, , 2.61 Hz, 1 H) 63dm 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.29 (t, J=7.13 Hz, 3 H) 1.43 - 1.62 (m,4 H) 1. 70- 1.83 (m, I H) 2.03 - 2.18 (m, 1 H) 2.79 (s, 1 I- 1) 2.90 (s, 1 H) 3.09 (s, 2 H) 3.17 (s, 3 H) 3.54 (br. s., 4 H) 3.65 (t, J=6.74 Hz, 2 H) 3.80 - 3.96 (m, 1 H) 4.21 (d, 1=7.03 Hz, 2 H) 5.57 (s, 1 H) 6.60 - 6.76 (m, 1 H) 7.52 (s, 1 H) 7.56 - 7.67 (m, 3 H) 7.68 - 7.79 (m, 2 H) 8.01 (d, J=8.20 Hz, l H) 63dn 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.28 (t, J=7.13 Hz, 3 H) 1.55 (dt, J=l 1.03, .37 Hz, 4 H) 1.89 (dd, J=13.32, 8.10 Hz, 1 H) 1.96 (s, 3 H) 1.97 (s, 3 H) 2.28 (dd, 1=13.40, 8.86 Hz, 1 H) 2.36 (s, 3 H) 2.97 -3.11 (m, 2 H) 3.41 - 3.68 (m, 4 H) 4.18 - 4.30 (m, 3 H) 4.39 (s, 2 H) 5.69 (s, 1 H) 6.37 (d, J=2.34 Hz, 1 H) 6.73 (q, J=6.30 Hz, 1 H) 7 .31 (d, J= 1.51 Hz, 1 H) 7.40 (dd, J=8.13, 1.59 Hz, 1 H), 7.67 (d, J=8.05 Hz, 1 H), 7.85 (d, J=2.25 Hz, 1 H) 63do 1HNMR (400 MHz, MeOH-d4): 8 ppm 1.31 (t, J=7.15 Hz, 3 H) 1.55 - 1.68 (m, 4 H) 1.97 (s, 1 H) 2.02 (dd, J=13.59, 8.96 Hz, 1 H) 2.12 (ddt, J=13.30, 7.49, 5.74, 5.74 Hz, 1 H) 2.39 (s, 3 H) 2.46 (dd, 1=13.57, 8.64 Hz, 1 H) 2.65 - 2.77 (m, 1 H) 2.91 (dt, J=13.74, 7.04 Hz, 1 H) 3.04 - 3.14 (m, 1 H) 3.24 (d, J=l.76 Hz, 2 H) 3.45 - 3.76 (m, 6 H) 3.81 (dd, J==8.52, 5.88 Hz, I H) 4.25 - 4.45 (m, 4 H) 4.55 (t, J=8.79 Hz, l H) 5.81 (s, 1 H) 6.41 (d, J=2.29 Hz, 1 H) 6.82 (q, 1=6.65 Hz, 1 H) 7.71 (s, 1 H) 7.77 - 7.84 (rn, 4 H) 7.90 - 8.01 (m, 3 H) 63dp 1H NMR (400 MHz, 4): o ppm 1.33 (t, 1=7.13 Hz, 3 H) 1.54 - 1.75 (m, 4 H) 2.02 (dd, J=13.57, 8.69 Hz, 1 H) 2.28 (s, 3 H) 2.31 (s,3 H) 2.45 (dd, J=13.54, 8.76 Hz, 1 H) 3.20 - 3.27 (m, 2 H) 3.23 (s, 3 H) 3.42 - 3.79 (m, 4 H) 4.32 (qd, J=7.13, 2.54 Hz, 2 H) 4.51 «. J=8.69 Hz, 1 H) 5.63 (s, 1 H) 6.63 (q, 1=6.64 Hz, 1 H) 7.19 (d, J=7.86 Hz, 1 H) 7.36 (dd, J=7.76, 1.76 Hz, 1 H) 7.41 (s, 1 H) 7.48 (d, J=l.81 Hz, 1 H) 7.65 - 7.72 (m, 1 H) 7.72 - 7.77 (m, 1 H) 7.80 - 7.85 (m, 2 H) 8.07 (dt, J=7.03, 1.93 Hz, 1 H) 8.47 (br, s., 1 H) 63dq 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.32 (t, J=7.13 Hz, 3 H) 1.53 - 1.73 (m, 4 H) 1.93 - 2.08 (m, 1 H) 2.41 (dd, J=13.45, 8.71 Hz, I H) 3. 1 1 - 3.23 (m, 2 H) 3.24 (s, 3 H) 3.46 - 3.79 (m, 4 H) 4.30 (qd, J=7.12, 2.46 Hz, 2 H) 4.43 (t, J=8.59 Hz, 1 H) 5.65 (s, 1 H) 6.67 (q, J=6.64 Hz, 1 H) 7.56 (dd, J=8.32, 4.32 Hz, 1 H) 7.70 (d, J=1.76 Hz, 1 H) 7.78 - 7.97 (m, 4 H) 8.07 8 8. 12 (m, 3 H) 8.23 (s, 1 H), 8.42 (dd, , 1.61 Hz, 1 H) 8.53 (br. s., 1 H) 8.85 (dd, J=4.32, 1.68 Hz, 1 H) 63dr 1H NMR (400 MHz, MeOH-d4): o ppm 1.32 (t, J=7.13 Hz, 3 H) 1.51 - 1.71 (m, 4 H) 1.99 - 2.08 (m, 1 H) 2.40 (s, 3 H) 2.41 (s, 3 H) 2.46 (dd, J=13.62, 8.74 Hz, I H) 3.25 (d, J=l.07 Hz, 2 H) 3.43 - 3.77 (m, 4 H) 4.32 (qd, J=7.13, 2.32 Hz, 2 H) 4.57 (t, J=8.79 Hz, 1 H) 4.68 (s, 2 H) 5.85 (s, 1 H) 6.42 (d, J=2.25 Hz, 1 H) 6.88 (q, J=6.65 Hz, 1 H) 7.34 - 7.54 (m, 4 H) 7.79 (dd, J=8.27, 2.12 Hz, 1 H) 7.91 (d, J=2.25 Hz, 2 H) 63ds 1H NMR (400 MHz, MeOH-d4): s ppm 1.32 (t, J=7.15 Hz, 3 H) 1.55 - 1.77 (m, 4 H) 2.04 (dd, J=9.32, 4.30 Hz, 1 H) 2.37 (s, 3 H) 2.40 (s, 3 H) 2.48 (dd, J=l3.62, 8.79 Hz, 1 H) 3.28 (s, 2 H) 3.50 - 3.87 (m, 4 H) 4.19 - 4.42 (m, 2 H) 4.59 (t, J=8.79 Hz, I H) 4.71 (s, 2 H) 6.14 (br. s., 1 H) 6.42 (d, J=2.34 Hz, 1 H) 6.91 (q, J=6.41 Hz, 1 H) 7.28 (d, J=7.91 Hz, 1 H) 7.44 (dd, J=7.76, 2.05 Hz, 1 H) 7.51 (d, J=8.25 Hz, 1 H) 7.65 (d, J=l.81 Hz, 1 H) 7.85 (dd, J=8.27, 2. 12 Hz, 1 H) 7.88 - 7.96 (m, 2 H) 63dt 1HNMR (400 MHz, MeOH-d4): o ppm 1.32 .13 Hz, 3 H) 1.52 - 1.71 (m, 4 H) 1.98 - 2.08 (m, 1 H) 2.41 (s, 3 H) 2.45 (dd, J=13.62, 8.79 Hz, 1 H) 3.24 (d, J=l.61 Hz, 2 H) 3.42 - 3.73 (m, 4 H) 3.93 (s, 3 H) 4.24 - 4.40 (m, 2 H) 4.54 (t, J=8.76 Hz, 1 H) .78 (s, 1 H) 6.43 (d, J=2.29 Hz, 1 H) 6.95 (q, J=6.62 Hz, 1 H) 7.54 (d, J=8.30 Hz, 1 H) 7.67 - 7.77 (m, 2 H) 7.85 (dd, J=8.30, 2.20 Hz, 1 H) 7.94 (d, J=2.34 Hz, 1 H) 7.98 (d, J=l.37 Hz, 1 H) 8.07 - 8.16 (m, 2 H) 63du 1H NMR (400 MHz, Me0H-d4): o nnm 1.29 (t, J=7.13 Hz, 3 H) 1.46 - 1.67 (m, 4 H) 1.90 (dd, J=13.35, 8.22 Hz, 1 H) 2.30 (dd, J=13.35, 8.71 Hz, 1 H) 2.40 (s, 3 H) 2.93 - 3.16 (m, 2 H) 3.38 - 3.74 (m, 4 H) 4.16 - 4.36 (m, 3 H) 5.77 (s, 1 H) 6.41 (d, J=2.29 Hz, 1 H) 6.91 (q, 1=6.62 Hz, 1 H) 7.51 (d, J=8.25 Hz, 1 H) 7.64 (d, J=8.40 Hz, 2 H) 7.82 (dd, J=8.30, 2.15 Hz, 1 H) 7.93 (d, 1=2.29 Hz, 1 H) 7.96 (s, 1 H) 8.07 (d, J=8.30 Hz, 2 H) 63dv 1H NMR (400 MHz, Me0H-d4): s ppm 1.35 (s, 4 H) 1.60- 1.76 (m, 3 H) 2.02 -2.13 (m, 1 H) 2.43 (s, 3 H) 2.46 - 2.56 (m, 1 H) 3.30 (s, 2 H) 3.53 - 3.83 (rn, 4 H) 4.30 - 4.40 (m, 2 H) 4.56 - 4.66 (m, 1 H) 5.48 (s, 2 H) 6.01 - 6.11 (m, I H) 6.44 - 6.50 (m, 1 H) 6.89 - 6.98 (m, 1 H) 7.80 - 7.84 (m, 1 H) 7.86 - 8.02 (m, 5 H) 8.03 - 8.08 (m, l H) 63dw 1H NMR (400 MHz, MeOH -d4): o ppm 1.28 (t, J=7 .13 Hz, 3 H) 1.55 (hr. s., 4 H) 1.70 - 1.83 (m, 1 H) 2.03 - 2.18 (m, 1 H) 2.70 - 2.82 (m, 1 H) 2.86 - 2.97 (m, 1 H) 3.41 - 3.59 (m, 4 H) 3.79 - 3.94 (m, 1 H) 4.09 - 4.30 {m, 2 H) 5.59 (s, 1 H) 6.60 - 6.77 (m, 1 H) 7.71 (d, J=8.20 Hz, 2 H) 7.84 (d, J=8.20 Hz, 2 H) 8.03 - 8.15 (m, 1 H) 8.34 (s, 2 H) 9.26 (s, 1 H) 9.59 (s, 1 H) 63dx 1HNMR (400 MHz, Chloroform-d) : o ppm 1.27 (m, 7H), 1.55 (m, 3H), 1.77 (dd, 1 = 13.1, 7.0 Hz, 1H), 2.11 (dd, J = 1 3 .1, 8.9 Hz, lH), 2.42 (s, 3H), 2.96 (m, 2H), 3.47 (dt, J = 1 1 . 6 , 5.7 Hz, 4H), 3.98 (dd, J = 8 .8, 6.9 Hz, lH), 4.21 (q, J = 7.1 Hz, 2H), 4.73 (s, 2H), 5.49 (s, lH), 5.99 (m, lH), 6.35 (d, J = 2.3 Hz, IH), 6.63 (q, J = 6.7 Hz, 1H), 7.61 (m, 2H), 7.73 (d, J = 2.3 Hz, lH), 7.88 (d, J = 8.3 Hz, lH), 8.96 (s, 2H), 9.24 (s, 63dy 1H NMR (400 MHz, MeOH-d4): s ppm 1.27 (m, 8H), 1.51 (dt, J = 10.8, 5.6 Hz, 8H), 1.74 (dd, J = 1 3 .1 , 7.3 Hz, 2H), 2.06 (m, 2H), 2.39 (s, 6H), 2.75 (d, J = 11.0 Hz, 2H), 2.89 (d, J = 11.0 Hz, 2H), 3.53 (dt, J = 22.5, 6.4 Hz, 8H), 3.82 (dd, J = 8.8, 7.2 Hz, 2H), 4.18 (qd, J = 7.1, 1.6 Hz, 3H), 5.73 (s, 2H), 6.00 (m, 1H), 6.42 (d, J = 2.4 Hz, 2H), 6.82 (q, J = 6.6 Hz, 2H), 7.35 (dt, J = 10.4, 8.4 Hz, 2H), 7.50 (m, 2H), 7.73 (111, 8H), 8.00 (d, J = 2A Hz, 2H) 63dz 1HNMR (400 MHz, Me0H-d4): s ppm 1.26 (t, J = 7.1 Hz, 3H), 1.50 (dt, J = 10.6, 5.6 Hz, 4H), 1.73 (dd, J = 13 . l , 7.2 Hz, lH), 2.07 (dd, J = 13 . 1 , 8.8 Hz, lH), 2.39 (s, 3H), 2.74 (d, J = 1 1 .0 Hz, IH), 2.88 (d, J = 11.0 Hz, lH), 3.52 (dq, J = 23.8, 7.6, 6.5 Hz, 4H), 3 .81 (dd, J = 8.8, 7.1 Hz, 1 H), 4.17 (qd, J = 7.1 , 1.6 Hz, 2H) , 5.73 (s, IH), 6.41 (d, J = 2.4 Hz, lH), 6.80 (q, J = 6.5 Hz, l H), 7.46 (m, 2H), 7.71 (m, SH), 7.98 (d, J = 2.3 Hz, lH) 63ea 1H NMR (400 MHz, DMSO-d6): o ppm 1.25 (t, J=7.10 Hz, 3 H) 1.42 - 1 .69 (m, 4 H) 1.92 (dd, 5, 9.35 Hz, 1 H) 2.35 (dd, J=13.25, 8.47 Hz, 1 H) 3.14 (br, s., 2 H) 3.60 (br. s., 4 H) 4.24 (qd, J=7.09, 2.10 Hz, 2 H) 4.54 (br. s., 1 H) 5.77 (br, s., 1 H) 6.70 (q, J=6.65 Hz, 1 H) 7.37 (d, J=2.10 Hz, 1 H) 7.43 - 7.52 (m, 3 H) 7.53 - 7.69 (m, 4 H) 9.23 (br. s., 1 H) 10.44 (br. s., 1 H) 63eb 1H NMR (400 MHz, MeOH-d4): s ppm 1.25 (t, J == 7.1 Hz, 4H), 1.49 (dt, J = 10.6, .6 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, IH), 2.06 (dd, J = 13. l, 8.8 Hz, IH), 2.39 (s, 3H), 2.74 (d, J = 11. 0 Hz, 1H) , 2.88 (d, J = 11.0 Hz, lH), 3.50 (rn, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, l H), 4.17 (qd, J = 7.1, 1.5 Hz, 21-l ), 5. 76 (s, lH), 6.41 (d, J = 2.4 Hz, IH), 6.89 (q, J = 6.6 Hz, IH), 7.51 (m, 6H), 7.76 (dd, J = 8.3, 2.2 Hz, lH), 7.92 (t, J = 2.2 Hz, 2H) 63ec 11-I NMR (400 MHz, MeOH-d4): s ppm 1.26 (t, J = 7.1 Hz, SH), 1.51 (dt, J = 10.1, 5.3 Hz, 4H), 1.77 (dd, J = 13.1, 7.4 Hz, 1H), 2.12 (dd, J = 13.2, 8.8 Hz, lH), 2.39 (s, 3H), 2.80 (d, J = 11.1 Hz, lH), 2.93 (d, J = 11. l Hz, lH), 3.53 (m, 4H), 3.91 (t, J = 8.0 Hz, lH), 4.19 (qd, J = 7.2, 1.7 Hz, 2H), 5.77 (s, lH), 6.41 (d, J = 2.3 Hz, 11-I), 6.91 (q, J = 6.6 Hz, IH), 7.37 (ddt, J = 16.6, 10.3, 8.6 Hz, 2H), 7.51 (m, 2H), 7.76 (dd, J = 8.3, 2.2 Hz, lH), 7.91 (dd, J = 9.9, 2.4 Hz, 2H) 63ed 1H NMR (400 MHz, MeOH-d4): s ppm 1.26 (m, 6H), 1.50 (dt, J = 10.4, 5.4 Hz, SH), 1.73 (dd, J = 13.1, 7.2 Hz, lH), 2.06 (m, IH), 2.39 (s, 3H), 2.74 (d, J = 11.0 Hz, lH), 2.88 (d, J = 11.0 Hz, nn, 3.53 (m, SH), 3.81 (dd, J = 8.7, 7.1 Hz, lH), 4.17 (qd, J = 7.1, 1.5 Hz, 2H), 5.77 (s, lH), 6.41 (d, J = 2.4 Hz, IH), 6.87 (q, J = 6.7 Hz, lH), 7.44 (m, 4H), 7.60 (m, 3H), 7.78 (dd, J = 8.3, 2.1 Hz, lH), 7.92 (t, J = 2.6 Hz, 2H) 63ee 11-I NMR (400 MHz, MeOH-d4): s ppm 1.27 (q, J = 8.3, 7.1 Hz, 6H), 1.49 (m, 4H), 1.72 (dd, J = 13.1, 7.2 Hz, HI), 2.06 (dd, J = 13.1 , 8.8 Hz, lH), 2.39 (s, 3H), 2.74 (d, J = 11 .0 Hz, IH), 2.88 (d, J = 11 . 0 Hz, lH), 3.50 (m, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, lH), 4.18 (qd, J = 7.1, 1.5 Hz, 2H), 5.77 (s, l H), 6.41 (d, J = 2.5 Hz, lH), 6.93 (q, J = 6.6 Hz, lH), 7.50 (m, 2H), 7.59 (d, J = 8.3 Hz, lH), 7.73 (m, 2H), 7.92 (dd, J = 7.7, 2.3 Hz, 2H) 63ef 1H NMR (400 MHz, MeOH-d4): o ppm 1.28 (t, J = 7.1 Hz, SH), 1.54 (tt, J = 7.3, 4.4 Hz, 4H), 1.80 (dd, J = 13.2, 7.6 Hz, l H), 2 .17 (dd, J = 13.2, 8.8 Hz, IH), 2.85 (d, J = 11.2 Hz, lH), 2.97 (d, J = 11.2 Hz, lH), 3.52 (ddt, J = 28.3, 12.4, 8.0 Hz, 4H), 3.97 (dd, J = 8.8, 7.5 Hz, lH), 4.21 (qd, J = 7.1, 1.7 Hz, 2H), 5.50 (s, 1H), 6.68 (q, J = 6.9 Hz, HI), 7.25 (m, 4H), 7.48 (m, 3H), 7.71 (m, lH) 63eg 1H NMR (400 MHz, MeOH-d4): s ppm 1.26 (t, J = 7.3 Hz, 4H), 1.51 (dt, J = 11.2, 5.5 Hz, 4H), 1.75 (dd, J = 13. r, 7.3 Hz, 1 H), 2.10 (dd, J = 13.1, 8.8 Hz, lH), 2.40 (s, 3H), 2.78 (d, J = 11.1 Hz, IH), 2.91 (d, J = , lH), 3.53 (m, SH), 3.86 (dd, J = 8.6, 7.4 Hz, lH), 4.18 (qd, J = 7.1 , 1.6 Hz, 2H), 5.77 (s, IH), 6.44 (d, J = 2.4 Hz, lH), 7.00 (q, J = 6.7 Hz, lH), 7.62 (d, J = 8.3 Hz, lH), 7.97 (m, 3H), 9.06 (s, 2H), 9. 17 (s, lH) 63eh 1H NMR (400 MHz, MeOH-d4): o ppm 1.26 (t, J = 7 .1 Hz, 4H), 1.52 (dq, J = 12.0, 8.6, 7.2 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, lH), 2.09 (dd, J = 13.1, 8.8 Hz, lH) , 2.75 (d, J = 11.0 Hz, IH), 2.90 (d, J = 11.0 Hz, IH), 3.51 (m, 4H), 3.82 (dd, J = 8.7, 7 .1 Hz, lH), 4.18 (qd, J = 7.1 , 1.6 Hz, 2H) , 5.52 (s, lH), 6.61 (q, J = 6.7 Hz, lH), 7.33 (m, 2H), 7.47 (m, 2H), 7.66 (m, 2H) 63ei 1H NMR (400 MHz, MeOH-d4): s ppm 1.26 (td, J = 7.1, 1.7 Hz, 6H), 1.41 (td, J = 7.0, 1.8 Hz, 3H), 1.52 (qd, J = 7.2, 4.7, 3.6 Hz, 4H), 1.75 (dd, J = 13 .1 , 7.3 Hz, lH), 2.10 (dd, J = 13.1 , 8.8 Hz, lH), 2.77 (d, J = 10.9 Hz, lH), 2.91 (d, J = 1 1.0 Hz, lH), 3.29 (s, IH), 3.51 (dq, J= 18.9, 6.1 Hz, 4H), 3.84 (m, l H), 4.16 (m, 3H), 5.48 (d, J = 2.0 Hz, lH), 6.73 (q, J = 6.8 Hz, lH), 7.02 (m, 2H), 7.20 (s, lH), 7.28 (d, J = 2.2 Hz, lH), 7.43 (m, 2H), 7.67 (d, J = 8.4 Hz, lH) 63ej 1H NMR (400 MHz, MeOH-d4): s ppm 1.26 (m, 4H), 1.50 (dt, J = 22.1, 6.5 Hz, 7H), 1.74 (dd, J = 13. 1 , 7.2 Hz, lH), 2.08 (dd, J = 13.1, 8.8 Hz, lH), 2.75 (d, J = 11.0 Hz, lH), 2.90 (d, J = 11.0 Hz, lH), 3.31 (d, J: 1.8 Hz, lH), 3.49 (dq, J = 25.8, 7.5, 6.6 Hz, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, lH), 4 .18 (m, 4H), 5.49 (s, lH), 6.62 (q, J = 6.8 Hz, lH), 7.20 (d, J = 8.5 Hz, lH), 7.26 (d, I =2.2 Hz, lH), 7.34 (m, lH), 7.42 (dd, J: 8.5, 2.2 Hz, IH), 7.58 (m, lH), 7.65 (d, J = 8.5 Hz, lH) 63ek 1H NMR (400 MHz, MeOH-d4): s ppm 1.26 (t, J = 7.0 Hz, 4H), 1.53 (m, 4H), 1.75 (dd, J = 13 . 1 , 7.2 Hz, lH), 2.10 (dd, J = 13.1, 8.7 Hz, IH), 2.76 (d, J = 10.9 Hz, lH), 2.90 (d, J = 11.0 Hz, II-I), 3.51 (dq, J = 26.1, 7.5, 6.6 Hz, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, lH), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.53 (s, lH), 6.59 (q, J = 6.7 Hz, IH), 7.27 (d, J = 8.8 Hz, IH), 7.34 (rn, 2H), 7.49 (m, 2H), 7.69 (d, J = 8.5 Hz, lH) 63el 1H NMR (400 MHz, MeOH-d4): s ppm 0.89 (m, 2H), 1.31 (m,15H), 1.52 (dt, J = 7.9, 4.5 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, lH), 2.09 (dd, J = 13.1, 8.8 Hz, lH), 2.75 (d, J = I 1.0 Hz, lH), 2.89 ( d, J= 11.0 Hz, 1 H), 3.49 ( ddt,J = 17.6, 11.8, 6.7 Hz, 4H), 3 .82 (dd, J = 8.7, 7.2 Hz, lI-I), 4.18 (qd, J = 7.2, 1.5 Hz, 2H), 5.44 (s, lH), 6.60 (q, J = 6.8 Hz, lH), 7.28 (m, 2H), 7.47 (m, 4H), 7.67 (d, J = 8.5 Hz, 1 H) 63em 1HNMR (400 MHz,MeOH-d4): o ppm 1.26 (m, 6H), 1.53 (m,4H), 1.75 (dd,J= 13.1, 7.2 Hz, lH), 2.10 (dd, J = 13.1, 8.7 Hz, IH), 2.76 (d, J = 10.9 Hz, lH), 2.91 (d, J = 11.0 Hz, lH), 3.52 (m, 4H), 3.83 (dd, J= 8.8, 7.2 Hz, IH), 4.18 (qd, J =7.1, 1.7 Hz, 2H), 5.53 (s, IH), 6.47 (q, J = 6.7 Hz, lH), 7.36 (d, J = 2.2 Hz, lH), 7.53 (dd, J = 8.6, 2.3 Hz, lH), 7.72 (m, 2H), 7.85 (m, 2H) 63en 1H NMR (400 MHz, MeOH-d4): s ppm 1.30 (t, J = 7.1 Hz, 7H), 1.59 (dt, J = 11.5, 5.7 Hz, SH), 1.95 (m,2H), 2.34 (dd, J = 13.3, 8.6 Hz, 2H) , 3.10 (m, 4H), 3.56 (m, 8H), 3.75 (s, l H), 4.28 (m, 6H), 5.55 (s, lH), 6.52 (q, J = 6.7 Hz, 2H), 7.38 (d, J = 2.2 Hz, 2H), 7.53 (dd,J = 8.5, 2.2 Hz, 2H), 7.66 (m, 8H) 63eo 1H NMR ( 400 MHz, Me0H-d4): 8 ppm 1.26 (td, J = 7 .0, 0.7 Hz, 4H), 1.53 , 1.75 (dd,J= 13.1 , 7.3 Hz, IH), 2.09 (dd,J = 13.1, 8.7 Hz, IH), 2.76 (d, J = 11.0 Hz, IH), 2.90 (d, J= 11. 0 Hz, lH), 3.30 (m, lH) , 3.51 (dtd, J = 19.2, 13.4, 7.5 Hz, 4H), 3.82 (dd, J= 8.7, 7.2 Hz, lH), 4.18 (m, 2H), 5.50 (s, lH), 6.63 (q, J = 6.9 Hz, IH), 7.25 (m, lH) , 7.47 (m, 6H), 7.71 (m, lH) 63ep 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.33 (t, J = 7.1 Hz, 4H), 1.65 (m, SH), 2.06 (dd, J = 13.6, 8.9 Hz, lH), 2.50 (dd, J = 13.6, 8.8 Hz, 1H), 3.28 (s, 2H), 3.57 (m, 5H), 3.86 (s, 3H), 4.32 (qd, J = 7.2, 2.5 Hz, 2H), 4.59 (t, J = 8.8 Hz, 1 H), 6.68 (q, J = 6.7 Hz, lH), 6.98 (d, J = 7.5 Hz, IH), 7.07 (m, 2H), 7.32 (d, J = 2.2 Hz, lH), 7.46 (m, 2H), 7.68 (d, J = 8.5 Hz, lH) 63eq 1H NMR (400 MHz, MeOH-d4): s ppm 1 .31 (m, lOH), 1.52 (m, 4H), 1.74 (dd, J = 13.1 , 7.2 Hz, lH), 2.09 (dd, J = 13.1 , 8.7 Hz, lH), 2.75 (d, J = 1 1 . 0 Hz, lH), 2.90 (d, J = 11.0 Hz, 1H), 3.50 (m,4H), 3.83 (dd, J = 8.7, 7.2 Hz, lH), 4.18 (qd, J = 7.1 , 1.5 Hz, 2H), 4.70 (h, J = 6.1 Hz, IH), 5.48 (s, HI), 6.73 (q, J = 6.9 Hz, lH), 6.95 (d, J = 7.6 Hz, lH), 7.04 (m, lH), 7.21 (s, lH), 7.27 (d, J = 2.3 Hz, lH), 7.42 (m, 2H), 7.66 (d, J = 8.5 Hz, lH) 63er 1H NMR (400 MHz, MeOH-d4): o ppm 1.26 (td, J = 7.1 , 1.4 Hz, 3H), 1.54 (m, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, lH), 2 .10 (dd, J = 13.1 , 8.7 Hz, IH), 2.46 (s, 3H), 2.76 (d, J = 10.9 Hz, lH), 2.91 (d, J = 11.0 Hz, lH), 3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, lH), 4 .18 (qd,J= 7.2, 1.6 Hz, 2H), 5.50 (d,J = 1 .5 Hz, lH), 6.60 (q, J = 6.8 Hz, lH), 7.29 (m, 2H), 7.45 (m, 2H), 7.57 (s, lH), 7.67 (m, lH) 63es 1H NMR (400 MHz, Me0H-d4): s ppm: 1. I 9 (s, 2H), 1.34 (m, l lH), 1.53 (m, 4H), 1.75 (dd,J= 1 3 .1 , 7.2 Hz, lH), 2 .10 (dd, J = 13.1, 8.8 Hz, lH), 2.76 (d, J = 11.0 Hz, lH), 2.91 (d, J = 1 1.0 Hz, II- I), 3.52 (rn, 4H), 3.83 (m, lH), 4 .18 (m, 2H), 4.73 (h, J = 6.1 Hz, lH), 5.50 (s, lH), 6.62 (q, J = 6.6 Hz, IH), 7.28 (m, 3H), 7.43 (dd, J = 8.5, 2.3 Hz, lH), 7.59 (s, lH), 7.65 (d, J = 8.5 Hz, lH) 63et 1H NMR (400 MHz, MeOH-d4): 8 ppm 0.88 (d, J = 8.3 Hz, HI), 1.30 (m, 1 HI), 1.53 (m, 4H), 1.75 (dd, J = 13.1 , 7.2 Hz, lH), 2.10 (dd,J = 13. 1, 8.8 Hz, lH), 2.76 (d, J= 1 1. 0 Hz, IH), 2.91 (d, J = 11.0 Hz,lH) , 3.52 (m, SH), 3.83 (dd, J = 8.7, 7.2 Hz, lH), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 4.71 (h, J = 6.2 Hz, lH), 5.49 (s, lH), 6.66 (q, J = 6.8 Hz, lH), 7.27 (m, 4H), 7.43 (dd, J = 8.5, 2.3 Hz, 1 H), 7.65 (rn, lH) 63eu 1H NMR (400 MHz, MeOH-d4): s ppm 1.30 (m, 4H), 1.60 (tt, J = 9.2, 4.2 Hz, 4H), 1.97 (m, lH), 2.37 (dd, J = 13.6 , 8.8 Hz, lH), 3.14 (q, J = 1 1 . 6 Hz, 2H), 3.56 (m, 4H), 4.31 (m, 3H), 4.87 (d, J = 1.7 Hz, 18H), 5.54 (s, lH), 6.49 (q, J = 6.6 Hz, lH), 7.35 (d, J = 2.2 Hz, lH), 7.51 (dd, J = 8.5, 2.2 Hz, lH), 7.68 (d, J = 8.6 Hz, IH), 7.82 (m, 3H) 63ev 1H NMR (400 MHz, Me0H-d4): s ppm 1.27 (m, 4H), 1.54 (m, 4.H), 1.78 (dd, J = 13.1, 7.4 Hz, lH), 2.13 (dd, J = 13.1, 8.8 Hz, IH), 2.81 (d, J = 1 1 . 1 Hz, lH), 2.93 (d, J = 11.0 Hz, lH), 3.53 (dq, J = 13.2, 6.0 Hz, 4H), 3.89 (dd, J = 8.8, 7.3 Hz, 11-l), 4.20 (qd, J = 7.1, 1.7 Hz, 2H), 5.51 (s, IH), 6.63 (q, J = 6.7 Hz, l H), 7.28 (m, 4H), 7.52 (m, 2H), 7.68 (d, J = 8.5 Hz, lH) 63ew 1H NMR (400 MHz, MeOH-d4): s ppm 0.90 (d, J = 8.0 Hz, lH), 1.27 (m, SH), 1.53 (dt, J = 7.7, 4.7 Hz, 4H), 1.76 (dd, J = 13.1, 7.2 Hz, lH), 2.11 (dd, J = 13.1, 8.8 Hz, IR), 2.45 (s, 3H), 2.78 (d, J = 11.0 Hz, lH), 2.91 (d, J = 1 1 . 0 Hz, II-I), 3.31 (s, 3H), 3.50 (dq, J = 27.7, 7.7, 6.6 Hz, 4H), 3.85 (t, J = 8.0 Hz, IH), 4.19 (m, 2H), 5.49 (s, lH), 6.61 (q, J = 6.8 Hz, 11-1), 7.32 (m, 3H), 7.45 (dd, J = 8.6, 2.3 Hz, lH), 7.52 (d, J = 8.1 Hz, lH), 7.67 (d, J = 8.5 Hz, IH) 63ex 1H NMR (400 MHz, MeOH-d4): s ppm 1.27 (t, J = 7.1 Hz, 4H), 1.54 (m, 4H), 1.76 (dd, J = 13.1 , 7.2 Hz, lH), 2.11 (dd, J = 13.1 , 8.8 Hz, l H), 2.77 (d, J = 1 1 . 0 Hz, lH), 2.91 (d, J = 11.0 Hz, 1H), 3.54 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, lH), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.53 (s, lH), 6.54 (q, J = 6.7 Hz, HI), 7.36 (d, J = 2.2 Hz, IH), 7.53 (dd, J = 8.6, 2.2 Hz, IH), 7.68 (dd, J = 23.2, 8.4 Hz, 2H), 7.84 (s, lH), 7.97 (d, J = 8.1 Hz, lH) 63ey 1H NMR (400 MHz, MeOH-d4): o ppm 1.27 (t, J = 7.1 Hz, 4H), 1.54 (ddd, J = 11 .9 , 6.5, 4.3 Hz, 4H), 1. 76 (dd, J = 13.1 , 7.2 Hz, lH), 2.11 (dd, J = 13. l, 8.7 Hz, lH), 2.77 (d, J = 11.0 Hz, lH), 2.91 (d, J = 11.0 Hz, lH) , 3.52 (dq, J = 26.9, 7.7, 6.7 Hz, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, lH),4.19 (qd, J = 7.2, 1.6 Hz, 2H), 5.53 (s, lH), 6.63 (q, J = 6.7Hz, 1H), 7.10(tt,J=9 .2, 2.4Hz, lH), , 2H), 7.34(d,J = 2.2Hz, lH), 7.50 (dd, J = 8.6, 2.2 Hz, lH), 7.70 (d, J = 8.5 Hz, JH) 63ez 1HNMR (400 MHz, MeOH-d4): o ppm 0.07 (d, J = 1.0 Hz, IH), 0.88 (dd, J = 14.3, 7.9 Hz, IH), 1.28 (m, 6H), 1.56 (m, 3H), 1.75 (dd, J = 13.1 , 6.7 Hz, lH), 2.07 (dd, J = 13.1 , 8.8 Hz, 2H), 2.84 (d, J = 10.5 Hz, lH) ,2.96 (d, J = 1 0.5 Hz, lH), 3.49 (m, 4H), 3.88 (m, IH) ,4.20 (m, 2H) , 4.56 (s, 2H), 5.44 (d, J = 1.0 Hz, 1 H), 6.52 (q, J = 6.7 Hz, lH), 7.23 (m, 3H), 7.40 (m, lH), 7.66 (m, 2H) 63fa 1H NMR (400 MHz, MeOH-d4): s ppm 1.27 (t, J = 7.1 Hz, 3H), 1.53 (m, 4H), 1.75 (dd, J = 13.1 , 7.2 Hz, IH), 2.10 (dd, J = 13 . 1 , 8.8 Hz, lH), 2.76 (d, J = 11.0 Hz, l H), 2.90 (d, J = 1 0.9 Hz, IH), 3.52 (m, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, HI), 4.18 (qd, J = 7.2, l.6H z,2H), 5.52(s, 1H), 6 . 60 (q ,J =6 .8Hz, lH), 7.31 (d,J= 2.3 Hz, IH), 7.45 (m, 3H), 7.67 (d, J = 8.5 Hz, lH) 63fb 1 HNMR (400 MHz, MeOH-d4): o ppm 0.89 (dd, J = 10.8, 3. 8 Hz, lH), 1.27 (t, J = 7.1 Hz, 4H), 1.53 (m, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, lH), 2.10 (dd, J = 13.1 , 8.7 Hz, lH), 2.25 (s, 1 H), 2.35 (d, J = 3.2 Hz, 6H), 2.77 (d, J = 1 1 . 0 Hz, lH), 2.91 (d, J = 1 1.0 Hz, lH), 3.50 (m, 4H), 3.85 (dd, J = 8.7, 7.2 Hz, lH), 4.19 (qd, J = 7.2, 1.6 Hz, 2H), 4.87 (d, J = 5.2Hz, 13H), 5.44 (s, IH), 6.64 (q, J = 6.8 Hz, HI), 7.18 (d, J = 7.7 Hz, 2H), 7.26 (m, 2H), 7.41 (dd, J = 8.5, 2.3 Hz, lH), 7.65 (d, J = 8.5 Hz, lH) 63fc 1H NMR (400 MHz, MeOH-d4): o ppm 0.89 (t, J = 6.7 Hz, lH), 1.30 (m, 1 lH), 1.59 (dt, J = 7.7, 4.0 Hz, 9H), 1.94 (dd, J = 13.4, 8.3 Hz, 2H), 2.45 (s, lSH), 2.80 (s, 3H), 3.12 (m, 4H), 3.55 (tdd, J = 24.1, 17.0, 12.0 Hz, 9H), 4.28 (m, 6H), 5.51 (s, 2H), 6.64 (q, J = 6.8 Hz, 2H), 7.21 (s, 4H), 7.28 (d, J = 2.3 Hz, 2H), 7.44 (dd, J = 8.5, 2.3 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H) 63fd 1H NMR (400 MHz, MeOH�d4): s ppm 0.08 (dd, J = 4.2, 1.7 Hz, lH), 0.90 (q, J = 7.7 Hz, IH), 1.26 (t, J = 7.1 Hz, 4H), 1.50 (dt, J = 33.9, 6.4 Hz, 7H), 1.75 (dd, J = 13.1, 7.2 Hz, lH), 2.10 (dd, J = 13.1, 8.8 Hz, lH), 2.76 (d, J = 11.0 Hz, lH), 2.91 (d, J = 11.0 Hz, 11-I), 3.50 (dq, J = 24.8, 7.5, 6.5 Hz, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, lH), 4.19 (ttd, J = 7.1, 4.5, 2.1 Hz, 4H), 5.49 (s, lH), 6.66 (q, J = 6.8 Hz, lH), 7.27 (m, 4H), 7.43 (dd, J = 8.5, 2.3 Hz, lH), 7.65 (d, J = 8.5 Hz, lH) 63fe 1H NMR (400 MHz, MeOH-d4): s ppm 1.26 (td, J = 7.2, 1.1 Hz, 4H), 1.52 (dt, J = 11.8, 5.7 Hz, 4H), 1.74 (dd, J = 13.2, 7.2 Hz, IH), 2.09 (dd, J = 13.2, 8.7 Hz, lH), 2.38 (s, 6H), 2.75 (d, J = 11.0 Hz, lH), 2.90 (d, J = 11.0 Hz, lH), 3.50 (m, 5H), 3.82 (t, J = 8.0 Hz, lH), 4 .18 (m, 2H), 5.45 (s, lH), 6.66 (q, J = 6.8 Hz, lH), 7.04 (s, 2H) , 7.12 (d, J = 1.8 Hz, lH), 7.25 (d, J = 2.1 Hz, lH), 7.41 (m, lH), 7.66 (d, J = 8.5 Hz, 63ff 1H NMR (400 MHz, MeOH-d4): s 7 (t, J = 7.1 Hz, 3H) , 1.54 (m, 4H), 1.76 (dd, J = 13.1, 7.3 Hz, lH), 2.11 (dd, J = 13 . 1, 8.7 Hz, lH), 2.43 (s, 3H), 2.78 (d, J = 11.0 Hz, IH), 2.92 (d, J = 11.0 Hz, lH), 3.52 (m, 4H), 3.86 (dd, J = 8.7, 7.3 Hz, 11-I), 4.1 9(q d , J=7 . l , 1.6Hz,2H),5.50(s, lH),6.61 (q, J=6.8 Hz, lH), 7.18(s, lH), 7.31 (m, 2H), 7.39 (s, lH), 7.46 (dd, J= 8.5, 2.3 Hz, IH), 7.68 (m, lH) 63fg 1H NMR (400 MHz, MeOH-d4): s ppm 0.89 (t, J = 6.9 Hz, lH), 1.27 (m, 6H) , 1.53 (dt, J = 7.9, 4.6 Hz, 4H), 1.76 (dd, J = 13.1 , 7.3 Hz, lH) , 2.11 (m, lH), 2.35 (d, J = 1.9 Hz, 3H), 2.77 (d, J = 11.0 Hz, lH), 2.91 (d, J = 11.0 Hz, IH), 3.49 (dp, J = 25.1, 5.9 Hz, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, lH), 4. 19 (qd, J = 7.1, 1.6 Hz, 2H), 4.87 (s, 13H), .49 (s, lH), 6.62 (q, J = 6.8 Hz, lH), 7.26 (m, 4H), 7.43 (dd, J = 8.6, 2.3 Hz, lH), 7.66 (d, J = 8.5 Hz, lH) 63fb 1H NMR (400 MHz, MeOH�d4): o ppm 1.27 (t, J = 7.1 Hz, 4H), 1.53 (dp, J = 7.3, 3.6, 2.9 Hz, 4H), 1.75 (dd, J = 13.1 , 7.3 Hz, 1 H), 2.10 (dd, J = 13.1, 8.7 Hz, lH), 2.40 (s, 3H), 2.77 (d, J = 11.0 Hz, lH), 2.91 (d, J = 11.0 Hz, lH), 3.51 (m, 4H) , 3.84 (dd, J = 8.7, 7.2 Hz, lH), 4.19 (qd, J = 7.1, 1.6 Hz, 2H), 5.50 (s, lH), 6.61 (q, J = 6.7 Hz, lH), 7.30 (d, J = 2.3 Hz, lH), 7.45 (m, 4H), 7.67 (d, J = 8.5 Hz, lH) 63fi 1HNMR (400 MHz, MeOH-d4): s ppm 1.26 (t, J = 7.1 Hz, SH), 1.53 (m, 4H), 1.75 (dd, J = 13 .l , 7.2 Hz, lH), 2.09 (dd, J = 13.l , 8.7 Hz, lH), 2.76 (d, J = 11.0 Hz, lH) , 2.90 (d, J = 11.0 Hz, lI-I), 3.51 (dtt, J = 18.9, 13.4, 7.4 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, lH), 4.18 (qd, J = 7.2, 1.6 Hz, 2H), 5.50 (d, J = 10.3 Hz, lH), 6.58 (q, J = 6.7 Hz, lH), 7.32 (d, J = 2.2 Hz, lH), 7.47 (m, 4H), 7.67 (m, 2H) 63fj 1H NMR (400 MHz, MeOH-d4): o ppm 0.87 (dd, J = 11.5, 4.7 Hz, lH), 1.26 (ddd, J = 19.3, 6.9,5.5 Hz, 12H), 1.48 (m, 4H), 1.72 (dd, J = 13.1, 7.3 Hz, IH), 2.05 (m, IH), 2.74 (d, J = 11.0 Hz, lH), 2.93 (m, 2H), 3.45 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1 H), 4.17 (qd, J = 7.1, 1.4 Hz, 2H), 5.44 (s, lH), 6.63 (q, J = 6.8 Hz, lH), 7.34 (rn , 7H), 7.66 (d, J = 8.5 Hz, lH) 63fk 1H NMR (400 MHz, MeOH-d4): o ppm 0.88 (d, J = 7.9 Hz, lH), 1.19 (s, 2H), 1.26 (t, J = 7.1 Hz, 4H), 1 .53 (dt, J = 8.3, 4.9 Hz, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, 11-:I ), 2.10 (dd, J = 1 3.1, 8.8 Hz, ll- 1), 2.76 (d, J = 11.0 Hz, lH), 2.90 (d, J = 10.9 Hz, lH), 3.51 (m, 4H), 3 .83 (dd, J = 8.8, 7.2 Hz, lH), 4.18 (qd, J = 7 . 1 , 1 .7 Hz, 2H), 4.87 (s, 7H), .52 (s, IH), 6.40 (q, J = 6.6 Hz, lH), 7.40 (d, J = 2.2 Hz, 11-I), 7.55 (dd,J = 8.5, 2.3 Hz, lH), 7.71 (d, J = 8.5 Hz, lH), 8.11 (s,2H) 63fl 11-I NMR (400 MHz, Me0H-d4): o ppm 1.27 (m, 6H), 1.54 (m,TH), 1.77 (dd, J = 13.1, 7.3 Hz, 2H), 2.12 (dd, J = 13.1, 8. 7 Hz, 2H), 2.23 (dd, J = 4.4, 1.5 Hz, 3H), 2.36 (d, J = 2.1 Hz, SH), 2.79 (d, J = 11.1 Hz, 2H), 2.93 (d, J = 11.0 Hz, 2H), 3.30 (d,J= 9.7 Hz, lH), 3.52 (dq, J = 19.4, 6.4 Hz, 7H), 3.88 (dd, J = 8.8, 7.3 Hz, 2H), 4.19 (dddd, J = 8.7, 7.1, 5.6, 1.7 Hz, 3H), 5.49 (q, J = 2.5, 1.9 Hz,2H), 6.65 (q, J = 6.7 Hz, 2H), 7.22 (m, 6H), 7.43 (m, 3H), 7.67 (d, J = 8.5 Hz, 2H) 63fm 1H NMR (400 MHz, MeOH-d4): s ppm 1.30 (m, SH), 1.61 (m, 4H), 1.96 (dd, J = 13.4, 8.4 Hz, lH), 2.37 (dd,J = 13.4, 8.7 Hz, lH), 2.81 (s, lH), 3.13 (q,J= 11.6 Hz, 2.H), 3.57 (m, 4H), 4.30 (m, 3H), 5.56 (s, lH), 6.55 (q, J = 6.7 Hz, lH), 7.34 (d, J = 2.2 Hz, lH), 7.55 (m, SH), 7.69 (d, J = 8.5 Hz, lH) 63fn 1H NMR (400 MHz, MeOH-d4): o ppm 1.27 (m, 4H), 1.53 (m,4H), 1.75 (dd, J = 13.1, 7.2 Hz, 11-I), 2.10 (dd, J = 13.1, 8.8 Hz, lH), 2.76 (d, J = 10.9 Hz, lH), 2.90 (d, J = 11.0Hz, lH), 3.51 (m,4H), 3.82 (dd,J = 8.8, 7.2 Hz, lH), 4.18 (qd,J= 7.1, 1.6 Hz, 2H), 5.53 (s, lH), 6.49 (q, J = 6.7 Hz, 1H), 7.34 (d, J = 2.2 Hz, lH), 7.52 (m, 2H), 7.68 (d, J = 8.6 Hz, HI), 7.81 (s, 2H) 63fo 'H NMR (400MHz, MeOH-d4): s ppml.27 (t, J = 7.1 Hz, 4H), 1.54 (m, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, lH), 2.10 (dd, J = 13.1, 8.8 Hz, lH), 2.77 (d, J= 11.0 Hz,lH), 2.83 (s, 11-I), 2.91 (d, J = 11.0 Hz, IH), 3.53 (m, 4H), 3.83 (dd,J= 8.7, 7.2 Hz, l H), 4.19 (qd, J= 7.2, 1.6 Hz, 2H), 5.53 (s, IH), 6.53 (q, J = 6.8 Hz, lH), 7.37 (d, J = 2.2 Hz, lH), 7.53 (dd, J = 8.5, 2.2 Hz, IH), 7.62 (ddd, J = 7.9, 5.0, 0.9 Hz, lH) , 7.72 (d, J = 8.6 Hz, lH), 7.98 (m, lH), 8.67 (dd,J = 5.0, 1.6 Hz, lH), 8.75 (d, J = 2.2 Hz, lH) 63fp 1H NMR (400 MHz, 4): o ppml .31 (m, lOH), 1.54 (m,4H), 1.75 (dd, J = 13.1 , 7.2 Hz, lH), 2.10 (dd, J = 13.1, 8.8 Hz, lH), 2.77 (d, J = 11.0 Hz, lH), 2.91 (d, J = 11.0 Hz, lH),3.53 (m, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, lH), 4.19 (qd, J = 7.1 , 1.6 Hz, 2H), 4.69 (p, J = 6.1 Hz, lH), 5.51 (s, 1H), 6.72 (q, J = 7.0 Hz, lH), 6.83 (dt, J = 11.3, 2.3 Hz, lH), 7.03 (m, II-I), 7.30 (d, J = 2.2 Hz, lH), 7.46 (dd, J = 8.5, 2.3 Hz, lH), 7.67 (d, J = 8.5 Hz, lH) 63fq 1H NMR (400 MHz , MeOH-d4): s ppm0.88 (m, lH), 1.37 (m,22H) , 1.75 (dd,J= 13. 1, 7.4 Hz, 2H), 2.09 (dd, J = 13.1, 8.8 Hz, 2H), 2.21 (s, 2H), 2.78 (d, J = 11.1 Hz, 2H), 2.91 (d, J = 11. 1 Hz,2H), 3.49 (m, 8H), 3.88 (dd,J = 8.8, 7.4 Hz, 2H), 4.12 (m, 8H), 5.49 (s, 2H), 6.79 (m, 7H), 7.03 (s, 2H), 7.28 (d, J = 2.3 Hz, 2H), 7.42 (dd, J = 8.6, 2.2 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H) 63fr 1H NMR (400 MHz, MeOH-d4): s ppml .32 (m, 15H), 1.52 (m, 4H), 1.74 (dd,J= 1 3. 1 , 7.2 Hz, lH), 2.09 (dd, J = 13.1 , 8.8 Hz, lH), 2.32 (d, J = 0.7 Hz, lH), 2.43 (d, J = 0.8 Hz, 3H), 2.76 (d, J = 11.0 , 2.90 (d, J = 11.0 Hz, lH), 3.48 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, IH), 4.18 (qd, J = 7.2, 1.5 Hz, 2H), 5.43 (s, IH), 6.63 (q, J = 6.8 Hz, IH), 7.06 (s, 1 H), 7.26 (m, 2H), 7.34 (q, J = 1.3 Hz, lH), 7.42 (dd, J = 8.5, 2.3 Hz, lH), 7.66 (d, J = 8.5 Hz, lH) 63fs 1H NMR (400 MHz, Me0H-d4): o ppm 1.27 (t, J = 7.2 Hz, 3H), 1.55 (m, 4H), 1.77 (dd, J = 13 .1, 7.3 Hz, 1H), 2.12 (dd,J= 13.2, 8.8 Hz, lH), 2.79 (d, J = 11.0Hz, l H), 2.92 (d, J = 11 .0 Hz, 1 H), 3.53 (rn, 4H), 3.86 (dd, J = 8.7, 7.3 Hz, l H), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 4.86 (s, 31-l ), 5.53 (s, IH), 6.57 (q, J = 6.8 Hz, IH), 7.34 (d, J = 2.2 Hz, lH), 7.51 (dd,J = 8.5, 2.3 Hz, lH), 7.72 (m, 2H), 7.84 (m, 2H), 7.92 (s, lH) 63ft 1H NMR (400 MHz, Me0H-d4): o ppm 0.88 (m, 2H), 1.24 (m, 4H), 1.39 (t, J = 7.0 Hz, 3H), 1.50 (q, J = 7.7, 5.2 Hz, 4H), 1.74 (ddd, J = 13.3, 7.3, 1.8 Hz, lH), 2.08 (ddd, J = 11.4, 8.7, 2.6 Hz, IH), 2.39 (s, 3H), 2.76 (d, J = 11.1 Hz, lH), 2.88 (dd, J = 11.0, .7 Hz, lH), 3.58 (m, 4H), 3.85 (m, IH), 4.13 (m, 41-I), 5.73 (s, 1 H), 6.42 (d, J = 2.4 Hz, 1H), 6.70 (dt, J = 10.7, 2.2 Hz, lH), 6.80 (p, J = 6.5 Hz, 11-I), 7.01 (m, 2H), 7.63 (d, J = 1.9 Hz, lH), 7.76 (m, 2H), 8.00 (d, J = 2.4 Hz, lH) 63fu 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.26 (t, J = 7.1 Hz, 4H), 1.50 (dt, J = 9.9, 5.2 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, lH), 2.07 (dd, J = 13.l, 8.7 Hz, lH), 2.22 (s, lH), 2.29 (d, J = 10.3 Hz, 6H), 2.39 (s, 3H), 2.75 (d, J = 11.0 Hz, lH), 2.88 (d, J = 11.0 Hz, lH), 3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, lH), 4.18 (qd, J = 7.1, 1.6 Hz, 21-I), 5.74 (s, lH), 6.41 (d, J = 2.3 Hz, lH), 6.75 (m, lH), 7.19 (d, J = 7.9 Hz, lH), 7.39 (m, 2H), 7.59 (d, J = 1.8 Hz, lH), 7.72 (m, 2H), 7.96 (d, J = 2.3 Hz, lH) 63fv 11-I NMR (400 MHz, MeOH-d4): 8 ppm 1.26 (m, 4H), 1.51 (dt, J = 10.6, 5.6 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, IH), 2.08 (dd, J = 13.1, 8.7 Hz, lH), 2.39 (s, 3H), 2.76 (d, J = 11.0 Hz, lH), 2.89 (d, J = 11.0 Hz, lH), 3.53 (m, 4H), 3.83 (m, lH), 4.18 (m, 2H), 4.85 (d, J = 10.8 Hz, lH), 5.73 (s, IH), 6.42 (d, J = 2.4 Hz, l H), 6.83 (q, J = 6.6 Hz, lH), 7.60 (m, 4H), 7.79 (m, 2H), 8.00 (d, J = 2.4 Hz, lH) 63fw 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.25 (t, J = 7.1 Hz, 3H), 1.46 (m, 7H), 1.73 (dd, J = 13.1 , 7.2 Hz, IH), 2.06 (dd, J = 13.1 , 8.8 Hz, l H), 2.39 (s, 3H), 2.73 (d, J = 11.0 Hz, lH), 2.87 (d, J = 11.0Hz, lH) , 3.52 (m, 4H), 3.80 (dd, J = 8.7, 7.1 Hz, lH), 4.16 (m, 4H), 5.73 (s, IH), 6.41 (d, J = 2.3 Hz, lH), 6.78 (q, J = 6.6 Hz, IH), 7.1 1 (d, J = 8.6 Hz , HI), 7.57 (m, 2H), 7.71 (m, 3H), 7.98 (d, J = 2.4 Hz, lH) 63fx 1H NMR (400 MHz, Me0H-d4): 8 ppm 1.26 (m, 4H), 1.39 (t, J = 7.0 Hz, 3H) , 1.51 (dt, J = 10.6, 5.6 Hz, 4H), 1.73 (dd, J = 13 .1 , 7.1 Hz, lH), 2.07 (dd, J = 13.0, 8.8 Hz, IH), 2.39 (s, 3H), 2.74 (d, J = 10.9 Hz, lH), 2.88 (d, J = 11.0 Hz, lH), 3.53 (m, 4H), 3.81 (dd, J = 8.8, 7.1 Hz, lH), 4.13 (m, 4H), 4.87 (s, 13H), 5.74 (s, lH), 6.41 (d, J = 2.4 Hz, lH), 6.78 (q, J = 7.6, 7.0 Hz, lH), 6.93 (m, lH), 7.20 (m, 2H), 7.34 (t, J = 7.9 Hz, HI), 7.62 (d, J = 1.8 Hz, IH), 7.75 (m, 2H), 7.98 (d, J = 2.4 Hz, lH) 63fy 1H NMR (400 MHz, MeOH-d4): o ppm 1.26 (m, 3H), 1.50 (dt, J = 10.5, 5.8 Hz, 4H), 1.73 (dd, J = 13.1 , 7.2 Hz, IH), 2.07 (dd, J = 13.0, 8.8 Hz, lH), 2.39 (s, 3H), 2.74 (d, J = 11.0 Hz, ll-I ), 2.88 (d, J = 1 1.0 Hz, lH), 3.52 (m, 4H), 3.80 (m, lH), 4.17 (qd, J = 7. 1 , 1.6 Hz, 2H), 5.73 (s, lH), 6.42 (d, J = 2.3 Hz, 1 H), 6.84 (q, J = 6.6 Hz, lH), 6.99 (tt, J = 9 .1 , 2.4 Hz, lH), 7.34 (m, 2H), 7.68 (d, J = 1.9 Hz, IH), 7.79 (m, 2H), 8.01 (d, J = 2.4 Hz, IH) 63fz 1H NMR (400 MHz, 4): s ppm 1.26 (m, 3H), 1.51 (dt, J = 10.6, 5.6 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, lH) , 2.07 (dd, J = 13.1, 8.8 Hz, II-I). 2.40 (s, 3H), 2.74 (d, J = 11 .0Hz, lH), 2.88 (d, J = 11.0 Hz, 1 H), 3.52 (dq, J = 25.8, 8.1 , 6.9 Hz, 4H), 3.81 (dd, J = 8.8, 7.1 Hz, lH), 4.17 (qd, J = 7.1, 1.6 Hz, 2H) , 5.73 (s, lH), 6.43 (d, J = 2.4 Hz, lH), 6.83 (q, J = 6.6 Hz, lH), 7.69 (m, 3H), 7.82 (rn, 2H), 7.98 (m, 3H) 63ga 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.27 (t, J = 7.1 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H), 1.53 (m, 4H), 1.75 (dd, J = 13.1 , 7.3 Hz, lH), 2.11 (m, l H), 2.77 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz, lH), 3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, lH), 4.17 (m, 4H), 5.49 (s, lH), 6.66 (q, J = 6.8 Hz, IH), 7.02 (s, IH), 7.27 (m, 3H), 7.45 (dd, J = 8.5, 2.3 Hz, lH), 7.66 (d, J = 8.5 Hz, IH) 63gb 1H NMR (400 MHz, Me0H-d4): 8 ppm 0.88 (m, 2H), 1.17 (t, J = 7.0 Hz, lH), 1.31 (m, 12H), 1.51 (dt, J = 11.3, 5.6 Hz, 4H), 1.74 (ddd, J = 13.1, 7.3, 1.9 Hz, lH), 2.08 (ddd, J = 1 1 .9 , 8.8, 2.8 Hz, lH), 2.39 (s, 3H), 2.76 (d, J = 11.0Hz, lH), 2.89 (dd, J = 11.0, 5.9 Hz, lH), 3.57 (m, SH), 3.84 (dt, J = 8.6, 7.2 Hz, lH), 4.18 (qd, J = 7.1, 1.7 Hz, lH), 4.64 (p, J = 6.1 Hz, lH), 5.74 (s, lH), 6.41 (d, J = 2.3 Hz, lH), 6.78 (q, J = 6.5 Hz, lH), 7.16 (t, J = 8.6 Hz, lH), 7.44 (m, 2H), 7.61 (d,J = 1.9 Hz, lH), 7.73 (m, 2H), 7.98 (d, J = 2.4 Hz, lH) 63gc 1H NMR (400 MHz, Me0H-d4): s ppm 1.26 (m, 4H), 1.51 (dt, J = 10.6, 5.7 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, lH), 2.07 (dd, J = 13.1, 8.8 Hz, lH), 2.28 (s, lH), 2.37 (d, J = 16.9 Hz, 9H), 2.75 (d, J = 11.0 Hz, IH), 2.89 (d, J = 11.0 Hz, 1 H), 3.53 (dt, J = 22.1, 6.0 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, lH), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.74 (s, IH), 6.41 (d, J= 2.3 Hz, lH), 6.77 (q, .l = 6.6 Hz, lH), 7.03 (m, IH), 7.27 (d, J = 1.5 Hz, 2H), 7.60 (d, J = 1.8 Hz, lH), 7.74 (m, 2H), 7.97 (d, J = 2.4 Hz, lH) 63gd 1H NMR (400 MHz, MeOH-d4): o ppm 1.26 (q, J = 7.1, 6.4 Hz, 4H), 1.50 (dt, J = .3, 5.6 Hz, 4H), 1.73 (dd, J = 13.0, 7.2 Hz, IH), 2.07 (dd, J = 13.1, 8.8 Hz, lH), 2.39 (d, J = 3.0 Hz, 6H), 2.74 (d, J = 10.9 Hz, lH), 2.88 (d, J = 10.9 Hz, lH), 3.52 (dt, J = 22.1, 6.1 Hz, 4H), 3 .81 (dd, J = 8.8, 7.1 Hz, IH), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 4.87 (s, 9H), 5.73 (s, lH), 6.42 (d, J = 2.3 Hz, IH), 6.81 (q, J = 6.6 Hz, IH), 7.23 (s, lH) , 7.42 (s, lH), 7.48 (d, J = 2.0 Hz, lH), 7.62 (d, J = 1.9 Hz, lH), 7.71 (dd, J = 8. 1 , 1.9 Hz, lH), 7.79 (d, J = 8.2 Hz, IH), 8.00 (d, J = 2.4 Hz, lH) 63ge 1H NMR (400 MHz, 4): o ppm 0.89 (t, J = 7.0 Hz, lH), 1.26 (m,SH), 1.50 (dt, J = 10.5, 5.4 Hz, 4H), 1.73 (dd, J = 13 . 1 , 7.2 Hz, lH) , 2.07 (dd, J = 13.1, 8.8 Hz, lH), 2.29 (d, J = 1.9 Hz, 31-I ), 2.39 (s, 3H) , 2.74 (d, J = 10.9 Hz, lH), 2.88 (d, J = 11.0 Hz, lH), 3.52 (m, 4H), 3.81 (dd, J= 8.8, 7.2 Hz, IH), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), .73 (s, UI), 6.41 (d, J = 2.4 Hz, lH), 6.79 (q, J = 6.6 Hz, lH), 7.37 (m, 3H), 7.63 (d, J = 1.9 Hz, 11-l), 7.76 (m, 2H) , 7.98 (d, J = 2.4 Hz, IH) 63gf 1H NMR (400 MHz, MeOH-d4): s ppm 0.08 (m, lH), 1.26 (rn, 4H), 1.36 (s, 9H), 1.51 (dt, J = 10.5, 5.5 Hz, SH), 1.74 (dd, J = 13.1 , 7.2 Hz, lH), 2.08 (dd, J = 13.1 , 8.8 Hz, 1H), 2.40 (s, 3H), 2.74 (d, J = 11.0 Hz, lH), 2.89 (d, J = 11 .0 Hz, lH), 3.53 (dt, J = 23.0, 6.0 Hz, 4H), 3.81 (dd, J = 8.8, 7.1 Hz, 1H) , 4.17 (qd, J=7 .1 , 1.6 Hz, 2H), 5.74 (s, lH), 6.42 (d, J = 2.4 Hz, IH), 6.76 (q, J = 6.6 Hz, IH), 7.43 (m, 3H), 7.61 (d, J = 1.9 Hz, lH) , 7.73 (m, 3H), 7.99 (d, J= 2.4 Hz, UI) 63gg 1H NMR (400 MHz, MeOH-d4): s ppm 1.26 (t, J = 7.3 Hz, 6H), 1.50 (dt, J = 10.5, .6 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, lH) , 2.08 (dd, J = 13.1, 8.8 Hz, lH), 2.39 (s, 3H), 2.75 (d, J = 11.0 Hz, IH), 2.89 (d, J = 11.0 Hz,lH), 3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, lH), 4 .18 (qd, J = 7.1, 1.6 Hz, 2H), 5.73 (s, lH), 6.42 (d, J = 2.4 Hz, IH), 6.82 (q, J = 6.6 Hz, lH), 7.41 (m, 2H), 7.61 (m, 2H), 7.74 (m, 3H), 8.00 (d, J = 2.4 Hz, 63gh 1H NMR (400 MHz, MeOH-d4): o ppm 1.26 (t, J = 7.2 Hz, 3H), 1.51 (dt, J = 10.4, 5.5 Hz, 4H), 1.75 (dd,J = 13.l, 7.3 Hz, HI), 2.10 (dd, J = 13.1, 8.8 Hz, lH), 2.39 (s, 3H), 2.84 (m, 2H), 3.52 (ddq, J = 25.3, 13.2, 7.1, 5.7 Hz, 4H) , 3.86 (dd,J = 8.8, 7.2 Hz, lH), 4.18 (qd, J = 7.2, 1.6 Hz, 2H), 5.73 (s, lH), 6.42 (d, J = 2.3 Hz, ll- 1), 6.82 (q, J= 6.6 Hz, lH), 7.33 (t,J= 8.8 Hz, lH), 7.63 (m, 2H), 7.73 (dd, J = 8.3, 1.9 Hz, lH), 7.82 (m, 2H), 8.00 (d, J = 2.3 Hz, lH) 63gi 1H NMR (400 MHz, MeOH-d4): o ppm 1.28 (m, 4H), 1.53 (dt, J = 10.2, 5.5 Hz, 4H), 1.82 (dd, J = 13.2, 7.7 Hz, IH), 2.19 (m, lH), 2.39 (s, 3H), 2.88 (d, J = 11.2Hz, lH), 2.99 (cl, J = 11.2 Hz, 11-I ), 3.55 (m, 4H), 4.02 (t, J = 8.2 Hz, lH), 4.22 (qd, J = 7.1, 1.9 Hz, 2H), 5.74 (s, H- I), 6.42 (d, J = 2.3 Hz, l H), 6.82 (m, lH), 7.35 (dt, J = 10.4, 8.4 Hz, lH), 7.50 (ddt,J= 7.9, 3.8, 1.8 Hz, lH), 7.72 (m, 4H), 8.00 (d, J = 2.4 Hz, HI) 63gj 1HNMR (400 MHz, MeOH-d4): s ppm 1.31 (m, 3H), 1.65 (dt, J = 12.8, 6.2 Hz, 4H), 2.03 (m, lH), 2.43 (m, 4H), 3.27 (s, 2H), 3.65 (m, 4H), 4.31 (qd, J = 7.1, 2.2 Hz, 2H), 4.58 (t, J = 8.8 Hz, lH), 4.85 (m, lH), 6.43 (d, J = 2.5 Hz, UI), 6.89 (q, J = 6.4 Hz, lH), 7.45 (m, lH), 7.72 (d, J = 1.8 Hz, lH), 7.81 (m, 2H), 8.00 (m, 3H) 63gk 1HNMR (400 MHz, MeOH-d4): o ppm 1.32 (t, J = 7.1 Hz, 3H), 1.64 (q, J = 10.3, 8.1 Hz, 4H), 2.04 (dd, J = 13.6, 8.9 Hz, lH), 2.44 (m, 4H), 2.80 (s, lH), 3.25 (m, 2H), 3.56 (m, lH), 3.70 (d, J = 5.7 Hz, 21-1), 4.32 (qd, J = 7.C 2.5 Hz, 2H), 4.57 (t, J = 8.8 Hz, lH), 6.44 (d, J = 2.4 Hz, lH), 6.90 (q, J = 6.5 Hz, lH), 7.76 (q, J = 1.5, 1.0 Hz, 2H), 7.85 (m, 2H) , 7.95 (m, lH), 8.04 (m, 2H) 63gl 1H NMR (400 MHz, Me0H-d4): s ppm 1.26 (t, J = 7.1 Hz, 4H), 1.51 (dt, J = 10.3, 5.5 Hz, 4H), 1.74 (dd, J = 13 .1 , 7.2 Hz, lH), 2.08 (dd, J = 13.1, 8.8 Hz, lH), 2.40 (s, 3H), 2.75 (d, J = 11.0 Hz, lH), 2.89 (d,J = 11.0 Hz, lH), 3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, lH), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.73 (s, l H), 6.42 (d, J = 2.3 Hz, lH), 6.82 (q, J = 6.6 Hz, lH), 7.31 (ddt, J = 8.1, 2.3, 1.1 Hz, lH), 7.57 (dd, J = 15.9, 7.9 Hz, 2H), 7.74(m, 4H), 8.01 (d, J = 2.4 Hz , lH) 63gm 1H NMR (400 MH z, MeOH-d4): s ppm 1.30 (d, J = 34.9 Hz, 12H), 1.51 (dt,J = 10.4, .7 Hz, 4H), 1.74 (dd, J = 13.1 , 7.2 Hz, lH), 2.06(m, lH), 2.39 (d, J = 3.3 Hz, 6H), 2.74 (d, J = 11.0 Hz, 2H), 2.89 (d, J = 11.0 Hz, lH), 3.53 (m, SH), 3.81 (dd, J = 8.7, 7.1Hz, lH) , 4.17 (qd, J= 7.2, 1.6 Hz, 2H), 4.87 (s, 3H), 5.73 (s, lH), 6.41 (d, J =2.4 Hz, l H), 6.75 (q, J = 6.8 Hz, IH), 7.28 (d, J = 9.0 Hz, 2H), 7.46 (t, J = 1.6 Hz, IH), 7.59 (d,J = 1.8 Hz, lH) , 7.75 (m, 2H),7.98 (d, J = 2.3 Hz, lH) 63gn 1H NMR (400 MHz, MeOH-d4): o ppm 1.26 (t, J = 7.1 Hz, 4H), 1.50 (dt, J = 10.8, 5.6 Hz, 4H), 1.73 (dd,J = 13.1 , 7.2 Hz, lH), 2.07 (dd, J = 1 3.1, 8.8 Hz, l H), 2.41 (d, J = 11.8 Hz, 6H), 2.74 (d, J = 11.0 Hz, lH), 2.88 (d, J = 11.0 Hz, lH), 3.52 (dq, J = 24.2, 7.6, 6.3 Hz, 4H), 3.81 (dd,J = 8.7, 7.2 Hz, lH), 4. 18 (qd, J = 7 .1, 1.6 Hz, 2H), 5.73 (s, lH), 6.41 (d, J = 2.4 Hz, IH), 6.79 (m, lH), 7.45 (m, 2H), 7.63 (dd, J = 7.6, 2.0 Hz, 2H), 7.75(m, 2H), 7.98 (d, J = 2.4 Hz, lH) 63go 1H NMR (400 MH z, MeOH-d4): o ppm 0.88 (d, J = 7.9 Hz, IH), 1.26 (t, J = 7.1 Hz, 71-I ), 1.50 (dt, J= 10.5, 5.6 Hz, 8H), 1.74 (dd, J = 13 . 1 , 7.2 Hz, 2H), 2.07 (dd, J= 13.1, 8.8 Hz, 2H), 2.34 (t, J = 0.6 Hz, lH), 2.40 (d, J = 9.3 Hz, l 6H), 2.75 (d, J = 11.0Hz, 2H), 2.89 (d, J = 11 .0 Hz, 2H),3.52 (m, 8H), 3.82 (dd, J = 8.8, 7.2 Hz, 2H), 4.18 (qd, J = 7.1 , 1.6 Hz, 4H), 5.73 (s, 2H) ,6.41 (d, J = 2.3 Hz, 2H), 6.79 (q, J = 6.6 Hz, 2H), 7.44(d, J = 0.9 Hz, 41-1), 7.62 (d, J = 1.8 Hz, 2H), 7.74 (m, 4H), 7.98 (d, J = 2.4 Hz, 63gp 1HNMR (400 MHz, MeOH-d4): s ppm 1.27 (q, J = 7.1, 5.7 Hz, 7H), 1.51 (dt, J = .7, 5.5 Hz, 4H), 1.74 (dd, J = 13 .1 , 7.2 Hz, lH), 2.06 (td,J = 15.3, 14.1 , 7.4 Hz, lH),2.32 (d, J = 2.1 Hz, 3H), 2.39 (s, 21-I ), 2.75 (d, J = 11. 0 Hz, lH), 2.89 (d, J = 11.0 Hz, 1H), 3.53 (dt, J = 22.2, 6. 1 Hz, 83 (dd, J = 8.8, 7.2 Hz, lH), 4.18 (m, 2H), .74 (s, lH), 6.41 (d, J = 2.4 Hz, lH), 6.78 (q, J = 6.5 Hz, lH), 7.10 (t, J = 9.0 Hz, lH), 7.56 (m, 3H), 7.74 (m, 2H), 7.98 (d,J = 2.4 Hz, 1 H) 63gq 1H NMR (400 MHz, MeOH-d4): 3 ppm 0.89 (m, lH), 1.26 (dq, J = 10.3, 5.8, 3.2 Hz, 6H), 1.46 (m, 7H), 1.74 (dd, J = 13.1 , 7.2 Hz, IH), 2.09 (m, IH), 2.39 (s, 3H), 2.75 (d, J = 11.0 Hz, lH), 2.89 (cl, J = 11.0 Hz, lH), 3.53 (m, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, lH), 4. 16 (m, 4H), 5.74 (s, IH), 6.41 (d, J = 2.3 Hz, lH), 6.78 (q, J = 6.5 Hz , lH), 7.15 (t, J =8.6 Hz, UI), 7.47 (m, 4H), 7.73 (m, 2H) , 7.97 (d, J = 2.3 Hz, lH) 63gr IH NMR (400 MHz, Me0H-d4): s ppm 1.26 (t, J = 7.1 Hz, 3H), 1 .52 (t, J = 8 .0 Hz, SH), 1.74 (dd, J = 13.1, 7.2 Hz, lH), 2.08 (dd, J = 13.0, 8.7 Hz, IH), 2.40 (s, 3H), 2.75 (d, J = 11.0 Hz, lH), 2.89 (d, J = 10.9 Hz, lI-1), 3.25 (p, J = 1.7 Hz, lH), 3.53 (m, SH), 3.81 (dd, J = 8.8, 7.1 Hz, lH), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 4.82 (s, 1 H), 5.73 (s, IH), 6.00 (m, lH), 6.42 (d, J = 2.4 Hz, lH), 6.85 (d, J = 6.6 Hz, lH), 7.48 (t, J = 1.9 Hz, lH), 7.69 (m, 3H), 7.80 (m, 3H), 8.03 (d, J = 2.4 Hz, lH) 63gs 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.26 (m, IOH), 1.50 (dt, I= 10.3, 5.6 Hz, 4H), 1.73 (dd, J = 13.l, 7.2 Hz, lH), 2.07 (dd, J = 13.1, 8.8 Hz, lH), 2.39 (s, 3H), 2.74 (d, J = 11.0 Hz, lH), 2.93 (m, 2H), 3.52 (m, SH), 3.82 (dd, J = 8.7, 7.2 Hz, IH), 4.17 (qd, J = 7.1, 1.5 Hz, 2H), 5.74 (s, lH), 6.41 (d, J = 2.3 Hz, lH), 6.78 (q, J = 6.6 Hz, 1H), 7.26(dt,J=7.6, 1.4Hz, lH), 7.36(t,J=7.7Hz, IH), ,2H), 7.61 (d,J= 1.9 Hz, lH), 7.75 (m, 2H), 7.98 (d, J = 2.4 Hz, lH) 63gt 1H NMR (400 MHz, MeOH-d4): s ppm 1.26 (m, 4H), 1. 51 (dt, J = 11.0 , 5.6 Hz, 4H), 1.74 (dd, J = 13.1 , 7.2 Hz, ll-I), 2.07 (dd, J = 13.2, 8.8 Hz, lH), 2.40 (s, 2H), 2.75 (d, J = 10. 9 Hz, lH), 2.89 (d, J = 11.0 Hz, lH), 3.53 (m, 4H), 3.82 (dd, J = 8.8, 7.2 Hz, IR), 4.18 (qd, J = 7.1, 1.6 Hz, 2H) , 5.72 (s, lH), 6.00 (m, lH), 6.43 (d, J = 2.4 Hz, IH), 6.84 (q, J = 6.5 Hz, lH), 7.71 (m, 2H), 7.82 (m, 2H), 7.92 (dd, J = 8.4, 2.3 Hz, lH), 8.05 (dd, J = 15.9, 2.3 Hz, 2H) 63gu 1H NMR (400 MHz , Me0H-d4): 8 ppm 1.26 (t, J = 7 .1 Hz, 3H), 1.51 (dt, J = 11.1, 5.5 Hz, 4H), 1.74 (dd, J = 13 . 1, 7.2 Hz, lH), 2.07 (dd, J = 13 . 1, 8.8 Hz, lH), 2.40 (s, 3H), 2.75 (d, J = 11.0 Hz, lH), 2.89 (d, J = 11.0 Hz, lH), 3.53 (dt, J = 22.4, 6.0 Hz, 4H) , 3.81 (dd, J = 8.7, 7.1 Hz, lH), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 5.73 (s, lH), 6.43 (d, J = 2.4 Hz, lH), 6.86 (q, J = 6.6 Hz, lH), 7.81 (m, SH), 7.97 (m, 1H), 8.03 (d, J = 2.4 Hz, 63gv 1H NMR (400 MHz, MeOH-d4): s ppm 0.08 (rn, 1 H), 1.26 (m, 4H), 1 . 5 1 (dt, J = 10.7, .5 Hz, SH), 1.73 (dd, J = 13.1, 7.2 Hz, II-I), 2.06 (m, UI), 2.40 (s, 3H), 2.74 (d, J = 1 1.0 Hz, lH), 2.88 (d, J = 11.0 Hz, lH), 3.26 (s, 1 H), 3.53 (dt, J = 22.3, 6.1 Hz, SH), 3.81 (dd, J = 8.7, 7.1 Hz, lH), 4.17 (qd, J = 7.1 , 1.6 Hz, 2H), 5.74 (s, lH), 6.42 (dd, J = 2.4, 0.6 Hz, lH) , 6.83 (q, J = 6.6 Hz, lH) , 7.57 (dd, J = 8.1 , 7.5 Hz, IH), 7.74 (t, J = 1. 1 Hz, lH), 7.87 (m, 4H), 8.00 (d, J = 2.4 Hz, 1H), 8.19 (m, 11-l ) 63gw 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.26 (t, J = 7.1 Hz, 3H), 1.52 (dt, J = 10.3, 5.5 Hz, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, ll-1) , 2.41 (s, 3H), 2.76 (d, J = 11.0 Hz, lH), 2.90 (d, J = 11.0 Hz, 1H) , 3.53 (dt, J = 23.4, 6.0 Hz, 4H), 3.83 (dd, J = 8.8, 7.1 Hz, IH), 4.18 (qd, J = 7.2, 1. 7 Hz, 2H), 5.72 (s, IH), 6.44 (d, J = 2.4 Hz, lH), 6.87 (q, J = 6.6 Hz, lH) , 7.80 (d, J = 1.6Hz, IH), 7.89 (m, 2H), 8.00 (s, lH), 8.07 (d, I=2.4 Hz, lH), 8.30 (d, J = 1.5 Hz, 2H) 63gx 1H NMR (400 MHz, Me0H-d4): s ppm 1.28 (m, lOH), 1.50 (dt, J = 10.2, 5.5 Hz, 41-I ), 1.73 (dd, J = 13 . 1 , 7.2 Hz, 11-l ), 2.06 (m, lH), 2.39 (s, 3H), 2.74 (d, J = 11.0 Hz, lH), 2.88 (d, J = l 0.9 Hz, lH), 3.53 (m, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, lH), 4.17 (qd, J = 7.2, 1.6 Hz, 2H), 4.65 (h, J = 5.9 Hz, lH), 5.73 (s, IR), 6.41 {d, J = 2.3 Hz, lH), 6.78 (q, J = 6.6 Hz, lH), 6.92 (m, lH), 7.19 (m, 2H), 7.33 (t, J = 7.9 Hz, lH), 7.60 (d, J = 1.8 Hz, lH), 7.74 (m, 2H), 7.98 (d, J = 2.3 Hz, lH) 63gy 1HNMR (400 MHz, MeOH-d4): 8 ppm 1.26 (t, J = 7.2 Hz, 4H), l.46 (m, 7H), 1.75 (dd, J = 13.1, 7.3 Hz, 11-I ), 2.09 (dd, J = 13.1, 8.8 Hz, IH), 2.39 (s, 3H), 2.76 (d, J = 11.0 Hz, IH), 2.90 (d, J = 11 .0Hz, lH), 3.52 (dq, J = 24.9, 7.0, 6.0 Hz, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, lH), 4.18 (ttd, J = 7.0, 5.2, 2.5 Hz, 4H), 5.74 (s, lH), 6.41 (d, J = 2.3 Hz, lH), 6.78 (q, J = 6.5 Hz, lH), 7.18 (m, 2H), 7.35 (dd, J = 8.0, 2.1 Hz, 1H), 7.62 (d, J = 1.8 Hz, lH), 7.74 (m, 2H), 7.99 (d, J = 2.3 Hz, lH) 63gz 1H NMR (400 MHz, MeOH-d4): s ppm 1.29 (m, 9H), 1.51 (dt, J = 10.4, 5.6 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, lH), 2.07 (dd, J = 13.0, 8.7 Hz, 1 H), 2.39 (s, 3H), 2.74 (d, J = 11.0 Hz, l H), 2.88 (d, J = 11.0 Hz, IH), 3.53 (m, 4H), 3.81 (dd, J = 8.7, 7.1 Hz, lH), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 4.66 (h, J = 6.1 Hz, lH), 5.73 (s, lH), 6.41 (d, J = 2.4 Hz, lH), 6.70 (dt, J = 10.8, 2.2 Hz, lH), 6.81 (q, J = 6.6 Hz, lH), 6.99 (m, 2H), 7.62 (d, J = 1.8 Hz, IH), 7.72 (dd, J = 8.3, 1.9 Hz, l H), 7.79 (d, J = 8.3 Hz, lH), 8.00 (d, J = 2.3 Hz, 1H) 63ha 1H NMR (400 MHz, MeOH-d4): o ppm 1.29 - 1.40 (m, 3 H), 1.55 - 1.76 (m, 4 H), 2.06 (br. s., 1 H), 2.35 - 2.54 (m, 4 H), 3.29 (s, 2 H) 3.50- 3.78 (m, 4H), 3.85 (s, 3H), 4.34 (dd, , 2.34 Hz, 2 H), 4.60 (s, 1 H), 5.96 (s, 1 H), 6.44 (d, J=2.15 Hz, 1 H), 6.81 (d, J=6.44 Hz, 1 H), 7.03 (d,J=8.79 Hz, 2 H), 7.50 - 7.68 (m, 3 H), 7.70 - 7.82 (m, 2 H), 7.97 (d, J=2.15 Hz, 1 H) 63hb 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.34 (t, J=7.13 Hz, 3 H), 1.43 (t, J=7.03 Hz, 3 H), 1.63 - 1.82 (m,4 H), 2.01 - 2.14 (m, 1 H), 2.43 (s, 3 H) 2.46 - 2.57 (m, 1 H), 3 .31 (br. s., 2 H), 3.59 - 3.93 (m, 4 H), 4.11 (d, J=7.03 Hz, 2 H), 4.26 - 4.41 (m, 2 H), 4.56 - 4.68 (m, 1 H), 6.44 (d, J=2.15 Hz, 1 H), 6.76 - 6.93 (m, 1 H), 7.04 (d, J=8.79 Hz, 2 H) , 7.66 (dd, J=S.17, 3.61 Hz, 3 H), 7.72 - 7.85 (m, 2 H), 7.93 - 8.02 (rn, 1 H) 63hc 11-l NMR (400 MHz, MeOH-d4): s ppm 1.26 (t, J = 7.2 Hz, 3H), 1.51 (dt, J = 1 1.0 , 5.6 Hz, 4H), 1.74 (dd, J = 13.1, 7.3 Hz, lH), 2.09 (dd, J = 13 . 1 , 8.8 Hz, lH), 2.39 (s, 3H), 2.76 (d, J = 1 1. 0Hz, lH), 2.90 (d, J = 11.0 Hz, lH), 3.52 (m, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, lI- 1), 4.18 (qd, J = 7.1, 1.6 Hz, 2H) , 4.88 (s, 7H), 5.72 (s, lH), 6.42 (d, J = 2.4 Hz, lH), 6.84 (q, J = 6.5 Hz, lH), 7.52 (m, 2H), 7. 67 (d, J = 1.9 Hz, lH), 7.74 (dd, J = 8.3, 1.9 Hz, lH), 7.81 (d, J = 8.3 Hz, IH), 8.01 (d, J = 2.4 Hz, lH) 63hd 1H NMR (400 MHz, MeOH-d4): s ppm 1.27 (m, 4H), 1.54 (dt, J = 8.1, 4.7 Hz, 4H), 1.76 (dd, J = 13. 1 , 7.3 Hz, 1H), 2.11 (dd, J = 13.1 , 8.8 Hz, IH), 2.77 (d, J = 10.9 Hz, 1H), 2.91 (d, J = 10.9 Hz, lH), 3.53 (dq, J = 16.3, 6.7, 6.2 Hz, 4H), 3.65 (s, 3H), 3.83 (dd, J = 8.8, 7.2 Hz, lH), 4.19 (qd, J = 7.2, 1.6 Hz, 2H), 5.51 (d, J = 18.6 Hz, lH), 6.49 (dd, J = 6.9, 2.0 Hz, 1H), 6.81 (q, J = 6.8 Hz, Ill), 6.91 (s, lH), 7.35 (d, J = 2.2 Hz, lH), 7.51 (dd, J = 8.5, 2.2 Hz, 1 H) , 7.70 (d, J = 8.6 Hz, lH), 7.80 (d, J = 6.8 Hz, 63he 1H NMR (400 MHz, MeOH-d4): s ppm 1.26 (t, J = 7.1 Hz, 4H), 1.51 (dt, J = 10.8, 5.6 Hz, SH), l .74 (dd, J = 13.1, 7.1 Hz, lH), 2.07 (dd, J = 13.0, 8.7 Hz, lH), 2.38 (d, J = 9.6 Hz, 6H), 2.74 (d, J = 10.9 Hz, lH), 2.88 (d, J = 11.0Hz, lH), 3.53 (dt, J = 21.9, 6.3 Hz, SH), 3.81 (dd, J = 8.7, 7.1 Hz, lH), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 4.88 (s, 15H), 5.74 (s, l H), 6.42 (d, J = 2.4 Hz, lH), 6.81 (q, J = 6.6 Hz, lH), 7.33 (m, IH), 7.58 (m, 1H), 7.66 (t, J = 2.6 Hz, 2H), 7.77 (m, 2H), 7.99 (d, J = 2.4 Hz, lH) 63hf 1H NMR (400 MHz, MeOH-d4): s ppm 0.08 (m, lH), 1.26 (t, J = 7.1 Hz, 4H), 1.51 (dt, J = 10.6, 5.6 Hz, 4H), 1.76 (dd, J = 13.2, 7.4 Hz, lH), 2.1 1 (dd, J = 13.2, 8.8 Hz, lH), 2.39 (s, 7H) , 2.79 (d, J = 11.0 Hz, IH), 2.92 (d, J = 1 1 .1 Hz, lH), 3.52 (dq, J = 29.5, 7.4, 6.4 Hz, SH), 3.89 (dd, J = 8.7, 7.4 Hz, lH), 4. 19 (qd, J = 7.2, 1.7 Hz, 2H), .73 (s, IH), 6.42 (d, J = 2.4 Hz, lH), 6.80 (q, J = 6.6 Hz, ll-:l ), 7.37 (d, J = 7.9 Hz, lH), 7.51 (dd, J = 7.9, 1.9 Hz, IH), 7.62 (d, J = 1.9 Hz, IH), 7.73 (m, 3H), 7.99 (d, J = 2.4 Hz, IH) 63hg 1H NMR (400 MHz, MeOH�d4): s ppm 1.26 (t, J = 7. I Hz, 3H), 1.51 ( dt, J= I0.5, 5.6 Hz, 4H), 1.75 (dd, J = 13.1, 7.3 Hz, l H), 2.10 (dd, J = 13.1 , 8.8 Hz, lH), 2.40 (s, 3H), 2.77 (d, J = 11.0 Hz, lH), 2.91 (d, J = 11.0 Hz, IH), 3.53 (m, 4H), 3.85 (dd, J = 8.7, 7.2 Hz, IH), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 5.73 (s, lH), 6.43 (d, J = 2.4 Hz, lH), 6.86 (q, J = 6.6 Hz, lH), 7.50 (dd, J = 8.4, 2.1 Hz, IH), 7.79 (m, 6H), 8.04 (d, J = 2.4 Hz, 63hh 1H NMR (400 MHz, MeOH-d4): 8 ppm 0.93 (m, 2H), 1.36 (m, 11H), 1.69 (td, J = 13.3, 6.6 Hz, lH), 2.04 (dd, J = 13.1, 8.8 Hz, lH), 2.39 (s, 3H), 2.72 (d, J = 11.0 Hz, 1 H), 2.86 (d, J = 11.0 Hz, lH), 3.50 (m, 4H), 3.80 (t, J = 7.9 Hz, 1 H), 4.17 (m, 2H), .71 (s, lH), 6.42 (d, J = 2.4 Hz, lH), 6.85 (q, J = 6.6 Hz, lH), 7.20 (dt, J = 8.5, 2.1 Hz, lH), 7.39 (dt, J = 9.7, 2.0 Hz, IH), 7.52 (t, J = 1.6 Hz, lH), 7.67 (m, 2H), 7.80 (d, J = 8.3 Hz, IH), 8.01 (d, J = 2.3 Hz, lH) 63bi 1H NMR (400 MHz, 4): 8 ppm 0.75 (m, 2H), 1.01 (dq, J = 8.4, 2.4 Hz, 2H), 1.19 (s, lH), l.26 (t, J = 7.1 Hz, 4H), 1.52 (m, 4H), I.74 (dd, J = 13.1, 7.2 Hz, lH), 2.02 (m, 2H), 2.75 (d, J = 11 .0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.49 (m, 4H), 3.82 (dd, J = 8.8, 7.2 Hz, lH), 4.18 (qd, J = 7 .1 , 1.5 1-Iz, 2H), 5.44 (s, lH), 6.60 (q, J = 6.9 Hz, lH), 7.20 (m, 4H), 7.41 (m, 2H), 7.66 (d, J = 8.5 Hz, lH) 63hj 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.25 (t, J = 7.1 Hz, 3H), 1.35 (d, J = 6.0 Hz, 6H), 1.49 (ddd, J = 12.1 , 7.6, 4.8 Hz, 4H), 1.72 (dd, J = 13.1 , 7.2 Hz, lH), 2.05 (dd, J = 13.1 , 8.8 Hz, lH), 2.39 (s, 3H) , 2.72 (d, J = 11. 0 Hz, l H), 2.87 (d, J = 11.0 Hz, lH), 3.51 (m, 4H), 3.80 (dd, J = 8.7, 7.1 Hz, l H), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 4.67 (hept, J = 6.1 Hz, lH), 5.73 (s, IH), 6.41 (d, J = 2.4 Hz, lH) , 6.78 (q, J = 6.6 Hz, lH), 7.12 (d, J = 8.6 Hz, IH), 7.54 (m, 2H), 7.67 (m, 2H), 7.75 (d, J = 8.3 Hz, lH), 7.98 (d, J = 2.4 Hz, lH) 63hk 1H NMR (400 MHz, Me0H-d4): 8 ppm 1.27 (m, 4H), 1.54 (m, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, IH), 2 .11 (dd, J = 1 3. 1, 8.8 Hz, lH), 2.77 (d, J = 11.0 Hz, lH), 2.91 (d, J = 11.0Hz, IH), 3.52 (dq, J = 27.4, 7.7, 6.5 Hz, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, l H), 4.19 (qd, J = 7.1 , 1.6 Hz, 2H), 5.51 (d, J = 14.8 Hz, 2H), 6.79 (q, J = 6.8 Hz, lH), 7.40 (d, J = 2.2 Hz, 11-I), 7.52 (m, 2H), 7.73 (d, J = 8.5 Hz, lH), 8.23 (d, J = 8.3 Hz, lH), 8.47 (s, lH), 9.34 (s, lH) 63hl 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.25 (t, J = 7.1 Hz, 3H), 1.50 (dt, J = 7.8, 4.8 Hz, 4H), 1.73 (dd, J = 13.1 , 7.2 Hz, lH), 2.07 (dd, J = 13.1 , 8.7 Hz, lH), 2.74 (d, J = .9 Hz, lH), 2.88 (d, J = 10.9 Hz, lH) , 3.10 (s, 6H), 3.49 (m, 4H), 3.81 (dd, J = 8.7, 7.2 Hz, lH), 4.1 7 (qd, J = 7.1 , 1.3 Hz, 2H), 5.47 (s, lH), 6.69 (m, 3H), 7.32 (d, J = 2.2 Hz, lH), 7.45 (dd, J = 8.5, 2.2 Hz, lH), 7.68 (d, J = 8.5 Hz, lH), 8.18 (d, J = 5.2 Hz , 63hm 11- 1 NMR (400 MHz, MeOH-d4): o ppm 1.24 (t, J = 7.1 Hz, 3H), 1.45 (dt, J = 9.4, 5.7 Hz, 4H), 1.70 (dd, J = 13. 1, 7.2 Hz, HI), 2.03 (dd, J = 13.1 , 8.7 Hz, IH), 2.70 (d, J = 11.0 Hz, l H), 2.85 (d, J = 11.0 Hz, lH), 3.40 (m, 4H), 3.79 (t, J = 7.9 Hz, lH), 4 .16 (q, J = 7.1 Hz, 2H), 5.45 (d, J = 17.0 Hz, 1H), 6.68 (q, J = 6.8 Hz, lH), 7.37 (d, J = 2.3 Hz, lH), 7.44 (dd, J = 8.6, 2.2 Hz, lH), 7.56 (m, 3H), 7.71 (d, J = 8.5 Hz , lH), 7.94 (m, 4H) 63hn 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.27 (t, J = 7.1 Hz, 3H), 1.36 (s, 91-I ), 1.52 (m, 4H), 1.77 (dd, J = 13.1 , 7.4 Hz, lH), 2.13 (dd, J = 13.1 , 8.7 Hz, IH), 2.80 (d, J = 11.1 Hz, HI), 2.93 (d, J = 1 1. l Hz, lH), 3.48 (m, 4H), 3.91 (dd, J = 8.7, 7.4 Hz, lH), 4.20 (qd, J = 7.2, 1.7 Hz, 2H), 5.41 (s, IH), 6.64 (q, J = 6.9 Hz, lH), 7.27 (m, 2H), 7.44 (m, SH), 7.69 (d, J = 7.3 Hz, lH) 63ho 1HNMR (400 MHz, MeOH-d4): o ppm 1.26 (td, J = 7.1, 2.3 Hz, 3H), 1.53 (dt, J = 13.2, 6.2 Hz, 4H), 1.74 (dt, J = 13.6, 7.0 Hz, lH), 2.09 (m, nn, 2.75 (dd, J = 10.9, 7.2 Hz, HI), 2.90 (dd, J = 11.0, 6.6 Hz, lH), 3.29 (s, 11-1), 3.52 (m, 4H), 3.83 (td, J = 8.2, 4.3 Hz, lH), 4.18 (q, J = 7.1 Hz, 2H), 5.47 (m, lH), 6.43 (dt, J = 11.2, 5.6 Hz, IH), 7.22 (m, IH), 7.38 (rn, 2H), 7.61 (dd, J = 5.0, 2.2 Hz, lH), 7.81 (m, 3H) 63hp 1H NMR (400 MHz, MeOH-d4): S ppm 1.27 (t, J = 7.1 Hz, 4H), 1.51 (dt, J = 10.0, 5.2 Hz, 4H), 1.80 (m, lH), 2.17 (dd, J = 13.3, 8.8 Hz, lH), 2.86 (d, J = 11.2 Hz, lH), 2.97 (d, J = 11.2 Hz, lH), 3.50 (m, 4H), 4.01 (t, J = 8.2 Hz, 11-l), 4.21 (qd, J = 7.1, 1.9 Hz, 2H), 5.63 (s, lH), 6.69 (q, J = 6.6 Hz, IH), 7.30 (ddd, J = 7.9, 6.9, 0.9 Hz, 11-1), 7.46 (m, 2H), 7.75 (m, 4H), 8.39 (d, J = 1.0 Hz, lH) 63hq 1H NMR (400 MHz, MeOH-d4): s ppm 1.28 (t, J = 7.1 Hz, 3H), 1.36 (dd, J = 6.9, 3.7 Hz, 6H), 1.50 (m, 2H), 1.73 (dd, J = 13.1, 6.7 Hz, lH), 2.05 (dd, J = 13.1, 8.8 Hz, IH), 2.81 (d, J = 10.5 Hz, l H), 2.94 (d, J = 10.5 Hz, lH), 3.14 (p, J = 6.9 Hz, 1H), 3.47 (dt, J = 12.2, 5.6 Hz, 4H), 3.85 (dd, J = 8.8, 6.7 Hz, IH), 4.19 (q, J = 7.1 Hz, 2H), 4.34 (s, 2H), 5.42 (s, lH), 6.53 (q, J = 6.7 Hz, IH), 7.25 (m, 3H), 7.42 (dd, J = 8.5, 2.2 Hz, lH), 7.68 (d, J = 8.5 Hz, 1H), 8.65 (dd, J = 5.0, 0.8 Hz, IH) 63hr 1H NMR (400 MHz, MeOH-d4): s ppm 1.27 (t, J = 7.1 Hz, 3H), 1.53 (m, 4H), 1.76 (dd, J = 13.1, 7.3 Hz, 1H), 2.11 (dd, J = 13.1, 8.7 Hz, lH), 2.77 (d, J = 11.0 Hz, lH), 2.91 (d, J = 11 .0 Hz, lH), 3.51 (dq, J = 17.7, 6.1 Hz, 4H), 3.84 (dd, J = 8.7, 7.3 Hz, IH), 4.19 (qd, J = 7.1 , 1.6 Hz, 2H), 5.50 (s, lH), 6.60 (q, J = 6.7 Hz, lH), 7.28 (m, 3H), 7.48 (ddd, J = 25.4, 8.2, 3.7 Hz, 3H), 7.66 (d, J = 8.5 Hz, HI) 63hs 1H NMR (400 MHz, MeOH-d4): s ppm 1.26 (t, J = 7.1 Hz, 3H), 1.52 (m, 4H), 1.75 (dd, J = 13.1 , 7.3 Hz, lH) , 2.10 (dd, J = 13.1, 8.8 Hz, lH) , 2.77 (d, J = 11.0 Hz, lH), 2.91 (d, J = 1 1. 0 Hz, lH), 3.50 (dq, J = 25.8, 7.7, 6.9 Hz, 4H), 3.85 (dd, J = 8.7, 7.3 Hz, lH), 4.19 (qd, J = 7.1, 1.5 Hz, 2H), 5.50 (s, lH), 6.60 (q, J = 6.7 Hz, lH), 7.28 (d, J = 2.2 Hz, lH), 7.52 (m, 6H) 63ht 1H NMR (400 MHz, MeOH-d4): s ppm 1.29 (t, J = 7.1 Hz, 3H), 1.56 (dt, J = 11.3, 5.3 Hz, 4H), 1.86 (dd, J = 13.3, 7.9 Hz, lH), 2.25 (dd, J = 13.3, 8.7 Hz, lH), 2.44 (s, 3H), 2.96 (d, J = 11.4 Hz, lH), 3.05 (d, J = 11.3 Hz, ll-1), 3.54 (m, 3H), 3.75 (s, 1 H), 4 .13 (t, J = 8.3 Hz, lH), 4.24 (qd, J = 7.2, 2.0 Hz, 2H), 5.48 (s, lH), 6.64 (q, J = 6.8 Hz, IH), 7.26 (d, J = 2.3 Hz, lH), 7.35 (s, 4H), 7.42 (dd, J = 8.5, 2.3 Hz, lH), 7.65 (d, J = 8.5 Hz, lH) 63hu 1H NMR (400 MH z, 4): s ppm 1.24 (m, 3H), 1.49 (dt, J = 10.2, 5.7 Hz, 4H), 1.72 (m, lH) , 2.04 (m, lH), 2.41 (s, 2H), 2.72 (d, J = 10.9 Hz, HI), 2.86 (d, J= 10.9 Hz, lH), 3.52 (m, 4H), 3.79 (dd, J = 8.8, 7.1 Hz, lH), 4.16 (qd, J = 7.1, 1.6 Hz, 2H), .76 (s, lH), 6.43 (d, J = 2.4 Hz, lH), 6.82 (q, J = 6.7 Hz, lH), 7.49 (m, 2H), 7.84 (m, 7H), 8.01 (d, J = 2.4 Hz, 1 H), 8 .14 (d, J = 1.9 Hz, lH) 63hv 1H NMR (400 MHz, MeOH-d4): o ppm 1.26 (t, J = 7.1 Hz, 3H) , 1.53 (rn, 4H), 1.78 (m, SH), 2.11 (m, 2H), 2.25 (dt, J = 7.9, 4.0 Hz, 2H) , 2.41 (d, J = 18 .1 Hz, lH), 2.76 (d, J = 11.0Hz, lH), 2.90 (d, J = 11.0 Hz, IH), 3.50 (dq, J = 24.8, 7.6, 6.8 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4 .18 (qd, J = 7.1, 1.5 Hz, 2H), 5.48 (s, lH) , 5.76 (h, J = 2.0 Hz, 1H), 6.93 (q, J = 6.9 Hz, lH), 7.15 (d, J = 2.3 Hz, IH), 7.30 (dd, J = 8.5, 2.3 Hz, lH), 7.58 (d, J = 8.5 Hz, lH) 63hw 1H NMR (400 MHz, Me0H-d4): s ppm 1.27 (t, J = 7.1 Hz, 3H), 1.52 (dt, J = 8.9, 5.7 Hz, 4H), 1.81 (dd, J = 13.3, 7.7 Hz, lH), 2.17 (dd, J = 13.3, 8.8 Hz, lH), 2.39 (s, 3H), 2.88 (d, J = 11.3 Hz, lH), 2.98 (d, J = 11.3 Hz, lH), 3.53 (m, 4H), 4.04 (t, J = 8.2 Hz, lH), 4.21 (qd, J = 7.2, 1.8 Hz, 2H), 4.90 (d, J = I.I Hz, SH), 5.74 (s, IH), 6.41 (d, J = 2.3 Hz, 11-I), 6.78 (q, J = 6.6 Hz, lH), 7.17 (t, J = 8.6 Hz, 11-I), 7.40 (m, 7H), 7.62 (m, 2H), 7.74 (d, J = 8.2 Hz, 11-1), 7.96 (d, J = 2.3 Hz, IH) 63hx 1H NMR (400 MHz, MeOH-d4): 3 ppm 1.32 (m, 91-I), 1.55 (dt, J = 10.7, 5.8 Hz, 4H), 1.87 (dd, J = 13.3, 8.0 Hz, lH), 2.24 (m, 4H), 2.39 (s, 3H), 2.98 (d, J = 11.4 Hz, lH), 3.06 (d, J = 11.4 Hz, lH), 3.58 (m, 4H), 4.22 (m, 3H), 4.63 (p, J = 6.0 Hz, lH), 5.76 (s, IH), 6.41 (d, J = 2.3 Hz, lH), 6.75 (q, J = 6.6 Hz, lH), 6.97 (d, J = 8.2 Hz, lH), 7.45 (d, J = 8.1 Hz, 21-1), 7.58 (d, J = 1.7 Hz, lI-1), 7.71 (m, 2H), 7.96 (d, J = 2.3 Hz, 63hy 1H NMR (400 MHz, MeOH-d4): o ppm 1.04 (m, 7H), 1.26 (t, J = 7.1 Hz, 4H), 1.52 (m, 4H), 1.74 (dd, J= 13.1, 7.3 Hz, lH), 2.08 (m, 2H), 2.75 (d, J = 11.0 Hz, ll-I), 2.90 (d, J = 11.0 Hz, lH), 3.50 (m, 4H), 3.80 (m, 3H), 4.18 (qd, J = 7.1, 1.4 Hz, 2H), 5.48 (s, IH), 6.70 (q, J = 6.9 Hz, lH), 7.02 (m, 2H), 7.19 (s, 2H), 7.28 (d, J = 2.3 Hz, lH), 7.42 (m, 21-I), 7.66 (d, J = 8.5 Hz, lH) 63hz 11-I NMR (400 MHz, Me0H-d4): s ppm 1.33 (t, J = 6.3 Hz, 9H), 1.68 (m, 4H), 2.04 (m, IH), 2.50 (dd, J = 13.6, 8.7 Hz, lH), 3.28 (s, 21-I ), 3.56 (m, SH), 4.32 (qd, J = 7.2, 2.2 Hz, 2H), 4.62 (m, 2H), 6.59 (m, IH), 6.97 (m, 2H), 7.53 (m, 9H), 7.66 (dd, J = 8.3, 2.0 Hz, lH), 7.75 (d, J = 8.4 Hz, IH) 63ia 1H NMR (400 MHz, MeOH-d4): s ppm 1.26 (t, J = 7.1 Hz, 3H), 1.52 (dt, J = 9.7, 5.5 Hz, 4H), 1.74 (dd, J = 13.0, 7.3 Hz, 11-I), 2.09 (dd, J = 13. 1 , 8.8 Hz, IR), 2.75 (d, J = 11.0 Hz, lH), 2.89 (d, J = 11. 0 Hz, 1H), 3 .51 (dq, J = 23.9, 7.7, 6.6 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, lH), 4 .18 (qd, J = 7.1, 1.5 Hz, 2H), 5.56 (s, lH), 6.68 (q, J = 7.2 Hz, lH), 7.67 (d, J= 8.1 Hz, 2H), 7.82 (m, 2H), 8.03 (dd, J = 8.9, 2.0 Hz, lH), 8.15 (m, 3H), 8.81 (dd, J = 2.9, 0.9 Hz, lH) 63ib 1HNMR (400 MHz, 4): s ppm 1.06 (t, J = 7.4 Hz, 3H), 1.24 (m, 31-1 ), 1.50 (dt, J = 10.7, 5.6 Hz, 4H), 1.79 (m, 3H), 2.07 (dd, J = 1 3.1 , 8.8 Hz, lH), 2.39 (s, 3H), 2.74 (d, J = 10.9 Hz, lH), 2.87 (m, lH), 3.55 (m, SH), 3.81 (dd, J = 8.8, 7.2 Hz, lH), 4.04 (t, J = 6.4 Hz, 2H), 4.17 (qd, J = 7.2, 1.7 Hz, 2H), 5.75 (s, lH), 6.41 (d, J = 2.4 Hz, 1 H), 6.78 (q, J = 6.6 Hz, IH), 7.15 (t, J = 8.6 Hz, 1H), 7.45 (m, 2H), 7.60 (d, J = 1.8 Hz, lH), 7.73 (m, 2H), 7.98 (d, J = 2.4 Hz, lH) 63ic 1H NMR (400 MHz, Me0H-d4): o ppm 1.00 (t, J = 7.4 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.51 (m, 6H), 1.76 (m, 3H), 2.07 (dd, J = 13.1, 8.8 Hz, IH), 2.39 (s, 3H), 2.74 (d, J = 1 1.0 Hz, lH), 2.88 (d, J = 11.0 Hz, 11-I), 3.53 (qd, J = 13.9, 7.7 Hz, 4H), 3.81 (dd, J = 8.7, 7.2 Hz, l H), 4.14 (m, 4H), 5.74 (s, lH), 6.41 (d, J = 2.3 Hz, lJ-I ), 6.78 (q, J = 6.6 Hz, II-I), 7. 1 5 (m, IH), 7.46 (m, 2H), 7.61 (d, J = 1.7 Hz, IH), 7.73 (m, 2H), 7.98 (d, J = 2.4 Hz, lH) 63id 1H NMR (400 MHz, Me0H-d4): o ppm 1.25 (t, J = 7.1 Hz, 3H), 1 .51 (m, 4H), 1.73 (dd, J = I 3.1, 7.2 Hz, lH), 2.07 (dd, J = 13.0, 8.8 Hz, lH), 2.40 (s, 3H), 2.64 (s, 3H), 2.74 (d, J = 11.0 Hz, Ill), 2.88 (d, J = 1 1 . 0 Hz, l H), 3.52 (m, 4H), 3.81 (dd, J = 8.7, 7.2 Hz, lH), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 5.74 (s, lH), 6.44 (d, J = 2.3 Hz, lH), 6.86 (q, J = 6.6 Hz, lH), 7.76 (m, 3H), 7.85 {d, J = I .2 Hz, 2H), 8.08 (m, 2H) 63ie 1H NMR (400 MHz, Me0H-d4): 8 ppm 0.89 (d, J = 6.7 Hz, 2H), 1.27 {t, J = 7.1 Hz, 3H), 1.53 (rn, 4H), 1.72 (ddd, J = 23.9, 13.2, 7.0 Hz, IH), 1.94 (m, 4H), 2.11 (dd, J = 13.l, 8.8 Hz, lH), 2.77 {d, J = 10.9 Hz, lH), 2.91 (d, J = 1 1 .0 Hz, lH), 3.55 (m, 9H), 3.85 (dd, J = 8.7, 7.3 Hz, lH), 4. 19 (qd, J = 7.1, 1.7 Hz, 2H), 5.53 (s, lH), 6.69 (q, J = 6.7 Hz, lH), 7.31 (d, J = 2.2 Hz, lH), 7.48 (m, 2I-I ), 7.64 (m, 3H), 7.93 (s, lH) 63if 1H NMR (400 MHz, 4): s ppm 1.27 (td, J = 7.1, 0.8 Hz, 4H), 1.53 (m, 4H), 1.76 (m, 9H), 1.97 (dd, J = 13.4, 6.8 Hz, 2H), 2.11 (dd, J = 13.l, 8.8 Hz, lH), 2.77 (d, J = 11.0 Hz, lH), 2.91 (d, J = 10.9 Hz, lH), 3.31 (m, 3H), 3.51 (dq, J = 19.6, 6.3 Hz, 4H), 3.84 (dd, J = 8.7, 7.3 Hz, lH), 4.19 (m, 2H), 5.48 (s, lH), 6.71 (q, J = 6.9 Hz, 11-I), 6.94 (d, J = 7.6 Hz, l H), 7.02 (dd, J = 8.4, 2.6 Hz, IH), 7.18 (s, l H), 7.28 (d, J = 2.2 Hz, lH), 7.43 (m, 2H), 7.66 (d, J = 8.5 Hz, lH) 63ig 1H NMR (400 MHz, Me0H-d4): o ppm 0.89 (dd, J = 6.7, 0.7 Hz, lH), 1.27 (rd, J = 7.1, 0.7 Hz, 3H), 1.53 (m, 4H), 1.75 (dd, J = 13.1, 7.3 Hz, lH), 2.11 (m, 11-1), 2.76 (d, J = 11.0 Hz, lH), 2.90 (d, J = 11 .0 Hz, lH), 3.30 (dq, J = 3.5, 1.8 Hz, SH), 3.54 (m, lOH), 3.82 (m, SH), 4.18 (qd, J = 7.2, 1.6 Hz, 2H), 5.53 (s, lH), 6.70 (q, J = 6.7 Hz, 1H), 6.84 (m, IH), 7.30 (rn , lH), 7.51 (m, 3H), 7.66 (m, 2H), 7.79 (s, lH) 63ih 1HNMR (400 MHz, MeOH-d4): s ppm 1.39 (m, 12H), 1.84 (dd, J = 13.2, 7.8 Hz, IH), 1.98 (m, SH), 2.24 (m, 1H), 2.92 (d, J = 11 .3 Hz, 1H), 3.02 (d, J = 11.2 Hz, lH), 3.54 (ddq, J = 27.6, 15.0, 7.8, 7.4 Hz, 6H), 3.89 (s, lH), 4.07 (t, J = 8.2 Hz, lH), 4.23 (qd, J = 7 .1, 2.0 Hz, 2H), 4.93 (d, J = 1.4 Hz, 1 lH), 5.55 (s, lH), 6.63 (q, J = 6.7 Hz, lH), 7.30 (d, J = 2.2 Hz, 1H), 7.46 (dd, J = 8.5, 2.3 Hz, lH), 7.63 (m, 3H), 7.89 (dt, J = 7.7, 1.6 Hz, lH), 8.35 (s, lH) 63ii 1H NMR (400 MHz, MeOH-d4): s ppm 1.27 (td, J = 7.4, 5.4 Hz, 7H), 1.52 (dt, J = 7.6, 4.7 Hz, 4H), 1.74 (dd, J = 13.1 , 7.2 Hz, 1H) , 2.09 (dd, J= 13.1, 8.7 Hz, lH), 2.74 (m, 3H), 2.90 (d, J = 11.0 Hz, lH), 3.30 (d, J = 9.9 Hz, 1 H), 3.49 (m, 41-I), 3 .83 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.1 , 1.5 Hz, 2H), 5.46 (s, lH), 6.64 (q, J= 6.8 Hz, lH), 7.30 (m, 4H), 7.43 (m, 2H), 7.67 (d, J = 8.5 Hz, lH) 63ij 1H NMR (400 MHz, MeOH-d4): o ppm 1.30 (dd, J = 6.9, 5.1 Hz, 6H), 1.59 (d, J = 5.6 Hz, 4H), 2.03 (dd, J = 13.4, 7.2 Hz, lH), 2.30 (dd, J = 13.4, 9.2 Hz, lH), 3.03 (m, 21-I), 3.22 (d, J = 11.7 Hz, lH), 3.46 (tt, J = 16.4, 7.0 Hz, 2H), 3.62 (q, J = 8.5 Hz, 2H), 4.05 (dd, J = 9.1, 7.1 Hz, lH), 5.48 (s, lH), 6.62 (q, J = 6.7 Hz, lH), 7.31 (m, 4H), 7.44 (m, 2H), 7.66 (d, J = 8.5 Hz, lH) 63ik 1HNMR (400 MHz, MeOH-d4): o ppm 1.05 (t, J = 7.4 Hz, 3H), 1.26 (td, J = 7.2, 0.6 Hz, 4H), 1.51 (dt, J = 10.0, 5.7 Hz, 4H), 1.77 (ddd, J = 27.5, 13.6, 7.1 Hz, 3H), 2.08 (dd, J = 13.1, 8.7 Hz, lH), 2.74 (d, J = 11.0 Hz, lH), 2.88 (d, J = 1 1.0 Hz, lH), 3.30 (p , J = 1 .6 Hz, SH), 3 .51 (m, 4H), 3 .81 (dd, J = 8.7, 7.2 Hz, lH), 3.95 (t, J = 6.5 Hz, 21-1), 4. 1 8 (qd, J = 7 .1, 1.5 Hz, 2H), 5.53 (s, 1H), 6.61 (q, J = 7.2 Hz, lH), 6.97 (m, 2H), 7.56(m, 6H) 63il 1H NMR (400 MHz, MeOH-d4): s ppm 1.26 (t, J = 7.1 Hz, 4H), 1.46 (m, 8H), 1.73 (dd, J = 13.0, 7.3 Hz, lH), 2.08 (m, IR), 2.74 (d, J = 1 1.0 Hz, lH), 2.89 (d, J = 1 1.0 Hz, lH), 3.02 (m, 2H), 3.50 (dd, J = 17.6, 11.2 Hz, 4H), 3.82 (dd, J= 8.7, 7.2 Hz, lH), 4.18 (qd, J = 7.2,1 .5 Hz, 2H), 5 .53 (s, lH), 6.99 (q, J = 6.9 Hz, lH), 7.67 (m, 3H), 8.03 (dd, J = 8.9, 2.1 Hz, 1 I-I), 8 .14 (m, 3H), 8.80 (dd, J = 2.8, 0.9 Hz, 1H) 63im 1H NMR (400 MHz, Me0H-d4): 8 ppm 1.26 (t, J = 7.1 Hz, SH), 1.53 (td, J = 7.3, 6.9, 4.5 Hz, 4H), 1.75 (dd, J = 13.l, 7.3 Hz, lH), 2.10 (m, lH), 2.29 (s, 3H), 2.39 (s, 3H), 2.53 (s, 2H), 2.76 (d, J = 11.0 Hz, lH), 2.90 (d, J = 11.0Hz, lH), 3 .52 (m, 6H), 3.83 (m, 3H), 4.18 (qd, J = 7. l, 1.7 Hz, 2H), 5.51 (d, J = 15.3 Hz, lH), 6.71 (q, J = 6.6 Hz, lH), 7.32 (d, J = 2.3 Hz, IH), 7.50 (m, 3H), 7.66 (m, 2H), 7.80 (s, lH) 63in 1H NMR (400 MHz, Me0H-d4): 8 ppm 1.25(m, 4H), 1.54 (m, 4H), 1.75 (dd, J = 13 . 1, 7.3 Hz, lH), 2 .1 0 (dd, J = 12.8, 8.5 Hz, lH), 2.66 (s, 3H), 2.76 (d, J = 11 .0 Hz, l H), 2.90 (d, J = 1 1 . 0 Hz, lH), 3.52 (dd, J = 14.8 , 8.9 Hz, SH), 3.83 (dd, J = 8.7, 7.3 Hz, l H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.54 (s, lH), 6.85 (t, J = 7.0 Hz, lH), 7.65 (d, J = 2.9 Hz, 3H), 8.04 (dd, J = 8.9, 2.0 Hz, lH), 8.15 (m, 3H), 8.81 (d, J = 2.8 Hz, lH) 63io 1H NMR (400 MHz, MeOH-d4): o ppm 1.15 (t, J = 7.0 Hz, 3H), 1.26 (t, J = 7.1 Hz, 6H), 1.53 (dt, J = 10.1, 5.5 Hz, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, lH), 2.10 (dd, J = 13.1, 8.7 Hz, 1 H), 2.76 (d, J = 11.0 Hz, lH), 2.90 (d, J = 11.0 Hz, lH), 3.36 (d, J = 7.7 Hz, lH), 3.54 (m, 6H), 3.83 (dd, J = 8.7, 7.2 Hz, lH), 4.18 (qd, J = 7.2, 1.6 Hz, 2H), 5.55 (s, 11-I), 6.65 (q, J = 7.1 Hz, 11-1), 7.46 (m, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.72 (m, 4H) 63ip 1H NMR (400 MHz, MeOH-d4): s ppm 1.26 (td, J = 7.1, 1.0 Hz, 7H), 1.53 (m, 8H), 1.74 (dd, J = 13.1, 7.2 Hz, 2H), 2.09 (dd, J = 13.1, 8.7 Hz, 2H), 2.75 (d, J = 11.0 Hz, 2H), 2.89 (d, J = 11.0 Hz, 2H), 3.28 (d, J = 14.7 Hz, HI), 3.53 (m, 9H), 3.82 (dd, J = 8.7, 7.2 Hz, 2H), 4.18 (qd, J = 7.1, 1.5 Hz, 4H), 5.55 (s, 2H), 6.66 (q, J = 7.1 Hz, 2H), 7.62 (d, J = 8.1 Hz, 41-1), 7.72 (m, 8H), 7.95 (m, 4H) 63iq 1H NMR (400 MHz, Me01-I-d4): o ppm 1.27 (m, 6H), 1.54 (m, 4H), 1.78 (dd, J = 13.1, 7.4 Hz, lH), 2.14 (dd, J= 13.2, 8.8 Hz, lH), 2.81 (d, J = 13.9 Hz, 4H), 2.94 (d, J = 11.0 Hz, lH), 3.22 (s, 2H), 3.52 (ddt, J = 19.7, 11.9 , 6.0 Hz, 4H), 3.92 (t, J = 8.0 Hz, lH), 4.21 (qd, J = 7.8, 6.4, 4.7 Hz, 2H), 4.88 (s, 11-I), 5 .51 (s, lH), 6.75 (q, J = 6.7 Hz, lH), 7.49 (m, 2H), 7.72 (m, 2H) 63ir 1H NMR (400 MHz, MeOH-d4): s ppm 1.04 (t, J = 7.4 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.51 (m, 4H), 1.76 (ddd, J = 25.2, 13.5 , 7.1 Hz, 3H), 2.08 (dd, J = 13.1, 8.8 Hz, lH), 2.74 (d, J = 1 1.0 Hz, lH) , 2.89 (d, J = 11.0Hz, IH), 3.47 (dq, J = 26.7, 7.9, 6.9 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, lH), 3.95 (t, J = 6.5 Hz, 2H) , 4.18 (m, 2H), 5.45 (s, lH), 6.66 (q, J = 6.9 Hz, lH), 6.97 (m, 2H), 7.55 (m, 9H), 7.73 (d, J = 8.3 Hz, lH) 63is 1H NMR (400 MHz, MeOH-d4): s ppm 1.28 (t, J = 7.1 Hz, 4H), 1.54 (m, 4H), 1.81 (dd, J = 13.2, 7.6 Hz, IH), 2.18 (dd, J = 13.3, 8.8 Hz, lH), 2.87 (d, J = 1 1.2 Hz, lH), 2.98 (d, J = 11.1 Hz, lH), 3.51 (m, 4H), 4.00 (t, J = 8.1 Hz, lH), 4.21 (qd, J = 7.1 , 1.8 Hz, 2H), 5.49 (d, J=2.0 Hz, lH), 6.82 (q, J = 6.7 Hz, lH), 7.13 (m, 2H), 7.46 (m, 2H), 7.67 (d, J = 8.5 Hz, lH) 63it IH NMR (400 MHz, Me0H-d4): o ppm 1.26 (t, J = 7 .1 Hz, 3H), 1.53 (dt, J = 10.5, 5.6 Hz, 4H), 1.75 (dd, J = 13.0, 7.2 Hz, 1H), 2.10 (dd, J = 1 3.1, 8.7 Hz, lH), 2.76 (d, J = , I H), 2.90 (d, J = 1 1 .0Hz, lH), 3 . 15 (s, 3H), 3.53 (m, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, IH), 4 .18 (qd, J = 7.1 , 1.6 Hz, 2H), 5.56 (s, lH), 6.67 (q, J = 7.1 Hz, lH) , 7.66 (d, J = 8.2 Hz, 2H), 7.74 (m, 2H), 7.89 (m, 2H), 8.02 (m, 2H) 63iu 1H NMR (400 MHz, MeOH-d4): o ppm 1.26 (t, J = 7.1 Hz, 3H), 1.51 (dt, J = 10.8, .6 Hz, 4H), 1.73 (dd, J = 13 . 1, 7.2 Hz, lH), 2.08 (dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s, 31-I ), 2.74 (d, J = 11.0Hz, lH), 2.88 (d, J = 11.0 Hz, IH), 3.15 (s, 3H), 3.53 (m, 4H), 3.81 (dd, J = 8.8, 7.2 Hz, lH), 4.18 (qd, J = 7.2, 1.7 Hz, 2H) , 5.74 (s, lH), 6.43 (d, J = 2.4 Hz, lH), 6.85 (q, J :::, 6.6 Hz, lH), 7.76 (dd, J = 1.7, 0.6 Hz, lH), 7.83 (m, 2H), 7.95 (m, 2H), 8.03 (m, 3H) 63iv 1H NMR (400 MHz, MeOH-d4): s ppm 1.05 (t, J = 7.4 Hz, 3H), 1.26 (m, 3H), 1.49 (dt, J = 10.7, 5.7 Hz,41-1), 1.78 (m, 3H), 2.08 (dd, J = 13.1, 8.8 Hz, lH), 2.25 (d, J = 14.0 Hz, lH), 2.39 (s, 3H), 2.75 (d, J = 11.0 Hz, lH), 2.88 (d, J = 11 .0 Hz, 1 H), 3.53 (m, 4H), 3.83 (t, J = 8.0 Hz, lH), 3.95 (t, J = 6.4 Hz, 2H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.76 (s, lH), 6.41 (d, J = 2.3 Hz, lH), 6.75 (t, J = 6.7 Hz, lH), 6.98 (m, 2H), 7.58 (rn, 3H), 7.71 (m, 2H), 7.96 (d, J = 2.4 Hz, lH) 63ix 1H NMR (400 MHz, MeOH-d4): s ppm 1.14 (t, J = 7.0 Hz, 3H), 1.26 (t, J = 7.1 Hz, 7H), 1.51 (dt, J = 10.8, 5.7 Hz, 4H), 1.73 (dd, J = 13.0, 7.2 Hz, IH), 2.08 (dd, J = 13.0, 8.8 Hz, IH), 2.39 (d, J = 1.7 Hz, 3H), 2.74 (d, J = 10.9 Hz, lH), 2.88 (d, J = 1 1 . 0 Hz, 1H), 3.31 (d, J = 16.3 Hz, 3H), 3.56 (s, 6H), 3.81 (dd, J = 8.7, 7.1 Hz, lH), 4.18 (m, 2H), 5.75 (s, IH), 6.42 (d, J = 2.4 Hz, lH), 6.82 (q, J = 6.5 Hz, 11-I), 7.47 (dd, J = 8.3, 2.0 Hz, 2H), 7.70 (d, J = 1.8 Hz, lH), 7.79 (m, 4H), 8.01 (d, J = 2.4 Hz, lH) 63iy 1I-I NMR (400 MHz, Me0H-d4): s ppm 1.26 (t, J = 7.1 Hz, SH), l.53 (dt, J = 9.7, 5.4 Hz, SH), 1.74 (dd, J = 13.0, 7.3 Hz, 2H), 2.09 (dd, J = 1 3 . 1 , 8.8 Hz, 2H), 2.76 (d, J = 1 1 . 0 Hz, 2H), 2.91 (d, J = 19.4 Hz, 7H), 3.36 (s, lH), 3.53 (m, 8H), 3.83 (dd, J = 8.7, 7.2 Hz, 2H), 4.18 (qd, J = 7.1, 1.6 Hz, 4H), 4.97 (s, lH), 5 .55 (s, 2H), 6.65 (q, J = 7.1 Hz, 2H), 7.62 (d, J = 8.1 Hz, 4H), 7.71 (m, 7H), 7.89 (m, 4H) 63iz 1H NMR (400 MHz, MeOH-d4): o ppm 1.26 (t, J = 7.1 Hz, 4H), 1.51 (dt, J = 10.6, 5.5 Hz, 4H), 1.76 (dd, J = 1 3 . 1 , 7.3 Hz, lH), 2.1 1 (dd, J = 13.1 , 8.8 Hz, lH), 2.40 (s, 3H), 2.78 (d, J = 1 1 . 1 Hz, 1H), 2.91 (d, J = 11 .0 Hz, lH), 3.54 (qq, J = 14.0, 7.5, 6.5 Hz, 4H), 3.88 (dd, J = 8.7, 7.4 Hz, lH) , 4.19 (qd, J = 7. 1 , 1.7 Hz, 2H), 5.75 (s, lH), 6.43 (d, J = 2.4 Hz, lH), 6.83 (q, J = 6.6 Hz, lH), 7.73 (d, J = 1.6 Hz, lH), 7.84 (m, 4H), 7.99 (m, 3H) 63ja 1H NMR (400 MHz, MeOH-d4): o ppm 1.27 (m, 7H), 1.53 (dt, J = 9.9, 5.5 Hz, 8H), 1.77 (dd, J = 1 3 . 1 , 7.4 Hz, 2H), 2.17 (m, 2H), 2.81 (d, J = 1 1 . 1 Hz, 2H), 2.93 (d, J = 11 . 1 Hz, 2H), 3 .33 (d, J = 12.6 Hz, lH), 3.52 (ddt, J = 17.5, 11.5 , 5.2 Hz, 8H), 3.90 (dd, J = 8.6, 7.5 Hz, 2H), 4.20 (qd, J = 7.2, 1 .7 Hz, 3H), 5.56 (s, 2H), 6.66 (q, J = 7.1 Hz, 2H), 7.64 (d, J = 8.1 Hz, 4H), 7.71 (d, J = 8.3 Hz, 4H), 7.79 (m, 4H), 7.96 (m, 4H) 63jb 1H NMR (400 MHz, MeOH-d4): o ppm 1.27 (t, J = 7.1 Hz, SH), 1 .53 (dt, J = 9.6, 5.3 Hz, SH), 1.76 (dd, J = 13.1, 7.3 Hz, lH), 2.11 (dd, J = 13.1, 8.7 Hz, lH), 2.61 (m, 7H), 2.77 (d, J = 1 1 . 0 Hz, lH), 2.91 (d, J = 11.0 Hz, lH), 3.56 (m, 8H), 3.71 (t, J = 4.7 Hz, SH), 3.85 (dd, J = 8.7, 7.2 Hz, 1 H), 4.19 (qd, J = 7.1, 1. 6 Hz, 2H), 5.55 (s, lH), 6.66 (q, J = 7.2 Hz, lH), 7.63 (d, J = 8.1 Hz, 2H), 7.73 (m, 4H), 7.91 (m, 2H) 63jc 1H NMR (400 MHz, MeOH-d4): s ppm 1.21 (dt, J = 33.8, 7.2 Hz, 4H), 1.51 (dt, J = . 8, 5.4 Hz, 4H), 1.74 (dd, J = 1 3 . 1 , 7.3 Hz, lH) , 2.08 (m, lH), 2.40 (s, 3H), 2.58 (dt, J = 23.6, 5.8 Hz, 6H), 2.75 (d, J = 1 1. 0 Hz, lH), 2.88 (dd, J = 11.0, 5.9 Hz, lH), 3.32 (s, lH), 3.57 (m, 6H), 3.70 (t, J = 4.7 Hz, 4H), 3.82 (m, lH), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 5.75 (s, lH), 6.43 (d, J = 2.4 Hz, lH), 6.82 (q, J = 6.6 Hz, lH), 7.72 (d, J = 1.5 Hz, lH), 7.81 (m, 4H), 7.96 (m, 4H) 63jd 1H NMR (400 MHz, MeOH-d4): o ppm 1.26 (td, J = 7 .1, 1.3 Hz, 3H), 1 .52 (dt, J = 9.5, 5.5 Hz, 4H), 1.74 (dd, J = 1 3.1, 7.2 Hz, lH), 2.09 (dd, J = 13.1 , 8.8 Hz, lH), 2.75 (d, J = 1 1 . 1 Hz, lH), 2.89 (d, J = 1 0.9 Hz, lH) , 3.04 (d, J = 1.3 Hz, 3H), 3 . 1 1 (s, 3H), 3.52 (m, 4H), 3.82 (m, lH), 4 . 1 8 (qt, J = 7.1, 1.4 Hz, 2H), 5.55 (d, J = 1.3 Hz, lH), 6.66 (q, J = 7.1 Hz, lH), 7. 51 (m, 2H), 7.68 (m, 6H) 63je 1HNMR (400 MHz, 4): s ppm 1.27 (t, J = 7.1 Hz, 4H), 1.53 (dt, J = 9.5, 5.3 Hz, 4H), 1.75 (dd, J = 13.0 , 7.3 Hz, lH), 2.11 (dd, J = 13.1 , 8.8 Hz, l H), 2.78 (t, J c= 9.8 Hz, 3H), 2.91 (d, J = 11.0 Hz, 4H), 3.50 (m, 7H), 3.75 (s, 2H), 3.85 (dd, J = 8.8, 7.3 Hz, II-I), 4.19 (qd, J = 7.2, 1.6 Hz, 2H), 5.5 5 (s, lH), 6.66 (q, J = 7.0 Hz, lH), 7 .51 (m, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.72 (m, 4H) 63jf 1H NMR (400 MHz, MeOH-d4): o ppm 1.26 (td, J = 7.4, 1.9 Hz, SH), 1.50 (dt, J = .8, 5.8 Hz, SH), 1.75 (dd, J = 1 3 . 1 , 7.4 Hz, IH), 2.10 (dd, J = 13. 2, 8.9 Hz, lH), 2.39 (s, 3H), 2.86 (m, SH), 3.26 (s, 1 H), 3.52 (m, 8H), 3.76 (s, 2H) , 3.88 (dd, J = 8.8, 7.3 Hz, lH), 4.1 8 (ddtd, J = 7.7, 5.3, 3.6, 2.0 Hz, 2H), 4.93 (s, 2H), 5.74 (s, lH), 6.43 (d, J = 2.4 Hz, IH), 6.82 (a, J = 6.6 Hz, lH), 7.51 (dd, J = 8.3, 2.0 Hz, 2H), 7.75 (m, 7H), 8.01 (d, J = 2.4 Hz, lH) 63jg 1H NMR (400 MHz, MeOH-d4): o ppm 1.31 (t, J = 7.2 Hz, 8H), 1.57 {s, 1 OH), 1.95 (dd, J = 13.4, 8.4 Hz, 2H), 2.37 (t, J = 11.1 Hz, 2H), 3.12 (m, 4H), 3.61 (m, l SH), 4.31 (m, 6H), 5.49 (s, lH), 5.62 (s, l H), 6.25 (d, J = 6.9 Hz, 2H), 6.50 (t, J = 6.8 Hz, 2H), 7.31 (d, J = 2.2 Hz, 2H), 7.46 (dd, J = 15.4, 7.7 Hz, 4H), 7.65 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 7.1 Hz, 2H) 63jh 1H NMR (400 MHz, MeOH-d4): s ppm 1.26 (t, J = 7.1 Hz, 3H), l.50 (dt, J = 10.4, 5.5 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, lH), 2.08 (dd, J = 13.1, 8.8 Hz, IH), 2.39 (s, 3H), 2.75 (d, J = 11.0 Hz, lH), 2.89 (d, J = 11.0 Hz, lH), 3.53 (m, 4H), 3.83 (m, lH), 3.90 (s, 3H), 4.18 (qd, J = 7.2, 1.6 Hz, 2H), 5.75 (s, lH), 6.41 (d, J = 2.4 Hz, lH), 6.78 (q, J = 6.7 Hz, lH), 7.17 (t, J = 8.9 Hz, lH), 7.48 (m, 2H), 7.61 (d, J = 1.8 Hz, IH), 7.73 (m, 2H), 7.99 (d, J = 2.4 Hz, lH) 63ji 1H NMR (400 MHz, Me0H-d4): s ppm 1.30 (d, J = 11.1 Hz, lH), 1.51 (q, J = 6.8, 6.0 Hz, 4H), 1.78 (dd, J = 13.0, 7.0 Hz, lH) , 1.89 (s, 2H) , 2.07 (dd, J = 1 3 .1, 9 .1 Hz, lH), 2.40 (s,3H), 2.68 (d, J = 11.1 Hz, IH), 2.95 (d, J = 11 . 1 Hz, lH), 3.03 (s, 3H), 3.11 (s, 3H), 3.22 (s, 2H), 3.45(m, 3H), 3.63 (q, J = 7.9, 7.5 Hz, 3H), 5.75 (s, lH), 6.43 (d, J = 2.4 Hz, lH), 6.82 (q, J = 6.6 Hz, lH), 7.53 (d, J = 7.9 Hz, 2H) , 7.70 (m, lH) , 7.80 (m, 4H), 8.01 (d, J = 2.5Hz, HI) 63jj 1H NMR (400 MHz, MeOH-d4): o ppm 1.06 (t, J = 7.4 Hz, 4H), 1.30 (t, J = 7.1 Hz, 3H), 1.57 (m, 4H), 1.86 (m, 3H), 2.30 (m, lH), 3.09 (m, 3H), 3.54 (m, 4H), 4.03 (t, J = 6.4 Hz, 2H), 4.27 (m, 3H), 5.55 (s, IH), 6.64 (q, J = 7.2 Hz, IH), 7.12 (t, J = 8.8 Hz, lH), 7.37 (m, 2H), 7.58 (q, J = 8.4 Hz, 4H) 63jk 1H NMR (400 MHz, MeOH-d4): s ppm 1.26 (t, J = 7.1 Hz, SH), 1.50 (dt, J = 10.2, 5.2 Hz, 4H), 1 .75 (dd, J = 13.1 , 7.4 Hz, lH), 2.10 (dd, J = 13.1, 8.8 Hz, IH), 2.40 (s, 3H), , J = 11.1 Hz, lH), 2.91 (d, J = 13.6 Hz, 4H) , 3.52 (m, 4H), 3.88 (dd, J = 8.7, 7.3 Hz, lH), 4.18 (qd, J = 7.1 , 1.6 Hz, 2H), 5.75(s, lH), 6.43 (d, J = 2.4 Hz, lH), 6.82 (q, J = 6.5 Hz, lH), 7.70 (d, J = 1.7 Hz, lH), 7.78 (m, 4H), 7.90 (m, 2H), 8.01 (d, J = 2.4 Hz, UI) 63jl 1H NMR (400 MHz, MeOH-d4): o ppm 1.25 (m, SH), 1.54 (dt, J = 11.2, 6.0 Hz, 4H), 1.75 (dd, J = 13.1 , 7.2 Hz, lH), 2.11 (dd, J = 13.1 , 8.8 Hz, lH), 2.58 (s, 3H), 2.77 (d, J = 11.0 Hz, lH), 2.91 (d, J = 11.0 Hz, lH), 3.55 (h, J = 7.5 Hz, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, lH), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 5.58 (s, HI), 6.65 (q, J = 6.6 Hz, lH) , 7.34 (d, J = 2.2 Hz, IH), 7.49 (dd, J = 8.5, 2.3 Hz, lH), 7.73 (m, 3H), 7.94 (ddd, J = 7.9, 1.8 , 1.1 Hz, lH), 8.32 (s, 1H) 63jm 1H NMR (400 MHz, Me0H-d4): o ppm 1.27 (t, J = 7.1 Hz, 4H), 1.54 (dt, J = 8.6, 4.8 Hz, 4H), 1.76 (dd, J = 13 . 1 , 7.2 Hz, IH), 2.11 (dd, J = 13.1 , 8.8 Hz, lH) , 2.73 (s, 7H), 2.91 (d, J = 10.9 Hz, lH) , 3.55 (dp, J = 20.2, 7.2, 6.0 Hz, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, 1H), 4 .19 (qd, J = 7.1, 1 .6 Hz, 2H), 5.59 (s, lH), 6.69 (q, J = 6.4 Hz, lH), 7.36 (d, J = 2.2 Hz, 11-I), 7.50 (dd, J = 8.5, 2.2 Hz, UI), 7.70 (dd, J = 13.1 , 8.0 Hz, 2H), 7.85 (m, 2H), 8.34 (s, lH) 63jn 1HNMR (400 MHz, MeOH-d4): 8 ppm 1.30 (m, lOH), 1.52 (dt, J = 10.2, 5.7 Hz, 4H), 1.74 (dd, J = 13.1, 7.3 Hz, lH), 2.08 (m, lH), 2.83 (m, 4H), 3.20 (ddd, J = 11.9 , 6.2, 3.0 Hz, 2H), 3.31 (s, lH), 3.49 (ddd, J = 30.2, 13.4, 6.0 Hz, 4H), 3.90 (dddd, J = 32.2, .9, 7.4, 5.0 Hz, SH), 4.18 (qd, J = 7.2, l.5 Hz, 2H), 4.64 (p, J = 6.0 Hz, lH), 5.52 (s, lH), 6.96 (m, 2H), 7.40 (m, 2H), 7.54 (m, 4H) 63jo 'H NMR (400 MHz, MeOH-d4): s nnm 1.27 (m, 4H), 1.54 (dt, J = 7.6, 4.8 Hz, SH), 1.76 (dd, J = 13.1, 7.3 Hz, IH), 2.11 (dd, J= 13.1, 8.8 Hz, lH), 2.77 (d, J= 11.0 Hz, lI-I), 2.92 (d, J = 18.5 Hz, 4H), 3.53 (m, 4H), 3.85 (dd, J = 8.7, 7.3 Hz, 1H), 4.19 (qd, J = 7.1, 1.6 Hz, 2H), 4.93 (s, 7H), 5.52 (d, J = 19.1 Hz, lH), 6.63 (q, J = 6.7 Hz, lH), 7.29 (d, J = 2.2 Hz, IH), 7.46 (dd, J = 8.5, 2.3 Hz, lI-1), 7.62 (m, 3H), 7.88 (dt, J = 7.7, 1.6 Hz, lH), 8.37 (s, lH) 63jp 1H NMR (400 MHz, Me0H-d4): o ppm 1.26 (t, J = 7.1 Hz, 3H), 1.53 (dt, J = 7.7, 4.7 Hz, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, lH), 2.10 (dd, J = 13.1, 8.8 Hz, lH), 2.76 (d, J = 11.0 Hz, IH), 2.90 (d, J = 11.0 Hz, lH), 3.06 (s, 3H), 3.12 (s, 3H), 3.51 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, IH), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.53 (s, lH), 6.70 (q, J = 6.7 Hz, lH), 7.32 (d, J = 2.2 Hz, lH), 7.56 (m, SH), 7.79 (s, lH) 63jq 1H NMR (400 MHz, MeOH-d4): o ppm l.26 (t, J = 7.1 Hz, SH), 1.46 (m, 7H), 1.74 (dd, J = 13.1, 7.3 Hz, l H), 2.09 (dd, J = 13.1, 8.7 Hz, IH) , 2.75 (d, J = 11.0 Hz, lH), 2.89 (d, J = 11.0 Hz, lH), 3.52 (m, 4H) , 3.82 (dd, J = 8.7, 7.2 Hz, lH), 4.15 (m, 4H), .53 (s, lH), 6.62 (q, J = 7.1 Hz, lH), 7.12 (t, J = 8.7 Hz, lH), 7.38 (m, 2H), 7.58 (q, J = 8.4 Hz, 4H) 63jr IH NMR (400 MHz, MeOH-d4): s ppm 1.26 (t, J = 7 .1 Hz, 3H), 1.39 (t, J = 7.0 Hz, 3H), 1.51 (m, 4H) , 1.73 (dd, J = 13.1 , 7.3 Hz, IH), 2.08 (dd, J = 13.1 , 8.8 Hz, lH), 2.74 (d, J = 11.0 Hz, lH), 2.88 (d, J = 11.0 Hz, lH), 3.49 (dtt, J = 19.6, 13.1, 6.9 Hz, 4H), 3.82 (dd, J = 8.8, 7.3 Hz, lH), 4.05 (q, J = 7.0 Hz, 2H), 4.18 (qd, J = 7. 1, 1.5 Hz, 2H), 5.53 (s, lH), 6.61 (q, J = 7.1 Hz, IH), 6.96 (m, 2H), 7.55 (m, 6H) 63js 1H NMR (400 MHz, MeOH-d4): o ppm 1.26 (t, J = 7.1 Hz, 3H), 1.52 (m, 4H), 1.75 (dd, J = 1 3.1, 7.3 Hz, 1H), 2.10 (dd, J = 13. 1 , 8.8 Hz, lH), 2.76 (d, J = 11.0 Hz, IH), 2.90 (d, J = 11.0 Hz, lH), 3. 16 (s, 3H), 3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.3 Hz, lH), 4.18 (qd, J = 7.2, 1 .5 Hz, 2H), 5.53 (s, lH), 6.75 (q, J = 6.7 Hz, lH), 7.56 (m, SH), 7.84 (d, J = 1.9 Hz, lH), 7.99 (m, 2H) 63jt 1H NMR (400 MHz, MeOH-d4): o ppm 1.13 (t, J = 7.2 Hz, 3H), 1.27 (q, J = 6.8 Hz, 7H), 1.55 (m, 4H) , 1 .81 (dd, J = 13.2, 7.6 Hz, lH), 2.18 (dd, J = 13.2, 8.7 Hz, lH), 2.86 (d, J = 11.2 Hz, IH), 2.98 (d, J = 11.2 Hz, lH), 3.36 (q, J = 7.1 Hz, 2H), 3.56 (m, 6H), 3.98 (t, J = 8.1 Hz, lH), 4.21 (qd, J = 7.2, 1 .8 Hz, 2H), 5.54 {s, lH), 6.74 (q, J = 6.8 Hz, 1H), 7.32 (d, J = 2.2 Hz, II- I), 7.49 (m, 3H), 7.65 (m, 3H) 63ju 1H NMR (400 MHz, MeOH-d4): o ppm 1.04 (dd, J = 6.8, 1 .9 Hz, 6H), 1.26 (t, J = 7.2 Hz, 3H), 1.50 (dt, J = 10.7, 5.7 Hz, 4H), 1.73 (dd, J = 13.1 , 7.2 Hz, lH), 2.07 (ddd, J = 13.0, 7.7, 4.9 Hz, 21-1), 2.39 (s, 2H), 2.74 (d, J = 10.9 Hz, lH), 2.88 (d, J = 11.0 Hz, 1H), 3.49 (d, J = 7.5 Hz, l H), 3.56 (d, J = 7.9 Hz, 3H), 3.78 (m, 3H), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 5.75 (s, lH) , 6.41 (d, J = 2.4 Hz, IH), 6.75 (q, J = 6.6 Hz, 1H), 6.99 (m, 2H), 7.60 (dd, J = 8.7, 1.9 Hz, 3H), 7.72 (m, 2H), 7.97 (d, J = 2.4 Hz, lH) 63jv 1H NMR (400 MHz, MeOH-d4): o ppm 1.04 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H), 1.48 (dt, J = 10.6, 5.7 Hz, 4H), 1.71 (dd, J = 13.1 , 7.2 Hz, IH), 2.05 (dd, J = 13.1 , 8.8 Hz, IH), 2.39 (s, 3H), 2.72 (d, J = 11.0 Hz, lH), 2.86 (d, J = 11.0 Hz, lH), 3.52 (m, 4H), 3.64 (s, 2H), 3.80 (dd, J = 8.7, 7.1 Hz, lH), 4.17 (qd, J = 7.1 , 1.5 Hz, 2H), 5.75 (s, lH), 6.41 (d, J = 2.3 Hz, IH), 6.76 (q, J= 6.6 Hz, IH), 6.98 (m, 2H), 7.57 (m, 3H), 7.70 (m, 2H), 7.96 (d, J = 2.4 Hz, IH) 63jw 1H NMR (400 MHz, 4): s ppm lH NMR (MeOH-d4) o: 1.29 (t, J = 7.1 Hz, 7H), 1.53 (s, 8H), 1.79 (s, 2H), 2.14 (s, 21-I), 2.81 (s, 2H), 2.94 (d, J = 10.8 Hz, 2H), 3.50 (s, 7H), 3.57 (s, 2H), 3.90 (t, J = 8.0 Hz, 2H), 4.22 (qd, J = 7.1, 1.7 Hz, 3H), 5.43 (s, IH), 6.51 (s, lH), 6.85 (s, lH), 7.25 (s, lH), 7.48 (d, J = 9.7 Hz, 4H), 7.55 (d, J = 7.5 Hz, 2H), 7.79 (s, 4H), 8.13 (s, 2H) 63jx 1H NMR (400 MHz, Me0H-d4): s ppm 1.26 (t, J = 7.1 Hz, 3H), 1.49 (dt, J = 10.8, 5.8 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, II-I), 2.03 (m, 3H), 2.39 (s, 3H), 2.73 (d, J = 11.0 Hz, lH), 2.85 (m, 3H), 3.53 (m, 4H), 3.81 (dd, J = 8.7, 7.1 Hz, lH), 4.17 (m, 4H), .75 (s, lH), 6.40 (d, J = 2.3 Hz, lH), 6.77 (dd, J = 17.0, 7.9 Hz, 2H), 7.36 (dq, J = 4.4, 2.5 Hz, 2H), 7.56 (d, J = 1.8 Hz, 11-1), 7.69 (m, 2H), 7.96 (d, J = 2.3 Hz, lH) 63jy 1H NMR (400 MHz, Me0H-d4): 3 1.27 (dd, J = 7.9, 6.4 Hz, 4H), 1.54 (dt, J = 10.7, .6 Hz, 4H), 1.76 (dd, J = 13.2, 7.4 Hz, lH), 2.12 (dd, J = 13.1, 8.8 Hz, lH), 2.78 (m, 3H), 2.92 (m, 3H), 3.53 (m, 6H), 3.76 (s, 2H), 3.85 (dd, J = 8.7, 7.2 Hz, lH), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.51 (d, J = 15.6 Hz, IH), 6.72 (q, J = 6.6 Hz, lH), 7.33 (d, J = 2.2 Hz, lH), 7.51 (m, 3H), 7.66 (111, 2H), 7.79 (s, lH) 63jz 1H NMR (400 MHz, Me01-I-d4): 6 0.46 (m, 41-I ), 1.27 (m, 4H), 1.53 (dt, J = 11.2 , 5.6 Hz, 4H) , 1.72 (m, 2H), 2.13 (dd, J = 13.1, 8.8 Hz, lI-1), 2.58 (s, 21-I ), 2.73 (s, 21-I ), 2.80 (d, J = 11 . l Hz, lH), 2.93 (d, J = 1 1 .0Hz, lH) , 3.52 (ddd, J = 25.7, 12.3, 6.8 Hz, 6H), 3.76 (s, 2H), 3.89 (dd, J = 8.7, 7.3 Hz, lH), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.52 (d, J = 17.0 Hz, lH), 6.71 (q, J = 6.7 Hz, lH), 7.33 (d, J = 2.3 Hz, ll- I), 7.57 (m, 5H), 7.80 (s, 63ka 1H NMR (400 MHz, MeOH-d4): s ppm 1.25 (t, J = 7.1 Hz, 31-I ), 1.50 (dt, J = 10.3, 5.3 Hz, 4H), 1.73 (dd, J = 13. 1, 7.3 Hz, lH), 2.07 (dd, J = 13. 1, 8.8 Hz, lH), 2.41 (s, 3H), 2.75 (d, J = 11 .0 Hz, lH), 2.88 (d, J = 11.0 Hz, lI-1), 3.51 (m, 4H), 3.82 (dd, J = 8.8, 7.2 Hz, lH), 4.17 (qd, J = 7.1 , 1.6 Hz, 21-I ), 5.76 (s, II-I ), 6.45 (d, J = 2.4 Hz, lH), 6.88 (q, J = 6.6 Hz, lH), 7.92 (m, 3H), 8.07 (d, J = 2.4 Hz, IH), 8.29 (m, 3H), 8.52 (d, J = 8.9 Hz, lH), 9.32 (d, J = 5.9 Hz, lH) 63kb 1H NMR (400 MHz, Me0H-d4): s ppm 1.35 (t, J=7.22 Hz, 3 H) 1.65 - 1.91 (m, 4 H) 2.12 (dd, J=13.67, 8.79 Hz, 1 H) 2.53 (dd, J=l3.67, 8.79 Hz, 1 H) 3.35 (s, 2 H) 3.56 - 3.91 (m, 4 H) 4.35 (qd, , 3.03 Hz, 2 H) 4.65 (t, J=8.69 Hz, 1 H) 6.66 (d, J=5.66 Hz, 1 H) 7.02 (d, J=2.34 Hz, lH) 7.69 - 7.78 (m, 2 H) 7.79 - 7.88 (m, 1 H) 8.29 (d, J=l .37 Hz, I H) 63kc 1HNMR (400 MHz, MeOH-d4): 6 ppm 1.35 (t, J=7.13 Hz, 3 H) 1.40 (s, 9 H) 1.64- 1.85 (m, 4 H) 2.03 - 2.18 (m, 1 I-I) 2.43 - 2.61 (m, I H) 3.53 - 3.87 (m, 4 H) 4.27 - 4.43 (m, 2 H) 4.56 - 4.70 (m, 1 H) 5.51 (s, 1 H) 6.56 (d, J=2.34 Hz, 1 H) 7.30 - 7.42 (m, I H) 7.53 - 7.61 (m, 1 H) 7.69 (d, J=l.95 Hz, 2 H) 8.01 (d, 1=2.54 Hz, 1 H) 63kd 1H NMR (400 MHz, MeOH-d4): o ppm 1.22 - 1.42 (m, 9 H) 1.51 - 1.72 (m, 4 H) 1.90 - 2.09 (m, 1 H) 2.33 - 2.52 (m, 1 I- 1) 3.09 (s, 1 H) 3.21 (d, 1=4.69 Hz, 2 H) 3.40 - 3.72 (m, 4 H) 4.31 (dd, J=7.13, 2.25 Hz, 2 H) 4.48 (s, 1 H) 5.64 (s, 1 H) 6.47 (d, J=2.34 Hz, 1 H) 7.02 (d, J=6.64 Hz, 1 H) 7.43 - 7.60 (m, 2 H) 7.72 (d, J=8.59 Hz, 1 H) 7.95 (d, J=2.34 Hz, 1 H) 63ke 1H NMR (400 MHz, MeOH-d4): o ppm 0.68 - 0.95 (m, 2 H) 1.05 (dd, J=8.40, 2.15 Hz, 2 H) 1.35 (t, J=7.13 Hz, 4 H) 1.63 - 1.89 (111, 4 H) 1.98 - 2.18 (m, 2 H) 2.44-2.63 (m, 1 H) 3.78 (d, J=5.08 Hz, 4 H) 4.35 (d, J=7.03 Hz, 2 H) 4.63 (s, 1 H) 6.31 (d, J=2.34 Hz, 1 H) 7.09 (d, J=6.25 Hz, 1 H) 7.51 - 7.67 (m, 2 H) 7.73 (d, J=8.20 Hz, 1 H) 7.93 (d, J=2.54 Hz, 1 H) 63kf 1H NMR (400 MH z, MeOH-d4): s ppm 1.35 (t, J=7.13 Hz, 4 H) 1.74 (br. s., 4 H) 2.04 - 2.1 5 (111, 1 H) 2.34 (s, 3 H) 2.37 (s, 3 H) 2.44 -2 .58 (m, 1 H) 3.31 (d, J=2.34 Hz, 2 H) 3.54 - 3.89 (m, 3 I-1) 4.34 (dd, J=7.13, 3.22 Hz, 2 H) 4.61 (s, 1 H) 6.10 (s, 1 H) 6.51 - 6.65 (m, 1 H) 7.03 (d, J=2.15 Hz, 1 H) 7.28 (s, 1 H) 7.42-7.50 (m, I H) 7.54 (s, 1 H) 7.76 - 7.88 (m, 2 H) 7.90 - 8.01 (m, 1 H) 8.33 (s, 1 H) 63kg 1H NMR (400 MHz, MeOH-d4): s ppm 1.29 (t, J = 7.1 Hz, 3H), 1.55 (s, 3H), 1.58 (d, J = 5.8 Hz, lH), 1.88 (m, lH), 2.29 (m, 6H), 3.04 (m, 2H), 3.43 (s, 2H), 3.56 (s, 2H), 4.24 (m, 2H), 6.68 {q, J = 6.9 Hz, lH), 7.17 (d, J = 7.9 Hz, lH), 7.36 (m, 2H), 7.45 (m, lH), 7.52 (s, 2H), 7.53 (d, J = 2.8 Hz, IH), 7.63 (dd, J = 8.2, 2.0 Hz, lH), 7.73 (d, J = 8.2 Hz, lH) 63kh 1H NMR (400 MHz, 4): o ppm 1.05 (t, J = 7.4 Hz, 3H), 1.26 (td, J = 7.1, 2.1 Hz, 3H), 1.50 (s, 3H), 1.53 (d, J = 5.7 Hz, lH), 1.79 (m, 3H), 2.09 (dd, J = 13.1, 8.8 Hz, lH), 2.75 (d, J = 11.0 Hz, lH), 2.89 (d, J = 11.0 Hz, 11-I), 3.50 (s, 3H), 3.83 (dd, J = 8.8, 7.2 Hz, lH), 4.02 (t, J = 6.5 Hz, 21-l), 4.17 (m, 2H), 5.46 (s, lH), 6.67 (q, J = 6.7 Hz, lH), 7.12 (t, J = 8.6 Hz, lH), 7.40 (m, 4H), 7.52 (s, 4H), 7.54 (s, lH), 7.62 (dd, J = 8.2, 2.1 Hz, lH), 7.74 (d, J = 8.3 Hz, lH) 63ki 1H NMR (400 MHz, MeOH-d4): o ppm 1.27 (t, J = 7.1 Hz, 3H), 1.53 (dd, J = 11.2, .2 Hz, SH), 1.75 (dd, J = 13.1, 7.3 Hz, lH), 2.10 (dd, J = 13.1, 8.8 Hz, II-I), 2.76 (d, J = 11.0 Hz, lH), 2.90 (d, J = 11.0 Hz, IH), 3.49 (m, 2H), 3.51 (s, 3H), 3.84 (dd, J = 8.7, 7.3 Hz, lH), 4.18 (qd, J= 7.1, 1.6 Hz, 2H), 5.44 (s, lH), 6.66 (q, J = 6.9 Hz, lH), 7.26 (m, UD, 7.45 (m, 8H), 7.70 (d, J = 7.2 Hz, lH) 63kj 1H NMR (400 MHz, MeOH-d4): s ppm 1.27 (t, J = 7.1 Hz, 3H), 1.53 (dd, J = 11.0, .2 Hz, 4H), 1.77 (dd, J = 13.2, 7.4 Hz, lH), 2.13 (dd, J :::: 13.1 , 8.8 Hz, lH), 2.80 (d, J = 11.1 Hz, lH), 2.93 (d, J = 11.1 Hz, lH), 3.46 (m, IH), 3.53 (m, 2H), 3.91 (t, J = 8.1 Hz, lH), 4.19 (qd, J = 7.1, 1.4 Hz, 2H), 5.47 (s, lH), 6.69 (q, J = 6.9 Hz, 11-I ), 7.35 (m, lH), 7.45 (m, 4H), 7.54 (d, J = 4.6 Hz, 4H), 7.65 (m, 3H), 7.77 (d, J = 8.2 Hz, IH) 63kk 1H NMR (400 MHz, MeOH-d4): o ppm 1.25 (t, J = 7.1 Hz, 3H), 1.51 (m, 4H), 1.74 (dd, J = 13.1, 7.4 Hz, lH), 2.10 (dd, J = 13.1, 8.8 Hz, lH), 2.29 (d, J = 9.9 Hz, 6H), 2.39 (s, 3H), 2.77 (d, J = 11.1 Hz, lH), 2.90 (d, J = 11.1 Hz, lH) , 3.54 (tq, J = 14.0, 7.9, 6.7 Hz, 4H), 3.88 (dd, J = 8.7, 7.4 Hz, lH), 4.17 (m, 21-l ), 5.74 (s, lH), 6.41 (d, J = 2.3 Hz, IH), 6.77 (q, J = 6.6 Hz, lH), 7.19 (d, J = 7.8 Hz, lH), 7.36 (dd, J = 7.6, 2.1 Hz, lH), 7.42 (d, J = 1 .5 Hz, lH), 7.59 (d, J = 1.9 Hz, lH), 7.72 (m, 2H), 7.97 (d, J = 2.4 Hz, lH) 63kl 1H NMR (400 MHz, MeOH-d4): s ppm 1.26 (t, J = 7.1 Hz, 3H), 1.51 (dd, J = 11.1, .8 Hz, SH), 1.74 (dd, J= 13.1 , 7.3 Hz, lH), 2.09 (dd, J = 13 .1, 8.8 Hz, lH), 2.39 (s, 3H), 2.76 (d, J = 11.0Hz, lH), 2.89 (d, J = 11.0 Hz, lH), 3.55 (d, J = 5.0 Hz, 4H), 3.85 (dd, J = 8.7, 7.2 Hz, lH), 4.18 (m, 2H), 4.65 (s, 2H), 5.78 (s, lH), 6.41 (d, J = 2.4 Hz, lH), 6.87 (q, J = 6.5 Hz, lH), 7.47 (dd, J = 10.9, 8.2 Hz, 3H), 7.59 (m, 2H), 7.79 (dd, J = 8.3, 2.1 Hz, lH), 7.93 (d, J = 2.3 Hz, 2H) 63km 1H NMR (400 MHz, MeOH-d4): s ppm 7.61 -7.49 (m, 4H), 7.35 - 7.27 (m, 2H), 6.77 (dd, J = 8.4, 1 .8 Hz, lH), 6.60 (q, J = 7.3 Hz, lH), 5.55 -5.46 (m, lH), 4.24 - 4.13 (m, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, l H), 2.93 -2.71 (m, 4H), 2.14 - 1.94 (m, 3H), 1.74 (dd, J = 13.1 , 7.3 Hz, IH), 1.56- 1.48 (m, lH), 1.51 (s, 3H), 1.27 (td, J = 7.1 , 2.0 Hz, 3H). 63kn 1H NMR (400 MHz, MeOH-d4): o ppm 8.71 (d, J = 5.2 Hz, 2H), 8.02 (td, J = 7.7, 1.7 Hz, lH), 7.78 -7.68 (m, 3H), 7.51 (tt, J = 7.9, 3.3 Hz, SH), 6.92 (d, J = 6.5 Hz, lH), .81 (d, J = 3.8 Hz, 2H), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 3.83 (s, lH), 3.56 (s, 6H), 3.57 - 3.46 (m, lH), 2.89 (d, J = 11.0 Hz, 2H), 2.76 (d, J = 11.0 Hz, 2H), 2.09 (dd, J = 13.1 , 8.9 Hz, lH), 1.74 (dd, J = 13.1, 7.3 Hz, lH), 1.52 (dd, J = 10.9, 5.5 Hz, SH), 1.31 - 1.22 (m, 6H) 63ko 1H NMR (400 MHz, MeOH-d4): o ppm 8.99 (d, J = 4.9 Hz, 2H), 8.03 (s, 1 H), 7.73 (dd, J = 15.2, 7.7 Hz, 2H), 7.60 - 7.48 (m, 2H), 5.69 (s, lH), 4.18 (q, J = 7. 1 Hz, 2H), 3.83 (t, J = 8.1 Hz, lH), 3.54 - 3.43 (m, 4H), 2.89 (d, J = 11.1 Hz, I H), 2.75 (d, J = 11.0 Hz, lH), 2.14 -2.04 (m, lH), 1.74 (dd, J = 13.0, 7.4 Hz, lH), 1.50 (dd, J = 10.6, .5 Hz, SH), 1.26 (t, J = 7 .2 Hz, 4H) 63kp 1H NMR (400 MHz, MeOH-d4): o ppm 7.97 (s, lH), 7.76 (s, 2H), 7.66 (d, J = 16.1 Hz, 2H), 7.49 (d, J = 7.9 Hz, lH), 7.25 (d, J = 8.1 Hz, lH), 6.77 (d, J = 7.1 Hz, 11-1), 6.41 (s, lH), 5.74 (d, J = 2.7 Hz, lH), 4.68 (s, 2H), 4.18 (d, J = 7.6 Hz, 2H), 3.84 (t, J = 8.1 Hz, lH), 3.56 (s, 3H), 3.49 (s, lH), 3.30 (d, J = 3.4 Hz, 9H), 2.89 (d, J = 11.1 Hz, HI), 2.76 (d, J = 11.0 Hz, lH), 2.37 (d, J = 14.1 Hz, SH), 1.79 -1.69 (m, lH), 1.51 (d, J = 8.8 Hz, 4H), 1.30 - 1.21 (m, 4H) 63kq 1HNMR (400 MHz, Me0H-d4): s ppm 7.98 (s, lH), 7.76 (d, J = 5.1 Hz, 2H), 7.63 (s, lH), 7.48 (d, J = 13.3 Hz, 3H), 6.77 (d, J = 6.8 Hz, lH), 6.41 (s, lH), 5.74 (s, lH), 4.66 (s, 2H), 4.18 (d, J = 7.4 Hz, 2H), 3.82 (t, J = 8.2 Hz, lH), 3.56 (s, 3H), 3.50 (s, 1H), 2.89 (d, J = 11.0 Hz, lH), 2.75 (d, J = 11.1 Hz, IH), 2.39 (s, 6H), 1.74 (dd, J = 13.0, 7.2 Hz, lH), 1.51 (s, 4H), 1.30 - 1.22 (m, 3H) 63kr 11-I NMR (400 MHz, Me0H-d4): o ppm 8.43 (d, J = 2.5 Hz, lH), 7.98 (d, J = I OJ Hz, 2H), 7.79 (d, J = 8.3 Hz, lH), 7.71 (d, J = 8.5 Hz, lH), 7.63 (s, lH), 6.83 (dd, J = 19.6, 7.7 Hz, 2H), 6.42 (d, J = 2.3 Hz, IH), 5.74 (s, lH), 4.35 (q, J = 7.0 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.55 (s, 3H), 3.48 (d, J = 13.0 Hz, lH), 2.88 (d, J = 11.0Hz, lH), 2.74 (d, J = 11.0Hz, lH), 2.39 (s, 3H), 2.07 (dd, J = 13.0, 8.9 Hz, lH), 1.73 (dd, J = 13.0, 7.2 Hz, lH), 1.50 (d, J = 8.3 Hz, 4H), 1.38 «, J = 7.1 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H). 63ks 1H NMR (400 MHz, MeOH-d4): s ppm 8.46 (s, lH), 7.99 (s, 2H), 7.83 - 7.69 (m, 2H), 7.64 (s, lH), 6.80 (d, J = 5.3 Hz, l H), 6.42 (s, lH), 5.74 (s, lH), 4.18 (d, J = 7.3 Hz, 2H), 3.94 (d, J = 2.7 Hz, 3H), 3.86 (t, J = 8.1 Hz, lH), 3.56 (s, 3H), 3.50 (s, lH), 2.91 (d, J = 1 1 .0 Hz, lH), 2.77 (d, J = 11.6 Hz, IR), 2.39 (d, J = 2.7 Hz, 3H), 2.10 (t, J = 10.9 Hz, lH), 1.80-1.70 (m, lH), 1.51 (s, 4H), 1.26 (dd, J = 8.3, 5.7 Hz, 3H). 63kt 1H NMR (400 MHz, MeOH-d4): o ppm 7.67 (d, J = 8.5 Hz, lH), 7.44 (ddd, J = 8.0, 4.8, 2.6 Hz, 2H), 7.32 - 7.24 (m, 2H), 7.07 (dd, J = 8.4, 2.5 Hz, lH), 6.99 (d, J = 7.6 Hz, lH), 6.76 (q, J = 6.9 Hz, lH), 5.51 (s, lH), 4.27 (dd, J = 7.0, 2.0 Hz, IH), 4.25 - 4.13 (m, 4H), 3.76 (s, 2H), 3.58 (s, 2H), 3.51 (d, J = 14.9 Hz, 2H), 3.42 (s, 3H), 3.08 (d, J = 11.4 Hz, lH), 2.99 (d, J = 11.4 Hz, lH), 2.28 (dd, J = 13.3, 8.7 Hz, lH), 1.88 (dd, J = 13.3, 8.0 Hz, lH), 1.57 (p, J = 5.4 Hz, 4H), 1.29 (t, J = 7.1 Hz, 3H) 63ku 1H NMR (400 MHz, MeOH-d4): s ppm 8.97 (d, J = 1.5 Hz, lH), 8.80 (dd, J = 2.6, 1.5 Hz, IH), 8.71 (d, J = 2.6 Hz, lH), 7.77 (d, J = 8.3 Hz, lH), 7.64 - 7.55 (m, lH), 6.87 (q, J = 6.7 Hz, lH), 5.62 (s, IH), 4.23 - 4.13 (m, 2H), 3.82 (dd, J = 8.7, 7.2 Hz, l H), 3.60- 3.42 (m, 3H), 2.89 (d, J = 1 1.0 Hz, lH), 2.75 (d, J = 11.0 Hz, lH), 2.09 (dd, J = 13. 1, 8.7 Hz, 1H), 1.74 (dd, J = 13.1 , 7.2 Hz, lH), 1.5 1 (dt, J = 10.9, 5.6 Hz, 3H), 1.26 (t, J = 7.1 Hz, 2H) Example 64a: tyl 8-(2-amino((R)(4-chloro(3-mcthyl-1H-1>yrazol-l- yl)phcnyJ)-2,2,2-friflu oroethoxy)pyrimiclinyl)-2,8-diazaspiro [4.5] dcca necarboxylate To a flask equipped with a Dean Stark trap were added (2S)[2-amino[(1R)[4-chloro (3-methyl pyrazolyl)phenyl]-2,2,2-trifluoroethoxy]pyrimidinyl]-3,8-diazaspiro[ 4.5]decane- 2-carboxylic acid (1 g, 1.78 mmol), toluene (25 mL), and p-toluene sulfonic acid monohydrate (336 mg, 1.77 mmol), and n-octanol (690 mg, 5.30 mmol). The reaction mixture was heated to reflux for 48 h, cooled to RT, and concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (CH2Cb/MeOH/ NH40H) provided the title compound as a white solid.
Applying the c scheme below, the following es of Table l 9a were ed as described above for (S)-octyl 8-(2-amino((R)(4-chloro(3-methyl-lH-pyrazol-l­ y1)phenyl)-2,2,2-trifluoroethoxy)pyr imidiny1)-2, 8-diazaspiro [4.5]decanecarboxylate (Example 64a), using the appropriate alcohol.
Table 19a.
Ex. R CAS Name LCMS No. (MH+) 64a (S)-Octyl 8-(2-amino((R)(4-chloro(3-methyl-1 H- 679.2 pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylate 64b (S)-cyclopentyl 8-(2-amino((R)-l-(4-chloro(3- 635.1 KJ methyl-I H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane- 3-carboxylate 64c (S)-pentyl 8-(2-amino((R)-l-(4-chlorn(3-methyl-lH- 637 pyrazol-l-yl)phenyl)-2,2,2-triflu oroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylate 64d o, (S)-cyclohexyl 8-(2-amino((R)(4-ch]oro(3- 648 methyl-1H-pyrazo1-l-yl)phenyl)-2,2,2- triflu oroethoxy)pyrim idinyl)-2,8-diazaspiro[4.5]decane- 3-carboxylate 64e i (S)-pro pyl 8-(2-amino((R)(4-chloro(3-methyl-1 H- 608 pyrazolyl)phenyl)-2,2,2-trifl hoxy)pyrimidin 8-diazaspiro[4.5]decanecarboxylate 64f l (S)-neopentyl 8-(2-amin o((R )(4-chloro(3-methyl- 636 1H-pyrazol -l-yl)phenyl)-2,2,2-triflu oroethoxy)pyrimidin- 2,8-diazaspiro[4.S]decan ecarboxylate 64g (S)-butyl mino((R)(4-chloro(3-methyl-lH- 622 pyrazol-l-yl)phenyl)-2,2,2-triflu oroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylate 64h ':( opropyl 8-(2-amino((R)(4-chloro(3-methyl- 622 1 H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylate Table 19b.
NMR Data for Compounds of Table 19a Ex. NMR 64a 1H NMR (400 MHz, MeOH-d4): 8 ppm 0.82 - 0.96 (m, 3 H), 1.20 - 1.47 (m, 10 H), 1.53 - 1.79 (m, 6 H), 2.04 (dd, J = 13.6, 8.8 Hz, 1 H), 2.38 (s, 3 H), 2.49 (dd, J = 13.6, 8.8 Hz, 1 H), 3.28 (s, 2 H), 3.42 - 3.85 (m, 4 H), 4.16 - 4.39 (m, 2 H), 4.60 (t, 1 = 8.8 Hz, 1 H), .81 (s, 1 H), 6.42 (d, J = 2.2 Hz, 1 H), 6.85 (q, J = 6.6 Hz, 1 H), 7.46 - 7.60 (m, 2 H), 7.71 (d, J = 8.3 Hz, 1 H), 7.93 (d, J = 2.4 Hz, 1 H) 64b 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.50 - 2.10 (m, 13 H), 2.38 (s, 3 H), 2.45 (dd, J = 13.6, 8.8 Hz, 1 H), 3.27 (d, J = 1.2 Hz, 2 H), 3.43 - 3.76 (m, 4 H), 4.55 (t, J = 8.7 Hz, 1 H), 5.26 - 5.39 (m, l H), 5.74 (s, 1 H), 6.42 (d, J = 2.3 Hz, 1 H), 6.83 (q, J = 6.6 Hz, l H), 7.45 - 7.59 (m, 2 H), 7.71 (d, J = 8.4 Hz, 1 H), 7.93 (d, J = 2.3 Hz, 1 H) 64c 1H NMR (400MHz, 4): 8 ppm 0.94 (t, J=7.2Hz, 3H), 1.35-1.39 (m, 4H), 1.52- 1.56 (m, 4 H), 1.64-1.71 (m, 2H), 1.74 - 1.79 (m, lH), 2.08-2.14 (m, lH), 2.40 (s, 3 H), 2.77 (d, J=l0.8 Hz ,IH), 2.92 (d, J=l0.8 Hz, 11-1), 3.48-3.58 (m, 4 H), .87 (m, IH), .18 (m, 2H), 5.69 (s, 1 H), 6.43 (d, 1=2.0 Hz, lH), 6.81-6.86 (m, lH), 7.51-7.55 (m, 2H), 7.72 (d, J=8.4 Hz, lH), 7.95 (d, J=2.0 Hz, 11- 1) 64d 1H NMR (400MHz, MeOH-d4): o ppm 1.31-1.56 (m, lOH), 1.75-1.80 (m, 3H), 1.85 - 1.89 (m, 2H), .13 (m, lH), 2.39 (s, 3H), 2.76 (d, J=l0.8 Hz ,1 H), 2.93 (d, J=l0.8 Hz, lH), 3.50-3.58 (m, 4H), 3.81-3.84 (m, lH), 4.77-4.83 (m, lH) , 5.69 (s, 1 H), 6.42 (d, 1=2.0 Hz, lH), 6.81-6.86 (m, lH), 7.51-7.55 (m, 2H), 7.72 (d, J=8.4 Hz, lH), 7.95 (d, J=2.4 Hz, lH) 64e 1H NMR (400MHz, MeOH-d4): 8 ppm 0.98 (t, J=7.6Hz, 3H), 1.54-1.59 (m, 4 H), 1.66 (m, 2H), 1.81 - 1 .86 (m, lH), 2.17-2.23 (m, 1H), 2.40 (s, 3H), 2.89 (d, J=ll.2 Hz ,IH), 3.00 (d, J=l 1.2 Hz, lI-1), 3.47-3.62 (m, 4H), 4.03 (t, J=8.0 Hz, lH), 4.11-4.18 (m, 2H), .70 (s, lH), 6.43 (d, J=2.4 Hz, lH), 6.84 (q, 1H), 7.51-7.55 (m, 2H), 7.73 (d, J=8.4 Hz, lI-1), 7.95 (d, J=2.4 Hz, lH) 64f 1H NMR (400MHz, Me0H-d4): 8 ppm 0.98 (s, 9H), 1.50-1.58 (m, 4 H), 1.77-1.82 (m, lH), 2.12-2.17 (m, lH), 2.40 (s, 3H), 2.79 (d, J=l 1.2 Hz ,lH), 2.94 (d, J=l 1.2 Hz, lH), 3.52-3.58 (m, 4H), 3.83-3.93 (m, 3H), 5.70 (s, 1 H), 6.43 (d, J=2.4 Hz, lH), 6.81-6.86 (m, lH), 7.52-7.55 (m, 2H), 7.73 (d, J=8.4 Hz, lH) , 7.95 (d, J=2.4 Hz, IH) 64g 1H NMR (400MHz, Me0H-d4): 8 ppm 0.95 (t, J=7.6Hz, 31-1), 1.37-1.43 (m, 2H), 1.50- 1.54 (m, 4H), 1.60-1.67 (m, 2H), .77 (m, l H), 2.06-2.12 (m, lH), 2.38 (s, 3 H), 2.75 (d, J=l 1.2 Hz ,1 H), 2.90 (d, J=l 1.2 Hz, 1H), 3.45-3.58 (m, 4 H), 3.83-3.86 (m, lH), 4.10-4.20 (m, 2H), 5.67 (s, lH), 6.40 (d, J=2.4 Hz, lH), 6.80-6.85 (m, 1 H) , 7.50-7.53 (m, 2H), 7.71 (d, J:=8.0 Hz, lH), 7.93 (d, J=2.0 Hz, lH) 64h 1H NMR (400MHz, Me0H-d4): s ppm 0.85 (d, J=6.8Hz, 6H), 1.42-1.47 (m, 4H), 1.68- 1.73 (m, lH), 1.82 - 1. 89 (m, l H), 2.05-2.10 (m, lH), 2.28 (s, 3H), 2.74 (d, J=l 1.2 Hz ,1 H), 2.87 (d, J=1 l.2 Hz, IH), 3.37-3.48 (rn, 4H), 3.81-3.91 (m, 3H), 5.58 (s, lH), 6.30 (d, J=2.0 Hz, lH), 6.70-6.75 (m, 1 H), 7.40-7.43 (m, 2H), 7.60 (d, J=8.4 Hz, lH), 7.83 (d, J=2.4 Hz, 1 H) Example 65a: (S)-Tert-butyl 8-(2-amino((R)(4-chloro(3-methyJ-lH-pyrazol y I)p heny 1)-2,2,2-trifluoro ethoxy)py l'imidiny1)-2 ,8-cliazas piru [4.5] dee anecarboxy Iate Step 1: To a mixture of (S)(2-amino((R)(4-chloro(3-methyl-1Il-pyra zol- l-yljphenyl)- 2,2,2-trifluoroethoxy)pyrimidinyl)((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane carboxylic acid (2.8 g, 4.1 mmol) in t-BuOH (50 mL) were added BOC20 (3.5 g, 16.5 mmol) and DMAP (0.201 g, 1.65 mmol), and the reaction was heated to 50°C for 45 min. Then the reaction was cooled to RT and concentrat ed in vacuo. Purifi cation on a 220 g Isco p silica dge (EtOAc/hepta ne) provided (S)benzyl 3-tert-butyl 8-(2-amino((R)(4- chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2-trifl uoro ) pyrimidinyl)-2,8- diazaspiro]4.S]decane-2,3-dicarboxylate as an off-white solid .
Step 2: To a solution of (S)benzyl 3-tert-butyl 8-(2-amino((R)(4-chloro (3-methyl-lH- pyrazolyl)phenyl)-2,2,2-trifl uoro ethoxy)pyrimidinyl)-2,8-diazaspiro[4.S]decane-2,3- dicarboxylate (1.35 g, 1.7 mmol) in EtOAc (130 mL) was added 5% (w/w) Pd/C (130 mg). The solution was degassed, charged with 1 atm H2 on), and stirr ed at RT for 3.5 h. Then the solids were fi ltered through celite, washed with EtOAc/methanol, and the fi ltrate was concentrated in vacuo. Purifi cation on a 220 g Isco RediSep silica cart ri dge (CH2Ch/M eOH/ NH40H) prov ided the title compound as an off-white solid. ng the generic scheme below, the following examples of Table 20a were prepared as described above for (S)-tert-butyl 8-(2-amino-6�((R)-l-(4-chloro(3-methyl-1H-pyrazol- l- yl)pheny1)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro(4.5]decanecarboxy1ate (Example 65).
STEP 2 Table 20a.
Ex. Ar CASName LCMS No. (MH+) 65a c,'C(, (Sj-tert-butyl 8-(2-amino((R)(4-chloro(3- 623 methyl-lH-pyrazolyl)phenyl)-2,2,2- , � oroethoxy)pyrimidiny1)-2, 8- /,. diazaspiro[4.5]decanecarboxylate 65b (Sj-tert-butyl 8-(2-amino((R)-2,2,2-trifluoro-l-(2- 630 N� (3-methyl-lH-pyrazol-l-yl) I � 'N propylphenyl)ethoxy)pyrimidinyl)-2,8- /,. diazaspiro [4.5]decanecarboxylate 65c (Sj-tert-butyl 8-(2-amino((R)(31,41-dimethyl 693 N�'N (3-methyl-1 Fl-pyrazol-l-yl)-]l,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxy1ate 65d (Sj-tert-butyl 8-(2-amino((R)-2,2,2-tl'ifluoro(41- 722 isopropoxy(3-methyl-lH-pyrazolyl)-[1, 1'­ biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylate Table 20b.
NMR Data for Compounds of Table 20a Ex. NMR 65a 1H NMR (400 MHz, 4): o ppm 1.54 (s, 9 H), 1.57 - 1.72 (m, 4 H), 2.02 (dd, J = 13.62, 8.44 Hz, 1 H), 2.38 (s, 3 H), 2.40 - 2.47 (m, 1 H), 3.18 - 3.37 (m, 2 H), 3.47 - 3.75 (m, 4 H), 4.49 (t, J = 8.61 Hz, 1 H), 5.76 (s, 1 H), 6.42 (d, J = 2.34 Hz, 1 H), 6.84 (q, J = 6.57 Hz, I H), 7.46 - 7.59 (m, 2 H), 7.71 (d, J = 8.35 Hz, 1 H), 7.93 (d, J = 2.39 Hz, 1 H) 65b 1H NMR (400 MHz, MeOH-d4): s ppm 0.96 (t, J=7.35 Hz, 3 H) 1.53 (s, 9 H) 1.56 - 1.77 (m, 6 H) 1.99 (dd, J=13.52, 8.25 Hz, 1 H) 2.37 - 2.42 (m, 4 H) 2.59 - 2.73 (m, 2 H) 3.14 - 3.29 (m, 2 H) 3.45 - 3.74 (m, 4 H) 4.43 (t, J=8.47 Hz, 1 H) 5.72 (s, 1 H) 6.38 (d, 1=2.29 Hz, 1 H) 6.72 (q, J=6.74 Hz, 1 H) 7.23 (d, J=l.61 Hz, 1 H) 7.33 (dd, J=8.10, 1.61 Hz, 1 H) 7.63 (d, J=8.10 Hz, 1 H) 7.85 (d, Hz, 1 H) 65c 1H NMR (400 MHz, MeOH-d4): 8 ppm .49 (s, 4 H) 1.50 (s, 5 H) 1 .53 - 1.64 (m, 4 H) 1.90 - 2.01 (m, 1 H) 2.27 (s, 3 H) 2.30 (s, 3 H) 2 .31 - 2.37 (rn, 1 H) 2.38 (s, 3 H) 3.09 - 3.25 (m, 2 H) 3.43 - 3.70 (m, 4 H) 4.32 - 4.42 (m, 1 H) 5.74 (s, I H) 6.39 (d, J=2.29 Hz, 1 I-I) 6.75 (q, J=6.67 Hz, 1 H) 7 .19 (d, J=7.91 Hz, 1 H) 7.36 (dd, J=7.81, 1.81 Hz, 1 H) 7.42 (s, 1 H) 7.58 (s, 1 H) 7.68 - 7.78 (m, 2 H) 7.93 (d, J=2.29 Hz, 1 65d 1H NMR (400 MHz, MeOH-d4): 8 ppm 1.31 (d, J=6.05 Hz, 6 H) 1.50 (s, 4 H) 1 . 51 (s, 5 H) 1.55 � I .70 (m, 4 H) 1.92 - 2.06 (m, 1 H) 2.38 (s, 3 H) 2.39 - 2.48 (m, 1 H) 3.1 6 - 3.27 (m, 2 H) 3.47 - 3.75 (m, 4 H) 4.46 (t, J=8.64 Hz, 1 H) 4.63 (dt, 1 =12.1 0, 6.05 Hz, 1 H) 5.85 (s, 1 H) 6.39 (d, J=2.29 Hz, 1 H) 6.76 (q, J=6.62 Hz, 1 H) 6.97 (d, J:== 8.79 Hz, 2 H) 7.55 - 7.63 (m, 3 H) 7.67 - 7.77 (m, 2 H) 7.93 (d, J=2.29 Hz, 1 Example 66a: (S)(Dimcthylamino)ethyl 8-(2-amino((R)(4-chloro(3-methyl-lH­ pyrazo1yl)pheny1)-2,2,2-trifluoroeth oxy)pyrim id inyl)-2,8-diazaspiro [4.5]decane carboxylate Step 1: To a e of (S)(2-amino((R)- l-(4-chloro(3-methyl-IH-pyrazolyl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid (85 mg, 0.16 mmol) in THF (10 mL) was added BOC20 (4 g, 18.6 mmol) in THF (10 ml.), and the reaction mixture was stirred at RT for 16 h. T hen the reaction was diluted with CH2Ch, cooled to O °C, and the pH ed to 2 with 2 N HCL The reaction mixture was then ted CH2Ch and concentrated in vacuo to prov ide (S)(2-amino((R)(4-chloro(3-rn ethyl-1 H-pyrazol yl )phenyl)-2 ,2,2-trifluoroethoxy) pyrimidinyl)(te11-butoxycarbonyl)-2,8- piro[4.5]decanecarboxylic acid as an off-white solid that was used directly without further purifi cation .
Step 2: To a solution of (S)(2-amino((R)(4-chloro(3-methyl-IH-pyrazol yl)phenyl)-2,2,2-trifl uoroethoxy)pyrimidinyl)(tert-butoxycarbonyl)-2,8-diazaspiro [4.S]decanecarboxylic acid (1.6 g, 2.45 mmol) in DMF (24 mL) were added (2-chloro- ethyl)­ dimethyl-amine hloride (535 mg, 3.7 mmol) and K2C03 (l.O g, 7.4 mmol), and the reaction mixture was heated at 65 °C for 16 h. Then the reaction was cooled to RT, partitioned between EtOAc and water, and extra cted. The combined organic layers were washed with bri ne, dried over Na2S04, fi ltered, and concentrated in vacuo. Purifi cation via prep-HPLC column chromatography (CH2Ch/MeOHINH.iO H) provided (S)teit-butyl 3-(2-(dimethylamino)ethyl) 8-(2-amino((R)(4-chl oro- 2-(3-methyl-IH-pyrazolyl)phenyl)-2,2,2- trifl uoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Step 3: To a solution of (S)tert-butyl dimethylamino)ethyl) 8-(2-amino((R)(4- chloro(3-methyl- lH-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate (1.4 g, 1.86 mmol) in CH2Ch (9 mL) was added TF A (4.5 ml.), and the reaction was stirred at RT for 2 h. Then the on was concentrated in vacuo and the e was partitioned between CH2Ch and aqueous NaI-ICQ3, and extracted.
The combined organic layers were washed with brine, dried over Na2S04, and concentrated in vacuo. Purification via prep-HPLC column chro aphy (CH2Ch/EtOH/NH40H) provided the title compound as an off-white solid.
Applying the generic scheme below, the following examples of Table 21 awere prepared as described above for (S)(dimethylamino)ethyl 8-(2-amino((R)(4-chloro(3-methyl­ IH-pyra zol-l-yl)phenyl)-2,2,2-trifl uoro ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate (Example 66a), using the appropriate alkylating agent.
Table 21a.
Ex. RX RY Rz CASName LCMS No. (MH+) H I-I (S)(dimethylamino)ethyl 8-(2-amino 638 66a (:"'N'- ((R)( ro(3-methyl-l H-pyrazol- 1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro]4. Sldecanecarboxylate H (S)(dimethylamino)oxoethyl 8-(2- 652 I 1r t"N'- amino((R)- l-(4-chloro(3-methyl- 66b 0 1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro [4.Sldecanecarboxylate H o;(H, H (((R)amino 710 methylbutanoyl)oxy)ethyl 8-(2-amino ((R)(4-chloro(3-methyl-lH-pyrazol- 66c yo 1-yl)phenyl)-2,2,2- trifl uoroethoxy)pyrimidinyl)-2,8- diazaspiro[4 anecarboxy1ate H .: H (S)(p ivaloyloxy)ethyl 8-(2-amino 695 ((R)(4-chloro(3-methyl-lH-pyrazol- 66d 1-yl)phenyl)-2,2,2- triflu oroethoxy)pyrimidinyl)-2,8- -i, diazaspiro]4.5]decanecarboxylate Table 21b.
NMR Data for Compounds of Table 2la Ex. NMR 1H NMR (400 MHz, DMSO-d6): o ppm 1.59 (d, J=S.08 Hz, 4 H) 2.00 (dd, J=13.15, 9.84 Hz, 1 H) 2.22 - 2.38 (m, 4 H) 2.77 (d, J=3.37 Hz, 6 H) 3.14 (br. s., 2 H) 3.41 (br. s., 66a 2 I-I) 3.60 (br. s., 2 I-I) 4.45 (dd, J=S.71, 3.90 Hz, 1 H) 4.49 - 4.68 (m, 2 H) 5.90 (br. s., l H) 6.39 (d, J=2.39 Hz, 1 H) 7.15 (d, J=S.86 Hz, 1 H) 7.53 - 7.73 (m, 3 H) 8.14 (d, J=2.39 Hz, 1 H) 9.65 (br, s., l H) 10.59 (hr. s., 1 H), 10.80 (br. s., 1 1-1 ). 66b 1H NMR (400 MHz, DMSO-d6): s ppm 1.46 - 1.77 (m, 4 I-I) 2.11 (dd, J=13.42, 8.40 Hz, 1 H) 2.31 (s, 3 H) 2.38 (dd, J=13.42, 9.08 Hz, 1 H) 2.78 - 2.88 (m, 3 H) 2.89 - 2.98 (m, 3 H) 3.16 (br. s., 2 H) 3.59 - 3.77 (m, 3 H) 4.65 (t, J=6.17 Hz, 1 H) 4.83 - 4.97 (m, 1 H) 5.00 - 5.12 (m, 1 H) 6.03 (br. s., 1 I-I) 6.42 (d, J=2.29 Hz, 1 H) 7.20 (d, J=5.47 Hz, 1 H) 7.57 - 7.76 (m, 3 H) 8.17 (d, J=2.34 Hz, 1 H) 9.22 (d, J=4.44 Hz, 1 H) 10.63 (br. s., 1 1H NMR (400 MHz, DMSO-d6): 8 ppm 0.98 (dd, J=15.52, 6.93 Hz, 6 H) 1.46 - 1.70 (m, 4 H) 1.94 (dd, J=13.15, 9.64 Hz, 1 H) 2.20 (td, J=6.91, 4.88 Hz, 1 H) 2.26 - 2.38 (m, 4 H) 3.14 (br. s., 2 H) 3.51 (br. s., 2 H) 3.58 - 3.70 (m, 3 H) 3.88 (br. s., 1 H) 4.29 - 4.49 (m, 4 H) 4.55 (br. s., 1 H) 5.84 (br, s., I H) 6.42 (d, J=2.34 Hz, 1 H) 7.16 (d, J=5.66 Hz, 1 H) 7.50- 7.76 (m, 3 H) 8.17 (d, J=2.34 Hz,1 H) 8.66 (br. s., 3 H) 9.47 (br. s., 1 H) .52 - 10.84 (m, 1 H). 1H NMR (400 MHz, DMSO-d6): 8 ppm 1.11 - 1.18 (m, 9 H) 1.48 (s, 3 H) 1.54 - 1.72 (m, 4 H) 1.74 - 2.01 (m, 1 I-I) 2.22 - 2.43 (m, 4 H) 3.15 (d, J=3.56 Hz, 2 H) 3.58 - 3.80 66d (m, 4 H) 4.60 (d, J=S.71 Hz, 1 H) 6.06 (br, s., l H) 6.42 (s, 1 H) 6.74 - 6.88 (m, 1 H) 7.22 (d, J=5.47 Hz, 1 H) 7.57 - 7.76 (m, 4 H) 8 .18 (s, 1 H) 9.19 - 9.56 (m, I H) 10.74 (br, s., 1 H).
Example 67a: (Sj-isopropyl 8-{2-amino((R)(3' ,4'-dimethyl(3-methyl-lH-pyrazol y1)-[1,1'-biphcnyl]y1)-2,2,2-trifluorocthoxy)pyrimidinyl)-2,8-diazaspiro [4.5)decane carboxylate To a solution of the compound of Example lm (400 mg, 0.53 mmol) in propanol (5 mL) was added thionyl chlori de (2 drops) at 0°C. The e was warmed to RT and then heated to reflux for 2 h. Then the on mixture was cooled to RT, tra ted and neutrali zed with saturate d aqueous NaHC03 solution to pH 7-8. The aqueous layer was extracte d with CH2Ch.
The combined organic layers were washed with brine, drie d over Na2S04, filte red, concentrated in vacuo and purified by fla sh column (0-10% MeOH in DCM) on silica gel to affo rd the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4): 8 ppm 7.96 (d, J = 2.3 Hz, lH), 7.75 (d, J = 8.2 Hz, IH), 7.70 (dd, J = 8.2, 1 . 8 Hz, lH), 7.59 (d, J = 1.8 Hz, lH), 7.43 (s, lH), 7.37 (d, J = 7.8 Hz, lH) , 7.19 (d, J= 8.0 Hz, JH), 6.76 (q, J = 6.8 Hz, lH), 6.41 (d, J = 2.3 Hz, lH), 5.74 (s, lH), 5.01 (m, IH), 3.76 (dd, J = 8.7, 7.0 Hz, IH), 3.61 - 3.42 (m, 4H), 2.88 (d, J = 11.1 Hz, IH), 2.72 (d, J = 11.0 Hz, lH), 2.39 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H), 2.05 (dd, J= 13.1, 8.9 Hz, lH), 1.71 (dd, J = 13.0, 7.0 Hz, lH), I.SO (m, 4H), 1.24 (dd, J = 6.2, 3.9 Hz, 6H). LCMS (MH+): 679.
Applying the generic scheme below, the following examples of Table 22 were prepared as described above for (S)-isopropyl 8-(2-amino((R)-l-(3',4'-dimethyl(3-methyl-1 H-pyrazol- 1-yl)-[1 ,1'-biphenyl]yl)-2,2,2-triflu oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.S]decane carboxylate le 67a), using the appropriate alcohol.
��N/) Table 22a.
Ex. Rt CASName LCMS No. (MH+) KJ (S)-cyclopentyl 8-(2-ami no((R)(3',4'-dimethyl 705 67b (3-methyl-1H-pyrazolyl)-[l,1'-biphenyl]yl)-2,2,2- triflu oxy)pyrimidinyl)-2,8-diazaspiro[4.5] decanecarboxylate CH3 (S)-methyl mino((R)(3',4'-dimethyl(3- 650 methyl-lH-pyrazolyl)-[1,1'-biphenyl)yl)-2,2,2- trifluo roethoxy)pyrimidinyl)-2,8-diazaspiro[4.5] i decanecarboxylate (S)-prop yl 8-(2-amino((R)-l-(3',4'-dimethyl(3- 679 methyl-I 1pyra zolyl)-[1, 1 '-biphenyl]yl)-2,2,2- trifluoroethoxy)pyri midinyl)-2,8-diazaspiro [4.5] decanecarboxylate Table 22b.
NMR Data for Compounds of Table 22 I Ex. NMR 1H NMR (400 MHzi Me0H-d4): s ppm 7.96 (d, J = 2.4 Hzi IH), 7.75 (d, J = 8.2 Hz, lH), 7.71 (dd, J = 8.2, 1.8 Hz, lH), 7.60 (d, J = 1.7 Hz, IH), 7.44 (s, l H), 7.37 (dd, J = 7.9, 1.9 Hz, lH), 7.20 (d, J = 7.8 Hz, lH), 6.76 (q, J = 6.9 Hz, lH), 6.41 (d, J = 2.3 Hz, IH), 5.74 (s, lH), 5.21 - 5.14 (m, IH), 3.76 (dd, J = 8.8, 6.9 Hz, 1 H), 3.61 - 3.42 (m, 41-I), 2.88 (d, J = 11.0 Hz, 1 H), 2.72 (d, J = 11.0 Hz, IH), 2.39 (s, 3H), 2.31 (s, 3H), 2.28 (s, 3H), 2.04 (dd, J = 13.1, 8.8 Hz, lH), 1.87 (d, J = 7.3 Hz, 2H), .56 (m, 7H), 1.50-1.45 (m, 4H) 11-I NMR (400 MHz, MeOH-d4): o ppm 7.96 (d, J = 2.3 Hz, lH), 7.76 (d, J = 8.3 Hz, lH), 7.71 (dd, J = 8.2, 1.6 Hz, 11-l), 7.60 (d, J = 1.6 Hz, lH), 7.44 (s, l H), 7.37 (dd, J = 7.8, 1.6 Hz, IH), 7.20 (d, J = 7.9 Hz, II-I), 6.76 (q, J = 6.5 Hz, lH), 6.41 (d, J = 2.3 Hz, Hl), 5.74 (s, lH), 3.83 (t, J = 8.0 Hz, lH), 3.71 (s, 3H), 3.61 - 3.41 (m, 4H), 2.86 (d, J = 11.0 Hz, lH), 2.74 (d, J = 11.0 Hz, lH), 2.39 (s, 3H)i 2.31 (s, 3H), 2.28 (s, 3H), 2.06 (dd, J = 13.0, 8.7 Hz, lH), 1.72 (dd, J = 13.0, 7.2 Hz, IH), 1.55 - 1.43 (m, 4H) 1H NMR (400 MHz, Me0H-d4): 8 ppm 0.95 (m, 3H), 1.49 (dt, J = 12.0, 6.0 Hz, 4H), 1.69 (m, 3H)i 2.06 (dd, J = 13.1, 8.8 Hz, lH), 2.29 (d, J = 10.3 Hz, 61-1), 2.39 (s, 3H), 2.73 (d, J = 11 . 0 Hz, lH), 2.87 (d, J = 11.0 Hz, lH), 3.30 (m, 4H), 3.51 (dt, J = 27.9, 6.6 Hz, 4H), 3.81 (dd, J = 8.7, 7.1 Hz, IH) , 4.08 (m, 2H), 5.74 (s, lH), 6.41 (d, J = 2.3 Hz, lH),6.76 (q, J = 6.7 Hz, IR), 7.19 (d, J = 7.9 Hz, lH), 7.40 (m, 2H), 7.59 (d, J = 1.8 Hz, lH), 7.72 (m, 2H), 7.96 (d, J = 2.4 Hz, lH) Example 68a: (S)-isopropyl 8-(2-amino((R)-2,2,2-trifluoro-l-(4'-isopropoxy(3-mcthyllH-pyrazolyl )-[l,11-biphcnyl]yl)etboxy)pyrimidinyl)-2,8-diazaspiro ecane carboxylate The title compound was prepared as described for (Sj-isopropyl 8-(2-amino((R )(3',4'­ dimethy1(3-methyl-1H-pyra zolyl)-[1,1 '-biphenyl]yl)-2,2,2-trifluoro ethoxy)pyri midin yl)-2,8-diazaspiro[4.5]decanecarboxylate (Example 67a) ng with (S)(2-amino((R)- 2,2,2-trifluoro- 1-(4'-isopropoxy(3-methyl-lH-pyrazol-l-yl)-[l, l '-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro [4.5]decanecarboxylic acid (Example 11).
Applying the generic scheme below, the following examples of Table 23 were prepared as described above for (S)-isopropyl 8-(2-amino((R)-2,2,2-trifluoro-l-(4'-isopropoxy(3- methyl-lH-pyrazolyl)-( 1,l'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane- 3-carboxylate (Example 68a), using the riate alcohol.
Table 23a.
Ex. Rt CASName LCMS No. (MH+) ':( (S)-isopropyl 8-(2-amino((R)-2,2,2-trifluoro(41- 709 68a isopropoxy(3-methyl-lH-py razolyl)-[1, 1 '- biphenyl]yl)ethoxy)pyrimi dinyl)-2,8- -o diazaspiro [4.SJdecanecarboxylate (S)-cyclopentyl 8-(2-amino((R )-2,2,2-triflu oro (4'- 735 isoprop oxy(3-methyl-1H-pyrazolyl)-[1,1 '- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro [4.S]decanecarboxylate (S)-propyl 8-(2-amino((R)-2,2,2-trifl uoro(4'- 709 isopropoxy(3-methyl-1H-pyrazolyl)-[1, l '- � yl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro [4.5]decanecarboxylate Table 23b.
NMR Data for nds of Table 23 Ex. NMR 1H NMR (400 MHz, MeOH-d4): s ppm 1.26 (m, 14H), 1.49 (dt, J = 10.9, 5.2 Hz, 4H), 1.72 (dd, J = 13 .1, 7.0 Hz, lH), 2.05 (dd, J = 13 .1 , 8 .8 Hz, lH), 2.39 (s, 3H), 2.72 (d, J = 68a 1 J .0 Hz, lH), 2.89 (d, J = 11.0 Hz, lH), 3.52 (m, 4I-Q, 3.77 (dd, J = 8.8, 7.0 Hz, lH), 4.63 (hept, J = 6.0 Hz, lH), 5.01 (p, J = 6.2 Hz, 1 H), 5.74 (s, lH), 6.40 (d, J = 2.3 Hz, lH), 6.76 (q, J = 6.6 Hz, lH), 6.96 (m, 2H), 7.57 (m, 3H), 7.70 (m, 2H), 7.95 (d, J = 2.3 Hz, lH) 11-I NMR (400 MHz, MeOH-d4): s ppm 1.32 (d, J = 6.0 Hz, 8H), 1.50 (m, 4H), 1.67 (ddd, J = 33.0, 12.8, 5.6 Hz, 8H), 1 .88 (m, 3H) , 2.05 (dd,J = 1 3. 1 , 8.9 Hz, IH), 2.39 (s, 3H) , 2.73 (d,J = 11 . 0 Hz, lH) , 2.89 (d, J = 1 1.0 Hz, lH), 3.52 (dt, J = 2 1. 1, 6.5 Hz, 4H), 3.78 (dd, J =8.8, 7.0 Hz, lH), 4.64 (p, J = 6.0 Hz, lH), 5.1 8 (td, J = 5.9, 2.7 Hz, lH), .75 (s, l H), 6.40 (di J = 2.4 Hz, lH), 6.75 (q, J = 6.6 Hz, IH), 6.97 (m, 2H), 7.59 (m, JI-I),7.71 (m, 2H), 7.95 (d, J = 2.4 Hz, lH) 1H NMR (400 MHz, MeOH-d4): 8 ppm 0.94 (t, J = 7.4 Hz, 3H), 1.32 (d, J = 6.0 Hz, 6H), 1.50 (dt, J = 12.3, 6.0 Hz, 4H), 1.69 (rn, 3H), 2.07 (dd, J = 13.1, 8.8 Hz, lH), 2.39 (s,3H), 2.73 (d, J = 11.0 Hz, 11-1), 2.88 (d, J = 11.0 Hzi lH), 3.52 (dp, J = 20.9, 7.5 Hz, 4H),3.81 (dd, J = 8.7, 7.1 Hz, lH), 4.09 (m, 2H), 4.64 (h, J = 6.0 Hz, lH), 5.74 (s, 11-1), 6.40 (d, J = 2.4 Hz, lH), 6.76 (q, J = 6.7 Hz, lH), 6.96 (m, 2H), 7.58 (m, 3H), 7.71 (m, 2H), 7.95 (d, J = 2.4 Hz, lH) Example 69a: (S)-isopropyl 8-(2-amino((R)(5-chloro-[1,1'-biphenyl]yl)-2,2,2- trifluorocthoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate O��NC CF3 N'f'N The title compound was prepared as described for (S)-isopropyl 8-(2-amino((R)(31,41- dimethyl(3-methyl-lH-pyrazolyl)-[1, l1-biphenyl]yl)-2,2,2-trifluoroeth oxy)pyrimidin yl)-2,8-diazaspir decanecarboxylate (Example 67a) starting with (S)(2-amino((R)­ l-(5-chloro-[1, 1'-biphenyl]yl)-2,2,2-trifluoro ethoxy)pyrimidinyl)-2,8- piro[4.5]decanecarboxylic acid (Example 34c).
Applying the generic scheme below, the following examp les of Table 24 were prepared as described above for (S)-isopropyl 8-(2-amino((R)-2,2,2-triflu oro(41-isopropoxy(3- - azolyl)-[1,1'-biphenyl]-4�yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5Jdecane- 3-carboxylate (Example 68a), using the approp riate alcohol.
TabJe24a.
Ex. R• CAS Name LCMS No. (MH+) 69a ':( (S)-isopropyl mino((R)(5-chloro-[1, 1 '- 605 yl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)- -o 2, 8-diazaspirof4. 5ldecanecarboxylate (S)-cyclopentyl 8-(2-amino((R)-l-(4'-chloro(3- 735 methyl- 1 Il-pyrazol- 1-yl)-[1,1 '-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8- i diazaspiro[4.5]decanecarboxylate (S)-propyl 8-(2-amino((R)(5-chloro-[1,l '- 605 69c biphenyl]yl)-2,2,2-tl'ifluoroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decanecarboxylate (S)-tetrahydro-2H-pyra ny1 8-(2-amino((R)(5- 645 69d p chloro-[1, 1 '-biphenyl]yl)-2,2,2- trifl uoroethoxy)pyrimidinyl)-2,8- diazaspiro]4.5ldecanecarboxylate Table 24b.
NMR Data for Compounds of Table 24 Ex. NMR 1H NMR (400 MHz, MeOH-d4): o ppm 1.25 (dd, J = 6.3, 3.2 Hz, 6H), 1.52 (rn, 4H), 1.74 (dd, J = 1 3. 1 , 7.1 Hz, lH), 2.09 (dd, J = 13 . 1 , 8.8 Hz, lH), 2.75 (d, J = 1 1.0 Hz, lH), 2.91 (d, J = 11.0 Hz, 1H), 3.49 (m, 4H), 3.80 (dd, J = 8.8, 7.1 Hz, lH), 5.02 (hept, J = 6.2 Hz, lH), 5.47 (d, J = 7.8 Hz, l H), 6.63 (q, J = 6.8 Hz, lH), 7.28 (d, J = 2.2 Hz, lH), 7.48 (m, 6H), 7.67 (d, J = 8.5 Hz, lH) 1HNMR (400 MHz, MeOH-d4): s ppm 1.32 (d, J = 6.0 Hz, 8H), 1.50 (m, 4H), 1.67 (ddd, J = 33.0, 12.8, 5.6 Hz, 8H), 1.88 (m, 3H), 2.05 (dd, J = 13.1, 8.9 Hz, lH), 2.39 (s, 3H), 2.73 (d, J= 11.0Hz, lH), 2.89 (d, J = 11.0 Hz, lH), 3.52 (dt, J= 21.1 , 6.5 Hz, 4H), 3.78 (dd, J = 8.8, 7.0 Hz, lI-1), 4.64 (p, J = 6.0 Hz, 1I-I), 5 .18 (td, J = 5.9, 2.7 Hz, lH), .75 (s, lH), 6.40 (d, J = 2.4 Hz, lH), 6.75 (q, J = 6.6 Hz, lH), 6.97 (m, 2H), 7.59 (m, 3H), 7.71 (m, 2H) , 7.95 (d, J = 2.4 Hz, IH) 1H NMR (MeOH-d4): o ppm 0.95 (t, J = 7.4 Hz, 3H), 1.52 (dt, J = 14.2, 4.9 Hz, 4H) , 1 .71 (ddd, J = 3 1.8 , 13.7, 7.1 Hz, 3H), 2.10 (dd, J = 13 . 1, 8.8 Hz, lH), 2.76 (d, J = 1 1 . 0 69c Hz, IH), 2.91 (d, J = 11.0 Hz, lH), 3.50 (ddd, J = 19.5, 7.9, 4.8 Hz, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, lH), 4 .10 (m, 2H), 4.88 (s, 8H), 5.48 (d, J = 7.9 Hz, IH), 6.63 (q, J = 6.9 Hz, lH), 7.28 (d, J = 2.2 Hz, lH), 7.47 (m, 6H) , 7.67 (d, J = 8.6 Hz, lH) 1H NMR (MeOHMd4): s ppm 1 . 6 1 (m, 6H) , 1.82 (dd, J = 13.2, 7.5 Hz, lH), 1.93 (dd, J = 11.6, 6.1 Hz, 2H), 2.03 (s, 1H), 2.20 (dd, J = 13.2, 8.8 Hz, lH), 2.89 (d, J = 1 1 .2Hz, 69d lH), 2.99 (d, J = 1 1 . 2 Hz, lH) , 3.54 (m, 6H) , 3.89 (dq, J = 12 .1, 3.9 Hz, 2H), 4.04 (dd, J = 8.7, 7.5 Hz, lH), 5.01 (tt, J = 8.3, 4.0 Hz, l H), 5.48 (s, lH), 6.64 (q, J = 6.9 Hz, lH), 7.28 (d, J = 2.2 Hz, 1H), 7.47 (m, 6H), 7.67 (d, J = 8.5 Hz, lH) Example 70: (S)-methyl 8-(2-amino((R)-l-(S-chloro-3'-(methylsulfonyl)-[1,1'-biphenyl]- 2-yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]dccanecarboxylate The title compound was prepared as bed for (S)-isopropyl 8-(2-amino((R)(31,41- dimethyl(3-methyl-1 H-pyrazolyl)-[1, 1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylate (Example 67a) starting with (S)(2-amino((R)- 1-(5-chloro-3'-(methylsulfonyl)-[1, l '-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- piro[4.5)decanecarboxylic acid (Example 34w). 1H NMR (400 MHz, Me0H-d4): s ppm 1.51 (q, J = 7.1, 6.7 Hz, 6H), 1.72 (dd, J = 13.0, 7.3 Hz, lH), 2.07 (dd, J = 13.2, 8.7 Hz, lH), 2.75 (d, J = 11. 0 Hz, UI), 2.87 (d, J = 11 .0 Hz, lH), 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, lH), 4.87 (m, lH), .57 (s, lH), 6.57 (q, J = 6.6 Hz, lH), 7.33 (d, J = 2.3 Hz, IH), 7.41 (s, 2H), 7.48 (dd, J = 8.5, 2.2 Hz, lH), 7.75 (m, 3H), 8.07 (d, J = 7.8 Hz, lH), 8.43 (s, lH). LCMS (MH+): 655.
Example 71: (S)-methyl 8-(2-amino((R)(5-chloro-3'-sulfamoyl-[1,1'-biphcnyl]yl)- 2,2,2-trifluorocthoxy)pyrimidiuyl)-2,8-diazaspiro[4.S]dccanecarboxylate O'j('y�N� CF3 NyN 1, \\ 0 0 The title compound was prepared as described for (S)-isopro pyl 8-(2-amino((R)(3',4'- dimethyl(3-methyl-1 l-l-pyrazol- l-yl)-[ 1, l'-biphenyl]yl)-2,2,2-triflu oro ethoxy)pyrimidin yl)-2,8-diazaspiro[4.S]decanecarboxylate le 67a) starting with (2-amino((R)- 1-(5-chloro-3'-sulfamoyl-[ 1, l'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid (Example 34u). 1H NMR (400 MHz, Me0H-d4): 8 ppm 1.54 (dt, J = 8.9, 6.0 Hz, SH), 1.75 (dd, J = 13.1, 7.4 Hz, lH), 2.10 (dd, J = 13.1, 8.7 Hz, 1H), 2.77 (d, J = 11 .0 Hz, lH), 2.89 (d, J = 11.0 Hz, lH), 3.53 (qt, J = 14.0, 7.8 Hz, 4H), 3.72 (s, 3H), 3.86 (dd, J = 8.7, 7.3 Hz, lH), 4.91 (s, l 3H), 5.57 (s, lH), 6.60 (q, J = 6.5 Hz, HI), 7.31 (d, J = 2.2 Hz, lH), 7.49 (dd, J = 8.5, 2.3 Hz, IH), 7.60 (d, J = 7.7 Hz, lH), 7.71 (m, 2H), 8.02 (ddd, J = 7.9, 1.9, 1.1 Hz, lH), 8.33 (s, lH). LCMS (MH+):656.
LCMS (MH+): 656.
Example A: In vitro Inhibition Assays TPHI and TPH2 Assays Recombinant human TPHl (rTPHl GenBank TM accession no. NP_004179) was expressed by cloning full length human TPHl cDNA in to a bacterial pMAL-c5E sion vector to produce maltose-binding protein (MBP) TPI-11 fusion proteins. E.coli BL21 (DE 3) containing pMAL-c5E-TPH1 was used for protein generation and the recombinant prote in was purifi ed utilizing standard column tography techniques. The MBP tagged TPHl (MBPTPHl ) was used directly to screen compounds as described below. Recombinant human TPH2 (rTPH2 GenBank TM accession no. 173353), PheOH (rPheOI-1 GenBank TM accession no. ) and TH (rTH GenB ank TM accession no. L20679) with an MBP tag were produced similarly.
TPH l ties were measured in an assay containing 200 mM amm onium sulfate, 7 mM DTT, 50 ug/ml, catalase, 25 �tM ammonium iron sulfate, 50 mM ME S, pH 7 .1. Test compounds were diluted in 100% DMSO and added to the assay plate in 1 ul, aliquots at 1 OOx fin al concentration. Fifty microliters of assay buffer containing 30 nM TPHl enzyme (MBP tagged) were added to the plate wells containing the test compound by the use of an Eppendorf repeater pipette. The reaction was ted by the addition of 50 ul. of assay buffer containing 60 pM tryptophan and 72 µM thyltetra-hydropterin (2x fi nal concentra tion) by the use of a Multidrop (LabSystems). Final reaction conditions were 15 nM TPHl enzyme, 30 �tM tryptophan, 36 �tM 6-methyltetra-hydropterin, 200 mM ammonium sulfate, 7 mM DTT, 25 ug/ml, catalase, 25 �tM ferrous um sulfate, 50 mM MES, pl-I 7 .1, with atmospheric oxygen at room temperature. The plate was ately placed onto an MS plate reader · (Molecular Devices) for kinetic fluorescence measurement using an excitation setting of 300 nm and an emission setting of 335 nm. scence reads are recorded in kinetic mode for 300 seconds (5 minutes).
Kinetic assay data for compounds at specifi c concentrations was translated into slopes using the Softmax Pro software on a Spectramax reader, and compound inhibition slopes were compared with wells containing enzyme, substrate and cofactor in the absence of inhibitor (100%), and wells containing substrate and cofactor in the absence of enzyme (0%). DMSO concentration in the assay was l %. Typically, in the absence of enzy me, reaction slopes were -0. ICso's were determined using Graphp ad Prism.
Compounds having an ICso of 10,000 nM or less were considered active.
Inhibition of TPH2 activity by the compounds of the invention was measured similarly.
In some ces, compounds of the invention showed dual inh ibition of both TPHl and TPH2.
Data related to TPHI inh n activity of the compounds of the invention is provided below in Table 25. Compounds that inhibit TPHl with an ICso from 3,000 nM to 10,000 nM are indicated by+. Compounds that inhibit TPHl with an ICso of less than 3,000 nM but more than 300 nM are indicated by++. Compounds that inhibit TPHl from 50 nM to 300 nM are indicated by+++. nds that inhibit TPHl with an ICso less than 50 nM are indicatead by++++.
Ester prodrugs listed, for example, in Tables 18a, 19a, 20a, and 21 a-24a, as well as in Examples 70 and 71, are not ed to be active in this in vitro assay.
Table 25. TPHl Inhibition Data TPHl Ex. TPHI Ex. TPHI TPHl Ex.No. Range Ex.No.
No. Ra112e No. Range Range la ++++ 19n ++++ 34cs +++ 55cb +++ lb + + + +. 190 ++++ 34ct ++++ 55cc +++ le ++++ 19p ++++ 34cu ++++ . 55cd ++ ld ++++ 19q ++++ 34cv ++++ 55ce ++ 1e ++++ 19r ++++ 35 +++ 55cf + If +++ 20 ++++ 36 + 55cg ++ lg ++++ 21 +++ + 36b +++ 55ch +++ lh ++++ 22a ++++ 36c ++++ 55ci ++ 1i +++ 22b ++++ 36d + 55cj ++ lj +++ 22c ++++ 36e ++ 55ck ++ lk ++++ 23 ++++ 36f +++ 55cl +++ 11 ++++ 24 +++ 36g ++++ 55cm ++ lm ++++ 25 ++++ 37 + 55cn ++ ln ++++ 26 + 38 ++ 55co +++ lo ++++ 27 +++ 39a ++ 55cp ++ lp ++++ 28 +++ 39b + 55cq +++ lq ++++: 29a ++++ 39c + 55cr ++ lr ++++ 29b ++++ 39d + 55cs ++ ls ++++ 29c +++ 39e ++ 55ct ++ lu ++++ 29d ++++ 40 ++ 55cu ++ lv ++++ : 29e +++ 41a ++ 55cv ++ lw ++++ 29f ++++ 41b ++ 55cw ++ lx ++++ 29g ++++ 41c + 55cx ++ ly ++++ 29h ++++ 4ld + 55cy ++ lz ++++ 29i ++++ 42a ++++ 55cz +++ laa ++++ ; 29.i ++++ 42b +++ 55da ++ lab ++++ 29k +++ 43 + 55db ++ lac ++++ 291 ++++ 44 ++ 55dc ++++ lad ++++ 29m +++ 45 +++ 55dd +++ lae ++++ 2911 +++ 46 + 55de +-H- laf ++++ 290 ++++ 47 ++ 55df +++ lag ++++ 29p ++++ 48 ++ 55dg +++ lah ++++ 29q ++++ 49 ++++ 55dh +++ lai ++++; 29r ++++ 50 +++ 55di +++ laj ++++ 29s ++++ 51 ++++ 55dj +++ lak +++ 29t +++ 52a ++++ 55dk +++ lal ++++ 29u +++ 52b ++++ 55dl +++ lam ++++ 33 +++ 53 ++++ 55dm +++ Ian ++++ 34a ++++ I 54a ++++ 55dn +++ lao ++++ 34b ++++ 54b +++ 55do ++++ lap ++++ 34c +++ 54c ++++ 55dp ++++ laq +++ 34d +++ 54d +++ 55dq ++++ l ar +++ 34e +++ 54e +++ 56 +++ las ++++ 34f +++ 54f ++++ 57 +++ lat ++++ 34g +++ 54g +++ 58 +++ lau +++ 34h ++ 54h + 59 ++ lav ++++ 34i +++ 54i + 59b ++ law +++ 34j +++ 54j ++ + 59c +++ I lax ++++ 34k +++ 54k +++ 59d +++ lay +++ 341 +++ 541 + 60 ++ laz +++ 34m +++ I 54m ++ 61 +++ lba ++++ 34n +++ 55a +++ 62 +++ lbb ++++ 340 +++ 55b ++++ lbc ++++ 34p +++ 55c +++ lbd ++++ 34q ++++ 55d ++++ lbe +++ 34r +++ ! SSe +++ lbf +++ 34s +++ SSf +++ lbg ++++ 34t +++ 55g ++ lbh ++++ 34u ++++ 55h +++ 1 bi ++++ 34v ++++ 55i ++++ lbj +++ 34w ++++ 55j +++ lbk ++++ 34x ++++ 55k +++ lbl ++++ 34y ++++ 551 +++ Ihm ++++ 34z +++ + 55m ++++ lbn ++++ 34aa ++++ 55n ++ Ibo +++ 34ab ++ 550 +++ lbp ++++ 34ac ++++ 55p +++ lbq ++++ 34ad ++ 55q ++++ lbv ++++ 34ae ++ 55r +++ lbw +++ 34af ++++ 55s ++++ lbx ++++ 34ag ++++ SSt +++ lby ++++ 34ah ++++ 55u +++ lbz ++++ 34ai +++ 55v ++++ lea ++++ 34aj +++ SSw ++++ . leb ++++ ' 34ak +++ 55x +++ lee ++++ 34al + SSy +++ led ++++ 34am +++ 55z +++ lee ++++ ! 34an ++++ 55aa +++ lcf +++ 34ao ++++ 55ab +++ leg ++++ 34ap +++ 55ac +++ lch +++ 34aq ++++ : 55ad +++ lei ++++ 34ar ++++ 55ae ++ lcj ++++ ' 34as ++++ 55af ++ lck ++++ 34at +++ 55ag +++ lcl ++++. .34au ++++ 55ah +++ lcm ++++ 34av ++++ 55ai ++++ lcn ++++ 34aw ++++ 55aj +++ lco ++++ 34ax +++ 55ak ++ lcp ++++ . 34ay +++ 55al +++ Icq ++++ 34az ++ 55am +++ lcr ++++ 34ba ++++ 55an +++ les ++++ 34bb +++ 55ao +++ lOj +++ 34bc +++ 55ap +++ 10k +++ 34bd ++++ 55aq +++ 101 +++ 34be ++++ 55ar +++ 10m ++++ 34bf +++ 55as +++ lOn ++++ 34bg +++ 55at +++ lOo ++++ 34bh ++ 55au +++ lOp +++ 34bi ++++ 55av +++ lOq ++++ 34bj ++++ 55aw ; lOr ++++ 34bk +++ 55ax +++ lOpa +++ 34bl +++ 55ay ++ 11 +++ 34bm +++ 55az ++++ 12a +++ r 34bn +++ 55ba ++++ 12b ++++ 34bo +++ 55bb ++++ 12c ++++ 34bp ++++ 55bc ++++ 13 +++ 34bq +++ 55bd ++++ 14 ++++ 34bu +++ 55be ++++ +++ 34bv +++ 55bf +++ 16 ++ 34bw +++ 55bg ++++ 17 ++++ 34bx +++ 55bh +++ 18a +++ 34by +++ 55bi ++++ 18b ++++ +++ ++++ ! 34ca 55bj 18c ++++ 34cb +++ 55bk +++ 18d ++++ 34cc +++ 55bl ++ 18e ++++ 34cd +++ 55bm ++ 18f ++++ . 34ce +++ 55bn + 19a ++++ 34cf ++ 55bo +++ 19b ++++ 34cg +++ 55bp +++ 19c ++++ ' 34ch ++++ 55bq ++ 19d +++ 34ci +++ 55br ++ 19e ++++ 34cj +++ 55bs ++ 19f ++++ 34ck +++ 55bt ++ 19g ++++ 34cl +++ 55bu ++ 19h ++++ 34cm +++ 55bv ++ 19i ++++ 34cn +++ 55bw +++ I 19j ++++ 34co +++ 55bx ++ 19k ++++ 34cp +++ 55by ++ 191 ++++ . 34cq ++++ 55bz +++ 19m ++++ 34cr +++ 55ca +++ PheOH and TH inhibition counter assays Certain compounds of the Examples were found to inhibit phan hydroxylase (TPH) selectively over phenylalanine hydroxylase (PheOH). tory activity against PheOH can be assessed according to the methods described for example in J Med Chem. 10, 64-66 (1967), or J Antibiot. 35, 458-462 (1982), or .
Certain nds of the invention were found to inhibit phan hydroxylase (TPH) selectively over tyrosine hydroxylase (TH). Inhibitory activity against TH can be assessed ing to the methods described for example in Life Sci. 39, 2185-2189 (1986), or Mol.
Pharmacol. 41, 339-344 (1992), or J Aniibiot. 35, 458-462 (1982), or .
Example B: Intestinal 5-HT depletion assay The efficacy of the TPHl inhibitors of the invention was assessed for the y to decrease intestinal serotonin concentration in mice. Mice (C57 BL6) were administered a single I 50 mg/kg dose of test article by oral . Each animal was euthanized by exsanguination under isoflurane anesthesia. l intestinal mucosa was ed and homogenized in 300 �1L of a buffer containing 0.3M trichloroacetic acid, O. IM sodium e, 10 mMEDTA, 20 mM sodium bisulfate and 50 mM ascorbic acid. Following centrifugation the 5-HT levels in the supernatants were measured by HPLC. The remaining mucosal pellet was solubilized overnight at 37 °C in a 0.1% sodium dodecyl sulfate buffer in O. lN NaOH followed by determination of n concentrations using a BCA pro tein assay (Pierce, Rockford, II. 5-HT levels were normalized to protein and data were expressed as mean percent reduction of mucosa! 5-HT levels relative to e control± SEM (p ercent 5-HT reduction). All animal studies were carried out with pro tocols approved by the Institutional Animal Care and Use Committee, 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 ani mals according to the abovedescribed in vivo assay. Pvvalues, indicating tical signifi cance of the data (ANOVA) are provided in the table: * refers to P<0.05, ** refers to , *** refers to P<0.005, and**** refers to P<0.0005.
Table 26. In Vivo Efficacy of TPHl Inhibitors In Mice (reduction of mucosa) 5-HT concentrations one day after oral administration of a single 150 mg/kg dose) Example Example Example Efficacy Efficacy Efficacy No. No. No. 1g *** 34u * 63bq **** lh ** 34v * 63bx *** 11 **** 34w *** 63by *** 1m *** 55k * 63bz ** ln ** 55ak ** 63ch *** lo ** 55al * 63cj *** ]p ** 55am *** 63cl *** ly ** 55an *** 63cp *** ** 55az *** 63da *** lOb *** 55bc ** 63dc *** lOd *** 55bd *** 63di *** lOg ** 55bg *** 64c **** lOh *** 63g *** 64e **** lOj **** 63ay *** 64f **** 10k * 63az *** 64g * 11 **** i 63ba *** 64h ** 12b * 63bd *** 65a **** 12c *** 63be *** 66c **** 16 ** 63bf **** 66d **** 22c "' 63bg **** j I01 *** 28 * 63bh ** 29z ** 63bi ** 31 * 63bn **** 34r *** 63bo **** 34s ** 63bp **** Example C: Reduction of mucosal 5-HT concentrations The Examples listed in Table 27 below were tested and found to elicit a reduction in mean mucosa! 5-HT concentrations relative to vehicle-treated animals according to the following in vivo assay.
The efficacy of the TPHI inhibitors of the invention was assessed for the ability to decrease intestinal serotonin concentration 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 hfollowing 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 appro priate test e was stered 12 h aft er dose 2. ing an ght fast, each animal was euthanized by exsanguination under isofl urane anesthesia. Jejunal intestinal mucosa was isolated and homogenized in 300 mL of a buffer containing 0.3M trichloroacetic acid, 0.1M sodium acetate, 10 mM EDTA, 20 mM sodium bisulfate and 50 mM ascorbic acid. ing centrifugation the 5-HT levels in the atants 1 5 were measured by HPLC. The remaining mucosa] pellet was solubilized overnight at 37 °C ina 0.1% sodium dodecyl sulfate buffe r in O. lN 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 of mucosal 5-HT levels relative to vehicle l± SEM (percent 5-HT reduction). All animal studies were carried out with protocols approved by the Institutional Animal Care and Use Committee. es, 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. 111 Vivo Efficacy ofTPHl Inhibitors In Mice (reduction of mucosal 5-HT concentrations two days after oral administration of a single 50 mg/kg dose) Example e Effi cacy Effic acy No. No. 11 *** 63cj ** lm * 63cl *** In *** 63cn **** 1t *** 63dc *** 12c *** 63el *** 55bg *** 63eo *** 63i *** 63ep *** 63ae *** 63ev *** 63aq *** 63ey ** 63ar **** 63fo * 63aw **** 63ha ** 63az *** 64hb *** 63bd *** 69a *** 63bf *** 69b *** 63bg *** 69c *** 63bn **** 63bo *** 63bp *** 63ch *** Example D: In vivo assay for infla mmatory bowel diseases The utility of the compounds of the invention for the treatment of infl ammatory bowel diseases can be measured, for example, using the mental models of colitis induced by trinitrobenzene sulfonic acid (TNBS), dinitrobenzene sulfonic acid (DNBS), and dextran sodium e (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 The utility of the compounds of the invention for the treatment of low bone mass diseases, such as osteoporosis, can be measured, for example, using the ovariectomy-induced osteopenia rat model, as described by Yadav, V. K. et al. in Nature Med. 16, 308-12 (2010).
Example F: In vivo assay for PAH The utility of the compounds of the ion for the treatment of pulmonary arterial hypertension (P AH), can be measured, for example, using the hypoxia mouse model, as described by Abid, S. et al. in Am. J Physiol., Lung ar and Molecular Physiology 303, LS00-8 (2012), or using the rat monocrotaline-induced PAH or the rat chronic a model, as described by Kay, J.M. et al. Respiration 47, 48-56 (1985).
Example G: In vivo assay for allergic airway inflammation The utility of the compounds of the invention for the treatment of allergic airway infl amm ation, can be measured, for e, using the mouse model of allergic asthma, as described by Durk, T. et al. in Am. J Respir. Crit. Care Med. 187, 476-48 5 (2013).
Example H: In vivo assay for gastrointestinal disorders The y of the compounds of the invention for the treatment of gastro intestinal disorders associated with dysregulation of the GI serotonergic , such as chemotherap y­ induced emesis and irr itable bowel syndrom e, can be measured, for example, using the a ferret model of chemotherapy-induced emesis, as described by Liu, Q. et al. in J. col. Exp.
Ther. 325, 47-55 (2008).
Example I: /11 vivo assay for tumor growth The y of the compounds of the invention for the treatment of tumor growt h, can be measured, for example, using the the xenograft model of cholangiocarcinoma tumor growth , as described by , G. et al. in Cancer Res. 68, 9184-93 (2008).
Example J: In vivo assay for leukemia The utility of the nds of the invention for the treatment and prevention of leukemia and other cancers of the blood, 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 .
Example K: In vivo assay for atherosclerosis The utility of the nds of the invention for the treatment of atherosclerosis, and the reduction of plasma terol and triglyceride levels, can be measured, for example, using the Apo E .t. or LDLR -/- mouse models of atherosclerotic plaque development, as described in WO 2012/058598.
Various modifications of the ion, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all , patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims (24)

What is claimed is:
1. A compound of Formula IIa: or a pharmaceutically acceptable salt thereof, wherein: Ring A is C3-10 cycloalkyl, C6-10 aryl, or 5 to 10-membered heteroaryl; L is O or NR4; R1 is H, C1-10 alkyl, or-(CR8R9)pOC(O)R10, wherein said C1-10 alkyl, is 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 selected from H and C1-4 kyl, wherein one of R2 and R3 is H and the other of R2 and R3 is a C1-4 haloalkyl; R4 is H or C1-4 alkyl; R5 is H; R7 is C1-4 alkyl or NR13R14; R8 and R9 are each independently selected from H and C1-4 alkyl; R10 is C1-6 alkyl optionally tuted 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, or C(O)ORa1, RA is H, Cy1, halo, C1-6 alkyl, C2-6 alkenyl, CN, NO2, ORa2, SRa2, C(O)Rb2, c2Rd2, C(O)ORa2, b2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, or Rc2Rd2, 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, C1-6 alkyl, C2- a2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, 6 alkenyl, C1-6 haloalkyl, CN, NO2, OR 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, ORa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, 3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, 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 Rc3Rd3; RC and RD are ndently ed from H, halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, ORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, b4, NRc4Rd4, O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, O)2Rb4, NRc4S(O)2NRc4Rd4, c4Rd4, 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 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, C1-6 alkyl, C2-6 l, C1-6 kyl, 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 Rc4Rd4; 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 ed 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, ORa5, 5, 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, O)2NRc5Rd5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5, wherein said C1-6 alkyl, C2-6 alkenyl C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally tuted 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; each of 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 cycloalkyl, 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, 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 ndently selected from C1-4 alkyl, halo, CN, ORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, Rc6Rd6, NRc6Rd6, 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 of Rb2, Rb3, Rb4, and Rb5 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 l, C6-10 aryl, C3-10 cycloalkyl, 5-10 ed 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 aryl, 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 ally tuted 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, 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 of Rc , Rd, Rc1, 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 ed heteroaryl, 4-10 membered heterocycloalkyl, C6-10 1-4 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 lkyl, 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 tuted 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, Rc6Rd6, 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 Rc6Rd6; each of 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 cycloalkyl, 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 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, and di(C1-4 amino; and p is 1, 2, or 3; wherein any aforementioned 4-10 or 4-7 membered heterocycloalkyl group optionally comprises 1, 2, or 3 oxo substituents, wherein each oxo tuent that is present is substituted on a ring-forming carbon, nitrogen, or sulfur atom of the 4-10 or 4-7 membered heterocycloalkyl group.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is H and R3 is C1-4 kyl.
3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 is H and R3 is trifluoromethyl.
4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-10 alkyl.
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt f, wherein R7 is NR13R14.
6. The compound of any one of claims 1-4, or a pharmaceutically able salt thereof, wherein R7 is NH2.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Ring A is C6-10 aryl.
8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl.
9. The nd of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein RA is C6-10 aryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
11. A compound of claim 1 which is selected from: (3S)(2-amino((1R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'- (methylsulfinyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'-(methylthio)- biphenyl]yl) )pyrimidinyl)-2,8-diazaspiro [4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-carboxy(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-carboxy(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-carboxy(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)(1,2,3,6- tetrahydropyridinyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)(pyridin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)(1-methyl-1H- pyrazolyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(isoxazolyl)(3-methyl-1H-pyrazol yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-(3,6-dihydro-2H-pyranyl)(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(4-(1-acetyl-1,2,3,6-tetrahydropyridinyl)(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-trifluoroethoxy)aminopyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-isopropoxy(3-methyl-1H-pyrazolyl)- [1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',4'-dimethyl(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(2-methoxypyridinyl)(3-methyl-1H- lyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(3-methyl-1H-indazolyl)(3-methyl-1H- lyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-(tert-butyl)(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-ethoxy(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(2-methoxypyrimidinyl)(3-methyl-1H- pyrazolyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(6-methoxypyridinyl)(3-methyl-1H- pyrazolyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-2',3',4',5'- tetrahydro-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)(3'-cyano(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(4'-(acetamidomethyl)(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(4'-(2-acetamidoethyl)(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)(quinolin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(4-(1H-indolyl)(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-(aminomethyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-fluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)(quinolin nyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-methyl(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',4'-dichloro(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',4'-difluoro(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-chloro(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)(pyrimidin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)(piperidin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)(1- (methylsulfonyl)piperidinyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(6-((R)(4-(1-acetylpiperidinyl)(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)(tetrahydro-2H- pyranyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-methoxy-4'-(methoxycarbonyl)(3-methyl- 1H-pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)(3'-(ethoxycarbonyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-(ethoxycarbonyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-(3-carboxypropyl)(3-methyl-1H-pyrazolyl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-(2-carboxyethyl)(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-(3-ethoxyoxopropyl)(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; 8-(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazol yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; 8-(2-amino((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (R)(2-amino((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazol yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl) (trifluoromethyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid (2-amino((R)-2,2,2-trifluoro(4-methyl(3-methyl-1H-pyrazol yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; 8-(2-amino((R)-2,2,2-trifluoro(4-fluoro(3-methyl-1H-pyrazol yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; 8-(2-amino((R)-2,2,2-trifluoro(4-methoxy(3-methyl-1H-pyrazol yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; 8-(2-amino((R)(5-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-methoxy(3-methyl-1H-pyrazol yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)(4-bromo(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-bromo(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(6-methyl(3-methyl-1H-pyrazolyl)pyridin- 3-yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-ethyl(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl) propylphenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)(4-butyl(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (3S)(2-amino((1R)(4-(1,2-dihydroxyethyl)(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-cyano(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-carbamoyl(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-carboxy(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-(ethoxycarbonyl)(3-methyl-1H-pyrazolyl)phenyl)- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(((1,1,1,3,3,3-hexafluoromethylpropan yl)oxy)carbonyl)(3-methyl-1H-pyrazolyl)phenyl)ethoxy)pyrimidinyl)-2,8- piro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl) (propoxycarbonyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)(4-(butoxycarbonyl)(3-methyl-1H-pyrazolyl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-(tert-butoxycarbonyl)(3-methyl-1H-pyrazolyl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(isobutoxycarbonyl)(3-methyl-1H-pyrazol- 1-yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-((cyclopentyloxy)carbonyl)(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl) vinylphenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)((E)-propen- 1-yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-((E)-butenyl)(3-methyl-1H-pyrazolyl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-((E)carboxyvinyl)(3-methyl-1H-pyrazolyl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',4'-dimethyl(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-carboxy(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-carboxy(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)(3'-((E)carboxyvinyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-((E)carboxyvinyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-(2-carboxyethyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-(2-carboxyethyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-(hydroxymethyl)-3'-methyl(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-(hydroxymethyl)-4'-methyl(3-methyl-1H- lyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',4'-difluoro(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',4'-dichloro(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-chloro(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(2'-(ethoxycarbonyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-(ethoxycarbonyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-ethyl(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl) propylphenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-butyl(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-Amino((R)(5-(ethoxycarbonyl)(3-methyl-1H-pyrazolyl)phenyl)- trifluoro ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-Amino((R)(5-carboxy(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-Amino((R)-2,2,2-trifluoro(4-(hydroxymethyl)(3-methyl-1H-pyrazol yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-((dimethylamino)methyl)(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(4-Bromo(3-methyl-1H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy) methylpyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy) methylpyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-methyl((R)-2,2,2-trifluoro(4-(2-methoxypyridinyl)(3-methyl-1H- pyrazolyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-methyl((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'- (methylsulfonyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(6-((R)(3',4'-difluoro(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)methylpyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(3',4'-dimethyl(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)methylpyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (6-((R)(3'-(ethoxycarbonyl)(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)methylpyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-methyl((R)-2,2,2-trifluoro(4-(6-methoxypyridinyl)(3-methyl-1H- pyrazolyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-methyl((R)-2,2,2-trifluoro(4-(2-methoxypyrimidinyl)(3-methyl-1H- pyrazolyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(2',4'-dimethoxy(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)methylpyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(4'-(ethoxycarbonyl)(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)methylpyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(4'-(dimethylcarbamoyl)(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)methylpyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-methyl((R)-2,2,2-trifluoro(4-(2-methoxypyridinyl)(3-methyl-1H- pyrazolyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-methyl((R)-2,2,2-trifluoro(3'-fluoro-4'-methoxy(3-methyl-1H-pyrazol- 1-yl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(3'-(dimethylcarbamoyl)(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)methylpyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-methyl((R)-2,2,2-trifluoro(2',4',6'-trimethyl(3-methyl-1H-pyrazolyl)- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-methyl((R)-2,2,2-trifluoro(4'-isopropoxy(3-methyl-1H-pyrazolyl)- [1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-methyl((R)-2,2,2-trifluoro(2'-methoxy(3-methyl-1H-pyrazolyl)-[1,1'- yl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-methyl((R)-2,2,2-trifluoro(3'-methoxy-4'-(methoxycarbonyl)(3-methyl- 1H-pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (6-((R)(4'-(tert-butyl)(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)methylpyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(4'-ethoxy(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)methylpyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-methyl((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'- (trifluoromethoxy)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-methyl((R)-2,2,2-trifluoro(3'-(methoxycarbonyl)(3-methyl-1H-pyrazol- 1-yl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-methyl((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)(pyrimidin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-methyl((R)-2,2,2-trifluoro(3'-methoxy(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-methyl((R)-2,2,2-trifluoro(3'-isopropyl(3-methyl-1H-pyrazolyl)- [1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-methyl((R)-2,2,2-trifluoro(3'-fluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-methyl((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)(pyridin nyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-methyl((R)-2,2,2-trifluoro(3'-methoxy(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-methyl((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)(pyridin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; 8-(6-((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy) phenoxypyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; 8-(6-((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy) (cyclohexyloxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; 8-(6-((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy) (cyclohexylamino)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy) (cyclobutanecarboxamido)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)(4-chloro(2-oxopyrrolidinyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',5-dichloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-methyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; 8-(2-amino((R)(5-chloro-[1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; 8-(2-amino((R)(2'-aminochloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; 8-(2-amino((R)(5-chloro-3'-nitro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; 8-(2-amino((R)(3'-aminochloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; 8-(2-amino((R)(5-chloro-4'-nitro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; 8-(2-amino((R)(4'-aminochloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-chloro(6-methylpyridinyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(ethylsulfonyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(propylsulfonyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-(butylsulfonyl)chloro-[1,1'-biphenyl]yl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)(5-chloro-3'-(hydroxymethyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(methylsulfonamido)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(2-oxopyrrolidinyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(3-methyloxoimidazolidinyl)-[1,1'-biphenyl]- 2-yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-[1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-chloro(5-chlorothiophenyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)(4-chloro(1-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-sulfamoyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)(5-chloro-3'-hydroxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(methylsulfonyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-cyano-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-methoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-(aminomethyl)chloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(3'-(acrylamidomethyl)chloro-[1,1'-biphenyl]yl)-2,2,2- oroethoxy)aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-carboxychloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-carbamoylchloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-4'-(methylsulfonyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-4'-sulfamoyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4',5-dichloro-3'-fluoro-[1,1'-biphenyl]yl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-isopropoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-ethoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)(3',5-dichloro-4'-ethoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',5-dichloro-4'-methyl-[1,1'-biphenyl]yl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',5-dichloro-4'-isopropoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-fluoro-4'-isopropoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4',5-dichloro-3'-(trifluoromethyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',5-dichloro-5'-fluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-(tert-butyl)chloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',5-dichloro-5'-(trifluoromethyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-fluoro-5'-(trifluoromethyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-methoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-fluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4',5-dichloro-3'-methyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)(5-chloro-3',5'-difluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',5-dichloro-4'-fluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3',4'-difluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',5-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(ethoxycarbonyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-chloro(2-methoxyethoxy)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (3S)(6-(1-((1r,3r,5S,7S)-adamantanyl)ethoxy)aminopyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid; (S)(6-((1r,3r,5S,7S)-adamantanylmethoxy)aminopyrimidinyl)-2,8- piro[4.5]decanecarboxylic acid; 8-(4-amino((naphthalenylmethyl)amino)-1,3,5-triazinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid; 8-(4-(([1,1'-biphenyl]ylmethyl)amino)amino-1,3,5-triazinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid; 8-(4-amino((2-(piperidinyl)benzyl)amino)-1,3,5-triazinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid; 8-(4-(([1,1'-biphenyl]ylmethyl)amino)amino-1,3,5-triazinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid; mino(((R)(naphthalenyl)ethyl)amino)-1,3,5-triazinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid; 8-(4-amino((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)-1,3,5-triazinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((2-(piperidinyl)benzyl)amino)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((2-phenoxy(piperidinyl)benzyl)amino)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid; (3S)(6-(((3S,5S)-adamantanylmethyl)amino)aminopyrimidinyl)-2,8- piro[4.5]decanecarboxylic acid; 3S)(6-((1-((1R,3S,5S)-adamantanyl)ethyl)amino)aminopyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-chloro-[1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)-2,2,2-trifluoro(3'-fluoro-[1,1'-biphenyl]yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(5-((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyridazinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(4-((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)phenyl)ethoxy)pyridin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(4-((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyridinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(4-((R)(4-Chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy) phenoxypyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (3S)(2-Amino(1-(2,6-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- piro[4.5]decanecarboxylic acid; (S)(2-Amino((R)(2,5-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid; (S)(2-Amino((R)-2,2,2-trifluoro(3'-(methylsulfonyl)propyl-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-Amino((R)-2,2,2-trifluoro(3'-(methylsulfonyl)((E)-propenyl)- [1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)([1,1':4',1''-terphenyl]-2'-yl)-2,2,2-trifluoroethoxy)aminopyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)([1,1':3',1''-terphenyl]-2'-yl)-2,2,2-trifluoroethoxy)aminopyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3,4-dimethyl-3''-(methylsulfonyl)-[1,1':3',1''-terphenyl]-4'-yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)-2,2,2-trifluoro(3'-(methylsulfonyl)(quinolinyl)-[1,1'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-(methylsulfonyl)((E)-propenyl)-[1,1'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-(methylsulfonyl)propyl-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)([1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)aminopyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(1-methyl-1H-indazol yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(1-methyl-1H-benzo[d]imidazol yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(4-(1H-benzo[d]imidazolyl)phenyl)-2,2,2-trifluoroethoxy) aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)-2,2,2-trifluoro(3'-fluoro-4'-methoxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-(benzo[d]isothiazolyl)phenyl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-(benzo[d]isoxazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(4-(1H-indazolyl)phenyl)-2,2,2-trifluoroethoxy)aminopyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(1-methyl-1H-indazol yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-(benzo[d]isothiazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-(benzo[d]thiazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(4-([1,2,4]triazolo[1,5-a]pyridinyl)phenyl)-2,2,2-trifluoroethoxy) aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)-2,2,2-trifluoro(4-(naphthalenyl)phenyl)ethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-methoxy-4'-methyl-[1,1'-biphenyl] oxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)-2,2,2-trifluoro(3'-methoxy-5'-methyl-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(5'-methoxy-2'-methyl-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',4'-dimethoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-methoxy-4'-(pyrrolidinecarbonyl)-[1,1'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(1-oxo-1,3-dihydroisobenzofuran yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(2-oxo-1,2-dihydroquinolin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(1-methyloxo-1,2-dihydroquinolin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(2-oxo-1,2,3,4-tetrahydroquinolin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(4-(1H-indazolyl)phenyl)-2,2,2-trifluoroethoxy)aminopyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-(1,3-dimethyl-1H-indazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-(1,3-dimethyl-1H-indolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-methoxy-5'-(trifluoromethyl)-[1,1'-biphenyl]- 4-yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-cyano-5'-methoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(2-oxo-2,3-dihydrobenzo[d]oxazol yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(3-methyl-1H-indol yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (6-((R)(3'-acetoxy-4'-(methoxycarbonyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(2-oxo-2H-chromen yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(1-methyloxo-1,6-dihydropyridin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-carboxy-3'-hydroxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(2-methoxyquinolin nyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(2-(methylthio)quinolin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(1-methyloxo-1,2,3,4-tetrahydroquinolin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (3S)(2-amino(2,2,2-trifluoro(3'-fluoro-[1,1'-biphenyl]yl)ethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; -(2-amino(2,2,2-trifluoro(3'-methoxy-[1,1'-biphenyl]yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-fluoro-[1,1'-biphenyl]yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-methoxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-fluoro-5'-methoxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',5'-difluoro-[1,1'-biphenyl]yl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)-2,2,2-trifluoro(4'-methoxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2'-methoxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-(trifluoromethyl)-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-(trifluoromethoxy)-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-ethoxy-[1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-isopropoxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(pyridinyl)phenyl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(pyridinyl)phenyl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(pyrimidinyl)phenyl)ethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(3-methyl-1H-indazol yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-(1,3-dimethyl-1H-indazolyl)phenyl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-(2,3-dimethyl-2H-indazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(1-oxo-1,2,3,4-tetrahydroisoquinolin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(isoquinolinyl)phenyl)ethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(isoquinolinyl)phenyl)ethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)(4'-((dimethylamino)methyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(quinolinyl)phenyl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(quinolinyl)phenyl)ethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(quinoxalinyl)phenyl)ethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(2-methyloxo-1,2,3,4- tetrahydroisoquinolinyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(quinazolinyl)phenyl)ethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-fluoro-2'-methoxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)-2,2,2-trifluoro(2'-fluoro-3'-methoxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2'-fluoro-5'-methoxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(6-methylpyridin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)-2,2,2-trifluoro(4'-(pyrrolidinecarbonyl)-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-carboxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-carboxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-propyl-[1,1'-biphenyl]yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)-2,2,2-trifluoro(3'-(hydroxymethyl)-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2'-(hydroxymethyl)-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-isopropoxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-(dimethylcarbamoyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)-2,2,2-trifluoro(3'-(piperidinecarbonyl)-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(2'-((dimethylamino)methyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-ethyl-[1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-hydroxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-hydroxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(2',4'-dimethoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-(trifluoromethyl)-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2'-(trifluoromethyl)-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(2',6'-difluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)(2',6'-dimethyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',4'-dimethyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)(4'-(tert-butyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-isopropyl-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-isopropyl-[1,1'-biphenyl] oxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',4'-dichloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-(trifluoromethoxy)-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(2',3'-dimethyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3',4',5'-trifluoro-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-chloro-2'-methyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',5'-dimethyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',4'-difluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(2',5'-dimethyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-butyl-[1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-fluoro-4'-methyl-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)-2,2,2-trifluoro(4'-(methylsulfonyl)-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-methyl-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-methyl-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-chloro-[1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-(benzofuranyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(5'-fluoro-2'-methoxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(2-oxochroman yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(1,2,3,4-tetrahydroquinoxalinyl) phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3,4-dihydroquinazolinyl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(1,2,3,4-tetrahydroquinazolinyl)ethoxy) pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(naphthalenyl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid; 9-(2-Amino((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-3,9-diazaspiro[5.5]undecanecarboxylic acid; (S)(2-Amino((4-(3-methyl-1H-indazolyl)phenoxy)methyl)pyrimidinyl)-2,8- piro[4.5]decanecarboxylic acid; (S)(2-amino((5-chloro-3'-(methylsulfonyl)-[1,1'-biphenyl]yl)methoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)-ethyl 8-(2-amino((R)(4-(benzo[d]thiazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(6-((R)(4-(1H-indazolyl)phenyl)-2,2,2-trifluoroethoxy) aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'-methoxy-4'-(pyrrolidinecarbonyl)- [1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-4'-nitro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-(benzo[d]isothiazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-(benzo[d]isothiazolyl)phenyl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; hyl 8-(2-amino((R)(3',4'-dimethoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(1-methyloxo-1,2-dihydroquinolin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)(3'-aminochloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)-2,2,2-trifluoro(3'-(methylsulfonyl)propyl-[1,1'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-(1,3-dimethyl-1H-indolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(6-((R)(3'-acrylamidochloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'-fluoro-4'-methoxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(1-methyloxo-1,6-dihydropyridin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(2-oxo-1,2,3,4-tetrahydroquinolin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(2-oxo-1,2-dihydroquinolin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'-(methylsulfonyl)((E)-propen yl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4'-chloro(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'-(methylsulfonyl)propyl-[1,1'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)-2,2,2-trifluoro(3'-(methylsulfonyl)((E)-propen yl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(ethylsulfonyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(propylsulfonyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(butylsulfonyl)-[1,1'-biphenyl]yl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(1-oxo-1,3-dihydroisobenzofuran yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)-2,2,2-trifluoro(4-(2-methoxyquinolin nyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(hydroxymethyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(2-oxopyrrolidinyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(3-methyloxoimidazolidinyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro-3'-(methylsulfonyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(methylsulfonamido)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(2-bromochlorophenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)-2,2,2-trifluoro(4-(1-methyloxo-1,2,3,4- tetrahydroquinolinyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(2-(methylthio)quinolin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(2,5-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(6-((R)([1,1':4',1''-terphenyl]-2'-yl)-2,2,2-trifluoroethoxy) aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(2'-(ethoxycarbonyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3'-(ethoxycarbonyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)(4'-(ethoxycarbonyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(2,6-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3',5-dichloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-methyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)(5-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'- (methylthio)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4'-methyl(3-methyl-1H-pyrazolyl)- [1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'-methyl(3-methyl-1H-pyrazolyl)- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3',4'-dichloro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro(2-oxopyrrolidinyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; ethyl 8-(2-amino((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; hyl mino((R)-2,2,2-trifluoro(3'-methoxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; hyl 8-(2-amino((R)-2,2,2-trifluoro(4-methoxy(3-methyl-1H-pyrazol yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'-fluoro-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3',4'-dimethyl(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-ethyl(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl) propylphenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-butyl(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-(ethoxycarbonyl)(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-(ethoxycarbonyl)(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)(5-((E)ethoxyoxopropenyl)(3-methyl-1H- pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)(5-(3-ethoxyoxopropyl)(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)-2,2,2-trifluoro(6-methyl(3-methyl-1H-pyrazol yl)pyridinyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)((E)-prop- 1-enyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3',4'-dimethyl(3-methyl-1H-pyrazolyl)-[1,1'- yl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; hyl 8-(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl) propylphenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-ethyl(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-butyl(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl) vinylphenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-((E)-butenyl)(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro(1-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(2-(1-methyl-1H-pyrazol yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-(1,3-dimethyl-1H-indazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-(2,3-dimethyl-2H-indazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(1-oxo-1,2,3,4-tetrahydroisoquinolin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(isoquinolin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-(3-ethoxyoxopropyl)(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(isoquinolin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-(4-ethoxyoxobutyl)(3-methyl-1H-pyrazol nyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-(4-ethoxyoxobutyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-(4-ethoxyoxobutyl)(3-methyl-1H-pyrazol nyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3'-cyano(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)(5-chloro-3'-cyano-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-methoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-sulfamoyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-hydroxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(methylsulfonyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3'-(aminomethyl)chloro-[1,1'-biphenyl]yl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(quinolinyl)phenyl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(quinolinyl)phenyl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4'-isopropoxy(3-methyl-1H-pyrazol yl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(quinoxalin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(6-((R)(4'-(acetamidomethyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)aminopyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl (R)(4'-(2-acetamidoethyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)aminopyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)(quinolin- 7-yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; hyl 8-(2-amino((R)-2,2,2-trifluoro(4-(2-methoxypyridinyl)(3-methyl- 1H-pyrazolyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(6-((R)(4-(1H-indolyl)(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(ethoxycarbonyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; 2'-((R)((2-amino((S)(ethoxycarbonyl)-2,8-diazaspiro[4.5]decanyl)pyrimidin- 4-yl)oxy)-2,2,2-trifluoroethyl)-5'-chloro-[1,1'-biphenyl]carboxylic acid; (S)-ethyl 8-(6-((R)(3'-(acrylamidomethyl)chloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3'-carbamoylchloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; hyl 8-(2-amino((R)(5-chloro-4'-(methylsulfonyl)-[1,1'-biphenyl]yl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-4'-sulfamoyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate (S)-ethyl 8-(2-amino((R)(2'-(ethoxycarbonyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3'-(ethoxycarbonyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4'-(ethoxycarbonyl)(3-methyl-1H-pyrazolyl)-[1,1'- yl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (3S)-ethyl 8-(2-amino((1R)(4-(1,2-dihydroxyethyl)(3-methyl-1H-pyrazol nyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4'-(aminomethyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3'-((E)ethoxyoxopropenyl)(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4'-((E)ethoxyoxopropenyl)(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylate; hyl 8-(2-amino((R)(3'-(3-ethoxyoxopropyl)(3-methyl-1H-pyrazolyl)- [1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)(4'-(3-ethoxyoxopropyl)(3-methyl-1H-pyrazolyl)- [1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'-fluoro(3-methyl-1H-pyrazolyl)- [1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)(quinolin- 6-yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (3S)-ethyl 8-(2-amino((1R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)(2-oxo- 1,3-dioxolanyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(2-methyloxo-1,2,3,4- tetrahydroisoquinolinyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(6-((R)(4-(acetamidomethyl)(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- oroethoxy)aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (3S)-ethyl 8-(2-amino((1R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'-((2-((2- oxotetrahydrofuranyl)thio)ethyl)carbamoyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3,4-dimethyl-3''-(methylsulfonyl)-[1,1':3',1''-terphenyl]-4'- yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'-(methylsulfonyl)(quinolinyl)-[1,1'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4'-(hydroxymethyl)-3'-methyl(3-methyl- 1H-pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane ylate; hyl 8-(2-amino((R)-2,2,2-trifluoro(3'-(hydroxymethyl)-4'-methyl(3-methyl- 1H-pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4'-(methoxycarbonyl)(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; 3'-((S)((2-amino((R)(ethoxycarbonyl)-2,8-diazaspiro[4.5]decanyl)pyrimidin- 4-yl)oxy)-2,2,2-trifluoroethyl)-4'-(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]carboxylic acid; (S)-ethyl mino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)(1-oxo- 1,3-dihydroisobenzofuranyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(quinazolin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl) (pyrimidinyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3',4'-difluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate (S)-ethyl 8-(2-amino((R)(4'-chloro(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4'-chloro(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; hyl mino((R)(3',4'-difluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3',4'-dichloro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'-fluoro-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl) (pyrimidinyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4',5-dichloro-3'-fluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-ethoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3',5-dichloro-4'-ethoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3',5-dichloro-5'-fluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3'-(tert-butyl)chloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; hyl 8-(2-amino((R)(3',5-dichloro-5'-(trifluoromethyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-fluoro-5'-(trifluoromethyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; hyl 8-(2-amino((R)(3'-chloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-methoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-isopropoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3',5-dichloro-4'-methyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3',5-dichloro-4'-isopropoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)(5-chloro-3'-fluoro-4'-isopropoxy-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4',5-dichloro-3'-(trifluoromethyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-fluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4',5-dichloro-3'-methyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3',5-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3',5'-difluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)(3',5-dichloro-4'-fluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3',4'-difluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-octyl 8-(2-amino((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-cyclopentyl 8-(2-amino((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; ntyl mino((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-cyclohexyl 8-(2-amino((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-propyl 8-(2-amino((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-neopentyl 8-(2-amino((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-butyl 8-(2-amino((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-isopropyl 8-(2-amino((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-tert-butyl 8-(2-amino((R)(4-chloro(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-tert-butyl 8-(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl) propylphenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)(dimethylamino)ethyl 8-(2-amino((R)(4-chloro(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)(dimethylamino)oxoethyl 8-(2-amino((R)(4-chloro(3-methyl-1H- pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)(((R)aminomethylbutanoyl)oxy)ethyl 8-(2-amino((R)(4-chloro(3- methyl-1H-pyrazolyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylate; and (3S)(pivaloyloxy)ethyl 8-(2-amino((R)(4-chloro(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; or a pharmaceutically acceptable salt of any of the aforementioned.
12. A compound of claim 1 which is selected from: (2-amino((R)(3',4'-dimethyl(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)(3'-chloro(3-methyl-1H-pyrazolyl)-5'-(trifluoromethyl)- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)(3'-chloro-4'-ethoxy(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-3'- (trifluoromethyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)(3'-chloro-5'-methyl(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-chloro-3'-fluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-ethoxy(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)-2,2,2-trifluoro(3'-fluoro-4'-methyl(3-methyl-1H-pyrazol yl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid (S)(2-amino((R)(3'-chloro-4'-fluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-3'- (trifluoromethoxy)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)(3',5'-dimethyl(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',4'-difluoro(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',5'-difluoro(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-fluoro(3-methyl-1H-pyrazolyl)-3'- (trifluoromethyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-fluoro-4'-isopropoxy(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)(3'-ethoxy-5'-fluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-(tert-butyl)(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-fluoro-3'-methyl(3-methyl-1H-pyrazol yl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-isopropyl(3-methyl-1H-pyrazolyl)-[1,1'- yl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)-2,2,2-trifluoro(3'-isopropoxy(3-methyl-1H-pyrazolyl)- [1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-chloro-3'-methyl(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-carbamoyl(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-3',5'- bis(trifluoromethyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)(3'-ethoxy-4'-fluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-chloro-3',5'-dimethyl(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',5'-dichloro(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-(tert-butyl)-5'-methyl(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-chloro(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-chloro(3-methyl-1H-pyrazolyl)-4'-(trifluoromethyl)- [1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-methoxy(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3',4'-dimethyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-4'-ethoxy-3'-fluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3',5'-dimethyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4',5-dichloro-3',5'-dimethyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-4'-fluoro-3'-methyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',5-dichloro-5'-methyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3',4',5'-trifluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(trifluoromethoxy)-[1,1'-biphenyl]yl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3',5'-bis(trifluoromethyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-isopropyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3',5,5'-trichloro-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-4'-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-fluoro-5'-isopropoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)(3'-(tert-butyl)chloro-5'-methyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-fluoro-4'-methyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-chloro(pyridinyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-ethoxy-4'-fluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)-ethyl 8-(2-amino((R)(5-chloro-3',4'-dimethyl-[1,1'-biphenyl]yl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4',5-dichloro-3',5'-dimethyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-4'-ethoxy-3'-fluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3',5'-dimethyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)(3',5-dichloro-5'-methyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-4'-fluoro-3'-methyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]- 2-yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(trifluoromethoxy)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-isopropyl-[1,1'-biphenyl]yl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; hyl 8-(2-amino((R)(5-chloro-3',5'-bis(trifluoromethyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-fluoro-4'-methyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3',5,5'-trichloro-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-4'-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro(pyridinyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; hyl 8-(2-amino((R)(5-chloro-3'-fluoro-5'-isopropoxy-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-ethoxy-5'-fluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3'-(tert-butyl)chloro-5'-methyl-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-cyano-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3'-ethoxy-5'-fluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)(4'-chloro-3'-fluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3'-chloro-4'-ethoxy(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3'-ethoxy(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]- 4-yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3',5'-difluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-3'- (trifluoromethyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-ethoxy-4'-fluoro-[1,1'-biphenyl]yl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'-fluoro-4'-isopropoxy(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)(3',5'-dimethyl(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3'-chloro-5'-methyl(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)-2,2,2-trifluoro(3'-fluoro-4'-methyl(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)(3'-(tert-butyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3'-chloro(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; hyl 8-(2-amino((R)(3'-chloro-4'-fluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3',4'-difluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4'-fluoro(3-methyl-1H-pyrazolyl)-3'- (trifluoromethyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)(3'-chloro(3-methyl-1H-pyrazolyl)-5'- uoromethyl)-[1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-3'- (trifluoromethoxy)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)(3'-(tert-butyl)-5'-methyl(3-methyl-1H-pyrazolyl)- [1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl mino((R)(4'-chloro-3'-methyl(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4'-chloro-3',5'-dimethyl(3-methyl-1H-pyrazolyl)- [1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl mino((R)-2,2,2-trifluoro(4'-fluoro-3'-methyl(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)(4'-ethoxy-3'-fluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3',5'-dichloro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'-isopropyl(3-methyl-1H-pyrazol yl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4'-chloro(3-methyl-1H-pyrazolyl)-3'- uoromethyl)-[1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3'-chloro(3-methyl-1H-pyrazolyl)-4'- uoromethyl)-[1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3'-carbamoyl(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-3',5'- bis(trifluoromethyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'-isopropoxy(3-methyl-1H-pyrazol yl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3'-ethoxy-4'-fluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'-fluoro-5'-isopropoxy(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4'-methoxy(3-methyl-1H-pyrazolyl)- [1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; and (S)-ethyl 8-(2-amino((R)(4'-ethoxy(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]- 4-yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; or a pharmaceutically acceptable salt of any of the aforementioned.
13. A compound of claim 1 which is selected from: (S)(2-amino((R)(4'-ethoxy-3'-fluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)-2,2,2-trifluoro(3',4',5'-trifluoro(3-methyl-1H-pyrazolyl)- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-chloro-4'-methyl(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-methyl(3-methyl-1H-pyrazolyl)-4'- (trifluoromethoxy)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (2-amino((R)-2,2,2-trifluoro(3'-fluoro-5'-isopropoxy(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)(3'-chloro-5'-fluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-chloro(3-methyl-1H-pyrazolyl)-3'-(trifluoromethyl)- [1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-fluoro(3-methyl-1H-pyrazolyl)-5'- (trifluoromethyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane ylic acid; (S)(2-amino((R)(3'-chloro-4'-isopropoxy(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl)(naphthalen yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-(benzyloxy)-3'-fluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-isopropoxy-3'-methyl(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-fluoro(3-methyl-1H-pyrazolyl)-4'- propoxy-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-butoxy-3'-fluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-fluoro-4'-(5-methyl-1,3,4-oxadiazolyl) (3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'- (methylsulfonyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'-propoxy-[1,1'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'-((2- morpholinoethyl)carbamoyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'-sulfamoyl- [1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-carbamoyl(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'- lcarbamoyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-fluoro-4'-methoxy(3-methyl-1H-pyrazol yl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'-(piperazine carbonyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-(dimethylcarbamoyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-isobutoxy(3-methyl-1H-pyrazolyl)- [1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-(diethylcarbamoyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'- (neopentyloxy)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)(4-(chromanyl)(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-(cinnolinyl)(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3'-(hydroxymethyl)-4'-methyl(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-(hydroxymethyl)-3'-methyl(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylic acid; (S)(2-amino((R)(4-(6-ethoxypyridinyl)(3-methyl-1H-pyrazolyl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((S)(3',4'-bis(hydroxymethyl)(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3',4'-dimethyl(3-(trifluoromethyl)-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-bromo(3-methyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-chloro(3-(trifluoromethyl)-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(2-(3-(tert-butyl)-1H-pyrazolyl)chlorophenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-chloro(3-isopropyl-1H-pyrazolyl)phenyl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-chloro(3-cyclopropyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-(hydroxymethyl)(3-methyl-1H-pyrazol yl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(3'-(tert-butyl)chloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(propenyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro [4.5]decanecarboxylic acid; (S)(2-amino((R)(4-chloro(2-(dimethylamino)pyridinyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-chloro(naphthalenyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-chloro(2-isopropylpyridinyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-4'-fluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)(4',5-dichloro-[1,1'-biphenyl]yl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-4'-methyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-2',3',4',5'-tetrahydro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-isobutoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(pyrrolidinecarbonyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(cyclopentyloxy)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(((1R,4R)hydroxycyclohexyl)carbamoyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-ethyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-isopropyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-((2-(pyrrolidinyl)ethyl)carbamoyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(morpholinecarbonyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(4-methylpiperazinecarbonyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-chloro(2-methylthiazolyl)phenyl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-chloro(1-methyloxo-1,2-dihydropyridinyl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(N-methylsulfamoyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(N,N-dimethylsulfamoyl)-[1,1'-biphenyl]yl)- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(methylcarbamoyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(dimethylcarbamoyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(diethylcarbamoyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(2-(1H-benzo[d]imidazolyl)chlorophenyl)-2,2,2-trifluoroethoxy) aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(piperazinecarbonyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(4-cyclopropylpiperazinecarbonyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-chloro(pyridinyl)phenyl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-chloro(pyrimidinyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-chloro(pyrazinyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(5-chloro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)(2-(1H-benzo[d]imidazolyl)chlorophenyl)-2,2,2-trifluoroethoxy) aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-chloro(1H-indazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-bromo(piperazinyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-isopropoxy(piperazinyl)-[1,1'-biphenyl]- thoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-isopropoxymorpholino-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)([1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)amino pyrimidinyl)- 2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-isopropoxy-[1,1':3',1''-terphenyl]-4'- oxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-propoxy-[1,1':3',1''-terphenyl]-4'- yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(5-(methylsulfonyl)-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(3-fluoropropoxy-[1,1':3',1''-terphenyl]-4'- yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)(3,4-dimethyl-[1,1':3',1''-terphenyl]-4'-yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(6-((R)([1,1':3',1''-terphenyl]-4'-yl)-2,2,2-trifluoroethoxy)aminopyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (R)(2-amino((R)(5-chloro-[1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (R)(2-amino((S)(5-chloro-[1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((S)(5-chloro-[1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((S)(3',4'-dimethyl(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((S)(3',4'-dimethyl(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (R)(2-amino((R)(3',4'-dimethyl(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(3-fluoroquinolin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-propoxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-(diethylcarbamoyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-carbamoyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-(methylcarbamoyl)-[1,1'-biphenyl] oxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-((2-morpholinoethyl)carbamoyl)-[1,1'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-(methylsulfonyl)-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-sulfamoyl-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-(dimethylcarbamoyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4'-(piperazinecarbonyl)-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (2-amino((R)-2,2,2-trifluoro(3'-fluoro-4'-propoxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-ethoxy-3'-fluoro-[1,1'-biphenyl]yl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4'-ethoxy-[1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-(cinnolinyl)phenyl)-2,2,2-trifluoroethoxy )pyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(4-(chromanyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)- 2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)-2,2,2-trifluoro(4-(3-fluoroquinolinyl) methylphenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; (S)(2-amino((R)(2-ethyl(3-fluoroquinolinyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid; hyl 8-(2-amino((R)-2,2,2-trifluoro(3',4',5'-trifluoro(3-methyl-1H-pyrazol- 1-yl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro(1-methyloxo-1,2-dihydropyridin yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'-methyl(3-methyl-1H-pyrazolyl)- 4'-(trifluoromethoxy)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)(3'-chloro-4'-methyl(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; hyl 8-(2-amino((R)-2,2,2-trifluoro(3'-fluoro(3-methyl-1H-pyrazolyl)-5'- uoromethyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)(3'-chloro-5'-fluoro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-cyclopropyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3'-chloro-4'-isopropoxy(3-methyl-1H-pyrazolyl)- [1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)(2-(benzo[d]thiazolyl)chlorophenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)(4-chloro(2-(dimethylamino)pyridinyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro(naphthalenyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(3'-(tert-butyl)chloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(6-((R)(2-(1H-benzo[d]imidazolyl)chlorophenyl)-2,2,2- trifluoroethoxy)aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro(1H-indazolyl)phenyl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro(2-isopropylpyridinyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-4'-fluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4',5-dichloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-4'-methyl-[1,1'-biphenyl]yl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(2-(3-methyl-1H-pyrazolyl) (naphthalenyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-2',3',4',5'-tetrahydro-[1,1'-biphenyl]yl)-2,2,2- oroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4'-(benzyloxy)-3'-fluoro(3-methyl-1H-pyrazolyl)- [1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4'-isopropoxy-3'-methyl(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; hyl 8-(2-amino((R)(5-chloro-3'-isobutoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-isopropoxy-[1,1':3',1''-terphenyl]-4'- yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(3-fluoroquinolin yl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'-fluoro(3-methyl-1H-pyrazolyl)-4'- propoxy-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4'-butoxy-3'-fluoro(3-methyl-1H-pyrazolyl)-[1,1'- yl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'-fluoro-4'-(5-methyl-1,3,4-oxadiazol yl)(3-methyl-1H-pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(pyrrolidinecarbonyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(cyclopentyloxy)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; hyl 8-(2-amino((R)(5-chloro-3'-(morpholinecarbonyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(((1R,4R)hydroxycyclohexyl)carbamoyl)- [1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane ylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-ethyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-isopropyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4'-propoxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(2-ethyl(3-fluoroquinolinyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(4-methylpiperazinecarbonyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(3-fluoroquinolinyl) phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4'-(diethylcarbamoyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4'-carbamoyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro(2-methylthiazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-propoxy-[1,1':3',1''-terphenyl]-4'- yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro(5-chlorothiophenyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4'-(methylsulfonyl)-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'- (methylsulfonyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'-propoxy- [1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)(4'-(diethylcarbamoyl)(3-methyl-1H-pyrazolyl)- [1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl mino((R)-2,2,2-trifluoro(4'-(methylcarbamoyl)-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'- sulfamoyl-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; hyl 8-(2-amino((R)-2,2,2-trifluoro(4'-sulfamoyl-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4'-((2-morpholinoethyl)carbamoyl)-[1,1'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'-((2- morpholinoethyl)carbamoyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8- diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)(4'-(dimethylcarbamoyl)-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4'-(piperazinecarbonyl)-[1,1'-biphenyl]- 4-yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'- azinecarbonyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane- 3-carboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro(1-methyloxo-1,2-dihydropyridin yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4'-(dimethylcarbamoyl)(3-methyl-1H-pyrazolyl)- [1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'-fluoro-4'-methoxy(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; hyl 8-(2-amino((R)-2,2,2-trifluoro(3'-fluoro-4'-propoxy-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'- (methylcarbamoyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(N-methylsulfamoyl)-[1,1'-biphenyl]yl)- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(N,N-dimethylsulfamoyl)-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4'-isopropoxymorpholino-[1,1'- biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(methylcarbamoyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(dimethylcarbamoyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4'-ethoxy-3'-fluoro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4'-ethoxy-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(5-(methylsulfonyl)-[1,1'-biphenyl] yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(diethylcarbamoyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4'-isobutoxy(3-methyl-1H-pyrazol yl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)-2,2,2-trifluoro(3-(3-methyl-1H-pyrazolyl)-4'- (neopentyloxy)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(6-((R)(2-(1H-benzo[d]imidazolyl)chlorophenyl)-2,2,2- trifluoroethoxy)aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; hyl 8-(2-amino((R)(4-(chromanyl)(3-methyl-1H-pyrazolyl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(piperazinecarbonyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(4-cyclopropylpiperazinecarbonyl)-[1,1'- yl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)(4-(cinnolinyl)(3-methyl-1H-pyrazolyl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro(3-(trifluoromethyl)-1H-pyrazolyl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(2-(3-(tert-butyl)-1H-pyrazolyl)chlorophenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro(3-isopropyl-1H-pyrazolyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro(3-cyclopropyl-1H-pyrazolyl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)(3',4'-dimethyl(3-(trifluoromethyl)-1H-pyrazolyl)- [1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane ylate; (S)-ethyl 8-(2-amino((R)(3,4-dimethyl-[1,1':3',1''-terphenyl]-4'-yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl mino((R)-2,2,2-trifluoro(3-fluoropropoxy-[1,1':3',1''-terphenyl]- 4'-yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; hyl 8-(6-((R)([1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)aminopyrimidin yl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(6-((R)([1,1':3',1''-terphenyl]-4'-yl)-2,2,2-trifluoroethoxy) aminopyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4'-(hydroxymethyl)(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)(4-(chromanyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro(pyridinyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro(pyrimidinyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(3'-(hydroxymethyl)-4'-methyl(3-methyl- 1H-pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4'-(hydroxymethyl)-3'-methyl(3-methyl- 1H-pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-ethyl mino((R)(4-(6-ethoxypyridinyl)(3-methyl-1H-pyrazol yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)-2,2,2-trifluoro(4-(6-methoxypyridinyl)(3-methyl- 1H-pyrazolyl)phenyl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(5-chloro-3'-(2-methoxyethoxy)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((R)(4-chloro(pyrazinyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-ethyl 8-(2-amino((S)(3',4'-bis(hydroxymethyl)(3-methyl-1H-pyrazolyl)- [1,1'-biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-tert-butyl 8-(2-amino((R)(3',4'-dimethyl(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-tert-butyl 8-(2-amino((R)-2,2,2-trifluoro(4'-isopropoxy(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; opropyl 8-(2-amino((R)(3',4'-dimethyl(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-cyclopentyl mino((R)(3',4'-dimethyl(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5] decanecarboxylate; (S)-methyl 8-(2-amino((R)(3',4'-dimethyl(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5] decanecarboxylate; (S)-propyl 8-(2-amino((R)(3',4'-dimethyl(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5] decanecarboxylate; (S)-isopropyl 8-(2-amino((R)-2,2,2-trifluoro(4'-isopropoxy(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decane carboxylate; (S)-cyclopentyl mino((R)-2,2,2-trifluoro(4'-isopropoxy(3-methyl-1H- pyrazolyl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro [4.5]decane carboxylate; (S)-propyl 8-(2-amino((R)-2,2,2-trifluoro(4'-isopropoxy(3-methyl-1H-pyrazol yl)-[1,1'-biphenyl]yl)ethoxy)pyrimidinyl)-2,8-diazaspiro [4.5]decanecarboxylate; (S)-isopropyl mino((R)(5-chloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; clopentyl 8-(2-amino((R)(4'-chloro(3-methyl-1H-pyrazolyl)-[1,1'- biphenyl]yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-propyl 8-(2-amino((R)(5-chloro-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; (S)-methyl 8-(2-amino((R)(5-chloro-3'-(methylsulfonyl)-[1,1'-biphenyl]yl)- 2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; and (S)-methyl 8-(2-amino((R)(5-chloro-3'-sulfamoyl-[1,1'-biphenyl]yl)-2,2,2- trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate; or a pharmaceutically acceptable salt of any of the aforementioned.
14. A compound of claim 1 which is (S)-ethyl 8-(2-amino((R)(5-chloro-[1,1'-biphenyl]- 2-yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate, or a pharmaceutically acceptable salt thereof.
15. A compound of claim 1 which is (S)-ethyl mino((R)(5-chloro-[1,1'-biphenyl]- 2-yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylate.
16. A compound of claim 1 which is (S)(2-amino((R)(5-chloro-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid, or a pharmaceutically able salt thereof.
17. A compound of claim 1 which is (S)(2-amino((R)(5-chloro-[1,1'-biphenyl] yl)-2,2,2-trifluoroethoxy)pyrimidinyl)-2,8-diazaspiro[4.5]decanecarboxylic acid.
18. A pharmaceutical ition comprising a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
19. Use of a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof in the manufacture of a ment for inhibiting TPH1 in a patient in need thereof.
20. Use of compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for lowering peripheral serotonin in a patient in need
21. Use of a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for ng or preventing a disease in a patient in need thereof, wherein said disease is selected from the group consisting of cardiovascular e and gastrointestinal disease.
22. The use of claim 21 wherein said cardiovascular e is pulmonary arterial hypertension (PAH).
23. The use of claim 22 wherein said PAH is associated pulmonary arterial hypertension (APAH).
24. The use of claim 21 wherein said gastrointestinal disease is diarrhea or carcinoid syndrome.
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US201462004385P 2014-05-29 2014-05-29
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