Spirocyclic compounds 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 (TPH1), that are useful in the treatment of diseases or disorders associated with peripheral serotonin including, for example, gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, and low bone mass diseases, as well as serotonin syndrome, and cancer.

BACKGROUND OF THE INVENTION

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that modulates central and peripheral functions by acting on neurons, smooth muscle, and other cell types. 5-HT is involved in the control and modulation of multiple physiological and psychological processes. In the central nervous system (CNS), 5-HT regulates mood, appetite, and other behavioral functions. In the GI system, 5-HT plays a general prokinetic role and is an important mediator of sensation (e.g., nausea and satiety) between the GI tract and the brain. Dysregulation of the peripheral 5-HT signaling system has been reported to be involved in the etiology of several conditions (see for example: Mawe, G. M. & Hoffman, J. M. Serotonin Signalling In The Gut-functions, Dysfunctions And Therapeutic Targets. Nature Reviews. Gastroenterology & Hepatology 10, 473-486 (2013); Gershon, M. D. 5-hydroxytryptamine (serotonin) In The Gastrointestinal Tract. Current Opinion in Endocrinology, Diabetes, and Obesity 20, 14-21 (2013); Lesurtel, M., Soll, C., Graf, R. & Clavien, P.-A. Role of Serotonin In The Hepato-gastrointestinal Tract: An Old Molecule For New Perspectives. Cellular And Molecular Life Sciences: CMLS 65, 940-52 (2008)). These include osteoporosis (e.g. Kode, A. et al. FOXO1 Orchestrates The Bone-suppressing Function Of Gut-derived Serotonin. The Journal of Clinical Investigation 122, 3490-503 (2012); Yadav, V. K. et al. Pharmacological Inhibition Of Gut-derived Serotonin Synthesis Is A Potential Bone Anabolic Treatment For Osteoporosis. Nature Medicine 16, 308-12 (2010); Yadav, V. K. et al. Lrp5 Controls Bone Formation By Inhibiting Serotonin Synthesis In The Duodenum. Cell 135, 825-37 (2008)), cancer (e.g. Liang, C. et al. Serotonin Promotes The Proliferation Of Serum-deprived Hepatocellular Carcinoma Cells Via Upregulation Of FOXO3a. Molecular Cancer 12, 14 (2013); Soll, C. et al. Serotonin Promotes Tumor Growth In Human Hepatocellular Cancer. Hepatology 51, 1244-1254 (2010); Pai, V. P et al. Altered Serotonin Physiology In Human Breast Cancers Favors Paradoxical Growth And Cell Survival. Breast Cancer Research: BCR 11, R81 (2009); Engelman, K., Lovenberg, W. & Sjoerdsma, A. Inhibition Of Serotonin Synthesis By Para-chlorophenylalanine In Patients With The Carcinoid Syndrome. The New England Journal of Medicine 277, 1103-8 (1967)), cardiovascular (e.g. Robiolio, P. A. et al. Carcinoid Heart Disease: Correlation of High Serotonin Levels With Valvular Abnormalities Detected by Cardiac Catheterization and Echocardiography. Circulation 92, 790-795 (1995)), diabetes (e.g. Sumara, G., Sumara, O., Kim, J. K. & Karsenty, G. Gut-derived Serotonin Is A Multifunctional Determinant To Fasting Adaptation. Cell Metabolism 16, 588-600 (2012)), atherosclerosis (e.g. Ban, Y. et al. Impact Of Increased Plasma Serotonin Levels And Carotid Atherosclerosis On Vascular Dementia. Atherosclerosis 195, 153-9 (2007)), as well as gastrointestinal (e.g. Manocha, M. & Khan, W. I. Serotonin and GI Disorders: An Update on Clinical and Experimental Studies. Clinical and Translational Gastroenterology 3, e13 (2012); Ghia, J.-E. et al. Serotonin Has A Key Role In Pathogenesis Of Experimental Colitis. Gastroenterology 137, 1649-60 (2009); Sikander, A., Rana, S. V. & Prasad, K. K. Role Of Serotonin In Gastrointestinal Motility And Irritable Bowel Syndrome. Clinica Chimica Acta; International Journal of Clinical Chemistry 403, 47-55 (2009); Spiller, R. Recent Advances In Understanding The Role Of Serotonin In Gastrointestinal Motility In Functional Bowel Disorders: Alterations In 5-HT Signalling And Metabolism In Human Disease. Neurogastroenterology and Motility: The Official Journal of The European Gastrointestinal Motility Society 19 Suppl 2, 25-31 (2007); Costedio, M. M., Hyman, N. & Mawe, G. M. Serotonin And Its Role In Colonic Function And In Gastrointestinal Disorders. Diseases of the Colon and Rectum 50, 376-88 (2007); Gershon, M. D. & Tack, J. The Serotonin Signaling System From Basic Understanding To Drug Development For Functional GI Disorders. Gastroenterology 132, 397-414 (2007); Mawe, G. M., Coates, M. D. & Moses, P. L. Review Article: Intestinal Serotonin Signalling In Irritable Bowel Syndrome. Alimentary Pharmacology & Therapeutics 23, 1067-76 (2006); Crowell, M. D. Role Of Serotonin In The Pathophysiology Of The Irritable Bowel Syndrome. British Journal of Pharmacology 141, 1285-93 (2004)), pulmonary (e.g. Lau, W. K. W. et al. The Role Of Circulating Serotonin In The Development Of Chronic Obstructive Pulmonary Disease. PloS One 7, e31617 (2012); Egermayer, P., Town, G. I. & Peacock, A. J. Role Of Serotonin In The Pathogenesis Of Acute And Chronic Pulmonary Hypertension. Thorax 54, 161-168 (1999)), inflammatory (e.g. Margolis, K. G. et al. Pharmacological Reduction of Mucosal but Not Neuronal Serotonin Opposes Inflammation In Mouse Intestine. Gut doi:10.1136/gutjnl-2013-304901 (2013); Duerschmied, D. et al. Platelet Serotonin Promotes The Recruitment Of Neutrophils To Sites Of Acute Inflammation In Mice. Blood 121, 1008-15 (2013); Li, N. et al. Serotonin Activates Dendritic Cell Function In The Context Of Gut Inflammation. The American Journal of Pathology 178, 662-71 (2011)), or liver diseases or disorders (e.g. Ebrahimkhani, M. R. et al. Stimulating Healthy Tissue Regeneration By Targeting The 5-HT2B Receptor In Chronic Liver Disease. Nature Medicine 17, 1668-73 (2011)). The large number of pharmaceutical agents that block or stimulate the various 5-HT receptors is also indicative of the wide range of medical disorders that have been associated with 5-HT dysregulation (see for example: Wacker, D. et al. Structural Features For Functional Selectivity At Serotonin Receptors. Science (New York, N.Y.) 340, 615-9 (2013)).

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

Two vertebrate isoforms of TPH, namely TPH1 and TPH2, have been identified. TPH1 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 neuronal cells, such as dorsal raphe or myenteric plexus cells. The peripheral and central systems involved in 5-HT biosynthesis are isolated, with 5-HT being unable to cross the blood-brain barrier. Therefore, the pharmacological effects of 5-HT can be modulated by agents affecting TPH in the periphery, mainly TPH1 in the gut.

A small number of phenylalanine-derived TPH1 inhibitors are known. One example, p-chlorophenylalanine (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, pCPA is distributed centrally and, as a result, its administration has been linked to the onset of depression and other alterations of CNS functions in patients and animals. p-Ethynyl phenylalanine is a more selective and more potent TPH inhibitor than pCPA (Stokes, A. H. et al. p-Ethynylphenylalanine: A Potent Inhibitor Of Tryptophan Hydroxylase. Journal of Neurochemistry 74, 2067-73 (2000), but also affects central 5-HT production and, like pCPA, is believed to irreversibly interfere with the synthesis of TPH (and possibly other proteins).

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

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

SUMMARY OF THE INVENTION

The present invention relates to a TPH-inhibiting compound of Formula I:

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or a pharmaceutically acceptable salt thereof, wherein constituent variables are defined herein.

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

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

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

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 compound of Formula I, or a pharmaceutically acceptable salt thereof.

The present invention further relates to a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of disease in a patient.

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

DETAILED DESCRIPTION

Compounds

The present invention relates to a TPH-inhibiting compound of Formula I:

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or a pharmaceutically acceptable salt thereof, wherein:

Ring A is C_3-10cycloalkyl, C_6-10aryl, 4 to 100-membered heterocycloalkyl, or 5 to 10-membered heteroaryl;

L is O or NR⁴;

W is N or CR⁵;

X is N or CR⁶;

Y is N or CR⁷;

wherein only one of X and Y is N;

R¹is H, C_1-10alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, —(CR⁸R⁹)_pOC(O)R¹⁰, —(CR⁸R⁹)_pNR¹¹R¹², or —(CR⁸R⁹)_pC(O)NR¹¹R¹², wherein said C_1-10alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from F, Cl, Br, CN, C_1-4alkyl, and C_1-4haloalkyl;

R²and R³are each independently selected from H, C_1-4alkyl, and C_1-4haloalkyl;

R⁴is H or C_1-4alkyl;

R⁵and R⁶are each independently selected from H, halo, and C_1-4alkyl;

R⁷is H, C_1-4alkyl, C_2-6alkenyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, C_6-10aryl, C_6-10aryl-C_1-4alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C_1-4alkyl, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-C_1-4alkyl, NR¹³R¹⁴, OR¹⁵, C(O)R¹⁶, S(O)_qR¹⁷, wherein said C_1-4alkyl, C_2-6alkenyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, C_6-10aryl, C_6-10aryl-C_1-4alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C_1-4alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-C_1-4alkyl are each optionally substituted by 1, 2, or 3 substituents selected from halo, C_1-4alkyl, C_2-6alkenyl, amino, C_1-4alkylamino, C_2-8dialkylamino, hydroxy, and C_1-4alkoxy;

R⁸and R⁹are each independently selected from H and C_1-4alkyl;

R¹⁰is C_1-6alkyl optionally substituted by 1, 2 or 3 substituents independently selected from C_1-6haloalkyl, C_3-10cycloalkyl, OR^a, and NR^cR^d;

R¹¹and R¹²are each independently selected from H and C_1-6alkyl;

R¹³is H or C_1-4alkyl;

R¹⁴is H, C_1-4alkyl, C_3-7cycloalkyl, C_3-7cycloalkyl-C_1-4alkyl, C_6-10aryl, C_6-10aryl-C_1-4alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C_1-4alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-C_1-4alkyl, C(O)R^b1, C(O)OR^a1, C(O)NR^c1R^d1, S(O)R^b1, S(O)₂R^b1, or S(O)₂NR^c1R^d1, wherein said C_1-4alkyl, C_3-7cycloalkyl, C_3-7cycloalkyl-C_1-4alkyl, C_6-10aryl, C_6-10aryl-C_1-4alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C_1-4alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-C_1-4alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4alkyl, C_1-4haloalkyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

or R¹³and R¹⁴together 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 C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, 5-6 membered heteroaryl, halo, CN, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)NR^c1R^d1, NR^c1C(O)OR^a1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, and S(O)₂NR^c1R^d1, wherein said C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)NR^c1R^d1, NR^c1C(O)OR^a1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, and S(O)₂NR^c1R^d1;

R¹⁵is H, C_1-4alkyl, C_3-7cycloalkyl, C_3-7cycloalkyl-C_1-4alkyl, C_6-10aryl, C_6-10aryl-C_1-4alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C_1-4alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-C_1-4alkyl, wherein said C_1-4alkyl, C_3-7cycloalkyl, C_3-7cycloalkyl-C_1-4alkyl, C_6-10aryl, C_6-10aryl-C_1-4alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C_1-4alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-C_1-4alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, 5-6 membered heteroaryl, CN, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)NR^c1R^d1, NR^c1C(O)OR^a1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, and S(O)₂NR^c1R^d1;

R¹⁶is C_1-4alkyl or NR^18aR^18bwherein said C_1-4alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, 5-6 membered heteroaryl, CN, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)NR^c1R^d1, NR^c1C(O)OR^a1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, and S(O)₂NR^c1R^d1;

R¹⁷is C_1-4alkyl, NR^18aR^18b, or OR^18c, wherein said C_1-4alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, 5-6 membered heteroaryl, CN, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)NR^c1R^d1, NR^c1C(O)OR^a1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, and S(O)₂NR^c1R^d1;

R^18aand R^18bare each independently selected from H and C_1-4alkyl wherein said C_1-4alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, 5-6 membered heteroaryl, CN, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)NR^c1R^d1, NR^c4C(O)OR^a1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, and S(O)₂NR^c1R^d1;

or R^18aand R^18btogether 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 C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, 5-6 membered heteroaryl, halo, CN, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)NR^c1R^d1, NR^c1C(O)OR^a1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, and S(O)₂NR^c1R^d1, wherein said C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)NR^c1R^d1, NR^c1C(O)OR^a1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, and S(O)₂NR^c1R^d1;

R^18cis H, C_1-6alkyl, C_3-10cycloalkyl, C_3-7cycloalkyl-C_1-4alkyl, C_6-10aryl, C_6-10aryl-C_1-4alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C_1-4alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-C_1-4alkyl, wherein said C_1-6alkyl, C_3-7cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, C_6-10aryl, C_6-10aryl-C_1-4alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C_1-4alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-C_1-4alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4alkyl, C_1-4haloalkyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

R^Ais H, Cy¹, halo, C_1-6alkyl, C_2-6alkenyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, or S(O)₂NR^c2R^d2, wherein said C_1-6alkyl and C_2-6alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy¹, halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a1, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2;

R^Bis H, Cy², halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, or S(O)₂NR^c3R^d3, wherein said C_1-6alkyl and C_2-6alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy², halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c1S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3;

R^Cand R^Dare each independently selected from H, halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, NO₂, OR^a4, SR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, OC(O)R^b4, OC(O)NR^c4R^d4, NR^c4R^d4, NR^c4C(O)R^b4, NR^c4C(O)OR^a4, NR^c4C(O)NR^c4R^d4, NR^c4S(O)R^b4, NR^c4S(O)₂R^b4, NR^c4S(O)₂NR^c4R^d4, S(O)R^b4, S(O)NR^c4R^d4, S(O)₂R^b4, and S(O)₂NR^c4R^d4; wherein said C_1-6alkyl and C_2-6alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, NO₂, OR^a4, SR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, OC(O)R^b4, OC(O)NR^c4R^d4, NR^c4R^d4, NR^c4C(O)R^b4, NR^c4C(O)OR^a4, NR^c4C(O)NR^c4R^d4, NR^c4S(O)R^b4, NR^c4S(O)₂R^b4, NR^c4S(O)₂NR^c4R^d4, S(O)R^b4, S(O)NR^c4R^d4, S(O)₂R^b4, and S(O)₂NR^c4R^d4;

Cy¹and Cy²are each independently selected from C_6-10aryl, C_3-10cycloalkyl, 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 R^Cy;

each R^Cyis independently selected from halo, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)OR^a5, NR^c5C(O)NR^c5R^d5, NR^c5S(O)R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, and S(O)₂NR^c5R^d5, wherein said C_1-6alkyl, C_2-6alkenyl C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, CN, NO₂, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)OR^a5, NR^c5C(O)NR^c5R^d5, NR^c5S(O)R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, and S(O)₂NR^c5R^d5;

each R^a, R^a1, R^a2, R^a3, R^a4, and R^a5is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_2-6alkenyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-10cycloalkyl-C_1-4alkyl, (5-10 membered heteroaryl)-C_1-4alkyl, or (4-10 membered heterocycloalkyl)-C_1-4alkyl, wherein said C_1-6alkyl, C_2-6alkenyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-10cycloalkyl-C_1-4alkyl, (5-10 membered heteroaryl)-C_1-4alkyl, and (4-10 membered heterocycloalkyl)-C_1-4alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_1-4alkyl, halo, CN, OR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, OC(O)R^b6, OC(O)NR^c6R^d6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)NR^c6R^d6, NR^c6C(O)OR^a6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, NR^c6S(O)₂R^b6, NR^c6S(O)₂NR^c6R^d6, and S(O)₂NR^c6R^d6;

each R^b1, R^b2, R^b3, R^b4, and R^b5is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_2-6alkenyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-10cycloalkyl-C_1-4alkyl, (5-10 membered heteroaryl)-C_1-4alkyl, or (4-10 membered heterocycloalkyl)-C_1-4alkyl, wherein said C_1-6alkyl, C_2-6alkenyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-10cycloalkyl-C_1-4alkyl, (5-10 membered heteroaryl)-C_1-4alkyl, and (4-10 membered heterocycloalkyl)-C_1-4alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_1-4alkyl, halo, CN, OR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, OC(O)R^b6, OC(O)NR^c6R^d6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)NR^c6R^d6, NR^c6C(O)OR^a6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, NR^c6S(O)₂R^b6, NR^c6S(O)₂NR^c6R^d6, and S(O)₂NR^c6R^d6;

each R^c, R^d, R^c1, R^d1, R^c2, R^d2, R^c3, R^d3, R^c4, R^d4, R^c5, and R^d5is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_2-6alkenyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-10cycloalkyl-C_1-4alkyl, (5-membered heteroaryl)-C_1-4alkyl, or (4-10 membered heterocycloalkyl)-C_1-4alkyl, wherein said C_1-6alkyl, C_2-6alkenyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkyl, C_3-10cycloalkyl-C_1-4alkyl, (5-10 membered heteroaryl)-C_1-4alkyl, and (4-10 membered heterocycloalkyl)-C_1-4alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_1-4alkyl, halo, CN, OR^a6, SR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, OC(O)R^b6, OC(O)NR^c6R^d6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)NR^c6R^d6, NR^c6C(O)OR^a6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, NR^c6S(O)₂R^b6, NR^c6S(O)₂NR^c6R^d6, and S(O)₂NR^c6R^d6;

or any R^cand R^dtogether 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 C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, 5-6 membered heteroaryl, halo, CN, OR^a6, SR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, OC(O)R^b6, OC(O)NR^c6R^d6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)NR^c6R^d6, NR^c6C(O)OR^a6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, NR^c6S(O)₂R^b6, NR^c6S(O)₂NR^c6R^d6, and S(O)₂NR^c6R^d6, wherein said C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR^a6, SR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, OC(O)R^b6, OC(O)NR^c6R^d6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)NR^c6R^d6, NR^c6C(O)OR^a6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, NR^c6S(O)₂R^b6, NR^c6S(O)₂NR^c6R^d6, and S(O)₂NR^c6R^d6;

or any R^c1and R^d1together 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 C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, 5-6 membered heteroaryl, halo, CN, OR^a6, SR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, OC(O)R^b6, OC(O)NR^c6R^d6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)NR^c6R^d6, NR^c6C(O)OR^a6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, NR^c6S(O)₂R^b6, NR^c6S(O)₂NR^c6R^d6, and S(O)₂NR^c6R^d6, wherein said C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR^a6, SR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, OC(O)R^b6, OC(O)NR^c6R^d6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)NR^c6R^d6, NR^c6C(O)OR^a6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, NR^c6S(O)₂R^b6, NR^c6S(O)₂NR^c6R^d6, and S(O)₂NR^c6R^d6;

or any R^c2and R^d2together 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 C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, and 5-6 membered heteroaryl, C_1-6haloalkyl, halo, CN, OR^a6, SR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, OC(O)R^b6, OC(O)NR^c6R^d6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)NR^c6R^d6, NR^c6C(O)OR^a6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, NR^c6S(O)₂R^b6, NR^c6S(O)₂NR^c6R^d6, and S(O)₂NR^c6R^d6, wherein said C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR^a6, SR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, OC(O)R^b6, OC(O)NR^c6R^d6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)NR^c6R^d6, NR^c6C(O)OR^a6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, NR^c6S(O)₂R^b6, NR^c6S(O)₂NR^c6R^d6, and S(O)₂NR^c6R^d6;

or any R^c3and R^d3together 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 C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, 5-6 membered heteroaryl, C_1-6haloalkyl, halo, CN, OR^a6, SR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, OC(O)R^b6, OC(O)NR^c6R^d6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)NR^c6R^d6, NR^c6C(O)OR^a6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, NR^c6S(O)₂R^b6, NR^c6S(O)₂NR^c6R^d6, and S(O)₂NR^c6R^d6, wherein said C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR^a6, SR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, OC(O)R^b6, OC(O)NR^c6R^d6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)NR^c6R^d6, NR^c6C(O)OR^a6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, NR^c6S(O)₂R^b6, NR^c6S(O)₂NR^c6R^d6, and S(O)₂NR^c6R^d6;

or any R^c4and R^d4together 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 C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, 5-6 membered heteroaryl, C_1-6haloalkyl, halo, CN, OR^a6, SR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, OC(O)R^b6, OC(O)NR^c6R^d6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)NR^c6R^d6, NR^c6C(O)OR^a6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, NR^c6S(O)₂R^b6, NR^c6S(O)₂NR^c6R^d6, and S(O)₂NR^c6R^d6, wherein said C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR^a6, SR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, OC(O)R^b6, OC(O)NR^c6R^d6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)NR^c6R^d6, NR^c6C(O)OR^a6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, NR^c6S(O)₂R^b6, NR^c6S(O)₂NR^c6R^d6, and S(O)₂NR^c6R^d6;

or any R^c5and R^d5together 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 C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, 5-6 membered heteroaryl, C_1-6haloalkyl, halo, CN, OR^a6, SR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, OC(O)R^b6, OC(O)NR^c6R^d6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)NR^c6R^d6, NR^c6C(O)OR^a6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, NR^c6S(O)₂R^b6, NR^c6S(O)₂NR^c6R^d6, and S(O)₂NR^c6R^d6, wherein said C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR^a6, SR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, OC(O)R^b6, OC(O)NR^c6R^d6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)NR^c6R^d6, NR^c6C(O)OR^a6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, NR^c6S(O)₂R^b6, NR^c6S(O)₂NR^c6R^d6, and S(O)₂NR^c6R^d6;

each R^a6, R^b6, R^c6, and R^d6is independently selected from H, C_1-4alkyl, C_2-4alkenyl, C_3-7cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said C_1-4alkyl, C_2-4alkenyl, C_3-7cycloalkyl, 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, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylthio, C_1-4alkylamino, and di(C_1-4alkyl)amino;

n is 1 or 2;

p is 1, 2, or 3; and

q is 1 or 2;

wherein any aforementioned 4-10 or 4-7 membered heterocycloalkyl group optionally comprises 1, 2, or 3 oxo substituents, wherein each oxo substituent that is present is substituted on a 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-inhibiting compound of Formula I:

embedded image

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is C_3-10cycloalkyl, C_6-10aryl, 4 to 10-membered heterocycloalkyl, or 5 to 10-membered heteroaryl;

L is O or NR⁴;

W is N or CR⁵;

X is N or CR⁶;

Y is N or CR⁷;

wherein only one of X and Y is N;

R¹is H, C_1-10alkyl, C_3-10cycloalkyl, phenyl, —(CR⁸R⁹)_pOC(O)R¹⁰, —(CR⁸R⁹)_pNR¹¹R¹², or —(CR⁸R⁹)_pC(O)NR¹¹R¹², wherein said C_1-10alkyl, C_3-10cycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from F, Cl, Br, CN, C_1-4alkyl, and C_1-4haloalkyl;

R²and R³are each independently selected from H, C_1-4alkyl, and C_1-4haloalkyl;

R⁴is H or C_1-4alkyl;

R⁵and R⁶are each independently selected from H, halo, and C_1-4alkyl;

R⁸and R⁹are each independently selected from H and C_1-4alkyl;

R¹⁰is C_1-6alkyl optionally substituted by 1, 2 or 3 substituents independently selected from C_1-6haloalkyl, C_3-10cycloalkyl, OR^a, and NR^cR^d;

R¹¹and R¹²are each independently selected from H and C_1-6alkyl;

R¹³is H or C_1-4alkyl;

R¹⁴is H, C_1-4alkyl, C_3-7cycloalkyl, C_3-7cycloalkyl-C_1-4alkyl, C_6-10aryl, C_6-10aryl-C_1-4alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C_1-4alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-C_1-4alkyl, C(O)R^b1, C(O)OR^a1, C(O)NR^c1R^d1, S(O)R^b1, S(O)₂R^b1, or S(O)₂NR^c1R^d1, wherein said C_1-4alkyl, C_3-7cycloalkyl, C_3-7cycloalkyl-C_1-4alkyl, C_6-10aryl, C_6-10aryl-C_1-4alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C_1-4alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-C_1-4alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4alkyl, C_1-4haloalkyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

or R^18aand R^18btogether 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 C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, 5-6 membered heteroaryl, halo, CN, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)NR^c1R^d1, NR^c1C(O)OR^a1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, and S(O)₂NR^c1R^d1, wherein said C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)NR^c1R^d1, NR^c1C(O)OR^a1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, and S(O)₂NR^c1R^d1;

R^Ais H, Cy¹, halo, C_1-6alkyl, C_2-6alkenyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, or S(O)₂NR^c2R^d2, wherein said C_1-6alkyl and C_2-6alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy¹, halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2;

Cy¹and Cy2 are each independently selected from C_6-10aryl, C_3-10cycloalkyl, 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 R^a6, R^b6, R^c6, and R^d6, is independently selected from H, C_1-4alkyl, C_2-4alkenyl, C_3-7cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said C_1-4alkyl, C_2-4alkenyl, C_3-7cycloalkyl, 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, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylthio, C_1-4alkylamino, and di(C_1-4alkyl)amino;

n is 1 or 2;

p is 1, 2, or 3; and

q is 1 or 2;

In some embodiments, L is O.

In some embodiments, L is NR⁴.

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

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

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

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

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

In some embodiments, R²is H and R³is H.

In some embodiments, R²is H and R³is C_1-4alkyl.

In some embodiments, R²is H and R³is methyl.

In some embodiments, R²is H and R³is C_1-4haloalkyl.

In some embodiments, R²is H and R³is trifluoromethyl.

In some embodiments, n is 1.

In some embodiments, n is 2.

In some embodiments, R¹is H.

In some embodiments, R¹is C_1-10alkyl, C_3-10cycloalkyl, phenyl, —(CR⁸R⁹)_pOC(O)R¹⁰, —(CR⁸R⁹)_pNR¹¹R¹², or —(CR⁸R⁹)_pC(O)NR¹¹, R¹², wherein said C_1-10alkyl, C_3-10cycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from F, Cl, Br, CN, C_1-4alkyl, and C_1-4haloalkyl.

In some embodiments, R¹is C_1-10alkyl.

In some embodiments, R¹is ethyl.

In some embodiments, R⁴is H.

In some embodiments, R⁵is H.

In some embodiments, R⁶is H.

In some embodiments, R⁷is other than H.

In some embodiments, R⁷is C_1-4alkyl, NR¹³R¹⁴, or OR¹⁵.

In some embodiments, R⁷is NR¹³R¹⁴.

In some embodiments, R⁷is NH₂.

In some embodiments, R⁷is C_1-4alkyl.

In some embodiments, R⁷is OR¹⁵.

In some embodiments, Ring A is C_3-10cycloalkyl.

In some embodiments, Ring A is C_6-10aryl.

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, adamantanyl, naphthyl, 1,2,3,4-tetrahydroquinoxalinyl, 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 R^A, R^B, R^C, and R^Dis other than hydrogen.

In some embodiments, at least two of R^A, R^B, R^C, and R^Dare other than hydrogen.

In some embodiments, R^Ais Cy¹.

In some embodiments, R^Ais C_6-10aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R^Cy.

In some embodiments, R^Ais 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R^Cy.

In some embodiments, R^Ais 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, R^Ais pyrazolyl which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R^Cy.

In some embodiments, R^Ais 3-methyl-1H-pyrazol-1-yl.

In some embodiments, R^Ais C_6-10aryl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, R^Ais phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, R^Bis H.

In some embodiments, R^Bis Cy², halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3, wherein said C_1-6alkyl and C_2-6alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy², halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

In some embodiments, R^Bis Cy².

In some embodiments, R^Bis C_6-10aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R^Cy.

In some embodiments, R^Bis halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3, wherein said C_1-6alkyl and C_2-6alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy², halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c1S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

In some embodiments, R^Bis halo.

In some embodiments, R^Cis H.

In some embodiments, R^Cis halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, NO₂, OR^a4, SR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, OC(O)R^b4, OC(O)NR^c4R^d4, NR^c4R^d4, NR^c4C(O)R^b4, NR^c4C(O)OR^a4, NR^c4C(O)NR^c4R^d4, NR^c4S(O)R^b4, NR^c4S(O)₂R^b4, NR^c4S(O)₂NR^c4R^d4, S(O)R^b4, S(O)NR^c4R^d4, S(O)₂R^b4, and S(O)₂NR^c4R^d4; wherein said C_1-6alkyl and C_2-6alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, NO₂, OR^a4, SR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, OC(O)R^b4, OC(O)NR^c4R^d4, NR^c4R^d4, NR^c4C(O)R^b4, NR^c4C(O)OR^a4, NR^c4C(O)NR^c4R^d4, NR^c4S(O)R^b4, NR^c4S(O)₂R^b4, NR^c4S(O)₂NR^c4R^d4, S(O)R^b4, S(O)NR^c4R^d4, S(O)₂R^b4, and S(O)₂NR^c4R^d4.

In some embodiments, R^Dis H.

In some embodiments, R^Dis halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, NO₂, OR^a4, SR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, OC(O)R^b4, OC(O)NR^c4R^d4, NR^c4R^d4, NR^c4C(O)R^b4, NR^c4C(O)OR^a4, NR^c4C(O)NR^c4R^d4, NR^c4S(O)R^b4, NR^c4S(O)₂R^b4, NR^c4S(O)₂NR^c4R^d4, S(O)R^b4, S(O)NR^c4R^d4, S(O)₂R^b4, and S(O)₂NR^c4R^d4; wherein said C_1-6alkyl and C_2-6alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, NO₂, OR^a4, SR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, OC(O)R^b4, OC(O)NR^c4R^d4, NR^c4R^d4, NR^c4C(O)R^b4, NR^c4C(O)OR^a4, NR^c4C(O)NR^c4R^d4, NR^c4S(O)R^b4, NR^c4S(O)₂R^b4, NR^c4S(O)₂NR^c4R^d4, S(O)R^b4, S(O)NR^c4R^d4, S(O)₂R^b4, and S(O)₂NR^c4R^d4.

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

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

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

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

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

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

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

In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R³is H.

In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R²is CF₃and R³is H.

In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R¹is H or C_1-10alkyl.

In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R^Ais Cy¹.

In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R^Ais C_6-10aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R^Ais 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R^Ais 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R^Ais C_6-10aryl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R^Ais phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R^Bis Cy².

In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R^Bis H, halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, OR^a3, C(O)NR^c3R^d3, or C(O)OR^a3, wherein said C_1-6alkyl and C_2-6alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C_1-6haloalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c1S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R^Cis H.

In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R^Dis H.

In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R⁵is H.

In some embodiments, where the compounds of the invention have Formula IIa, IIb, IIc, IId, or IIe, R⁶is H.

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

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In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, R²is CF₃.

In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, R¹is H or C_1-10alkyl.

In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, R^Ais Cy¹.

In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, R^Ais C_6-10aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, R^Ais 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, R^Ais 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, R^Ais C_6-10aryl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, R^Ais phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, R^Bis Cy².

In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, R^Bis H, halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, OR^a3, C(O)NR^c3R^d3, or C(O)OR^a3, wherein said C_1-6alkyl and C_2-6alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C_1-6haloalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c1S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, R^Cis H.

In some embodiments, where the compounds of the invention have Formula IIIa or IIIb, R^Dis H.

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

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In some embodiments, where the compounds of the invention have Formula IV, R²is CF₃.

In some embodiments, where the compounds of the invention have Formula IV, R¹is H or C_1-10alkyl.

In some embodiments, where the compounds of the invention have Formula IV, R^Ais Cy¹.

In some embodiments, where the compounds of the invention have Formula IV, R^Ais C_6-10aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula IV, R^Ais 5-membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula IV, R^Ais 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula IV, R^Ais C_6-10aryl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula IV, R^Ais phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula IV, R^Bis Cy².

In some embodiments, where the compounds of the invention have Formula IV, R^Bis H, halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, OR^a3, C(O)NR^c3R^d3, or C(O)OR^a3, wherein said C_1-6alkyl and C_2-6alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C_1-6haloalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c1S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

In some embodiments, where the compounds of the invention have Formula IV, R^Cis H.

In some embodiments, where the compounds of the invention have Formula IV, R^Dis H.

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

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In some embodiments, where the compounds of the invention have Formula Va, R²is CF₃.

In some embodiments, where the compounds of the invention have Formula Va, R¹is H or C_1-10alkyl.

In some embodiments, where the compounds of the invention have Formula Va, R^Ais Cy¹.

In some embodiments, where the compounds of the invention have Formula Va, R^Ais C_6-10aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula Va, R^Ais 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula Va, R^Ais 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula Va, R^Ais C_6-10aryl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula Va, R^Ais phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula Va, R^Bis Cy².

In some embodiments, where the compounds of the invention have Formula Va, R^Bis H, halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, OR^a3, C(O)NR^c3R^d3, or C(O)OR^a3, wherein said C_1-6alkyl and C_2-6alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C_1-6haloalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c1S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

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

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In some embodiments, where the compounds of the invention have Formula Vb, R²is CF₃.

In some embodiments, where the compounds of the invention have Formula Vb, R¹is H or C_1-10alkyl.

In some embodiments, where the compounds of the invention have Formula Vb, R^Ais Cy¹.

In some embodiments, where the compounds of the invention have Formula Vb, R^Ais C_6-10aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula Vb, R^Ais 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula Vb, R^Ais 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula Vb, R^Ais C_6-10aryl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula Vb, R^Ais phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula Vb, R^Bis Cy².

In some embodiments, where the compounds of the invention have Formula Vb, R^Bis H, halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, OR^a3, C(O)NR^c3R^d3, or C(O)OR^a3, wherein said C_1-6alkyl and C_2-6alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C_1-6haloalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c1S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

In some embodiments, the compounds of the invention have Formula VI:

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In some embodiments, where the compounds of the invention have Formula VI, R²is CF₃.

In some embodiments, where the compounds of the invention have Formula VI, R¹is H or C_1-10alkyl.

In some embodiments, where the compounds of the invention have Formula VI, R^Bis Cy².

In some embodiments, where the compounds of the invention have Formula VI, Cy²is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula VI, R^Bis H, halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, OR^a3, C(O)NR^c3R^d3, or C(O)OR^a3, wherein said C_1-6alkyl and C_2-6alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C_1-6haloalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c1S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

In some embodiments, where the compounds of the invention have Formula VI, R^Cis H.

In some embodiments, where the compounds of the invention have Formula VI, R^Dis H.

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

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In some embodiments, where the compounds of the invention have Formula VIA, R²is CF₃.

In some embodiments, where the compounds of the invention have Formula VIA, R¹is H or C_1-10alkyl.

In some embodiments, where the compounds of the invention have Formula VIA, R^Bis Cy².

In some embodiments, where the compounds of the invention have Formula VIA, Cy²is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R^Cy.

In some embodiments, where the compounds of the invention have Formula VIA, R^Bis H, halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, OR^a3, C(O)NR^c3R^d3, or C(O)OR^a3, wherein said C_1-6alkyl and C_2-6alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C_1-6haloalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c1S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

In some embodiments, the compounds of the invention have Formula VII:

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wherein a is 0, 1, 2, or 3.

In some embodiments, where the compounds of the invention have Formula VII, R²is CF₃.

In some embodiments, where the compounds of the invention have Formula VII, R¹is H or C_1-10alkyl.

In some embodiments, where the compounds of the invention have Formula VII, R^Bis Cy².

In some embodiments, where the compounds of the invention have Formula VII, R^Bis H, halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, OR^a3, C(O)NR^c3R^d3, or C(O)OR^a3, wherein said C_1-6alkyl and C_2-6alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C_1-6haloalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c1S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

In some embodiments, where the compounds of the invention have Formula VII, R^Bis H or halo.

In some embodiments, where the compounds of the invention have Formula VII, R^Bis halo.

In some embodiments, where the compounds of the invention have Formula VII, R^Cis H.

In some embodiments, where the compounds of the invention have Formula VII, R^Dis H.

In some embodiments, where the compounds of the invention have Formula VII, R^Cyis halo, C_1-6alkyl, C_1-6haloalkyl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, NR^c5R^d5, S(O)₂R^b5, and S(O)₂NR^c5R^d5, wherein said C_1-6alkyl and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, CN, NO₂, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)OR^a5, NR^c5C(O)NR^c5R^d5, NR^c5S(O)R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, and S(O)₂NR^c5R^d5.

In some embodiments, the compounds of the invention have Formula VIII:

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wherein a is 0, 1, 2, or 3.

In some embodiments, where the compounds of the invention have Formula VIII, R²is CF₃.

In some embodiments, where the compounds of the invention have Formula VIII, R¹is H or C_1-10alkyl.

In some embodiments, where the compounds of the invention have Formula VIII, R^Bis Cy².

In some embodiments, where the compounds of the invention have Formula VIII, R^Bis H, halo, C_1-6alkyl, C_2-6alkenyl, C_1-6haloalkyl, CN, OR^a3, C(O)NR^c3R^d3, or C(O)OR^a3, wherein said C_1-6alkyl and C_2-6alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C_1-6haloalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c1S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

In some embodiments, where the compounds of the invention have Formula VIII, R^Bis H or halo.

In some embodiments, where the compounds of the invention have Formula VIII, R^Bis halo.

In some embodiments, where the compounds of the invention have Formula VIII, R^Cis H.

In some embodiments, where the compounds of the invention have Formula VIII, R^Dis H.

In some embodiments, where the compounds of the invention some embodiments have Formula VIII, R^Cyis halo, C_1-6alkyl, C_1-6haloalkyl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, NR^c5R^d5, S(O)₂R^b5, and S(O)₂NR^c5R^d5, wherein said C_1-6alkyl and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C_1-6alkyl, CN, NO₂, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)OR^a5, NR^c5C(O)NR^c5R^d5, NR^c5S(O)R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, and S(O)₂NR^c5R^d5.

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)OR¹is attached has an S configuration.

In some embodiments, the carbon to which —R²is attached is chiral and has an R configuration.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided 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 “substituted” means that an atom or group of atoms formally replaces hydrogen as a “substituent” attached to another group. The hydrogen atom is formally removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. The term “optionally substituted” means unsubstituted or substituted. The substituents are independently 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 “C_i-j” indicates a range which includes the endpoints, wherein i and j are integers and indicate the number of carbons. Examples include C_1-4, C_1-6, and the like.

The term “n-membered” where n is an integer typically describes the number of ring-forming 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 example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

At various places in the present specification various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “a pyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

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

As used herein, the term “C_1-jalkyl,” employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, 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 limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl.

As used herein, the term “C_i-jalkoxy,” employed alone or in combination with other terms, refers to a group of formula —O-alkyl, wherein the alkyl group has i to j carbon atoms. Example 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, “C_i-jalkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having i to j carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6 or to 2 to 4 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, the term “C_i-jalkylamino” refers to a group of formula —NH(alkyl), wherein the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “di-C_i-j-alkylamino” refers to a group of formula —N(alkyl)₂, 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 “C_i-jalkylthio” refers to a group of formula —S-alkyl, wherein the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “C_i-jaryl,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon having i to j ring-forming carbon atoms, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl is C_6-10aryl. 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 “arylalkyl” refers to a group of formula —C_i-jalkyl-(C_i-jaryl). In some embodiments, arylalkyl is C_6-10aryl-C_1-3alkyl. In some embodiments, arylalkyl is C_6-10aryl-C_1-4alkyl. In some embodiments, arylalkyl is benzyl.

As used herein, the term “carbonyl,” employed alone or in combination with other terms, refers to a —C(═O)— group.

As used herein, the term “carboxy” refers to a group of formula —C(═O)OH.

As used herein, the term “C_i-jcycloalkyl,” employed alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon moiety having i to j ring-forming carbon atoms, which may optionally contain 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 cycloalkyl are moieties that have one or more aromatic rings (aryl or heteroaryl) fused to the cycloalkyl ring, for example, benzo or pyrido derivatives of cyclopentane, cyclopentene, cyclohexane, and the like. Where the cycloalkyl group includes a fused aromatic ring, the cycloalkyl group 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 C_3-10or C_3-7cycloalkyl, which can be monocyclic or polycyclic. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantanyl and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, the term “cycloalkylalkyl” refers to a group of formula —C_i-jalkyl-(C_i-jcycloalkyl). In some embodiments, cycloalkylalkyl is C_3-7cycloalkyl-C_1-3alkyl, wherein the cycloalkyl portion is monocyclic. In some embodiments, cycloalkylalkyl is C_3-7cycloalkyl-C_1-4alkyl.

As used herein, “C_i-jhaloalkoxy” refers to a group of formula —O-haloalkyl having i to j carbon atoms. An example haloalkoxy group is OCF₃. An additional example haloalkoxy group is OCHF₂. In some embodiments, the alkyl group has 1 to 6 or 1 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 embodiments, the halo group is F.

As used herein, the term “C_i-jhaloalkyl,” 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 group, wherein the alkyl group has i to j carbon atoms. In some embodiments, the haloalkyl group is fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, the haloalkyl group is trifluoromethyl. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms.

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 fused rings) aromatic moiety, having one or more heteroatom ring members selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl ring, which is monocyclic or bicyclic and which has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl ring, which is monocyclic and which has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. When the heteroaryl group contains more than one heteroatom ring member, 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. Example heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, thiazole, imidazole, furan, thiophene, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole, imidazo[1,2-b]thiazole, purine, and the like.

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

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

As used herein, the term “heteroarylalkyl” refers to a group of formula C_i-jalkyl-(heteroaryl). In some embodiments, heteroarylalkyl 5-10 membered heteteroaryl-C_1-4alkyl, wherein the heteroaryl portion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroarylalkyl is 5-6 membered heteteroaryl-C_1-3alkyl or 5-6 membered heteteroaryl-C_1-4alkyl, wherein the heteroaryl portion is monocyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur 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 selected from nitrogen, sulfur and oxygen. When the heterocycloalkyl groups contains more than one heteroatom, the heteroatoms may be the same or different. Heterocycloalkyl groups can include mono- or polycyclic (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 quaternized. In some embodiments, the heterocycloalkyl group is 5- to 10-membered, which can be monocyclic or bicyclic and which has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heterocycloalkyl group is 5- to 6-membered or 5- to 7-membered. Examples of heterocycloalkyl groups include 1,2,3,4-tetrahydroquinoline, dihydrobenzofuran, azetidine, azepane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, and pyran. Further examples of heterocycloalkyl groups include 2-oxotetrahydrofuranyl, 2-oxopyrrolidinyl, 2-oxoimidazolidinyl, 1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl, and 2-oxo-1,3-dioxolan-4-yl.

As used herein, the term “heterocycloalkylalkyl” refers to a group of formula —C_i-jalkyl-(heterocycloalkyl). In some embodiments, heterocycloalkylalkyl is 5-10 membered heterocycloalkyl-C_1-3alkyl or 5-10 membered heterocycloalkyl-C_1-4alkyl, wherein the heterocycloalkyl portion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, heterocycloalkylalkyl is 5-6 membered heterocycloalkyl-C_1-4alkyl wherein the heterocycloalkyl portion is monocyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereoisomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention 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 methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

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 invention can also include tautomeric forms. Tautomeric forms result from 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 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.

Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

The term “compound,” as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. Compounds herein identified by name or structure without specifying the particular configuration of a stereocenter are meant to encompass all the possible configurations at the stereocenter. For example, if a particular stereocenter in a compound of the invention could be R or S, but the name or structure of the compound 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 isolated” is meant that the compound is at least partially or substantially separated from the environment 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 include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 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 phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, 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, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room 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 herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of 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 inorganic 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 prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or 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, 17^thEd., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002).

The below Table is a key to some abbreviations used throughout.

ABBREVIATIONS

atm atmosphere

BOC tert-butyl-oxy-carbonyl

CAS# Chemical Abstract Service registry number

CBS Corey-Bakshi-Shibata (catalyst)

CH₃CN Acetonitrile

CBZ Carbobenzyloxy

DIPEA N,N-diisopropylethylamine

DMAP 4-dimethylaminopyridine

DME dimethylether

DMF dimethyl formamide

dppf 1,1′-bis(diphenylphosphino)ferrocene

EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

ee enantiomeric excess

EtOAc ethyl acetate

h hour(s)

min minute(s)

HOAT 1-hydroxy-7-azabenzotriazole

HOAc acetic acid

HPLC high-performance liquid chromatography

KOAc potassium acetate

LAH lithium aluminum hydride

LDA lithium diisopropylamide

mCPBA 3-meta-chloroperoxybenzoic acid

MeOH Methanol

MS mass spectrometry

MTBE methyl t-butyl ether

NH₄OH ammonium hydroxide

NMP 1-methyl-2-pyrrolidone

PAH pulmonary arterial hypertension

PE petroleum ether

PheOH phenylalanine hydroxylase

Prep-TLC preparative thin-layer chromatography

p-TSA para-toluene sulfonic acid

RT room temperature

SNAr nucleophilic aromatic substitution

TBAF tetrabutylammonium fluoride

tBuOH tert-butanol

TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate

TEA Triethylamine

TFA trifluoroacetic acid

TH tyrosine hydroxylase

THF Tetrahydrofuran

TLC thin-layer chromatography

TMS Trimethylsilyl

TMSI Trimethylsilyl iodide

TPH tryptophan hydroxylase

Synthesis

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

Typically, reaction progress may be monitored by thin layer chromatography (TLC) or HPLC-MS if desired. Intermediates and products may be purified 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 groups. Starting materials used in the following schemes can be purchased or prepared by methods described in the chemical literature, or by adaptations thereof, using methods known by those skilled in the art. The order in which the steps are performed can vary depending on the protecting or functional groups introduced and the reagents and reaction conditions used, but would be apparent to those skilled in the art.

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

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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-methylpyrazole and an aryl bromide E (e.g., 1,4-dibromo-2-fluorobenzene), and the mixture is heated for several hours (e.g. 12-24 h) to provide a compound of formula F. In step 2, a compound of formula F is treated with a Grignard reagent (e.g., i-PrMgCl) in a solvent (e.g., THF), then reacted with ethyl trifluoroacetate in a solvent (e.g., THF) to provide a ketone of formula G.

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

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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 of B (e.g., (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate) in dioxane is added a di-halo heterocycle (e.g., 2-amino-4,6-dichloropyrimidine) in the presence of a base (e.g., Cs₂CO₃) under solvent reflux (e.g., dioxane) to provide a compound of formula M. In step 2, to a compound of formula M in a solvent (e.g., dioxane) is added an alcohol or an amine of formula O (e.g., Intermediate 7 or 16) in the presence of a base (e.g., Cs₂CO₃). After heating at reflux for several hours (e.g., 12-24 h), a compound of formula P is obtained. In step 3, the amino protecting group (P) (e.g., CBZ or BOC) of a compound of formula P is 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.

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For certain substituents and substitution patterns, palladium-mediated coupling reactions (e.g., Suzuki or Stille reactions) can be used, as shown in Schemes 4a, 4b, and 4c. Briefly, in step 1, to a compound of formula R in a solvent (e.g., aqueous dioxane) is added a boronic acid or boronate (e.g., phenyl boronic acid) in the presence of a palladium catalyst (e.g., PdCl₂(dppf)-CH₂Cl₂) and a base (e.g., KHCO₃), and the mixture heated to reflux for several hours (e.g., 12-24) to provide a compound of formula S. In step 3, the amino protecting group (P) (e.g., CBZ or BOC) 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 formula W or AA, respectively (Schemes 4b and 4c).

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

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Ester group substituents can be introduced by the general method of Scheme 6. Briefly, in step 1, to a solution of an acid of formula AG in an inert solvent (e.g., CH₂Cl₂) is added a coupling reagent (e.g., EDCI and DMAP), followed by an alcohol (e.g., propanol) to provide a compound of formula AH. In step 2, the benzyl groups of the benzyl ester and of the N-CBZ group can be removed with reagents such as TMSI or by transition metal-catalyzed hydrogenation (e.g., H₂with Pd/C), affording a compound of formula AI. In case the amino protecting group is a BOC, an additional step 3, involving treatment with a strong acid (e.g., TFA), can be used for the final deprotection.

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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 dealkylating agent (e.g., TMSI) or via transition metal-catalyzed hydrogenation (e.g., H₂with Pd/C) if the protecting group is CBZ, or with a strong acid (e.g., TFA or HCl), if the protecting group is BOC, to provide AK. It will be recognized by those skilled in the art that many other protecting groups can be used alternatively (for example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)).

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Various esters can be made via direct alcohol coupling 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 presence of acid (e.g., p-TSA) for several 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. Alternatively, in step 1, an acid of formula AN is dissolved in a solvent (e.g., DMF) in the presence of a base (e.g., K₂CO₃) and treated with an alkyl halide (e.g., 2-chloro-ethyl-dimethyl-amine). After heating the solution for several hours (e.g., 12-24 h), an ester of formula AO is obtained. In step 2, removal of the amino protecting group (e.g., with an acid like TFA in an inert solvent such as CH₂Cl₂in case of a BOC protecting group) provides an ester of formula AP. Other compatible deprotection methods apparent to those skilled in the art can be applied for other types of amino protecting groups.

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t-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 solvent (e.g., DMF) in the presence of t-butanol, and treated with a coupling agent (e.g., EDCI and DMAP) to provide a compound of formula AR. In step 2, removal of the amino protecting group is achieved as described earlier to afford a compound of formula AS.

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Methods of Use

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

Compounds of the invention can also lower peripheral serotonin levels in an animal, individual, or patient, by administering an effective amount of a compound of the invention to the animal, individual, or patient. In some embodiments, 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., 5-HT 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, 50-fold or more, or 100-fold or more.

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

Biological assays, some of which are described herein, can be used to determine the inhibitory effect of compounds against TPH (such as TPH1) in vitro and/or in vivo. In vitro biochemical assays for human, mouse, and rat TPH1 and human TPH2, PheOH, and TH may be used to measure inhibition of enzyme activity and the selectivity among TPH1, 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 treatable or preventable by administering a TPH1 inhibitor of the invention 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).

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

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

The types of PAH treatable according to the methods of the invention include (1) idiopathic (IPAH), (2) familial (FPAH), and (3) associated (APAH) which is the most common type of PAH. The latter is PAH which is associated with other medical conditions including, for example, (1) collagen vascular disease (or connective tissue disease) which include autoimmune diseases such as scleroderma or lupus; (2) congenital heart and lung disease; (3) portal hypertension (e.g., resulting from liver disease); (4) HIV infection; (5) drugs (e.g., appetite suppressants, cocaine, and amphetamines; (6) other conditions including thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, and splenectomy. APAH 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 associated with persistent pulmonary hypertension of the newborn (PPHN).

Further diseases treatable 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 syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, or other gastrointestinal inflammatory conditions; liver diseases such as chronic liver disease; cancers such as liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, and bone cancer (e.g., osteosarcoma, chondrosarcoma, Ewings sarcoma, osteoblastoma, osteoid osteoma, osteochondroma, enchondroma, chondromyxoid fibroma, aneurysmal bone cyst, unicameral bone cyst, giant cell tumor, and bone tumors); blood diseases (e.g., myeloproliferative syndrome, myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myeloma, and anemia such as aplastic anemia and anemia associated with kidney disease; and blood cancers (e.g., leukemias such as acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML)).

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

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

The compounds of the invention are also useful in the treatment and prevention of inflammatory disease, such as allergic airway inflammation (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 “contacting” 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 TPH1 enzyme, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the TPH1 enzyme.

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

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

As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).

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

Combination Therapy

One or more additional pharmaceutical agents or treatment methods 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 therapy 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 include leuprolide, goserelin, buserelin, flutamide, nilutamide, ketoconazole, aminoglutethimide, mitoxantrone, estramustine, doxorubicin, etoposide, vinblastine, paclitaxel, carboplatin, and vinorelbine. Therapies that can be combined with TPH inhibition include radiation therapy, high-intensity focused ultrasound, or surgery (e.g., removal of diseased tissues). Other drugs for use in treating cancer include testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, GnRH-analogues, temozolomide, bavituximab, cyclophosphamide, fluorouracil, fulvestrant, gefitinib, trastuzumab, IGF-1 antibodies, lapatinib, methotrexate, olaparib, BSI-201, pazopanib, rapamycin, ribavirin, sorafenib, sunitinib, tamoxifen, docetaxel, vatalinib, bevacizumab, and octreotide.

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

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

Example pharmaceutical agents that may be useful in combination therapy for bone disorders and diseases include bisphosphantes such as etidronate, clodronate, tiludronate, pamidronate, neridronate, olpadronate, alendronate, ibandronate, risedronate, cimadronate, zoledronate, and the like. Serotonin receptor modulators, such as 5-HT_1B, 5-HT_2A, and 5-HT_2Bagonists or antagonists, may also be useful in combination therapy for bone disease. Other useful agents for combination therapy include selective serotonin reuptake inhibitors (SSRI), anti-serotonin antibodies, and beta blockers such as IPS339, ICI1 18,551, butaxamine, metipranolol, nadol, oxprenolol, penbutolol, pindolol, propranolol, timolol, and sotalol. Further useful agents for combination therapy for the treatment of bone disorders, such as osteoporosis, include teriparatide, strontium ranelate, raloxifene, and denosumab.

Administration, Pharmaceutical Formulations, Dosage Forms

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

A compound of this invention can be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration can involve subcutaneous injections, intravenous 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 desired result, for example a particular therapeutic effect, is achieved. Or a treatment period can be continued indefinitely.

In some embodiments, the pharmaceutical compositions can be prepared as solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules and the like). A tablet can be prepared by compression or molding. Compressed 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 coatings, such as enteric coatings.

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

Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.

Compositions and compounds of the present invention can be administered by aerosol which can be administered, for example, by a sonic 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 injectable solutions or dispersion just prior to use.

The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. The compounds of the Examples were found to be inhibitors of TPH1 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 synthetic 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 standard 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 compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.

¹H NMR Spectra were acquired on one or more of three instruments: (1) Agilent UnityInova 400 MHz spectrometer equipped with a 5 mm Automation Triple Broadband (ATB) probe (the ATB probe was simultaneously tuned to ¹H, ¹⁹F and ¹³C); (2) Agilent UnityInova 500 MHz spectrometer; or (3) Varian Mercury Plus 400 MHz spectrometer. Several NMR probes were used with the 500 MHz NMR spectrometer, including both 3 mm and 5 mm ¹H, ¹⁹F and ¹³C probes and a 3 mm X¹H¹⁹F 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 collected during the 5.1 second acquisition time, and the recycle delay was set to 1 second. Spectra were collected at 25° C. ¹H NMR Spectra were typically 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 tetramethylsilane. The following abbreviations are used herein: br=broad signal, s=singlet, d=doublet, dd=double doublet, ddd=double double doublet, dt=double triplet, t=triplet, td=triple doublet, tt=triple triplet q=quartet, m=multiplet.

Liquid chromatography-mass spectrometry (LCMS) experiments to determine retention times and associated mass ions were performed using one or more of the following Methods A, B, and C:

Method A:

Waters BEH C18, 3.0×30 mm, 1.7 μm, was used at a temperature of 50° C. and at a flow rate of 1.5 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 A details: (I) ran on a Binary Pump G1312B with UV/Vis diode array detector G1315C 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 gradient (IV) hold for 0.29 min at 15% (B);

Method B:

An Agilent Zorbax Bonus RP, 2.1×50 mm, 3.5 μm, 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 G1312B with UV/Vis diode array detector G1315C and Agilent 6130 mass spectrometer in positive and negative ion electrospray mode with UV-detection at 220 and 254 nm with a gradient of 5-95% (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 linked to a Shimadzu LC-10AT LC system with a diode array detector was used. The spectrometer had an electrospray source operating in positive and negative ion mode. LC was carried out using an Agilent ZORBAX XDB 50×2.1 mm C18 column and a 0.5 mL/minute flow rate. 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 Initiator™, which uses a single-mode resonator and dynamic field tuning. Temperatures from 40-250° C. were achieved, and pressures of up to 20 bars were reached.

Preparative HPLC purification was carried out using either a C18-reverse-phase column from Genesis (C18) or a C6-phenyl column from Phenomenex (C6 Ph) (100×22.5 mm i.d. with 7 micron particle size, UV detection at 230 or 254 nm, flow 5-15 mL/min), eluting with gradients from 100-0 to 0-100% water/acetonitrile or water/MeOH containing 0.1% formic acid. Fractions containing the required product (identified by LCMS analysis) were pooled, the organic fraction removed by evaporation, and the remaining aqueous fraction lyophilised, to give the product.

Chiral HPLC was carried out using a Chiralpak AD column, 4.4 mm×250 mm, particle size 5 micron

Compounds which required column chromatography were purified manually or fully automatically using either a Biotage SP 1™ Flash Purification system with Touch Logic Control™ or a Combiflash Companion® with pre-packed silica gel Isolute® SPE cartridge, Biotage SNAP cartridge or Redisep® Rf cartridge respectively.

Preparation 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 analysis and analyzed as described in the literature (Dale, J. A. & Mosher, H. S, Nuclear Magnetic Resonance Enantiomer Regents. Configurational Correlations Via Nuclear Magnetic Resonance Chemical Shifts Of Diastereomeric Mandelate, O-Methylmandelate, and alpha-Methoxy alpha-Trifluoromethylphenylacetate (MTPA) Esters. J. Am. Chem. Soc. 95, 512-519 (1973)). The chiral alcohols of the invention are preferably enantiomerically enriched, for example, to ≧95% ee.

Representative Mosher Ester Preparation

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

Intermediate 1: (R)-1-(4-Bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol

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Step 1:

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

Step 2:

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

Step 3: Method A:

Pentamethylcyclopentadienyl iridium (III) chloride dimer (CAS#12354-84-6) (10.4 mg) and (1R,2R)-(−)-N-(4-toluene sulfonyl)-1,2-diphenyl ethylene diamine (CAS#144222-34-4) (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-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethanone (16 g, 48 mmol) was dissolved in acetonitrile (120 mL) to which the Iridium 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, partitioned between water and EtOAc, and extracted. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Recrystallization from hot heptane (200 mL) provided the title compound.

Method B:

Alternatively, the trifluoromethyl (or other prochiral) ketones of formula G or J (scheme 2) were asymmetrically reduced as follows (see for example: Corey, E. J. & Link, J. O. A General, Catalytic, and Enantioselective Synthesis of Alpha-amino Acids. J. Am. Chem. Soc. 114, 1906-1908 (1992)): Catechol borane (95 mL, 1 M in THF) and (S)-2-methyl-CBS oxazaborolidine (2.6 g, 9.6 mmol) were mixed in a jacketed glass reactor. The mixture was stirred at RT for 20 min, then the jacket was cooled to −78° C. At a reaction temperature of −65° C., 1-[4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethanone (16 g, 48 mmol) in THF (150 mL) was added dropwise over 2 h. The reaction was then 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 warmed to 0° C. and H₂O₂(30%, 100 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, dried over Na₂SO₄, and concentrated in vacuo. Purification on normal phase silica gel chromatography (EtOAc/heptane) provided the product as a viscous oil.

Intermediate 2: (R)-1-(5-Bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol

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Step 1:

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

Step 2:

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

Step 3:

The title compound was prepared using the Iridium complex-catalyzed hydrogenation as described for Intermediate 1, (R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoro ethanol.

Intermediate 3: (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol

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Step 1:

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

Step 2:

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

Step 3:

The title compound was prepared using the Iridium complex-catalyzed hydrogenation, as described for Intermediate 1 (R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol.

Intermediate 4: (R)-1-(5-chloro-2-(2,2,2-fluoro-1-hydroxyethyl)phenyl)pyrrolidin-2-one

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To a solution of (R)-1-(4)-2,2,2-trifluoroethanol (300 mg, 1.04 mmol) in toluene (7 mL) was added pyrrolidin-2-one (89 mg, 1.04 mmol), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (74 mg, 0.52 mmol), CuI (50 mg, 0.26 mmol) and K₂CO₃(360 mg, 2.6 mmol). The reaction was heated in a sealed tube to 130° C. for 12 h and then cooled to RT. The solids were filtered and the product was purified by normal phase silica gel chromatography (EtOAc:petroleum ether) to to provide the title compound as a white solid.

Intermediate 5: (R)-2,2,2-Trifluoro-1-(2-methyl-1H-benzo[d]imidazol-4-yl)ethanol

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Step 1:

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

Step 2:

The title compound was prepared using the Iridium complex-catalyzed hydrogenation, as described for Intermediate 1 (R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol.

Intermediate 6: 1-(4-Chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethanol

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Step 1:

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

Step 2:

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

Intermediate 7: 1-(2,6-dibromophenyl)ethanol

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To a solution of 1-(2,6-dibromophenyl)-2,2,2-trifluoroethanone (CAS#1208078-23-2) (3 g, 9 mmol) in EtOH (50 mL) was added NaBH₄(340 mg, 9 mmol) at 5° C. The reaction was warmed to RT for 1 h, then extracted with EtOAc NaHCO₃, brine, and dried over Na₂SO₄filtered and concentrated in vacuo to provide 1-(2,6-dibromophenyl)-2,2,2-trifluoroethanol as a light yellow oil.

Intermediate 8: 1-(2,5-dibromophenyl)ethanol

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This compound was made as described above for Intermediate 7, 1-(2,6-dibromophenyl)-2,2,2-trifluoroethanol, starting with 1-(2,5-dibromophenyl)-2,2,2-trifluoroethanone to provide a light yellow oil.

Intermediate 9: (4-Chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)methanol

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Step 1:

1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole/1-(2-bromo-5-chlorophenyl)-5-methyl-1H-pyrazole mixture (Intermediate 3, step 1) (1.00 g, 3.68 mmol) was dissolved in THF (6 mL) then cooled to 0° C. i-Propyl magnesium chloride (2.76 mL, 2.0 M in THF, 5.52 mmol) was added dropwise and the reaction was 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 reaction was quenched with HCl (2 N, 4 mL), diluted with water, extracted with EtOAc, washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 4-chloro-2-(3-methyl-pyrazol-1-yl)-benzaldehyde.

Step 2:

4-Chloro-2-(3-methyl-pyrazol-1-yl)-benzaldehyde (446 mg, 2.03 mmol) from Step 1 was dissolved in MeOH (14 mL) and cooled to 0° 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 partitioned between water and EtOAc and then extracted. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided the title compound.

Using the procedure described for Intermediate 3, (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol, the following alcohols (Intermediates 10-15) shown in the Table below were prepared starting with the appropriately substituted 1-bromo-2-fluorobenzene.

LCMS

No.
Name
Structure
(MH+)

Intermediate 10
(R)-2,2,2-trifluoro-1-(4-methyl-2-(3- methyl-1H-pyrazol-1- yl)phenyl)ethanol

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271

Intermediate 11
(R)-2,2,2-trifluoro-1-(4-methoxy-2- (3-methyl-1H-pyrazol-1- yl)phenyl)ethanol

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287

Intermediate 12
(R)-1-(3-chloro-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2- trifluoroethanol

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291

Intermediate 13
(R)-2,2,2-trifluoro-1-(2-(3-methyl- 1H-pyrazol-1-yl)-4-(trifluoromethyl) phenyl)ethanol

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325

Intermediate 14
(R)-2,2,2-trifluoro-1-(4-fluoro-2-(3- methyl-1H-pyrazol-1- yl)phenyl)ethanol

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274

Intermediate 15
(R)-2,2,2-trifluoro-1-(6-methyl-2-(3- methyl-1H-pyrazol-1-yl)pyridin-3- yl)ethanol

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272

Intermediate 16: (2-Phenoxy-6-(piperidin-1-yl)phenyl)methanamine

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Step 1:

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

Step 2:

To 2-phenoxy-6-(piperidin-1-yl)benzonitrile (250 mg, 0.9 mmol) from Step 1 in 20 mL of MeOH was added Raney Nickel (5%) and NH₄OH (2 mL). The reaction was stirred under 1 atm of H₂at 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: (R)-1-(4-Chloro-2-(2-methoxyethoxy)phenyl)-2,2,2-trifluoroethanol

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Step 1:

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

Step 2:

The title compound was prepared using the Iridium complex-catalyzed hydrogenation as described for Intermediate 1 (R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol.

Intermediate 18: (R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol

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

Intermediate 19: (R)-1-(4-chloro-2-(5-chlorothiophen-2-yl)phenyl)-2,2,2-trifluoroethanol

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This compound was made in the same way as described for Intermediate 18 (R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol to provide a white solid.

Intermediate 20: (R)-2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)ethanol

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Step 1:

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

Step 2:

To a solution of 3-methyl-1H-pyrazole (1.1 g, 13.4 mmol) in DMF (5 ml) was added sodium hydride (1.0 g, 60% in oil) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and then. A solution of methyl 2-chloro-6-methylnicotinate (4.3 g, 23.16 mmol) in DMF (5 mL) was added dropwise to the reaction mixture at 0° C. After addition, 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 organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo and then purified by normal phase silica gel column (EtOAc/hepate) to provide methyl 6-methyl-2-(3-methyl-1H-pyrazol-1-yl)nicotinate as a brown semi-solid.

Step 3:

To a solution of methyl 6-methyl-2-(3-methyl-1H-pyrazol-1-yl)nicotinate (3.7 g, 16 mmol) and trimethyl(trifluoromethyl)silane (11.4 g, 80.2 mmol) in toluene (60 ml), was added dropwise at −78° C. and then the solution of tetrabutyl ammonium fluoride (1.6 mL, 1.0 M in THF) was added dropwise to the reaction mixture at −78° C. After addition, the mixture was warmed slowly up to RT and stirred for 12 h. The reaction mixture was concentrated 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.NaHCO₃and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo and purified by normal phase silica gel column (EtOAc/hepate) to provide 2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)ethanone as a brown semi-solid.

Step 4:

A solution of (S)-(−)-2-Butyl-CBS-oxazaborolidine solution (3.0 ml 1.0 M in toluene) and catecholborane (30 ml 1.0 M in THF) was stirred at RT for 30 min. The mixture was then cooled to −70° C. and 2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)ethanone (1 g, 2.9 mmol) in THF (16 mL) was added dropwise. After addition, the reaction mixture was warmed up to −32° C. and stirred for 12 h. After this time, 3N NaOH (18 mL) was added followed by H₂O₂(18 mL) and the temperature of the reaction mixture was increased to RT for 30 min and then extracted with ethyl. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo and purified by normal phase silica gel column (EtOAc/hepate) to provide the title compound as a yellow solid.

Intermediate 38: (R)-1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol

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Step 1:

A solution of 2,4-dibromo-benzoic acid, (2.3 g, 18.8 mmol), phenyl boronic acid (5 g, 17.9 mmol), Pd₂(dba)₃(818 mg, 8.9 mmol) and LiOH (1.65 g, 39.3 mmol) in a 1:1 mixture of NMP/water (100 mL) was heated 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 HCl. The mixture was then extracted with ethyl acetate and the combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo and purified by normal phase silica gel column (EtOAc/PE 10:1 to 1:1) to afford 5-bromo-[1,1′-biphenyl]-2-carboxylic acid as a colorless oil.

Step 2:

To a solution of 5-bromo-[1,1′-biphenyl]-2-carboxylic acid (5 g, 18.2 mmol) in MeOH (30 mL) was added SOCl₂(10 mL) dropwise. The reaction mixture was heated to 70° C. for 2 h, then cooled to RT. The mixture was concentrated, adjusted to pH=7-8 with saturated aqueous NaHCO₃and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo and purified by normal phase silica gel column (EtOAc/PE 50:1) to afford methyl 5-bromo-[1,1′-biphenyl]-2-carboxylate as a colorless oil.

Step 3:

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

Step 4:

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

Step 5:

To a solution of 5-bromo-[1,1′-biphenyl]-2-carbaldehyde (1.9 g, 7.3 mmol) and was added TMSCF₃(1.2 g, 8.7 mmol) in THF (20 mL) and cooled to 0° C. To this solution was added TBAF (1.46 mL, 1M 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 stirred for 12 h. Then the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, concentrated in vacuo and purified by normal phase silica gel column (EtOAc:PE=1:10) to afford 1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol as a colorless oil.

Step 6:

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

Step 7:

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

Using the procedure described for Intermediate 3, (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol, the following alcohols (Intermediates 39-42) shown in the Table below were prepared starting with the appropriately substituted pyrazole.

LCMS

No.
Name
Structure
(MH+)

Intermediate 39
(R)-1-(4-chloro-2-(3- (trifluoromethyl)-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethanol

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345

Intermediate 40
(R)-1-(2-(3-(tert-butyl)-1H-pyrazol-1- yl)-4-chlorophenyl)-2,2,2- trifluoroethanol

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334

Intermediate 41
(R)-1-(4-chloro-2-(3-isopropyl-1H- pyrazol-1-yl)phenyl)-2,2,2- trifluoroethanol

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319

Intermediate 42
(R)-1-(4-chloro-2-(3-cyclopropyl-1H- pyrazol-1-yl)phenyl)-2,2,2- trifluoroethanol

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317

Intermediate 43: (R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol

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A solution of dichloro(pentamethylcyclopentadienyl)iridium (III) dimer ([Cp*IrCl₂]₂, 14 mg, 0.02 mmol) and (1R,2R)-(−)-(4-toluenesulfonyl)-1,2-diphenylethylenediamine (14 mg, 0.04 mmol) in water (7 mL) was prepared at RT. The resulting mixture was heated to 40° C. for 3 h to provide a homogeneous orange solution. To this active catalyst solution at 40° C. was added potassium formate (143 mg, 171 mmol), and a solution of 1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanone (CAS#1033805-23-0, 98 mg, 0.34 mmol) in CH₃CN (70 mL). The reaction mixture was then stirred at 40° C. for 2 h and then cooled to RT and the layers were separated. The aqueous layer was extracted with MTBE and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo to provide the title compound that was used without further purification.

The following alcohols and amines in the table below are useful in preparing compounds of the invention. They are either commercially available or can be prepared by known synthetic procedures. CAS registry numbers are provided for each.

No.
Name
CAS Registry #
Structure
Ex#

21
(R)-2,2,2-trifluoro-1-(2-(3- methyl-1H-pyrazol-1- yl)phenyl)ethanol
1033805-15-0

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10a & 10e

22
(R)-1-(2-bromo-4- chlorophenyl)-2,2,2- trifluoroethanol
1033805-25-2

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34a-34ae

23
(R)-1-(5-chloro-2-(3-methyl- 1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethanol
1033805-72-9

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10k

24
1-(adamantan-1- yl)ethanamine
13392-28-4

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38

25
(adamantan-1- yl)methanamine
17768-41-1

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41c

26
[1,1′-biphenyl]-3- ylmethanamine
177976-49-7

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39d

27
naphthalen-2-ylmethanamine
2018-90-8

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39a

28
1-(adamantan-1-yl)ethanol
26750-08-3

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41c

29
(R)-1-(naphthalen-2- yl)ethanamine
3906-16-9

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39e

30
(R)-2,2,2-trifluoro-1- (naphthalen-2-yl)ethanol
68200-42-0

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59b

31
[1,1′-biphenyl]-4- ylmethanamine
712-76-5

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39b

32
(2-(piperidin-1- yl)phenyl)methanamine
72752-54-6

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41a

33
(R)-1-(4-bromophenyl)-2,2,2- trifluoroethanol
80418-12-8

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55a-55db

No. = Intermediate number; Ex# = Used in the preparation of the following example(s)

Preparation of Boronic 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 synthetic methods. The following Intermediate 34 is a representative example.

Intermediate 34: 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one

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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(dppf)₂C1 (30 mg, 0.09 mmol), 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 filtered away, and the solvent was removed in vacuo, then extracted with EtOAc, water, brine and dried over Na₂SO₄. 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)-2-Benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate

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Step 1:

(3S)-8-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 CH₂Cl₂(500 mL), and Et₃N (51.7 g, 512 mmol) was cooled to 0° C. Benzyl chloroformate (34.1 g, 205 mmol) was added dropwise and the mixture was stirred at 0° C. for 3 h. The reaction mixture was washed with water, extracted with CH₂Cl₂, dried over Na₂SO₄, and concentrated in vacuo to provide (S)-2-benzyl 8-tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3,8-tricarboxylate as a light yellow oil which was used directly without further purification.

Step 2:

To a solution of (S)-2-benzyl 8-tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3,8-tricarboxylate (79 g, 160 mmol, Step 1) in CH₂Cl₂(400 mL) was added TFA (182 g, 1600 mmol) dropwise at RT. The reaction mixture was stirred for 3 h then concentrated in vacuo. The residue was quenched with saturated NaHCO₃and solid NaHCO₃was added until no further gas evolution was noted. The mixture was extracted with EtOAc and the combined organic layers were concentrated in vacuo. Purification by normal phase silica gel column chromatography (CH₂Cl₂/MeOH/NH₄OH) provided the title compound as a light yellow solid.

Intermediate 36: (S)-2-Tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate

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Step 1:

(S)-2-Benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (2.4 g, 6.9 mmol) in HCl/dioxane (50 mL, 3.3 N) was stirred for 2 h at RT. The solvent was then removed in vacuo to provide (S)-2-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)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate hydrochloride and BOC₂O (1.5 g, 6.9 mmol) in EtOH (50 mL) was added Pd/C (10%, 2.4 g) and HOAc (cat.). The mixture was degassed and blanked under H₂then stirred at 45° C. at 50 psi of H₂for 12 h. The solid was filtered away and the filtrate concentrated in vacuo to provide the title compound as a viscous solid.

Intermediate 37: Methyl 3,9-diazaspiro[5.5]undecane-2-carboxylate

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To a solution of 3,9-diazaspiro[5.5]undecane-2-carboxylic acid, 3-[(4-methoxyphenyl)methyl]-9-(phenylmethyl)-methyl ester [CAS#1314388-32-3](50 mg, 0.12 mmol) in MeOH (2 mL) and water (2 mL) was added a catalytic amount of TFA. The mixture was hydrogenated using a H-cube apparatus under 80° C./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

Methods for Removal of N-Carbobenzyloxy (N-CBZ) Protecting Group

Method A—Hydrogenation over Pd/C:

To a solution of N-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 through a pad of celite that was rinsed with 1:9 MeOH:EtOAc. The filtrate was concentrated in vacuo. The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (H₂O:HOAc: 99:1 to MeOH:AcOH 99:1).

Method B—Dealkylation with TMSI:

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

General Ester Hydrolysis with Lithium Hydroxide:

To a solution of an ethyl ester compound (1 eq) in THF (0.18 M) and water (1.4 M) was added LiOH—H₂O (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 HCl. THF was removed in 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 HCl salt.

Example 1u
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

To a solution of (R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (160 mg, 0.2 mmol, Intermediate 1) in dioxane (2 mL) was added 2-amino-4,6-dichloropyrimidine (100 mg, 0.16 mmol) and Cs₂CO₃(48 μg, 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 dissolved in a mixture of CH₂Cl₂and heptane, concentrated to half the volume, filtered, and concentrated again in vacuo. Purification via normal phase silica gel chromatography (CH₂Cl₂/Heptane) provided 4-[(1R)-1-[4-bromo-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]-6-chloro-pyrimidin-2-amine as an off-white solid.

Step 2:

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

Step 3:

To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added phenylboronic acid (143 mg, 0.8 mmol), PdCl₂(PPh₃)₂(41 mg, 0.058 mmol), and Cs₂CO₃(390 mg, 1.2 mmol). The reaction was heated to 60° C. for 16 h, then cooled to RT, filtered through celite and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

Step 4:

A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (240 mg, 0.4 mmol, Step 3) in EtOAc (5 mL) was hydrogenated using an H-Cube 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-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.

Step 5:

To a solution of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (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 concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided the title compound as an off-white solid as the zwitterionic form.

Example 1m
(S)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (220 mg, 0.3 mmol) in EtOAc (5 mL) was hydrogenated using an H-Cube 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-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.

Step 3:

To a solution of (S)-ethyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (50 mg, 0.08 mmol) 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 concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided the title compound as an off-white solid as the zwitterionic form.

Example 1cq
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (200 mg, 0.24 mmol) in EtOAc (5 mL) was hydrogenated using an H-Cube 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-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.

Step 3:

To a solution of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (50 mg, 0.08 mmol) from Step 2 in THF (2.0 mL) and water (0.2 mL), 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 concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided the title compound as an off-white solid as the zwitterionic form.

Example 1cr
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-(hydroxymethyl)-3′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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

Using the generic scheme below, the following examples of Table 1a were prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 1u). The boronic acid was generally used to make the analogues below, however, where it was not available, the corresponding boronate was used.

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TABLE 1a

Ex.

LCMS

No.
Cy
CAS Name
(MH+)

1a

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(3S)-8-(2-amino-6-((1R)-2,2,2-trifluoro-1-(3- (3-methyl-1H-pyrazol-1-yl)-4′-(methylsulfinyl)- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
671

1b

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3- methyl-1H-pyrazol-1-yl)-4′-(methylthio)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
655

1c

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(S)-8-(2-amino-6-((R)-1-(3′-carboxy-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
652

1d

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(S)-8-(2-amino-6-((R)-1-(3′-carboxy-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
652.5

1e

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(S)-8-(2-amino-6-((R)-1-(4′-carboxy-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
652.6

1f

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3- methyl-1H-pyrazol-1-yl)-4-(1,2,3,6- tetrahydropyridin-4- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
613.5

1g

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3- methyl-1H-pyrazol-1-yl)-4-(pyridin-4- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
609.6

1h

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3- methyl-1H-pyrazol-1-yl)-4-(1-methyl-1H- pyrazol-4-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
612.6

1i

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(S)-8-(2-amino-6-((R)-2,2,2-trifuoro-1-(4- (isoxazol-4-yl)-2-(3-methyl-1H-prazol-1- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
599.6

1j

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(S)-8-(2-amino-6-((R)-1-(4-(3,6-dihydro-2H- pyran-4-yl)-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
614.6

1k

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(S)-8-(6-((R)-1-(4-(1-acetyl-1,2,3,6- tetrahydropyridin-4-yl)-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
655.7

1l

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
666.7

1m

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(S)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
636.7

1n

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2- methoxypyridin-4-yl)-2-(3-methyl-1H-pyrazol- 1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
639.6

1o

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3- methyl-1H-indazol-6-yl)-2-(3-methyl-1H- pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
662.3

1p

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(S)-8-(2-amino-6-((R)-1-(4′-(tert-butyl)-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
664.8

1q

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(S)-8-(2-amino-6-((R)-1-(4′-ethoxy-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
652.7

1r

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2- methoxypyrimidin-5-yl)-2-(3-methyl-1H- pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
639.6

1s

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(6- methoxypyridin-3-yl)-2-(3-methyl-1H-pyrazol- 1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
639.6

1u

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
608.6

1v

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3- methyl-1H-pyrazol-1-yl)-2′,3′,4′,5′-tetrahydro- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
636

1w

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(S)-8-(2-amino-6-((R)-1-(3′-cyano-3-(3-methyl- 1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
633

1x

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(S)-8-(6-((R)-1-(4′-(acetamidomethyl)-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
679

1y

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(S)-8-(6-((R)-1-(4′-(2-acetamidoethyl)-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
693

1z

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3- methyl-1H-pyrazol-1-yl)-4-(quinolin-7- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
659

1aa

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(S)-8-(6-((R)-1-(4-(1H-indol-6-yl)-2-(3-methyl- 1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)- 2-aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
567

1ab

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(S)-8-(2-amino-6-((R)-1-(4′-(aminomethyl)-3- (3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
637

1ac

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
626

1ad

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3- methyl-1H-pyrazol-1-yl)-4-(quinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
659

1ae

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
622

1af

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(S)-8-(2-amino-6-((R)-1-(3′,4′-dichloro-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
677

1ag

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(S)-8-(2-amino-6-((R)-1-(3′,4′-difluoro-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
644

1ah

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(S)-8-(2-amino-6-((R)-1-(4′-chloro-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
643

1ai

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3- methyl-1H-pyrazol-1-yl)-4-(pyrimidin-5- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
610

1ak

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(S)-8-(2-amino-6-((R)-1-(3′-chloro-3-(3- methyl-1H-pyrazol-1-yl)-5′-(trifluoromethyl)- [1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
711

1al

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(S)-8-(2-amino-6-((R)-1-(3′-chloro-4′-ethoxy-3- (3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
687

1am

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3- methyl-1H-pyrazol-1-yl)-3′-(trifluoromethyl)- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
676

1an

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(S)-8-(2-amino-6-((R)-1-(3′-chloro-5′-methyl-3- (3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
657

1ao

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(S)-8-(2-amino-6-((R)-1-(4′-chloro-3′-fluoro-3- (3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
661

1ap

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(S)-8-(2-amino-6-((R)-1-(3′-ethoxy-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
652

1aq

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- fluoro-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
640

1ar

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(S)-8-(2-amino-6-((R)-1-(3′-chloro-4′-fluoro-3- (3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
661

1as

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3- methyl-1H-pyrazol-1-yl)-3′-(trifluoromethoxy)- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
692

1at

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(S)-8-(2-amino-6-((R)-1-(3′,5′-dimethyl-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
637

1au

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(S)-8-(2-amino-6-((R)-1-(3′,4′-difluoro-3-(3- methyl-1H-pyrazol-1-yl)- [1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
644

1av

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(S)-8-(2-amino-6-((R)-1-(3',5'-difluoro-3-(3- methyl-1H-pyrazol-1-yl)- [1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
644

1aw

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- fluoro-3-(3-methyl-1H-pyrazol-1-yl)-3′- (trifluoromethyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
694

1ax

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- fluoro-4′-isopropoxy-3-(3-methyl-1H-pyrazol- 1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
684

1ay

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(S)-8-(2-amino-6-((R)-1-(3′-ethoxy-5′-fluoro-3- (3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
670

1az

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(S)-8-(2-amino-6-((R)-1-(3′-(tert-butyl)-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
664

1ba

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- fluoro-3′-methyl-3-(3-methyl-1H-pyrazol-1-yl)- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
640

1bb

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- isopropyl-3-(3-methyl-1H-pyrazol-1-yl)- [1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
650

1bc

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'- isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
666

1bd

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(S)-8-(2-amino-6-((R)-1-(4′-chloro-3′-methyl-3- (3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
656

1be

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(S)-8-(2-amino-6-((R)-1-(3′-carbamoyl-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
651

1bf

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3- methyl-1H-pyrazol-1-yl)-3′,5′- bis(trifluoromethyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
744

1bg

embedded image

(S)-8-(2-amino-6-((R)-1-(3′-ethoxy-4′-fluoro-3- (3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
670

1bh

embedded image

(S)-8-(2-amino-6-((R)-1-(4′-chloro-3′,5′- dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
671

1bi

embedded image

(S)-8-(2-amino-6-((R)-1-(3′,5′-dichloro-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
677

1bj

embedded image

(S)-8-(2-amino-6-((R)-1-(3′-(tert-butyl)-5′- methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
778

1bk

embedded image

(S)-8-(2-amino-6-((R)-1-(3′-chloro-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
642

1bl

embedded image

(S)-8-(2-amino-6-((R)-1-(3′-chloro-3-(3- methyl-1H-pyrazol-1-yl)-4′-(trifluoromethyl)- [1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
711

1bm

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4'- methoxy-3-(3-methyl-1H-pyrazol-1-yl)- [1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
638

1bn

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(S)-8-(2-amino-6-((R)-1-(4′-ethoxy-3′-fluoro-3- (3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
670

1bo

embedded image

(S)-8-(2-amino-6-((R)-4-2,2,2-trifluoro-1-(3′,4′,5′- trifluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
662

1bp

embedded image

(S)-8-(2-amino-6-((R)-1-(3′-chloro-4′-methyl-3- (3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
657

1bq

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- methyl-3-(3-methyl-1H-pyrazol-1-yl)-4′- (trifluoromethoxy)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
706

1br

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- fluoro-5′-isopropoxy-3-(3-methyl-1H-pyrazol- 1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
684

1bs

embedded image

(S)-8-(2-amino-6-((R)-1-(3′-chloro-5′-fluoro-3- (3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
661

1bt

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(S)-8-(2-amino-6-((R)-1-(4′-chloro-3-(3- methyl-1H-pyrazol-1-yl)-3′-(trifluoromethyl)- [1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
710

1bu

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'- fluoro-3-(3-methyl-1H-pyrazol-1-yl)-5′- (trifluoromethyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
694

1bv

embedded image

(S)-8-(2-amino-6-((R)-1-(3'-chloro-4'- isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2, 8- diazaspiro[4.5]decane-3-carboxylic acid
701

1bw

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(S)-8-(2-amino-6((R)-2,2,2-trifluoro-1-(2-(3- methyl-1H-pyrazol-1-yl)-4-(naphthalen-2- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
659

1bx

embedded image

(S)-8-(2-amino-6-((R)-1-(4′-(benzyloxy)-3′- fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
733

1by

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- isopropoxy-3′-methyl-3-(3-methyl-1H-pyrazol- 1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
681

1bz

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- fluoro-3-(3-methyl-1H-pyrazol-1-yl)-4′- propoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
685

1ca

embedded image

(S)-8-(2-amino-6-((R)-1-(4′-butoxy-3′-fluoro-3- (3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
698

1cb

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- fluoro-4′-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
709

1cc

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3- methyl-1H-pyrazol-1-yl)-4′-(methylsulfonyl)- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
687

1cd

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3- methyl-1H-pyrazol-1-yl)-4′-propoxy-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
668

1ce

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3- methyl-1H-pyrazol-1-yl)-4′-((2- morpholinoethyl)carbamoyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
764

1cf

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3- methyl-1H-pyrazol-1-yl)-4′-sulfamoyl-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
689

1cg

embedded image

(S)-8-(2-amino-6-((R)-1-(4′-carbamoyl-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
652

1ch

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3- methyl-1H-pyrazol-1-yl)-4′-(methylcarbamoyl)- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
666

1ci

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- fluoro-4′-methoxy-3-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
657

1cj

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3- methyl-1H-pyrazol-1-yl)-4′-(piperazine-1- carbonyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
721

1ck

embedded image

(S)-8-(2-amino-6-((R)-1-(4′- (dimethylcarbamoyl)-3-(3-methyl-1H-pyrazol- 1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
680

1cl

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- isobutoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
681

1cm

embedded image

(S)-8-(2-amino-6-((R)-1-(4′- (diethylcarbamoyl)-3-(3-methyl-1H-pyrazol-1- yl)[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
707

1cn

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3- methyl-1H-pyrazol-1-yl)-4′-(neopentyloxy)- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
695

1co

embedded image

(S)-8-(2-amino-6-((R)-1-(4-(chroman-6-yl)-2- (3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
665

1cp

embedded image

(S)-8-(2-amino-6-((R)-1-(4-(cinnolin-6-yl)-2- (3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
661

1cq

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- (hydroxymethyl)-4′-methyl-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
652

1cr

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- (hydroxymethyl)-3′-methyl-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
653

1cs

embedded image

(S)-8-(2-amino-6-((R)-1-(4-(6-ethoxypyridin-3- yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
654

1ct

embedded image

(S)-8-(2-amino-6-((S)-1-(3′,4′- bis(hydroxymethyl)-3-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
669

TABLE 1b

1H NMR Data for Compounds of Table 1a

Ex.

No.
1H NMR

1a

¹H NMR (MeOH-d4): δ ppm 1.29 (m, 3H), 1.68 (q, J = 6.3 Hz, 4H), 2.10 (dd, J = 13.6,

8.1 Hz, 1H), 2.41 (s, 4H), 2.85 (s, 3H), 3.24 (m, 2H), 3.62 (m, 1H), 3.71 (s, 2H),

3.79 (dd, J = 13.7, 5.8 Hz, 2H), 4.44 (t, J = 8.5 Hz, 1H), 4.83 (s, 2H), 6.44 (d, J = 2.4 Hz,

1H), 6.92 (q, J = 6.2 Hz, 1H), 7.88 (m, 8H)

1b

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (m, 3H), 1.60 (t, J = 5.6 Hz, 4H), 2.06 (dd,

J = 13.4, 7.0 Hz, 1H), 2.40 (s, 4H), 2.51 (s, 3H), 2.80 (s, 1H), 3.13 (d, J = 11.5 Hz, 1H),

3.25 (d, J = 11.0 Hz, 1H), 3.53 (dd, J = 22.1, 9.7 Hz, 2H), 3.69 (d, J = 14.9 Hz, 2H),

4.14 (t, J = 8.1 Hz, 1H), 4.93 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.79 (q, J = 6.5 Hz, 1H),

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, 1H)

1c

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.4 (d, J = 18.0 Hz, 1H), 1.68 (q, J = 6.8, 5.6 Hz,

4H), 2.4 (dd, J = 13.6, 8.1 Hz, 1H), 2.41 (s, 4H), 2.85 (s, 1H), 3.25 (m, 2H),

3.64 (m, 1H), 3.72 (s, 1H), 3.79 (d, J = 13.8 Hz, 2H), 4.44 (q, J = 8.6 Hz, 1H), 6.5 (d, J = 2.4 Hz,

1H), 6.92 (dd, J = 10.5, 4.4 Hz, 1H), 7.95 (m, 5H), 8.1 (d, J = 2.5 Hz, 1H), 8.4 (m,

2H)

1d

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H),

6.44 (d, J = 2.3 Hz, 1H), 6.90 (q, J = 6.2 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.75 (d, J = 1.7 Hz,

1H), 7.85 (m, 2H), 7.98 (m, 2H), 8.08 (dt, J = 7.8, 1.3 Hz, 1H), 8.34 (t, J = 1.8 Hz,

1H)

1e

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H),

6.44 (d, J = 2.3 Hz, 1H), 6.90 (q, J = 6.2 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.75 (d, J = 1.7 Hz,

1H), 7.85 (m, 2H), 7.98 (m, 2H), 8.08 (dt, J = 7.8, 1.3 Hz, 1H), 8.34 (t, J = 1.8 Hz,

1H)

1f

¹H NMR (400 MHz, MeOH-d4): δ 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 = 1.81 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)

1g

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.49-1.69 (m, 4 H) 2.06 (dd, J = 13.47, 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 = 12.00 Hz, 1 H) 3.25 (d,

J = 11.76 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, J = 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)

1h

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.61-1.84 (m, 5 H) 2.10 (dd, J = 13.62, 8.49 Hz,

1 H) 2.40 (s, 3 H) 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)

1i

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.35-1.40 (m, 5 H), 1.60-1.65 (m, 8 H),

2.40 (m, 5 H) 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), 5.6 (s, 1H), 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)

1j

¹H NMR (400 MHz, MeOH-d4): δ 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 = 1.32 Hz, 1 H) 7.60-7.73 (m, 2 H) 7.91 (d, J = 2.34 Hz, 1 H)

1k

¹H NMR (400 MHz, MeOH-d4): δ 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 H) 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, 1 H)

7.52 (s, 1 H) 7.62-7.74 (m, 2 H) 7.92 (d, J = 2.34 Hz, 1 H)

1l

¹H NMR (400 MHz, MeOH-d4): δ 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 = 11.13 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 = 1.37 Hz, 1 H) 7.67-7.78 (m, 1 H) 7.93 (d, J = 2.15 Hz, 1 H)

1m

¹H NMR (400 MHz, MeOH-d4): δ 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 = 1.37 Hz,

1 H) 7.70 (s, 1 H) 7.75 (s, 1 H) 7.96 (d, J = 2.15 Hz, 1 H)

1n

¹H NMR (400 MHz, MeOH-d4): δ 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 = 1.17 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)

1o

¹H NMR (400 MHz, MeOH-d4): δ 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, 1 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)

1p

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.24-1.42 (m, 9 H) 1.60 (br. s., 4 H)

2.02-2.12 (m, 1 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)

1q

¹H NMR (400 MHz, MeOH-d4): δ 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 (m, 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, 1H) 7.00 (d, J = 8.79 Hz, 2 H) 7.52-7.65 (m, 3 H) 7.72 (d, J = 1.56 Hz,

1 H) 7.76 (s, 1 H) 7.97 (d, J = 2.34 Hz, 1 H)

1r

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H) 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 = 1.56 Hz, 1 H) 7.81 (d, J = 1.56 Hz, 1 H) 7.86 (s, 1 H) 8.03 (d, J = 2.15 Hz,

1 H) 8.92 (s, 2 H))

1s

¹H NMR (400 MHz, MeOH-d4): δ 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, 2 H) 3.95 (s, 3 H) 4.09 (d, J = 1.17 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 = 1.56 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)

1u

¹H NMR (400 MHz, MeOH-d4): δ 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, J = 9.10, 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 (m, 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)

1v

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.24 (t, J = 7.59 Hz, 3 H) 1.50-1.69 (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) 3.08-3.27 (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, J = 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)

1w

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.51-1.64 (m, 4 H) 1.96 (s, 2 H) 2.04 (dd,

J = 13.23, 7.32 Hz, 1 H) 2.25-2.34 (m, 1 H) 2.38 (s, 3 H) 3.09 (d, J = 11.67 Hz, 1 H)

3.23 (d, J = 11.81 Hz, 1 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, 1 H) 6.41 (d, J = 2.34 Hz, 1 H) 6.79-6.89 (m, 1 H) 7.61-7.67 (m, 1 H)

7.69-7.88 (m, 4 H) 7.96-8.02 (m, 2 H) 8.08 (t, J = 1.59 Hz, 1 H)

1x

¹H NMR (400 MHz, MeOH-d4): δ 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 H) 2.29 (dd, J = 13.47, 9.18 Hz, 1 H) 2.38 (s, 3 H)

3.05-3.26 (m, 2 H) 3.39-3.73 (m, 4 H) 4.05 (dd, J = 9.18, 7.22 Hz, 1 H) 4.38 (s, 2 H) 5.73 (s,

1 H) 6.40 (d, J = 2.29 Hz, 1 H) 6.77 (q, J = 6.67 Hz, 1 H) 7.37 (d, J = 8.40 Hz, 2 H)

7.59-7.66 (m, 3 H) 7.71-7.81 (m, 2 H) 7.95 (d, J = 2.34 Hz, 1 H)

1y

¹H NMR (400 MHz, MeOH-d4): δ 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 = 13.28, 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, 1 H) 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)

1z

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.53-1.61 (m, 4 H) 1.97 (s, 3 H) 2.04 (dd,

J = 13.32, 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 = 1.71 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)

1aa

¹H NMR (400 MHz, MeOH-d4): δ 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 H)

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, J = 8.20 Hz,

2 H)

1ab

¹H NMR (400 MHz, MeOH-d4): δ 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 H) 2.38 (s, 3 H) 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 H) 5.72 (s, 1 H) 6.41 (d, J = 2.29 Hz, 1 H)

6.78 (q, J = 6.49 Hz, 1 H) 7.53 (d, J = 8.30 Hz, 2 H) 7.66 (d, J = 1.66 Hz, 1 H) 7.73-7.84 (m, 4

H) 7.97 (d, J = 2.25 Hz, 1 H)

1ac

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.51-1.70 (m, 4 H) 2.06 (dd, J = 13.37, 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) 3.20-3.29 (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 H) 7.06-7.19 (m, 1 H) 7.37-7.52 (m, 3 H) 7.65 (d, J = 1.56 Hz, 1

H) 7.70-7.77 (m, 1 H) 7.78-7.86 (m, 1 H) 8.00 (d, J = 2.15 Hz, 1 H)

1ad

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.53-1.68 (m, 4 H) 2.00-2.11 (m, 1 H)

2.25-2.36 (m, 1 H) 2.44 (s, 3 H) 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 H) 8.16 (s, 2 H) 8.28-8.38 (m, 1 H), 8.42-8.55 (m, 1 H) 8.80-8.97 (m, 1 H)

1ae

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J = 6.7 Hz, 1H), 1.30 (d, J = 16.8 Hz,

3H), 1.57 (q, J = 8.1, 5.5 Hz, 4H), 1.98 (m, 1H), 2.24 (m, 1H), 2.38 (d, J = 10.5 Hz, 6H),

2.99 (d, J = 11.6 Hz, 1H), 3.16 (d, J = 11.5 Hz, 1H), 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, 1H), 5.75 (s, 1H), 6.41 (d, J = 2.3 Hz,

1H), 6.77 (q, J = 6.6 Hz, 1H), 7.26 (d, J = 7.8 Hz, 2H), 7.58 (m, 3H), 7.74 (m,

2H), 7.96 (d, J = 2.4 Hz, 1H)

1af

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.90 (m, 1H), 1.27 (m, 5H), 1.51 (dt, J = 10.5,

5.6 Hz, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.09 (dd, J = 13.1, 8.7 Hz, 1H), 2.40 (s,

3H), 2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.54 (m, 4H), 3.84 (dd, J = 8.7,

7.2 Hz, 1H), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.73 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H),

6.84 (q, J = 6.5 Hz, 1H), 7.64 (m, 3H), 7.80 (m, 3H), 8.01 (d, J = 2.4 Hz, 1H)

1ag

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 14.8 Hz, 1H), 1.58 (s, 8H),

2.05 (m, 2H), 2.39 (s, 8H), 3.12 (d, J = 11.1 Hz, 2H), 3.24 (d, J = 11.2 Hz, 3H), 3.47 (s, 3H),

3.53 (s, 1H), 3.64 (s, 4H), 4.11 (s, 2H), 4.96 (s, 1H), 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, 6H), 7.79 (d, J = 8.1 Hz,

2H), 7.99 (d, J = 2.0 Hz, 2H)

1ah

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 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, 1H), 4.83 (s, 2H),

4.93 (s, 1H), 5.74 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.81 (q, J = 6.7 Hz, 1H), 7.45 (d, J = 8.2 Hz,

2H), 7.65 (m, 3H), 7.76 (m, 3H), 7.98 (d, J = 2.3 Hz, 1H)

1ai

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.91 (tt, J = 8.8, 4.7 Hz, 1H), 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, 5H),

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)

1ak

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.67 (dt, J = 11.3, 5.3 Hz, 4H),

2.08 (dd, J = 13.6, 8.1 Hz, 1H), 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, 1H), 6.44 (d, J = 2.4 Hz, 1H), 6.95 (q, J = 6.3 Hz, 1H), 7.77 (dt,

J = 5.4, 1.8 Hz, 2H), 7.86 (d, J = 1.4 Hz, 2H), 7.96 (m, 1H), 8.05 (d, J = 2.4 Hz, 2H)

1al

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 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, 1H), 2.28 (dd, J = 13.3, 9.1 Hz, 1H), 2.39 (s,

3H), 3.06 (d, J = 11.6 Hz, 1H), 3.21 (d, J = 11.6 Hz, 1H), 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, 1H), 4.14 (q, J = 7.0 Hz, 2H),

4.93 (s, 2H), 5.75 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78 (q, J = 6.6 Hz, 1H), 7.12 (d, J = 8.7 Hz,

1H), 7.57 (m, 2H), 7.73 (m, 3H), 7.98 (d, J = 2.4 Hz, 1H)

1am

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 3.7 Hz, 2H), 1.55 (m, 4H), 1.92 (dd,

J = 13.4, 7.2 Hz, 1H), 2.19 (t, J = 10.6 Hz, 1H), 2.40 (s, 3H), 2.88 (d, J = 11.4 Hz, 1H),

3.10 (d, J = 11.5 Hz, 1H), 3.47 (dd, J = 22.2, 15.6 Hz, 3H), 3.64 (s, 3H), 3.85 (t, J = 8.1 Hz,

1H), 5.74 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.83 (q, J = 6.6 Hz, 1H), 7.69 (m, 3H),

7.82 (m, 2H), 7.99 (m, 3H)

1an

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.17 (t, J = 7.0 Hz, 1H), 1.29 (m, 1H), 1.57 (d, J = 5.9 Hz,

4H), 2.00 (dd, J = 13.4, 7.0 Hz, 1H), 2.26 (dd, J = 13.1, 9.4 Hz, 1H), 2.38 (d, J = 9.1 Hz,

6H), 3.03 (d, J = 11.6 Hz, 1H), 3.18 (d, J = 11.5 Hz, 1H), 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, 1H), 4.89 (s, 9H),

5.74 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.82 (q, J = 6.9, 6.4 Hz, 1H), 7.21 (s, 1H), 7.40 (s,

1H), 7.45 (s, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.68 (dd, J = 8.0, 1.8 Hz, 1H), 7.78 (d, J = 8.2 Hz,

1H), 7.99 (d, J = 2.3 Hz, 1H)

1ao

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (m, 2H), 1.55 (q, J = 7.5, 5.1 Hz, 4H),

1.94 (dd, J = 13.2, 6.9 Hz, 1H), 2.21 (dd, J = 13.1, 8.9 Hz, 1H), 2.39 (s, 3H), 2.94 (d, J = 11.5 Hz,

1H), 3.12 (d, J = 11.2 Hz, 1H), 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, 1H), 4.85 (d, J = 9.0 Hz, 1H), 5.73 (s, 1H),

6.42 (d, J = 2.4 Hz, 1H), 6.83 (q, J = 6.6 Hz, 1H), 7.57 (m, 4H), 7.77 (m, 2H), 8.00 (d, J = 2.4 Hz,

1H)

1ap

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.39 (s, 4H), 3.12 (d, J = 11.6 Hz,

1H), 3.24 (d, J = 11.7 Hz, 1H), 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, 1H),

6.79 (q, J = 6.6 Hz, 1H), 6.93 (dd, J = 8.2, 2.5 Hz, 1H), 7.19 (m, 2H), 7.34 (t, J = 7.9 Hz, 1H),

7.62 (d, J = 1.8 Hz, 1H), 7.75 (m, 2H), 7.97 (d, J = 2.4 Hz, 1H)

1aq

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J = 7.2 Hz, 1H), 1.28 (s, 4H), 1.58 (t, J = 5.6 Hz,

4H), 2.05 (dd, J = 13.5, 7.1 Hz, 1H), 2.29 (d, J = 1.8 Hz, 4H), 2.39 (s, 3H),

3.10 (d, J = 11.8 Hz, 1H), 3.24 (d, J = 11.5 Hz, 1H), 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, 1H), 5.75 (s, 1H), 6.41 (d, J = 2.3 Hz,

1H), 6.80 (q, J = 6.5 Hz, 1H), 7.37 (m, 3H), 7.63 (d, J = 1.8 Hz, 1H), 7.76 (m, 2H),

7.98 (d, J = 2.3 Hz, 1H)

1ar

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (t, J = 5.8 Hz, 4H), 1.99 (dd, J = 13.3, 7.0 Hz,

1H), 2.25 (dd, J = 13.3, 9.1 Hz, 1H), 2.39 (s, 3H), 3.00 (d, J = 11.3 Hz, 1H), 3.17 (d,

J = 11.5 Hz, 1H), 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, 1H), 5.74 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.83 (q, J = 6.6 Hz, 1H),

7.33 (t, J = 8.8 Hz, 1H), 7.65 (m, 2H), 7.73 (dd, J = 8.2, 1.9 Hz, 1H), 7.82 (m, 2H),

8.00 (d, J = 2.3 Hz, 1H)

1as

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.60 (m, 4H), 2.05 (dd, J = 13.4,

7.1 Hz, 1H), 2.32 (dd, J = 13.4, 9.1 Hz, 1H), 2.40 (s, 3H), 3.12 (d, J = 11.7 Hz, 1H),

3.24 (d, J = 11.7 Hz, 1H), 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, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.83 (q, J = 6.3 Hz, 1H),

7.32 (m, 1H), 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,

1H)

1at

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.57 (m, 4H), 1.97 (dd, J = 13.1,

6.8 Hz, 1H), 2.23 (m, 2H), 2.37 (d, J = 18.2 Hz, 9H), 2.98 (d, J = 11.6 Hz, 1H), 3.15 (d,

J = 11.5 Hz, 1H), 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, 1H), 5.75 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78 (q, J = 6.6 Hz,

1H), 7.03 (s, 1H), 7.27 (d, J = 1.6 Hz, 2H), 7.59 (d, J = 1.8 Hz, 1H), 7.73 (m, 2H),

7.97 (d, J = 2.4 Hz, 1H)

1au

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.39 (s, 4H), 3.13 (d, J = 11.7 Hz, 1H), 3.25 (d, J = 11.7 Hz,

1H), 3.52 (m, 2H), 3.67 (dt, J = 12.0, 6.4 Hz, 2H), 4.14 (dd, J = 9.1, 7.2 Hz,

1H), 4.91 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.83 (q, J = 6.6 Hz, 1H), 7.36 (dt, J = 10.4,

8.4 Hz, 1H), 7.51 (ddt, J = 8.1, 3.9, 1.6 Hz, 1H), 7.65 (m, 2H), 7.77 (m, 2H), 7.99 (d, J = 2.3 Hz,

1H)

1av

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (dt, J = 6.7, 3.0 Hz, 4H), 1.98 (dd, J = 13.3,

7.0 Hz, 1H), 2.24 (dd, J = 13.4, 9.2 Hz, 1H), 2.40 (s, 3H), 2.99 (d, J = 11.5 Hz,

1H), 3.16 (d, J = 11.5 Hz, 1H), 3.48 (ddt, J = 20.5, 13.2, 5.9 Hz, 2H), 3.65 (dq, J = 11.1,

5.0 Hz, 2H), 3.95 (t, J = 8.2 Hz, 1H), 5.74 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.84 (q, J = 6.6 Hz,

1H), 6.99 (tt, J = 9.0, 2.3 Hz, 1H), 7.35 (m, 2H), 7.68 (d, J = 1.9 Hz, 1H),

7.79 (m, 2H), 8.02 (d, J = 2.4 Hz, 1H)

1aw

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, 1H), 1.30 (d, J = 13.3 Hz, 2H), 1.51 (q,

J = 6.5, 5.7 Hz, 5H), 1.77 (dd, J = 13.0, 6.9 Hz, 1H), 2.05 (dd, J = 13.0, 8.9 Hz, 1H),

2.40 (s, 3H), 2.62 (d, J = 11.0 Hz, 1H), 2.93 (d, J = 11.0 Hz, 1H), 3.42 (d, J = 14.2 Hz,

2H), 3.49 (s, 1H), 3.62 (dt, J = 16.7, 6.6 Hz, 3H), 5.72 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H),

6.83 (q, J = 6.6 Hz, 1H), 7.44 (m, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.81 (m, 2H), 8.01 (m,

3H)

1ax

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, 2H), 1.32 (m, 13H), 1.57 (t, J = 5.4 Hz,

4H), 2.01 (m, 1H), 2.29 (dd, J = 13.4, 9.2 Hz, 1H), 2.39 (s, 3H), 2.80 (s, 1H),

3.07 (d, J = 11.6 Hz, 1H), 3.17 (s, 1H), 3.50 (m, 2H), 3.66 (d, J = 13.8 Hz, 2H), 4.03 (t, J = 8.1 Hz,

1H), 4.65 (p, J = 6.1 Hz, 1H), 5.75 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.78 (q, J = 6.6 Hz,

1H), 7.16 (t, J = 8.6 Hz, 1H), 7.45 (m, 2H), 7.61 (d, J = 1.8 Hz, 1H), 7.74 (m,

2H), 7.98 (d, J = 2.4 Hz, 1H)

1ay

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.39 (s, 4H), 3.10 (d, J = 11.7 Hz,

1H), 3.24 (m, 1H), 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, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.71 (dt,

J = 10.8, 2.2 Hz, 1H), 6.80 (p, J = 6.6 Hz, 1H), 7.01 (m, 2H), 7.63 (d, J = 1.8 Hz, 1H),

7.76 (m, 2H), 8.00 (d, J = 2.4 Hz, 1H)

1az

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.90 (m, 1H), 1.36 (s, 13H), 1.59 (m, 4H),

2.05 (dd, J = 13.4, 6.9 Hz, 1H), 2.33 (dt, J = 13.7, 6.0 Hz, 1H), 2.40 (s, 3H), 3.12 (d, J = 11.4 Hz,

1H), 3.24 (d, J = 12.1 Hz, 1H), 3.40 (s, 1H), 3.53 (d, J = 14.7 Hz, 1H), 3.68 (d, J = 13.4 Hz,

2H), 4.10 (s, 1H), 4.76 (m, 5H), 4.83 (s, 2H), 5.01 (s, 1H), 6.42 (d, J = 2.2 Hz,

1H), 6.77 (q, J = 6.6 Hz, 1H), 7.42 (m, 3H), 7.65 (m, 4H), 7.76 (m, 2H), 7.98 (d, J = 2.3 Hz,

1H)

1ba

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (d, J = 12.1 Hz, 3H), 1.59 (t, J = 5.2 Hz,

4H), 2.05 (dd, J = 13.4, 7.0 Hz, 1H), 2.34 (m, 7H), 3.11 (d, J = 11.7 Hz, 1H), 3.24 (d, J = 11.8 Hz,

1H), 3.51 (m, 2H), 3.68 (dt, J = 13.1, 6.3 Hz, 2H), 4.09 (dd, J = 9.2, 6.9 Hz,

1H), 6.41 (d, J = 2.3 Hz, 1H), 6.79 (q, J = 6.7 Hz, 1H), 7.11 (t, J = 9.1 Hz, 1H), 7.55 (m,

3H), 7.74 (m, 2H), 7.98 (d, J = 2.3 Hz, 1H)

1bb

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.32 (dd, J = 13.4, 8.9 Hz, 1H), 2.40 (s, 3H),

2.96 (h, J = 6.8 Hz, 1H), 3.12 (d, J = 11.8 Hz, 1H), 3.24 (d, J = 11.7 Hz, 1H), 3.51 (m, 2H),

3.67 (m, 2H), 4.10 (t, J = 8.3 Hz, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78 (q, J = 6.5 Hz, 1H),

7.27 (m, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.48 (m, 2H), 7.62 (d, J = 1.8 Hz, 1H), 7.76 (m,

2H), 7.98 (d, J = 2.4 Hz, 1H)

1bc

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, 1H), 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, 1H), 2.39 (s, 3H), 3.04 (d, J = 11.6 Hz,

1H), 3.17 (d, J = 11.6 Hz, 1H), 3.47 (ddt, J = 20.9, 13.0, 5.9 Hz, 2H), 3.62 (dq, J = 11.5,

5.7 Hz, 2H), 4.01 (m, 1H), 4.64 (hept, J = 5.9 Hz, 1H), 5.74 (s, 1H), 6.41 (d, J = 2.4 Hz,

1H), 6.79 (q, J = 6.6 Hz, 1H), 6.91 (dd, J = 8.1, 2.4 Hz, 1H), 7.16 (ddd, J = 8.5, 5.3, 1.7 Hz,

2H), 7.32 (t, J = 7.9 Hz, 1H), 7.64 (m, 3H), 7.77 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 2.4 Hz,

1H)

1bd

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.59 (d, J = 5.6 Hz, 4H), 2.05 (dd,

J = 13.4, 7.0 Hz, 1H), 2.31 (dd, J = 13.4, 9.3 Hz, 1H), 2.41 (d, J = 11.1 Hz, 6H), 3.11 (d,

J = 11.7 Hz, 1H), 3.24 (d, J = 11.7 Hz, 1H), 3.49 (ddd, J = 27.1, 12.8, 5.9 Hz, 2H),

3.66 (dq, J = 13.8, 6.0 Hz, 2H), 4.07 (dd, J = 9.2, 7.0 Hz, 1H), 5.75 (s, 1H), 6.42 (d, J = 2.4 Hz,

1H), 6.80 (q, J = 6.6 Hz, 1H), 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, 1H)

1be

¹H NMR (400 MHz, MeOH-d4): δ 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, 5H),

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, 1H), 4.93 (s, 1H), 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)

1bf

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (t, J = 5.7 Hz, 4H), 1.99 (dd, J = 13.3, 7.0 Hz,

1H), 2.25 (dd, J = 13.3, 9.1 Hz, 1H), 2.41 (s, 3H), 3.01 (d, J = 11.6 Hz, 1H), 3.17 (d,

J = 11.5 Hz, 1H), 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, 1H), 5.73 (s, 1H), 6.44 (d, J = 2.4 Hz, 1H), 6.87 (q, J = 6.6 Hz,

1H), 7.79 (d, J = 1.8 Hz, 1H), 7.88 (m, 2H), 8.00 (s, 1H), 8.07 (d, J = 2.3 Hz, 1H),

8.29 (s, 2H)

1bg

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 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, 1H), 2.40 (s, 4H), 3.23 (m, 2H), 3.64 (m, 4H),

4.18 (q, J = 7.0 Hz, 2H), 4.32 (t, J = 8.4 Hz, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.83 (q, J = 6.4 Hz,

1H), 7.20 (m, 2H), 7.36 (dd, J = 8.0, 2.1 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H),

7.77 (m, 2H), 7.99 (d, J = 2.4 Hz, 1H)

1bh

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.59 (d, J = 5.4 Hz, 4H), 2.04 (dd,

J = 13.4, 7.0 Hz, 1H), 2.29 (m, 2H), 2.41 (d, J = 9.6 Hz, 9H), 3.10 (d, J = 11.7 Hz, 1H),

3.24 (m, 1H), 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, 1H), 5.75 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.79 (q, J = 6.6 Hz, 1H),

7.45 (s, 2H), 7.62 (d, J = 1.8 Hz, 1H), 7.75 (m, 2H), 7.98 (d, J = 2.4 Hz, 1H)

1bi

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (m, 4H), 1.99 (dd, J = 13.4, 7.1 Hz, 1H),

2.26 (dd, J = 13.3, 9.1 Hz, 1H), 2.40 (s, 3H), 3.02 (d, J = 11.6 Hz, 1H), 3.18 (d, J = 11.6 Hz,

1H), 3.48 (dq, J = 23.5, 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, 1H), 5.73 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.85 (q, J = 6.6 Hz, 1H),

7.46 (t, J = 1.9 Hz, 1H), 7.66 (t, J = 1.8 Hz, 3H), 7.73 (dd, J = 8.3, 2.0 Hz, 1H), 7.82 (d, J = 8.1 Hz,

1H), 8.02 (d, J = 2.4 Hz, 1H)

1bj

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (m, 1H), 1.34 (s, 10H), 1.61 (t, J = 5.9 Hz,

4H), 2.06 (dd, J = 13.5, 7.3 Hz, 1H), 2.39 (m, 7H), 3.14 (d, J = 11.6 Hz, 1H), 3.25 (m,

1H), 3.55 (m, 2H), 3.68 (s, 2H), 4.18 (dd, J = 9.0, 7.3 Hz, 1H), 6.42 (d, J = 2.3 Hz, 1H),

6.78 (q, J = 6.5 Hz, 1H), 7.28 (m, 2H), 7.45 (t, J = 1.7 Hz, 1H), 7.60 (d, J = 1.8 Hz, 1H),

7.75 (m, 2H), 7.98 (d, J = 2.3 Hz, 1H)

1bk

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 2H), 1.58 (t, J = 5.5 Hz, 4H), 2.04 (dd,

J = 13.3, 6.9 Hz, 1H), 2.30 (dd, J = 13.3, 9.1 Hz, 1H), 2.40 (s, 3H), 3.09 (d, J = 11.7 Hz,

1H), 3.23 (d, J = 12.2 Hz, 1H), 3.51 (m, 2H), 3.66 (dd, J = 13.9, 6.6 Hz, 2H), 4.05 (t, J = 8.2 Hz,

1H), 4.62 (s, 1H), 5.75 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.82 (q, J = 6.5 Hz,

1H), 7.43 (m, 2H), 7.63 (m, 2H), 7.75 (m, 3H), 8.00 (d, J = 2.3 Hz, 1H)

1bl

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (t, J = 5.6 Hz, 4H), 2.00 (dd, J = 13.5, 7.0 Hz,

1H), 2.26 (dd, J = 13.3, 9.1 Hz, 1H), 2.40 (s, 3H), 3.03 (d, J = 11.6 Hz, 1H), 3.18 (d,

J = 11.5 Hz, 1H), 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, 1H), 5.74 (s, 1H), 6.43 (d, J = 2.3 Hz, 1H), 6.86 (q, J = 6.6 Hz, 1H),

7.81 (m, 5H), 7.98 (d, J = 1.6 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H)

1bm

¹H NMR (400 MHz, MeOH-d4): δ 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), 7.50-7.63 (m, 3 H), 7.64-7.71 (m, 1 H),

7.71-7.80 (m, 1 H), 7.95 (d, J = 2.15 Hz, 1 H)

1bn

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, 1H), 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, 1H), 2.31 (dd, J = 13.4, 9.0 Hz,

1H), 2.39 (s, 3H), 3.11 (d, J = 11.8 Hz, 1H), 3.24 (d, J = 11.7 Hz, 1H), 3.51 (m, 2H),

3.67 (m, 2H), 4.13 (m, 3H), 4.63 (s, 1H), 5.75 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78 (q,

J = 6.6 Hz, 1H), 7.15 (t, J = 8.6 Hz, 1H), 7.45 (m, 2H), 7.60 (d, J = 1.8 Hz, 1H),

7.73 (m, 2H), 7.97 (d, J = 2.4 Hz, 1H)

1bo

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 8.3 Hz, 1H), 1.59 (t, J = 5.3 Hz,

4H), 2.05 (dd, J = 13.5, 7.0 Hz, 1H), 2.32 (dd, J = 13.6, 9.2 Hz, 1H), 2.39 (s, 3H),

3.12 (d, J = 11.6 Hz, 1H), 3.25 (m, 1H), 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, 1H), 5.76 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H),

6.85 (q, J = 6.6 Hz, 1H), 7.54 (m, 2H), 7.68 (d, J = 1.8 Hz, 1H), 7.78 (m, 2H), 8.01 (d, J = 2.3 Hz,

1H)

1bp

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 8.6 Hz, 1H), 1.59 (d, J = 5.9 Hz,

4H), 2.05 (dd, J = 13.5, 7.3 Hz, 1H), 2.39 (m, 7H), 3.13 (d, J = 11.6 Hz, 1H), 3.24 (m,

2H), 3.52 (dq, J = 25.3, 6.3 Hz, 2H), 3.68 (dd, J = 13.7, 5.9 Hz, 2H), 4.16 (m, 1H),

6.42 (d, J = 2.3 Hz, 1H), 6.82 (q, J = 6.5 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.51 (dd, J = 7.9,

2.0 Hz, 1H), 7.63 (d, J = 1.9 Hz, 1H), 7.73 (m, 3H), 7.98 (d, J = 2.4 Hz, 1H)

1bq

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 8.0 Hz, 1H), 1.59 (m, 4H), 2.05 (dd,

J = 13.4, 7.0 Hz, 1H), 2.38 (d, J = 13.7 Hz, 7H), 3.13 (d, J = 11.7 Hz, 1H), 3.25 (d, J = 11.6 Hz,

1H), 3.53 (dt, J = 31.7, 10.3 Hz, 2H), 3.67 (dd, J = 13.5, 7.0 Hz, 2H), 4.15 (m,

1H), 4.89 (s, 17H), 6.42 (d, J = 2.4 Hz, 1H), 6.82 (q, J = 6.6 Hz, 1H), 7.32 (m, 1H),

7.61 (m, 4H), 7.76 (m, 2H), 7.99 (d, J = 2.3 Hz, 1H)

1br

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.90 (s, 1H), 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, 1H), 3.25 (d, J = 11.4 Hz, 1H),

3.51 (m, 2H), 3.66 (dd, J = 13.6, 6.6 Hz, 2H), 4.11 (dt, J = 21.0, 7.6 Hz, 1H), 4.65 (h, J = 6.0 Hz,

1H), 6.42 (d, J = 2.3 Hz, 1H), 6.69 (dt, J = 10.9, 2.2 Hz, 1H), 6.82 (q, J = 6.3 Hz,

1H), 6.99 (m, 2H), 7.61 (d, J = 1.8 Hz, 1H), 7.71 (m, 1H), 7.78 (d, J = 8.1 Hz, 1H),

7.99 (d, J = 2.3 Hz, 1H)

1bs

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.09 (s, 1H), 0.90 (q, J = 8.4, 7.7 Hz, 1H),

1.29 (d, J = 8.6 Hz, 3H), 1.59 (d, J = 5.7 Hz, 5H), 2.05 (dd, J = 13.5, 6.9 Hz, 1H), 2.31 (dd, J = 13.6,

9.4 Hz, 1H), 2.40 (s, 3H), 3.13 (d, J = 11.6 Hz, 1H), 3.25 (m, 1H), 3.61 (m, 5H),

4.08 (m, 1H), 5.74 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.85 (q, J = 6.7 Hz, 1H), 7.24 (dt, J = 8.5,

2.1 Hz, 1H), 7.45 (dt, J = 9.6, 2.0 Hz, 1H), 7.58 (t, J = 1.7 Hz, 1H), 7.68 (d, J = 1.9 Hz,

1H), 7.79 (m, 2H), 8.02 (d, J = 2.3 Hz, 1H)

1bt

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (d, J = 1.7 Hz, 1H), 1.58 (t, J = 5.7 Hz,

4H), 2.03 (dd, J = 13.4, 7.0 Hz, 1H), 2.29 (dd, J = 13.4, 9.2 Hz, 1H), 2.40 (s, 3H),

3.07 (d, J = 11.6 Hz, 1H), 3.22 (d, J = 11.6 Hz, 1H), 3.49 (m, 2H), 3.65 (dd, J = 13.0, 6.7 Hz,

2H), 4.04 (dd, J = 9.2, 7.0 Hz, 1H), 5.73 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.84 (q, J = 6.6 Hz,

1H), 7.77 (m, 5H), 7.92 (dd, J = 8.4, 2.2 Hz, 1H), 8.04 (dd, J = 14.2, 2.3 Hz, 2H)

1bu

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.60 (d, J = 5.4 Hz, 4H), 2.05 (dd, J = 13.5, 7.1 Hz,

1H), 2.40 (s, 4H), 3.11 (d, J = 11.7 Hz, 1H), 3.24 (d, J = 11.7 Hz, 1H), 3.49 (ddt, J = 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, 1H),

5.74 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.86 (q, J = 6.6 Hz, 1H), 7.50 (m, 1H), 7.80 (m,

5H), 8.04 (d, J = 2.4 Hz, 1H)

1bv

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.35 (d, J = 6.0 Hz, 7H), 1.55 (d, J = 5.9 Hz,

4H), 1.98 (dd, J = 13.3, 7.0 Hz, 1H), 2.25 (dd, J = 13.3, 9.1 Hz, 1H), 2.39 (s, 2H),

3.01 (d, J = 11.5 Hz, 1H), 3.17 (d, J = 11.6 Hz, 1H), 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, 1H), 4.67 (p, J = 6.1 Hz, 1H),

4.89 (s, 11H), 5.74 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.79 (q, J = 6.6 Hz, 1H), 7.13 (d, J = 8.7 Hz,

1H), 7.55 (m, 2H), 7.71 (m, 4H), 7.98 (d, J = 2.4 Hz, 1H)

1bw

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.54 (t, J = 5.7 Hz, 4H), 1.95 (dd, J = 13.3, 7.0 Hz,

1H), 2.22 (dd, J = 13.3, 9.0 Hz, 1H), 2.41 (s, 3H), 2.95 (d, J = 11.5 Hz, 1H), 3.13 (d,

J = 11.4 Hz, 1H), 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, 1H), 4.91 (s, 10H), 5.77 (s, 1H), 6.43 (d, J = 2.3 Hz, 1H), 6.83 (q, J = 6.6 Hz,

1H), 7.49 (m, 2H), 7.83 (m, 7H), 8.01 (d, J = 2.4 Hz, 1H), 8.13 (d, J = 1.9 Hz,

1H)

1bx

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.59 (m, 4H), 2.05 (dd, J = 13.5, 7.2 Hz, 1H),

2.39 (s, 4H), 3.12 (d, J = 11.7 Hz, 1H), 3.24 (d, J = 11.8 Hz, 1H), 3.51 (m, 2H),

3.67 (dd, J = 13.7, 6.2 Hz, 2H), 4.13 (dd, J = 9.1, 7.2 Hz, 1H), 5.19 (s, 2H), 6.41 (d, J = 2.3 Hz,

1H), 6.79 (q, J = 6.5 Hz, 1H), 7.21 (t, J = 8.6 Hz, 1H), 7.42 (m, 7H), 7.60 (d, J = 1.8 Hz,

1H), 7.72 (m, 2H), 7.97 (d, J = 2.3 Hz, 1H)

1by

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.22 (s, 3H), 2.35 (m, 4H), 3.10 (d, J = 11.8 Hz,

1H), 3.23 (d, J = 11.8 Hz, 1H), 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, 1H), 4.63 (p, J = 6.1 Hz, 1H), 5.76 (s, 1H),

6.41 (d, J = 2.4 Hz, 1H), 6.75 (q, J = 6.7 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 8.2 Hz,

2H), 7.57 (d, J = 1.8 Hz, 1H), 7.71 (m, 2H), 7.96 (d, J = 2.3 Hz, 1H)

1bz

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.06 (t, J = 7.4 Hz, 3H), 1.29 (m, 1H), 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, 1H), 2.29 (dd, J = 13.3,

9.1 Hz, 1H), 2.39 (s, 3H), 3.08 (d, J = 11.6 Hz, 1H), 3.21 (d, J = 11.5 Hz, 1H),

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, 1H), 5.75 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78 (q, J = 6.5 Hz,

1H), 7.14 (t, J = 8.6 Hz, 1H), 7.44 (m, 2H), 7.59 (d, J = 1.9 Hz, 1H), 7.72 (m, 2H),

7.98 (d, J = 2.3 Hz, 1H)

1ca

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.20 (dd, J = 13.3, 9.1 Hz, 1H),

2.39 (s, 3H), 2.91 (d, J = 11.4 Hz, 1H), 3.11 (d, J = 11.4 Hz, 1H), 3.47 (ddt, J = 20.0,

13.0, 5.9 Hz, 2H), 3.64 (dd, J = 13.8, 5.7 Hz, 2H), 3.88 (t, J = 8.0 Hz, 1H), 4.07 (t, J = 6.4 Hz,

2H), 5.75 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.78 (q, J = 6.7 Hz, 1H), 7.14 (t, J = 8.6 Hz,

1H), 7.43 (m, 2H), 7.59 (d, J = 1.9 Hz, 1H), 7.71 (m, 2H), 7.98 (d, J = 2.4 Hz,

1H)

1cb

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (s, 1H), 1.28 (s, 1H), 1.62 (d, J = 6.2 Hz,

8H), 2.06 (dd, J = 13.3, 7.3 Hz, 2H), 2.41 (s, 8H), 2.65 (s, 5H), 3.15 (d, J = 12.0 Hz,

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,

2H), 5.89 (s, 1H), 6.00 (m, 1H), 6.44 (d, J = 2.3 Hz, 2H), 6.89 (q, J = 6.4 Hz, 2H),

7.80 (m, 10H), 8.04 (d, J = 2.3 Hz, 2H), 8.12 (t, J = 7.9 Hz, 2H)

1cc

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 6.2 Hz, 1H), 1.57 (m, 4H), 1.99 (dd,

J = 13.4, 7.0 Hz, 1H), 2.25 (dd, J = 13.4, 9.1 Hz, 1H), 2.40 (s, 3H), 3.01 (d, J = 11.6 Hz,

1H), 3.15 (m, 4H), 3.32 (s, 1H), 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, 1H), 4.89 (m, 2H), 5.75 (s, 1H), 6.44 (d, J = 2.4 Hz,

1H), 6.85 (q, J = 6.6 Hz, 1H), 7.75 (d, J = 1.7 Hz, 1H), 7.84 (m, 2H), 7.94 (d, J = 8.5 Hz,

2H), 8.03 (m, 3H)

1cd

¹H NMR (400 MHz, MeOH-d4): δ 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,

1H), 2.39 (s, 3H), 2.67 (d, J = 11.2 Hz, 1H), 2.94 (t, J = 11.8 Hz, 1H), 3.40 (m, 3H),

3.64 (m, 3H), 3.96 (t, J = 6.4 Hz, 2H), 4.89 (m, 1H), 5.75 (s, 1H), 6.41 (d, J = 2.3 Hz,

1H), 6.75 (m, 1H), 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,

1H)

1ce

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (d, J = 16.9 Hz, 4H), 1.57 (s, 5H), 2.02 (m,

1H), 2.27 (dd, J = 13.3, 8.8 Hz, 1H), 2.40 (s, 3H), 2.60 (m, 6H), 3.06 (d, J = 11.4 Hz,

1H), 3.20 (d, J = 11.3 Hz, 1H), 3.34 (s, 1H), 3.48 (s, 3H), 3.56 (t, J = 6.7 Hz, 2H),

3.70 (m, 7H), 4.02 (s, 1H), 4.98 (d, J = 6.2 Hz, 1H), 5.76 (s, 1H), 6.43 (d, J = 2.3 Hz, 1H),

6.82 (q, J = 6.5 Hz, 1H), 7.71 (s, 1H), 7.80 (m, 4H), 7.93 (d, J = 8.0 Hz, 2H), 8.01 (d, J = 2.3 Hz,

1H)

1cf

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.90 (t, J = 6.4 Hz, 1H), 1.30 (dd, J = 12.6, 4.9 Hz,

6H), 1.55 (m, 5H), 1.93 (dd, J = 13.2, 7.0 Hz, 1H), 2.19 (qd, J = 9.4, 3.3 Hz, 1H),

2.40 (s, 3H), 2.92 (d, J = 11.4 Hz, 1H), 3.11 (d, J = 11.3 Hz, 1H), 3.48 (m, 2H),

3.65 (dd, J = 13.7, 6.3 Hz, 2H), 3.88 (dd, J = 8.9, 7.2 Hz, 1H), 4.87 (d, J = 12.3 Hz, 1H),

4.97 (d, J = 12.9 Hz, 2H), 5.75 (s, 1H), 6.43 (d, J = 2.3 Hz, 1H), 6.83 (q, J = 6.7 Hz, 1H),

7.73 (s, 1H), 7.84 (m, 4H), 8.00 (m, 3H)

1cg

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (s, 1H), 1.58 (d, J = 5.9 Hz, 4H), 2.03 (dd,

J = 13.4, 6.9 Hz, 1H), 2.30 (dd, J = 13.3, 9.2 Hz, 1H), 2.40 (s, 3H), 3.11 (d, J = 11.7 Hz,

1H), 3.23 (d, J = 11.5 Hz, 1H), 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, 1H), 5.76 (s, 1H), 6.43 (d, J = 2.3 Hz, 1H), 6.82 (q, J = 6.5 Hz,

1H), 7.70 (d, J = 1.7 Hz, 1H), 7.79 (dt, J = 13.1, 8.1 Hz, 4H), 7.99 (m, 3H)

1ch

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 3.6 Hz, 1H), 1.63 (q, J = 5.8 Hz,

5H), 2.07 (dd, J = 13.5, 7.5 Hz, 1H), 2.37 (dd, J = 13.5, 9.0 Hz, 1H), 3.04 (s, 3H),

3.15 (d, J = 24.6 Hz, 6H), 3.27 (m, 1H), 3.52 (dt, J = 24.6, 8.3 Hz, 2H), 3.65 (m, 2H), 4.23 (t,

J = 8.1 Hz, 1H), 6.66 (q, J = 7.0 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.68 (m, 6H)

1ci

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.58 (d, J = 5.6 Hz, 4H), 2.03 (dd, J = 13.3, 7.1 Hz,

1H), 2.30 (dd, J = 13.4, 9.2 Hz, 1H), 2.39 (s, 3H), 3.09 (d, J = 11.7 Hz, 1H), 3.22 (d,

J = 11.7 Hz, 1H), 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, 1H), 5.76 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H),

6.78 (q, J = 6.6 Hz, 1H), 7.17 (t, J = 8.9 Hz, 1H), 7.46 (m, 2H), 7.60 (d, J = 1.8 Hz, 1H),

7.73 (m, 2H), 7.98 (d, J = 2.3 Hz, 1H)

1cj

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (d, J = 17.0 Hz, 1H), 1.57 (d, J = 5.5 Hz,

4H), 2.01 (dd, J = 13.2, 7.0 Hz, 1H), 2.28 (dd, J = 13.3, 9.0 Hz, 1H), 2.40 (s, 3H),

2.79 (s, 2H), 2.91 (s, 2H), 3.07 (d, J = 12.1 Hz, 1H), 3.20 (d, J = 11.4 Hz, 1H), 3.49 (m, 4H),

3.65 (dd, J = 13.5, 6.9 Hz, 2H), 3.74 (s, 2H), 4.02 (t, J = 8.1 Hz, 1H), 4.99 (s, 1H),

5.76 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.82 (q, J = 6.6 Hz, 1H), 7.52 (d, J = 7.9 Hz, 2H),

7.76 (m, 5H), 8.01 (d, J = 2.4 Hz, 1H)

1ck

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (d, J = 11.1 Hz, 1H), 1.51 (q, J = 6.8, 6.0 Hz,

4H), 1.78 (dd, J = 13.0, 7.0 Hz, 1H), 1.89 (s, 2H), 2.07 (dd, J = 13.1, 9.1 Hz, 1H),

2.40 (s, 3H), 2.68 (d, J = 11.1 Hz, 1H), 2.95 (d, J = 11.1 Hz, 1H), 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, 1H), 6.43 (d, J = 2.4 Hz,

1H), 6.82 (q, J = 6.6 Hz, 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.70 (m, 1H), 7.80 (m,

4H), 8.01 (d, J = 2.5 Hz, 1H)

1cl

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.04 (d, J = 6.7 Hz, 6H), 1.29 (m, 1H), 1.60 (d,

J = 6.0 Hz, 5H), 2.05 (ddd, J = 13.7, 7.0, 3.9 Hz, 2H), 2.36 (m, 4H), 3.13 (d, J = 11.9 Hz,

1H), 3.24 (d, J = 11.6 Hz, 1H), 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, 1H), 4.93 (s, 8H), 6.41 (d, J = 2.3 Hz,

1H), 6.77 (q, J = 6.6 Hz, 1H), 6.99 (m, 2H), 7.60 (m, 3H), 7.72 (m, 2H), 7.96 (d,

J = 2.3 Hz, 1H)

1cm

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.18 (dd, J = 13.2, 9.0 Hz, 1H), 2.40 (s, 3H),

2.87 (d, J = 11.4 Hz, 1H), 3.09 (d, J = 11.3 Hz, 1H), 3.30 (m, 4H), 3.54 (dddd, J = 37.2, 30.6,

15.1, 5.9 Hz, 6H), 3.84 (dd, J = 9.0, 6.9 Hz, 1H), 5.76 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H),

6.83 (q, J = 6.6 Hz, 1H), 7.48 (m, 2H), 7.70 (d, J = 1.6 Hz, 1H), 7.80 (m, 4H), 8.01 (d, J = 2.3 Hz,

1H)

1cn

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.84 (s, 3H), 1.06 (s, 10H), 1.30 (m, 1H),

1.56 (t, J = 5.4 Hz, 4H), 2.00 (dd, J = 13.4, 6.8 Hz, 1H), 2.27 (dd, J = 13.2, 9.0 Hz, 1H),

2.41 (s, 3H), 3.04 (d, J = 11.5 Hz, 1H), 3.19 (d, J = 11.4 Hz, 1H), 3.48 (ddt, J = 20.4, 13.0,

5.9 Hz, 2H), 3.65 (s, 4H), 4.03 (t, J = 8.1 Hz, 1H), 5.77 (s, 1H), 6.43 (d, J = 2.2 Hz, 1H),

6.79 (q, J = 6.6 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 7.60 (m, 4H), 7.75 (d, J = 8.2 Hz, 1H),

7.97 (d, J = 2.3 Hz, 1H)

1co

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (d, J = 5.8 Hz, 1H), 1.55 (t, J = 5.7 Hz,

4H), 1.98 (m, 3H), 2.25 (dd, J = 13.3, 9.2 Hz, 1H), 2.39 (s, 3H), 2.80 (t, J = 6.5 Hz, 2H),

3.02 (d, J = 11.6 Hz, 1H), 3.17 (d, J = 11.6 Hz, 1H), 3.47 (ddt, J = 20.5, 13.0, 5.9 Hz,

2H), 3.64 (dt, J = 13.8, 5.9 Hz, 2H), 4.00 (dd, J = 9.2, 7.1 Hz, 1H), 4.16 (m, 2H),

5.75 (s, 1H), 6.40 (d, J = 2.3 Hz, 1H), 6.76 (m, 2H), 7.33 (d, J = 6.5 Hz, 2H), 7.54 (d, J = 1.8 Hz,

1H), 7.63 (dd, J = 8.3, 1.9 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 2.4 Hz,

1H)

1cp

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.59 (t, J = 5.3 Hz, 4H), 2.05 (dd, J = 13.5, 7.1 Hz,

1H), 2.31 (dd, J = 13.4, 9.3 Hz, 1H), 2.42 (s, 3H), 3.11 (d, J = 11.7 Hz, 1H), 3.24 (d,

J = 11.7 Hz, 1H), 3.51 (m, 2H), 3.67 (s, 2H), 4.07 (dd, J = 9.3, 7.1 Hz, 1H), 4.89 (s, 1H),

5.78 (s, 1H), 5.99 (m, 1H), 6.46 (d, J = 2.3 Hz, 1H), 6.89 (q, J = 6.5 Hz, 1H), 7.91 (m,

2H), 8.00 (dd, J = 8.3, 2.0 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 8.34 (m, 3H), 8.55 (d, J = 8.9 Hz,

1H), 9.33 (d, J = 5.9 Hz, 1H)

1cq

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.97 (s, 1H), 7.77 (s, 2H), 7.67 (d, J = 15.8 Hz,

2H), 7.51 (s, 1H), 7.26 (d, J = 7.8 Hz, 1H), 6.42 (s, 1H), 4.69 (s, 2H), 4.14 (s, 1H),

3.68 (s, 2H), 3.51 (s, 3H), 3.23 (s, 1H), 3.13 (d, J = 11.6 Hz, 1H), 2.38 (d, J = 14.0 Hz, 6H),

2.05 (s, 1H), 1.60 (s, 4H), 1.29 (s, 3H)

1cr

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.97 (s, 2H), 7.74 (q, J = 8.3 Hz, 4H), 7.62 (s,

2H), 7.46 (d, J = 7.4 Hz, 5H), 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, 1H), 3.46 (d, J = 16.2 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, 10H),

2.29 (s, 1H), 2.03 (dd, J = 13.4, 7.0 Hz, 2H), 1.58 (d, J = 5.6 Hz, 7H), 1.30 (d, J = 13.4 Hz,

5H)

1cs

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.43 (d, J = 2.5 Hz, 1H), 7.99 (q, J = 3.3 Hz,

2H), 7.79 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.63 (s, 1H), 6.83 (dd, J = 20.4,

7.6 Hz, 2H), 6.42 (d, J = 2.3 Hz, 1H), 5.74 (s, 1H), 4.35 (q, J = 7.0 Hz, 2H), 3.96 (d, J = 8.9 Hz,

1H), 3.64 (s, 3H), 3.48 (dd, J = 25.9, 11.9 Hz, 2H), 3.15 (d, J = 11.7 Hz, 1H),

2.99 (d, J = 11.4 Hz, 1H), 2.39 (s, 3H), 2.24 (s, 1H), 2.02-1.94 (m, 1H), 1.56 (s, 4H),

1.38 (t, J = 7.1 Hz, 3H), 1.28 (s, 1H).

Example 1cp
(S)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

embedded image

The title compound was prepared as described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 1u) starting with (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d).

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (br. s., 4H) 1.91-2.01 (m, 1H) 2.18-2.27 (m, 1H) 2.33 (d, J=11.71 Hz, 6H) 2.88-3.00 (m, 1H) 3.08-3.19 (m, 1H) 3.38-3.56 (m, 2H) 3.58-3.75 (m, 2H) 3.85-3.98 (m, 1H) 5.65 (s, 1H) 6.55-6.70 (m, 1H) 6.92-7.04 (m, 1H) 7.19-7.28 (m, 1H) 7.38-7.46 (m, 1H) 7.46-7.53 (m, 1H) 7.72 (s, 1H) 7.83 (s, 2H) 8.22-8.35 (m, 1H) LCMS (MH+): 690.

Example 2
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

embedded image

Step 1:

A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (Example 1f) (150 mg, 0.15 mmol) in MeOH (5 mL) was hydrogenated in an H-Cube apparatus using a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. The resulting eluent was concentrated in vacuo and The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (100% CH₂Cl₂to 90:9:1 CH₂Cl₂:MeOH:conc. NH₄OH) to provide (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

Step 2:

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

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.49-1.69 (m, 4H) 2.00-2.18 (m, 3H) 2.21-2.35 (m, 1H) 2.38 (s, 3H) 2.92-3.05 (m, 1H) 3.08 (d, J=0.44 Hz, 2H) 3.10-3.18 (m, 2H) 3.25 (d, J=11.71 Hz, 1H) 3.38-3.72 (m, 7H) 4.09 (t, J=7.88 Hz, 1H) 5.69 (s, 1H) 6.41 (d, J=2.29 Hz, 1H) 6.74 (q, J=6.80 Hz, 1H) 7.34 (d, J=1.12 Hz, 1H) 7.43 (d, J=8.15 Hz, 1H) 7.71 (d, J=8.44 Hz, 1H) 7.91 (d, J=2.20 Hz, 1H). LCMS (MH+): 613.

Example 3a
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (320 mg, 0.413 mmol) in CH₂Cl₂(5.0 mL) was added methanesulfonyl chloride (47 mg, 0.41 mmol) and triethylamine (94 mg, 0.83 mmol), and the reaction was stirred for 1.5 h at RT and then concentrated in vacuo. The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (100% CH₂Cl₂to 90:9:1 CH₂Cl₂:MeOH:conc. NH₄OH) to provide (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.

Step 2:

A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (290 mg, 0.340 mmol, Step 1) in MeOH (10 mL) was hydrogenated in an H-Cube apparatus using a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. The resulting eluent was concentrated in vacuo and The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (100% CH₂Cl₂to 90:9:1 CH₂Cl₂:MeOH:conc. NH₄OH) to provide (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.

Step 3:

Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.53-1.65 (m, 4H) 1.80 (qd, J=12.57, 3.98 Hz, 2H) 1.94-2.02 (m, 2H) 2.02-2.12 (m, 1H) 2.31 (dd, J=13.42, 9.27 Hz, 1H) 2.38 (s, 3H) 2.67-2.94 (m, 3H) 2.86 (s, 3H) 3.07-3.28 (m, 2H) 3.37-3.74 (m, 4H) 3.78-3.92 (m, 2H) 4.08 (dd, J=9.15, 7.20 Hz, 1H) 5.71 (s, 1H) 6.39 (d, J=2.29 Hz, 1H) 6.64-6.82 (m, 1H) 7.31 (d, J=1.71 Hz, 1H) 7.42 (dd, J=8.25, 1.76 Hz, 1H) 7.67 (d, J=8.10 Hz, 1H) 7.89 (d, J=2.29 Hz, 1H). LCMS (MH+): 693.

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

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TABLE 2a

Ex. No.
Cy
CAS Name
LCMS (MH+)

3b

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(S)-8-(6-((R)-1-(4-(1-acetylpiperidin-4-yl)-2-(3- methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
656.7

3c

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl- 1H-pyrazol-1-yl)-4-(tetrahydro-2H-pyran-4- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
615.6

TABLE 2b

NMR Data for Compounds of Table 2a

Ex.

No.
1H NMR

3b

¹H NMR (400 MHz, MeOH-d4): δ 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 = 13.69, 8.86 Hz, 1 H) 2.66-2.81 (m, 1

H) 2.88-3.03 (m, 1 H) 3.19-3.27 (m, 1 H) 3.31-3.40 (m, 1 H) 3.60-3.95 (m, 4 H)

4.05 (d, J = 13.08 Hz, 1 H) 4.55 (t, J = 8.66 Hz, 1 H) 4.67 (d, J = 13.13 Hz, 1 H) 6.39 (d,

J = 2.39 Hz, 1 H) 6.50 (br. s., 1 H) 6.79-6.87 (m, 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, MeOH-d4): δ ppm 1.59 (d, J = 5.08 Hz, 4 H) 1.72-1.89 (m, 4 H)

2.06 (dd, J = 13.45, 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, J = 11.76 Hz, 1 H) 3.36-3.74 (m, 6 H)

4.03 (dt, J = 11.16, 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, 1 H) 7.29 (d, J = 1.71 Hz, 1 H) 7.41 (dd, J = 8.20,

1.76 Hz, 1 H) 7.67 (d, J = 8.10 Hz, 1 H) 7.88 (d, J = 2.34 Hz, 1 H)

Example 4
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-4′-(methoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

N-CBZ Deprotection was accomplished via method B to yield (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-4′-(methoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.66 (d, J=5.47 Hz, 4H) 2.03-2.17 (m, 1H) 2.42 (s, 4H) 3.16-3.30 (m, 2H) 3.47-3.81 (m, 4H) 3.89 (s, 3H) 3.97 (s, 3H) 4.26-4.45 (m, 1H) 6.40-6.52 (m, 1H) 6.82-6.96 (m, 1H) 7.30-7.37 (m, 1H) 7.40 (s, 1H) 7.76 (s, 1H) 7.80-7.93 (m, 4H) 7.99-8.09 (m, 1H). LCMS: 696.7.

Example 5a
(S)-8-(2-amino-6-((R)-1-(3′-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was made according to the procedures described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-4′-(methoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 4).

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.42 (t, J=7.13 Hz, 3H) 1.61 (br. s., 4H) 2.02-2.14 (m, 1H) 2.28-2.40 (m, 1H) 2.42 (s, 3H) 3.06-3.19 (m, 1H) 3.21-3.30 (m, 1H) 3.40-3.60 (m, 2H) 3.62-3.80 (m, 2H) 4.01-4.19 (m, 1H) 4.41 (d, J=7.22 Hz, 2H) 5.76 (s, 1H) 6.45 (d, J=2.34 Hz, 1H) 6.79-6.92 (m, 1H) 7.60 (s, 1H) 7.70 (d, J=1.56 Hz, 1H) 7.80 (d, J=1.56 Hz, 1H) 7.84 (s, 1H) 7.90-7.97 (m, 1H) 8.02 (d, J=2.15 Hz, 1H) 8.05 (s, 1H) 8.31 (s, 1H) 680.7. LCMS (MH+): 578.7.

Example 5b
(S)-8-(2-amino-6-((R)-1-(4′-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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¹H NMR (400 MHz, MeOH-d4): δ ppm 0.88 (m, 4H), 1.30 (d, J=17.4 Hz, 10H), 1.40 (t, J=7.1 Hz, 4H), 1.59 (d, J=5.8 Hz, 5H), 2.05 (dd, J=13.5, 7.2 Hz, 1H), 2.35 (m, 5H), 3.11 (d, J=11.7 Hz, 1H), 3.24 (d, J=11.7 Hz, 1H), 3.49 (ddd, J=28.1, 12.7, 5.7 Hz, 2H), 3.66 (dd, J=13.2, 7.3 Hz, 3H), 4.07 (t, J=8.1 Hz, 1H), 4.38 (q, J=7.1 Hz, 2H), 4.82 (d, J=9.7 Hz, 1H), 4.91 (s, 2H), 5.75 (s, 1H), 6.42 (d, J=2.4 Hz, 1H), 6.83 (q, J=6.5 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.81 (m, 4H), 8.00 (d, J=2.4 Hz, 1H), 8.10 (m, 2H). LCMS (MH+): 681.

Example 6
(S)-8-(2-amino-6-((R)-1-(4-(3-carboxypropyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

To a solution of (S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (250 mg, 0.32 mmol) in THF (2 mL) was added sequentially PdCl₂(dppf)CH₂Cl₂(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 Na₂SO₄and concentrated in vacuo. The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (100% CH₂Cl₂to 90:9:1 CH₂Cl₂:MeOH:conc. NH₄OH) to provide (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(4-methoxy-4-oxobutyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.

Step 3:

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

Step 4:

Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(4-methoxy-4-oxobutyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate was carried out using the LiOH general method providing the title compound as an off-white solid.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.40-1.61 (m, 4H) 1.76-1.93 (m, 3H) 2.24 (t, J=7.35 Hz, 2H) 2.27-2.37 (m, 4H) 2.58-2.74 (m, 2H) 3.10 (br. s., 2H) 3.53 (br. s., 4H) 4.42 (br. s., 1H) 5.71 (br. s., 1H) 6.00 (br. s., 2H) 6.38 (d, J=2.20 Hz, 1H) 7.00 (q, J=6.87 Hz, 1H) 7.29 (d, J=1.51 Hz, 1H) 7.32-7.41 (m, 1H) 7.60 (s, 1H) 8.05 (d, J=2.29 Hz, 1H) 8.94 (br. s., 1H) 10.20 (br. s, 1H) 12.14 (br. s., 1H). LCMS (MH+): 618.6.

Example 7
(S)-8-(2-amino-6-((R)-1-(4-(2-carboxyethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was made as described for (S)-8-(2-amino-6-((R)-1-(4-(3-carboxypropyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 6).

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.56 (t, J=5.54 Hz, 4H) 1.97 (s, 2H) 2.04 (dd, J=13.30, 7.10 Hz, 1H) 2.29 (dd, J=13.67, 9.18 Hz, 1H) 2.35 (s, 3H) 2.59-2.68 (m, 2H) 2.97 (t, J=7.49 Hz, 2H) 3.06-3.13 (m, 1H) 3.23 (d, J=11.86 Hz, 1H) 3.39-3.55 (m, 2H) 3.57-3.75 (m, 2H) 4.06 (dd, J=9.05, 7.30 Hz, 1H) 5.72 (s, 1H) 6.36 (d, J=2.29 Hz, 1H) 6.71 (q, J=6.61 Hz, 1H) 7.28 (d, J=1.61 Hz, 1H) 7.37 (dd, J=8.20, 1.46 Hz, 1H) 7.62 (d, J=8.10 Hz, 1H) 7.83 (d, J=2.25 Hz, 1H). LCMS (MH+): 604.

Example 9
(S)-8-(2-amino-6-((R)-1-(4-(3-ethoxy-3-oxopropyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

To a solution of ((S)-8-(2-amino-6-((R)-1-(4-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((((2E,4Z)-2-vinylhexa-2,4-dien-1-yl)oxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (180 mg, 0.15 mmol) in MeOH (5 mL) was hydrogenated in an H-Cube apparatus using a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. The resulting eluent was concentrated in vacuo and the product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (100% CH₂Cl₂to 90:9:1 CH₂Cl₂:MeOH:conc. NH₄OH) to provide the title compound as a white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.14 (t, J=7.15 Hz, 3H) 1.50-1.68 (m, 4H) 1.94-1.99 (m, 2H) 2.04 (dd, J=13.45, 7.20 Hz, 1H) 2.30 (dd, J=13.47, 9.27 Hz, 1H) 2.35 (s, 3H) 2.66 (t, J=7.54 Hz, 2H) 2.97 (t, J=7.52 Hz, 2H) 3.07-3.14 (m, 1H) 3.23 (d, J=11.76 Hz, 1H) 3.39-3.72 (m, 4H) 4.01-4.11 (m, 3H) 5.70 (s, 1H) 6.36 (d, J=2.34 Hz, 1H) 6.72 (q, J=6.72 Hz, 1H) 7.27 (d, J=1.61 Hz, 1H) 7.35 (dd, J=8.15, 1.61 Hz, 1H) 7.62 (d, J=8.05 Hz, 1H) 7.83 (d, J=2.34 Hz, 1H). LCMS (MH+): 632.1

Example 10d
(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

To a solution of (1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethanol (40 g, 138 mmol) in dioxane (400 mL) was added 4,6-dichloropyrimidin-2-amine (113 g, 690 mmol) and Cs₂CO₃(132 g, 405 mmol). 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 CH₂Cl₂and 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-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-2-amine as a white solid.

Step 2:

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

Step 3:

N-CBZ Deprotection was accomplished via method B to provide (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate an off-white solid.

Step 4:

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

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

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TABLE 3a

Ex. No.
R′
R″
R′″
CAS Name
LCMS (MH+)

10a
H
H
H
8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-
532

pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-

diazaspiro[4.5]decane-3-carboxylic acid

10b
H
Cl
H
8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-
566

pyrazol-1-yl)phenyl)-2,2,2-

trifluoroethoxy)pyrimidin-4-yl)-2,8-

diazaspiro[4.5]decane-3-carboxylic acid

10c
H
Cl
H
(R)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-
566

pyrazol-1-yl)phenyl)-2,2,2-

trifluoroethoxy)pyrimidin-4-yl)-2,8-

diazaspiro[4.5]decane-3-carboxylic acid R-Spiro

10d
H
Cl
H
(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-
566

pyrazol-1-yl)phenyl)-2,2,2-

trifluoroethoxy)pyrimidin-4-yl)-2,8-

diazaspiro[4.5]decane-3-carboxylic acid

10e
H
H
H
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-
532

1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-

diazaspiro[4.5]decane-3-carboxylic acid

10f
H
H
Cl
(S)-8-(2-amino-6-((R)-1-(3-chloro-2-(3-methyl-1H-
566.9

pyrazol-1-yl)phenyl)-2,2,2-

trifluoroethoxy)pyrimidin-4-yl)-2,8-

diazaspiro[4.5]decane-3-carboxylic acid

10g
H
CF₃
H
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-
600.6

1H-pyrazol-1-yl)-4-

(trifluoromethyl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-

diazaspiro[4.5]decane-3-carboxylic acid

10h
H
CH₃
H
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-methyl-2-
546.6

(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-

4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

10i
H
F
H
8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-fluoro-2-(3-
550.5

methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-

yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

10j
H

embedded image

H
8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-methoxy-2-(3- methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
564.6

10k
Cl
H
H
8-(2-amino-6-((R)-1-(5-chloro-2-(3-methyl-1H-
566.9

pyrazol-1-yl)phenyl)-2,2,2-

trifluoroethoxy)pyrimidin-4-yl)-2,8-

diazaspiro[4.5]decane-3-carboxylic acid

10l
H

embedded image

H
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-methoxy- 2-(3-methyl-1H-pyrazol-1- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
564.6

10m
H
Br
H
(S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-
611

pyrazol-1-yl)phenyl)-2,2,2-

trifluoroethoxy)pyrimidin-4-yl)-2,8-

diazaspiro[4.5]decane-3-carboxylic acid

10n
Br
H
H
(S)-8-(2-amino-6-((R)-1-(5-bromo-2-(3-methyl-1H-
611.5

pyrazol-1-yl)phenyl)-2,2,2-

trifluoroethoxy)pyrimidin-4-yl)-2,8-

diazaspiro[4.5]decane-3-carboxylic acid

TABLE 3b

NMR Data for Compounds of Table 3a

Ex.

No.
NMR

10a

¹H NMR (400 MHz, MeOH-d4): δ 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 (br. 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 = 12.93, 7.57 Hz, 2 H) 7.75 (d, J = 7.52 Hz, 1 H) 7.87 (s, 1 H)

10b

¹H NMR (400 MHz, MeOH-d4) δ 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)

3.58-3.77 (m, 2H) 3.85-4.05 (m, 1H) 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)

10c

¹H NMR (400 MHz, MeOH-d4): δ 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 H) 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): δ 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 = 11.76 Hz, 1 H) 3.25 (d, J = 11.71 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, J = 8.35 Hz,

1 H) 7.93 (d, J = 2.34 Hz, 1 H)

10e

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.71 (dt, J = 18.13, 5.48 Hz, 4 H) 2.08 (dd,

J = 13.62, 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, 1.07 Hz, 1 H) 7.52-7.59 (m, 1 H)

7.61-7.67 (m, 1 H) 7.70 (d, J = 7.76 Hz, 1 H) 7.84 (d, J = 2.39 Hz, 1 H)

10f

¹H NMR (400 MHz, MeOH-d4): δ 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 (m, 5 H)

4.06 (dd, J = 9.10, 7.15 Hz, 1 H) 5.60 (s, 1 H) 6.18 (q, J = 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)

10g

¹H NMR (400 MHz, MeOH-d4): δ 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, 1 H)

10h

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.58 (t, J = 5.25 Hz, 4 H) 2.05 (dd, J = 13.45, 7.15 Hz,

1 H) 2.30 (dd, J = 1.00 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, J = 9.10, 7.25 Hz, 1 H) 5.73 (s, 1 H) 6.37 (d,

J = 2.25 Hz, 1 H) 6.71 (d, J = 6.69 Hz, 1 H) 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)

10i

¹H NMR (400 MHz, MeOH-d4): δ 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 = 17.28 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, J = 2.29 Hz,

1H)

10j

¹H NMR (400 MHz, MeOH-d4): δ 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, J = 11.71 Hz, 1 H) 3.48 (dd,

J = 1.17, 0.20 Hz, 2 H) 3.66 (d, J = 5.52 Hz, 2 H) 3.85 (s, 3 H) 4.08 (dd, J = 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, 1 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)

10k

¹H NMR (400 MHz, CHLOROFORM-d): δ 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., 1 H), 6.36 (s, 1 H) 6.59 (br. s., 1 H) 7.48 (d, J = 7.96 Hz, 1 H),

7.61 (br. s. 1 H) 8.16 (d, J = 8.05 Hz, 1 H) 8.34 (br. s., 1 H)

10l

¹H NMR (400 MHz, DICHLOROMETHANE-d2): δ ppm 1.40-1.61 (m, 4 H) 1.95 (dd,

J = 12.89, 5.86 Hz, 1 H) 2.14-2.28 (m, 1 H) 2.36 (s, 3 H) 3.07 (d, J = 1.00 Hz, 1 H) 3.16 (d,

J = 1.00 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, 2.61 Hz, 1 H), 7.61 (d, J = 8.74 Hz, 1 H) 7.65 (d,

J = 2.20 Hz, 1 H)

10m

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.64 (d, J = 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 = 2.15 Hz, 1 H)

10n

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.47-1.71 (m, 4 H) 1.90 (dd, J = 13.15, 9.15 Hz,

1 H) 2.24-2.39 (m, 4 H) 3.13 (t, J = 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 = 5.27 Hz, 1 H) 7.51 (d, J = 8.59 Hz, 1 H)

7.78 (s, 1 H) 7.85 (dd, J = 8.54, 2.29 Hz, 1 H) 8.11 (d, J = 2.34 Hz, 1 H) 8.95 (d, J = 6.69 Hz,

1 H) 10.20 (br. s., 1 H)

Example 10o
(S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylic acid

embedded image

The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol (Intermediate 38).

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J=7.7 Hz, 2H), 1.61 (q, J=6.5, 5.3 Hz, 4H), 2.06 (dd, J=13.5, 7.4 Hz, 1H), 2.36 (dd, J=13.5, 9.1 Hz, 1H), 3.15 (d, J=11.9 Hz, 1H), 3.26 (d, J=11.7 Hz, 1H), 3.47 (ddt, J=21.7, 13.4, 5.8 Hz, 2H), 3.63 (m, 2H), 4.18 (t, J=8.2 Hz, 1H), 6.63 (q, J=6.8 Hz, 1H), 7.50 (m, 7H). LCMS (MH+): 607.

Example 10p
(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

embedded image

The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(4-chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (Intermediate 39).

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.53 (d, J=5.08 Hz, 4H) 1.77-1.87 (m, 1H) 2.03-2.20 (m, 1H) 2.75 (s, 1H) 2.99 (s, 1H) 3.37-3.53 (m, 2H) 3.54-3.66 (m, 2H) 3.66-3.77 (m, 1H) 5.56 (s, 1H) 6.53-6.70 (m, 1H) 6.96 (d, J=2.34 Hz, 1H) 7.62 (dd, J=4.30, 2.34 Hz, 2H), 7.76 (s, 1H) 8.25 (d, J=1.37 Hz, 1H). LCMS (MH+): 620.

Example 10pa
(S)-8-(2-amino-6-((R)-1-(2-(3-(tert-butyl)-1H-pyrazol-1-yl)-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

embedded image

The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(2-(3-(tert-butyl)-1H-pyrazol-1-yl)-4-chlorophenyl)-2,2,2-trifluoroethanol (Intermediate 40).

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.40 (s, 9H) 1.51-1.68 (m, 4H) 1.99-2.12 (m, 1H) 2.25-2.41 (m, 1H) 3.05-3.16 (m, 1H) 3.20-3.28 (m, 1H) 3.38-3.55 (m, 2H) 3.56-3.73 (m, 2H) 4.00-4.16 (m, 1H) 5.57 (s, 1H) 6.52 (d, J=2.34 Hz, 1H) 7.15-7.28 (m, 1H) 7.44-7.53 (m, 1H) 7.56 (d, J=1.95 Hz, 1H) 7.68-7.79 (m, 1H) 7.95 (d, J=2.34 Hz, 1H). LCMS (MH+): 609.

Example 10q
(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-isopropyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

embedded image

The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(4-chloro-2-(3-isopropyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (Intermediate 41).

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.36 (dd, J=6.93, 1.07 Hz, 6H) 1.57 (br. s., 4H) 1.86-2.03 (m, 1H) 2.15-2.30 (m, 1H) 2.86-3.00 (m, 1H) 3.02-3.19 (m, 2H) 3.39-3.55 (m, 2H) 3.57-3.73 (m, 2H) 3.82-3.98 (m, 1H) 5.63 (s, 1H) 6.40-6.56 (m, 1H) 6.93-7.10 (m, 1H) 7.54 (s, 2H) 7.67-7.78 (m, 1H) 7.91-8.02 (m, 1H). LCMS (MH+): 595.

Example 10r
(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-cyclopropyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

embedded image

The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(4-chloro-2-(3-cyclopropyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (Intermediate 42).

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.77-0.90 (m, 2H) 0.95-1.08 (m, 2H) 1.49-1.65 (m, 4H) 1.80-1.95 (m, 1H) 1.99-2.10 (m, 1H) 2.10-2.24 (m, 1H) 2.74-2.85 (m, 1H) 3.00-3.11 (m, 1H) 3.38-3.69 (m, 4H) 3.72-3.84 (m, 1H) 5.56-5.70 (m, 1H) 6.29-6.38 (m, 1H) 6.89-7.05 (m, 1H) 7.52 (s, 2H) 7.67-7.77 (m, 1H) 7.86-7.98 (m, 1H). LCMS (MH+): 593.

Example 11
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

embedded image

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

Example 12a
(S)-8-(2-amino-6-((R)-1-(4-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (300 mg, 0.388 mmol, see Example 1u) in EtOH:H₂O (15 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (90 mg, 0.58 mmol), KHCO₃(389 mg, 3.88 mmol), and PdCl₂(PPh₃)₂(41 mg, 0.058 mmol). The reaction mixture was heated 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, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification with a 40 g Isco RediSep silica cartridge (EtOAc:heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

Step 2:

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

Step 3:

Hydrolysis of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate using the 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)-8-(2-amino-6-((R)-1-(4-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 12a).

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TABLE 4a

Ex. No.
R
CAS Name
LCMS (MH+)

12a

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(S)-8-(2-amino-6-((R)-1-(4-ethyl-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
560

12b

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H- pyrazol-1-yl)-4-propylphenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
575

12c

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(S)-8-(2-amino-6-((R)-1-(4-butyl-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
588

TABLE 4b

NMR Data for Compounds of Table 4a

Ex.

No.
NMR

12a

¹H NMR (400 MHz, MeOH-d4): δ 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, 1 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, 1.59 Hz, 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, MeOH-d4): δ 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,

1 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 NMR (400 MHz, MeOH-d4): δ 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)-8-(2-amino-6-((1R)-1-(4-(1,2-dihydroxyethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

N-CBZ deprotection was accomplished via method A to provide (3S)-ethyl 8-(2-amino-6-((1R)-1-(4-(1,2-dihydroxyethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.

Step 3:

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

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.49-1.66 (m, 4H) 2.05 (dd, J=13.50, 7.20 Hz, 1H) 2.31 (dd, J=13.45, 9.20 Hz, 1H) 2.38 (s, 3H) 3.04-3.28 (m, 2H) 3.38-3.76 (m, 6H) 4.08 (dd, J=8.98, 7.27 Hz, 1H) 4.67-4.79 (m, 1H) 5.72 (d, J=2.15 Hz, 1H) 6.39 (d, J=2.29 Hz, 1H) 6.77 (q, J=6.65 Hz, 1H) 7.45 (s, 1H) 7.52 (d, J=8.20 Hz, 1H) 7.71 (d, J=8.15 Hz, 1H) 7.88 (dd, J=4.20, 2.34 Hz, 1H). LCMS (MH+): 592.

Example 14
(S)-8-(2-amino-6-((R)-1-(4-cyano-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

To a solution of (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (730 mg, 1.0 mmol), 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 115° C. for 2 h, then cooled to RT, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/hepate) provided (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(1-(4-cyano-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a viscous oil.

Step 2:

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

Step 3:

Hydrolysis of (3S)-ethyl 8-(2-amino-6-(1-(4-cyano-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provides the title compound as an off-white solid.

¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.47-1.71 (m, 4H) 1.95-2.10 (m, 1H) 2.20-2.33 (m, 1H) 2.36 (s, 3H) 2.96-3.24 (m, 2H) 3.35-3.54 (m, 2H) 3.55-3.79 (m, 2H) 3.92-4.13 (m, 1H) 5.65 (s, 1H) 6.42 (d, J=2.15 Hz, 1H) 6.95 (q, J=6.72 Hz, 1H) 7.70-7.91 (m, 3H) 7.97 (d, J=2.25 Hz, 1H). LCMS (MH+): 556.

Example 15
(S)-8-(2-amino-6-((R)-1-(4-carbamoyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

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

Step 3:

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

¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.56 (t, J=4.98 Hz, 5H) 2.03 (dd, J=13.47, 7.03 Hz, 1H) 2.23-2.33 (m, 2H) 2.35-2.39 (m, 3H) 3.04-3.12 (m, 1H) 3.22 (d, J=11.71 Hz, 1H) 3.37-3.72 (m, 5H) 4.05 (dd, J=9.20, 7.05 Hz, 1H) 5.70 (s, 1H) 6.40 (d, J=2.39 Hz, 1H) 6.82-6.92 (m, 1H) 7.80 (d, J=8.10 Hz, 1H) 7.87-7.97 (m, 4H). LCMS (MH+): 575.

Example 16
(S)-8-(2-amino-6-((R)-1-(4-carboxy-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

N-CBZ Deprotection was accomplished via Method A to provide the title compound as a white solid.

¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.57 (t, J=5.42 Hz, 4H) 2.03 (dd, J=13.42, 7.42 Hz, 1H) 2.25-2.35 (m, 2H) 2.37 (s, 2H) 3.04-3.13 (m, 1H) 3.16-3.25 (m, 1H) 3.38-3.75 (m, 5H) 4.06 (dd, J=9.03, 7.32 Hz, 1H) 5.72 (s, 1H) 6.39 (d, J=2.29 Hz, 1H) 6.78-6.89 (m, 1H) 7.76 (d, J=8.15 Hz, 1H) 7.90 (d, J=2.34 Hz, 1H) 7.95 (d, J=1.42 Hz, 1H) 8.04 (dd, J=8.13, 1.59 Hz, 1H). LCMS (MH+): 576.

Example 17
(S)-8-(2-amino-6-((R)-1-(4-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (1.50 g, 1.94 mmol, See Ex. 1u) in THF (20 mL), MeOH (10 mL) and water (10 mL) was added LiOH—H₂O (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 brine, dried over Na₂SO₄, filtered, then concentrated in vacuo to provide (2S)-8-[2-amino-6-[(1R)-1-[4-bromo-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-4-yl]-3-benzyloxycarbonyl-3,8-diazaspiro[4.5]decane-2-carboxylic acid as a white solid that is used directly without further purification.

Step 2:

To a solution of (2S)-8-[2-amino-6-[(1R)-1-[4-bromo-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-4-yl]-3-benzyloxycarbonyl-3,8-diazaspiro[4.5]decane-2-carboxylic acid (74 mg, 0.10 mmol, Step 2) in EtOH (4 mL) was added KHCO₃(84 mg, 1.0 mmol). The reaction mixture was degassed, fitted with a 1 atm CO balloon, then treated with PdCl₂(PPh₃)₂(14 mg, 0.02 mmol). The reaction 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 extracted. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (CH₂Cl₂/AcOH/EtOH) provided (2S)-8-[2-amino-6-[(1R)-1-[4-ethoxycarbonyl-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-4-yl]-3-benzyloxycarbonyl-3,8-diazaspiro[4.5]decane-2-carboxylic acid as a white solid.

Step 3:

N-CBZ Deprotection was accomplished via Method A to provide the title compound as a white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.37 (t, J=7.13 Hz, 3H) 1.58 (d, J=4.30 Hz, 4H) 1.97 (s, 2H) 2.04 (dd, J=13.47, 7.27 Hz, 1H) 2.30 (dd, J=13.59, 9.25 Hz, 1H) 2.38 (s, 3H) 3.05-3.27 (m, 2H) 3.39-3.76 (m, 4H) 3.99-4.10 (m, 1H) 4.37 (q, J=7.13 Hz, 2H) 5.68 (s, 1H) 6.41 (d, J=2.34 Hz, 1H) 6.84 (q, J=6.67 Hz, 1H) 7.83 (d, J=8.10 Hz, 1H) 7.94 (d, J=2.34 Hz, 1H) 7.99 (d, J=1.61 Hz, 1H) 8.09 (dd, J=8.27, 1.68 Hz, 1H). LCMS (MH+): 604.

Example 18a
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(((1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl)oxy)carbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

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

Step 3:

To a solution of 4-[(1R)-1-[2-amino-6-[(2S)-2,3-bis(benzyloxycarbonyl)-3,8-diazaspiro[4.5]decan-8-yl]pyrimidin-4-yl]oxy-2,2,2-trifluoro-ethyl]-3-(3-methylpyrazol-1-yl)benzoic acid (80 mg, 0.1 mmol) in CH₂Cl₂(4 mL) was added DMAP (73 mg, 0.6 mmol), (CF₃)₂MeCOH (108 mg, 0.6 mmol), followed by EDCI (114 mg, 0.6 mmol). The reaction mixture was stirred at RT for 12 h, diluted with CH₂Cl₂and washed with water. The aqueous solution was extracted with CH₂Cl₂. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided dibenzyl (2S)-8-[2-amino-6-[(1R)-2,2,2-trifluoro-1-[2-(3-methylpyrazol-1-yl)-4-[2,2,2-trifluoro-1-methyl-1-(trifluoromethyl)ethoxy]carbonyl-phenyl]ethoxy]pyrimidin-4-yl]-3,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

Step 4:

N-CBZ Deprotection was accomplished via Method A to provide the title compound as a white solid.

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

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TABLE 5a

Ex. No.
R
CAS Name
LCMS (MH+)

18a

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4- (((1,1,1,3,3,3-hexafluoro-2-methylpropan-2- yl)oxy)carbonyl)-2-(3-methyl-1H-pyrazol-1- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
740

18b

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl- 1H-pyrazol-1-yl)-4- (propoxycarbonyl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
618

18c

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(S)-8-(2-amino-6-((R)-1-(4-(butoxycarbonyl)-2-(3- methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
632

18d

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(S)-8-(2-amino-6-((R)-1-(4-(tert-butoxycarbonyl)-2- (3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
632

18e

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4- (isobutoxycarbonyl)-2-(3-methyl-1H-pyrazol-1- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
632

18f

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(S)-8-(2-amino-6-((R)-1-(4-((cyclopentyloxy)carbonyl)- 2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
644

TABLE 5b

NMR Data for Compounds of Table 5a

Ex.

No.
NMR

18a

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.58 (br. s., 4 H) 1.97 (s, 1 H) 2.04 (dd,

J = 13.50, 7.20 Hz, 1 H) 2.12 (s, 3 H) 2.31 (dd, J = 13.45, 9.30 Hz, 1 H) 2.38 (s, 3 H)

3.04-3.27 (m, 2 H) 3.38-3.55 (m, 2 H) 3.64 (dd, J = 13.23, 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, 1 H) 6.85 (q, J = 6.69 Hz, 1 H) 7.90 (d, J = 8.20 Hz,

1 H) 7.96 (dd, J = 8.20, 2.00 Hz, 2 H) 8.06 (dd, J = 8.27, 1.73 Hz, 1 H)

18b

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.01 (t, J = 7.44 Hz, 3 H) 1.58 (d, J = 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 H) 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, 1H) 7.98 (d, J = 1.61 Hz, 1 H) 8.09 (dd,

J = 8.22, 1.64 Hz, 1 H)

18c

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.97 (t, J = 7.42 Hz, 3 H) 1.46 (dq, J = 15.01, 7.48 Hz,

2 H) 1.58 (d, J = 4.83 Hz, 4 H) 1.68-1.82 (m, 2 H) 1.97 (s, 1 H) 2.04 (dd, J = 13.52,

7.03 Hz, 1 H) 2.30 (dd, J = 13.42, 9.18 Hz, 1 H) 2.38 (s, 3 H) 3.07-3.25 (m, 2 H)

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, J = 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 = 1.61 Hz, 1 H) 8.08 (dd, J = 8.25, 1.71 Hz, 1 H)

18d

¹H NMR (400 MHz, MeOH-d4): δ 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 (m, 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, J = 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 H)

18e

¹H NMR (400 MHz, MeOH-d4): δ 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 H)

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 = 1.61 Hz, 1 H) 8.09 (dd,

J = 8.27, 1.68 Hz, 1 H)

18f

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.54-1.94 (m, 11 H) 1.97 (s, 3 H) 2.04 (dd,

J = 13.35, 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 (m, 4 H) 3.95-4.22 (m, 1H) 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 = 1.85 Hz, 2 H)

8.06 (dd, J = 8.15, 1.71 Hz, 1 H)

Example 19a
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

embedded image

Step 1:

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

Step 2:

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

Step 3:

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

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

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TABLE 6a

Ex. No.
R
CAS Name
LCMS (MH+)

19a

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H- pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
558.6

19b

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H- pyrazol-1-yl)-5-((E)-prop-1-en-1- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
572.6

19c

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(S)-8-(2-amino-6-((R)-1-(5-((E)-but-1-en-1-yl)-2-(3- methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
585.5

19d

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(S)-8-(2-amino-6-((R)-1-(5-((E)-2-carboxyvinyl)-2-(3- methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
602.6

TABLE 6b

NMR Data for Compounds of Table 6a

Ex.

No.
NMR

19a

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.59 (m, 4 H) 2.06 (dd, J = 13.42, 7.17 Hz, 1 H)

2.31 (dd, J = 13.42, 9.18 Hz, 1 H) 2.38 (s, 3 H) 3.18 (m, 2 H) 3.59 (m, 4 H) 4.07 (dd,

J = 9.20, 7.20 Hz, 1 H) 5.36 (d, J = 10.98 Hz, 1 H) 5.75 (s, 1 H) 5.85 (d, J = 17.62 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 = 8.25, 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): δ ppm 1.59 (m, 3 H) 1.90 (dd, J = 6.32, 1.20 Hz, 3 H)

2.06 (dd, J = 13.47, 7.13 Hz, 1 H) 2.31 (dd, J = 13.45, 9.25 Hz, 1 H) 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, 1 H) 7.32 (d, J = 8.25 Hz, 1 H) 7.52 (dd, J = 8.30, 2.00 Hz, 1 H) 7.65 (s, 1 H)

7.84 (d, J = 2.34 Hz, 1 H)

19c

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.11 (t, J = 7.47 Hz, 3 H) 1.59 (d, J = 4.59 Hz, 4 H)

2.06 (dd, J = 13.37, 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 = 8.25 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

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H) 2.37 (s, 3 H) 3.07-3.25 (m, 2 H)

3.40-3.55 (m, 2 H) 3.65 (dd, J = 9.27, 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 = 16.20 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, J = 8.32, 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)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 19a), by substituting the alkylidene borolane with a boronic acid or ester.

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TABLE 7a

Ex. No.
Cy
CAS Name
LCMS (MH+)

19e

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(S)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-4-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid
536.7

19f

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(S)-8-(2-amino-6-((R)-1-(3′-carboxy-4-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid
652

19g

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(S)-8-(2-amino-6-((R)-1-(4′-carboxy-4-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid
652

19h

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(S)-8-(2-amino-6-((R)-1-(3′-((E)-2-carboxyvinyl)-4-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid
678

19i

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(S)-8-(2-amino-6-((R)-1-(4′-((E)-2-carboxyvinyl)-4-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid
678

19j

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(S)-8-(2-amino-6-((R)-1-(3′-(2-carboxyethyl)-4-(3-methyl- 1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid
680

19k

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(S)-8-(2-amino-6-((R)-1-(4′-(2-carboxyethyl)-4-(3-methyl- 1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid
680

19l

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- (hydroxymethyl)-3′-methyl-4-(3-methyl-1H-pyrazol-1-yl)- [1,1′-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
652

19m

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- (hydroxymethyl)-4′-methyl-4-(3-methyl-1H-pyrazol-1-yl)- [1,1′-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
652

19n

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
608

19o

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(S)-8-(2-amino-6-((R)-1-(3′,4′-difluoro-4-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid
644

19p

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(S)-8-(2-amino-6-((R)-1-(3′,4′-dichloro-4-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid
677

19q

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(S)-8-(2-amino-6-((R)-1-(4′-chloro-4-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid
643

19r

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- (hydroxymethyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
639

TABLE 7b

NMR Data for Compounds of Table 7a

Ex.

No.
NMR

19e

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (m, 4 H) 2.04 (dd, J = 13.62, 6.98 Hz, 1 H)

2.32 (d, J = 11.96 Hz, 6 H) 2.40 (s, 3 H) 3.16 (m, 2 H) 3.55 (m, 4 H) 4.07 (dd, J = 9.18, 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, MeOH-d4): δ ppm 1.53-1.67 (m, 4 H) 2.05 (dd, J = 13.42, 7.17 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 H)

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 = 1.42 Hz, 1 H) 8.04 (dt, J = 7.79, 1.23 Hz, 1 H) 8.24 (t, J = 1.61 Hz, 1 H)

19g

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.47-1.67 (m, 4 H) 2.05 (dd, J = 13.45, 7.20 Hz, 1

H) 2.31 (dd, J = 13.37, 9.27 Hz, 1 H) 2.40 (s, 3 H) 2.99-3.28 (m, 2H) 3.39-3.78 (m, 4H)

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, 1 H) 7.99 (d, J = 1.32 Hz, 1 H) 8.08-8.18 (m, 2 H)

19h

¹H NMR (400 MHz, MeOH-d4): δ 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 = 16.01 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,

J = 16.01 Hz, 1 H) 7.77 (bs, 1 H) 7.83 (dd, J = 8.25, 2.10 Hz, 1 H) 7.93-7.96 (m, 2 H)

19i

¹H NMR (400 MHz, MeOH-d4): δ 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, 1 H) 6.54 (d, J = 16.01 Hz,

1 H) 6.91 (q, J = 6.72 Hz, 1 H) 7.51 (d, J = 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

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.51-1.66 (m, 4 14) 2.04 (dd, J = 13.50, 7.15 Hz, 1

H) 2.31 (dd, J = 13.37, 9.18 Hz, 1 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 H) 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, MeOH-d4): δ 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 H) 3.03-3.26 (m, 2 H) 3.39-3.76 (m, 4 H) 4.07 (dd, J = 9.03, 7.32 Hz, 1 H)

5.78 (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, 1 H)

7.89-7.92 (m, 2 H)

19l

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.45-1.65 (m, 4 H) 2.00-2.09 (m, 1 H)

2.30 (dd, J = 13.40, 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

H)

19m

¹H NMR (400 MHz, MeOH-d4): δ 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, 1 H) 7.64 (d, J = 1.81 Hz, 1 H) 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): δ ppm 1.29 (d, J = 7.2 Hz, 1H), 1.56 (d, J = 6.3 Hz, 4H),

2.03 (d, J = 12.8 Hz, 1H), 2.30 (d, J = 12.4 Hz, 1H), 2.39 (s, 3H), 3.09 (d, J = 11.5 Hz,

1H), 3.22 (d, J = 11.7 Hz, 1H), 3.47 (t, J = 18.6 Hz, 2H), 3.63 (s, 2H), 4.07 (s, 1H),

4.64 (s, 1H), 5.78 (s, 1H), 6.41 (d, J = 2.1 Hz, 1H), 6.87 (q, J = 6.5 Hz, 1H), 7.44 (m, 4H),

7.59 (d, J = 7.4 Hz, 2H), 7.64 (s, 1H), 7.77 (m, 1H), 7.91 (m, 2H)

19o

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (d, J = 18.0 Hz, 1H), 1.57 (d, J = 6.1 Hz,

4H), 2.04 (dd, J = 13.9, 6.4 Hz, 1H), 2.30 (dd, J = 13.5, 8.4 Hz, 1H), 2.39 (s, 3H), 3.11 (d,

J = 11.6 Hz, 1H), 3.23 (d, J = 11.4 Hz, 1H), 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, 1H), 4.87 (s, 12H), 5.78 (s, 1H), 6.41 (d, J = 2.0 Hz, 1H),

6.91 (q, J = 6.6 Hz, 1H), 7.36 (m, 2H), 7.50 (t, J = 9.3 Hz, 2H), 7.74 (dd, J = 8.3, 2.2 Hz,

1H), 7.90 (dd, J = 7.9, 2.1 Hz, 2H)

19p

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (s, 1H), 1.44 (s, 1H), 1.52 (q, J = 5.9 Hz,

4H), 1.85 (m, 1H), 2.11 (dd, J = 13.2, 8.8 Hz, 1H), 2.39 (s, 3H), 2.77 (d, J = 11.3 Hz, 1H),

3.01 (d, J = 11.3 Hz, 1H), 3.45 (ddt, J = 19.8, 12.8, 5.8 Hz, 2H), 3.61 (m, 2H), 3.74 (t, J = 8.0 Hz,

1H), 5.78 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.93 (q, J = 6.6 Hz, 1H), 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): δ ppm 1.28 (s, 1H), 1.57 (t, J = 5.0 Hz, 4H), 2.03 (dd, J = 13.3,

6.9 Hz, 1H), 2.29 (dd, J = 13.4, 9.0 Hz, 1H), 2.39 (s, 3H), 3.08 (d, J = 11.6 Hz,

1H), 3.22 (d, J = 11.6 Hz, 1H), 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, 1H), 5.77 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.89 (q, J = 6.6 Hz,

1H), 7.47 (m, 3H), 7.58 (m, 2H), 7.77 (dd, J = 8.3, 2.2 Hz, 1H), 7.91 (t, J = 2.4 Hz,

2H)

19r

¹H NMR (400 MHz, MeOH-d4): δ 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,

5H), 4.38 (t, J = 8.4 Hz, 3H), 3.73 (s, 6H), 3.63-3.55 (m, 1H), 3.29-3.18 (m, 5H),

2.40 (s, 9H), 2.07 (dd, J = 13.5, 7.8 Hz, 3H), 1.70-1.61 (m, 10H), 1.28 (s, 1H).

Example 20
(S)-8-(2-amino-6-((R)-1-(2′-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was made using the procedure described for (S)-8-(2-amino-6-((R)-1-(3′-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 5a) starting with (S)-8-(2-amino-6-((R)-1-(5-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J=7.15 Hz, 3H) 1.60 (t, J=5.54 Hz, 4H) 2.06 (dd, J=13.50, 7.25 Hz, 1H) 2.33 (dd, J=13.42, 9.27 Hz, 1H) 2.40 (s, 3H) 3.08-3.28 (m, 2H) 3.39-3.73 (m, 4H) 3.74-3.98 (m, 2H) 4.08 (dd, J=9.08, 7.32 Hz, 1H) 5.74 (s, 1H) 6.42 (d, J=2.34 Hz, 1H) 6.88 (q, J=6.75 Hz, 1H) 7.38 (dd, J=7.71, 0.93 Hz, 1H) 7.45-7.56 (m, 4H) 7.58-7.65 (m, 1H) 7.82 (dd, J=7.69, 1.20 Hz, 1H) 7.95 (d, J=2.34 Hz, 1H). LCMS (MH+): 680.

Example 21
(S)-8-(2-amino-6-((R)-1-(4′-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was made using the procedure described for (S)-8-(2-amino-6-((R)-1-(3′-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 5) starting with (S)-8-(2-amino-6-((R)-1-(5-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.41 (t, J=7.15 Hz, 3H) 1.58 (br. s., 4H) 2.05 (dd, J=13.50, 7.15 Hz, 1H) 2.30 (dd, J=13.42, 9.18 Hz, 1H) 2.40 (s, 3H) 3.03-3.28 (m, 2H) 3.37-3.76 (m, 4H) 4.07 (dd, J=9.13, 7.22 Hz, 1H) 4.39 (q, J=7.13 Hz, 2H) 5.78 (s, 1H) 6.42 (d, J=2.25 Hz, 1H) 6.86-7.01 (m, 1H) 7.53 (d, J=8.30 Hz, 1H) 7.66-7.77 (m, 2H) 7.84 (dd, J=8.30, 2.20 Hz, 1H) 7.94 (d, J=2.29 Hz, 1H) 7.99 (d, J=1.51 Hz, 1H) 8.06-8.17 (m, 2H). LCMS (MH+): 680.

Example 22a
(S)-8-(2-amino-6-((R)-1-(5-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

(S)-Ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (100 mg, 0.171 mmol) in MeOH (2 mL) was hydrogenated 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 residue was lyophilized from 1:1 H₂O:CH₃CN to provide (S)-ethyl 8-(2-amino-6-((R)-1-(5-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid which was used directly in the next step.

Step 2:

Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(5-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general 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)-8-(2-amino-6-((R)-1-(5-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 22a).

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TABLE 8a

Ex. No.
R
CAS Name
LCMS (MH+)

22a

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(S)-8-(2-amino-6-((R)-1-(5-ethyl-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
561

22b

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S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H- pyrazol-1-yl)-5-propylphenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
575

22c

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(S)-8-(2-amino-6-((R)-1-(5-butyl-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
589

TABLE 8b

NMR Data for Compounds of Table 8a

Ex.

No.
NMR

22a

¹H NMR (400 MHz, MeOH-d4): δ 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 (m, 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 (m, 1 H) 7.56 (s, 1 H)

7.82 (d, J = 2.29 Hz, 1 H)

22b

¹H NMR (400 MHz, MeOH-d4): δ 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, J = 9.13, 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, 1 H)

22c

¹H NMR (400 MHz, MeOH-d4): δ 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,

1 H) 5.75 (s, 1 H) 6.36 (d, J = 2.15 Hz, 1 H) 6.69 (q, J = 6.62 Hz, 1 H) 7.30 (m, 1 H)

7.37 (m, 1 H) 7.53 (s, 1 H) 7.82 (d, J = 2.29 Hz, 1 H)

Example 23
(S)-8-(2-Amino-6-((R)-1-(5-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

N-CBZ Deprotection of (S)-8-(2-amino-6-((R)-1-(5-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid was accomplished via Method A to provide the title compound as an off-white solid.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.34 (t, J=7.10 Hz, 3H) 1.51-1.71 (m, 4H) 1.90 (dd, J=13.28, 9.18 Hz, 1H) 2.26-2.40 (m, 4H) 3.13 (br. s., 2H) 3.66 (br. s., 4H) 4.29-4.52 (m, 4H) 6.07 (s, 1H) 6.47 (d, J=2.39 Hz, 1H) 7.48 (d, J=6.05 Hz, 1H) 7.72 (d, J=8.40 Hz, 1H) 8.15 (dd, J=8.40, 1.95 Hz, 1H) 8.19-8.29 (m, 2H) 8.96 (d, J=5.56 Hz, 1H) 10.36 (d, J=4.49 Hz, 1H). LCMS (MH+): 604.

Example 24
(S)-8-(2-Amino-6-((R)-1-(5-carboxy-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Hydrolysis of (S)-8-(2-amino-6-((R)-1-(5-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 23) using the LiOH general method provides the title compound as a white solid.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.45-1.65 (m, 4H) 1.83-1.95 (m, 1H) 2.26-2.38 (m, 4H) 3.12 (br. s., 2H) 3.61 (br. s., 4H) 4.36-4.51 (m, 1H) 5.93 (br. s., 1H) 6.46 (d, J=2.39 Hz, 1H) 7.40 (m, J=5.80 Hz, 1H) 7.67 (d, J=8.35 Hz, 1H) 8.11 (dd, J=8.35, 1.95 Hz, 1H) 8.21 (d, J=2.39 Hz, 1H) 8.25 (s, 1H) 8.93 (m, J=4.40 Hz, 1H) 10.09 (br. s., 1H). LCMS (MH+): 576.

Example 25
(S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-1-(4-(hydroxymethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

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

Step 3:

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

Step 4:

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

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (t, J=5.15 Hz, 4H) 1.91-2.12 (m, 7H) 2.30 (dd, J=13.23, 9.42 Hz, 1H) 2.36 (s, 3H) 3.07-3.26 (m, 2H) 3.39-3.54 (m, 2H) 3.58-3.70 (m, 2H) 3.99-4.13 (m, 1H) 4.65 (s, 2H) 5.71 (s, 1H) 6.37 (d, J=2.34 Hz, 1H) 6.74 (q, J=6.65 Hz, 1H) 7.39 (s, 1H) 7.45 (d, J=8.20 Hz, 1H) 7.68 (d, J=8.10 Hz, 1H) 7.84 (d, J=2.34 Hz, 1H). LCMS (MH+): 562.

Example 26
(S)-8-(2-amino-6-((R)-1-(4-((dimethylamino)methyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 3:

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

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.66-1.81 (m, 4H) 2.10 (dd, J=13.62, 8.54 Hz, 1H) 2.38 (s, 3H) 2.49 (dd, J=13.62, 8.88 Hz, 1H) 2.88 (s, 3H) 2.90 (s, 3H) 3.58-3.90 (m, 4H) 4.37-4.49 (m, 2H) 4.56 (t, J=8.69 Hz, 1H) 6.37 (br. s., 1H) 6.43 (d, J=2.34 Hz, 1H) 7.06-7.12 (m, 1H) 7.71-7.78 (m, 2H) 7.85 (d, J=8.10 Hz, 1H) 7.98 (d, J=2.39 Hz, 1H). LCMS (MH+): 589.

Example 27
(S)-8-(6-((R)-1-(4-Bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

To a solution of 1(R)-1-[4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethanol (15.7 g, 46.3 mmol, Intermediate 1) in dioxane (200 mL) was added 4,6-dichloro-2-methylpyrimidine (30.6 g, 51 mmol) and Cs₂CO₃(61.2 g, 187 mmol). The reaction mixture was heated to 80° C. for 30 h, then cooled to RT, and filtered. The residue was concentrated in vacuo and purified by normal phase column chromatography on silica gel (CH₂Cl₂/heptane) to provide (R)-4-(1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-chloro-2-methylpyrimidine as a white solid.

Step 2:

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

Step 4:

N-CBZ Deprotection was accomplished via Method A to provide (S)-ethyl 8-(6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate an off-white solid.

Step 5:

Hydrolysis of (S)-ethyl 8-(6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.64 (br. s., 4H) 2.10 (d, J=7.03 Hz, 1H) 2.28 (s, 3H) 2.35 (dd, J=13.37, 9.27 Hz, 1H) 2.39 (s, 3H) 3.10-3.20 (m, 1H) 3.28 (d, J=11.91 Hz, 1H) 3.45-3.67 (m, 2H) 3.75 (br. s., 2H) 4.10 (dd, J=8.98, 7.22 Hz, 1H) 6.17 (s, 1H) 6.43 (d, J=2.15 Hz, 1H) 7.01 (d, J=6.44 Hz, 1H) 7.58-7.75 (m, 3H) 8.03 (d, J=2.15 Hz, 1H). LCMS (MH+): 609.

Example 28
(S)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described above for (S)-8-(6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (by replacing 1(R)-1-[4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethanol with 1(R)-1-[4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethanol, Intermediate 3) and obtained as an off-white solid.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.34-1.54 (m, 4H) 1.82 (dd, J=13.01, 6.76 Hz, 1H) 1.99-2.08 (m, 1H) 2.11 (s, 3H) 2.30 (s, 3H) 2.92 (d, J=11.52 Hz, 1H) 3.06 (d, J=11.52 Hz, 1H) 3.42-3.65 (m, 4H) 3.70 (dd, J=8.91, 7.00 Hz, 1H) 6.15 (s, 1H) 6.42 (s, 1H) 7.43 (q, J=6.93 Hz, 1H) 7.54-7.61 (m, 1H) 7.64 (d, J=2.10 Hz, 1H) 7.70 (d, J=8.44 Hz, 1H) 8.19 (d, J=2.39 Hz, 1H) 8.70 (br. s., 1H). LCMS (MH+): 565.

General Biaryl Coupling (Suzuki) Procedures

Biaryl Coupling Method A

Step 1:

To a mixture of (S)-2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (150 mg, 0.2 mmol), an arylboronic acid (0.4 mmol), Pd(N,N-dimethyl μ-alaninate)₂(3.42 mg, 0.01 mmol), and K₃PO₄(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 extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The target biaryl compounds were purified by normal phase silica gel column (CH₂Cl₂:MeOH).

Step 2:

Subsequent N-CBZ deprotection via method A afforded the final target spirocyclic amino acids.

Biaryl Coupling Method B

Step 1:

To a mixture of (S)-2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (150 mg, 0.2 mmol), an arylboronic acid (0.4 mmol), Pd(OAc)₂.(1,1,3,3-tetramethyl-2-N-butylguanidine)₂(5.7 mg, 0.01 mmol), and K₂CO₃(83.5 mg, 0.61 mmol) 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 Na₂SO₄, filtered, and concentrated in vacuo. The target biaryl compounds were purified by normal phase silica gel column (CH₂Cl₂: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 following examples of Table 9 were prepared.

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TABLE 9

Ex. No.
Cy
CAS Name
LCMS (MH+)

29a

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(4-(2- methoxypyridin-4-yl)-2-(3-methyl-1H-pyrazol-1- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
638

29b

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3-(3- methyl-1H-pyrazol-1-yl)-4′-(methylsulfonyl)- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
686

29c

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(S)-8-(6-((R)-1-(3′,4′-difluoro-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
645

29d

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(S)-8-(6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
635

29e

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(S)-8-(6-((R)-1-(3′-(ethoxycarbonyl)-3-(3-methyl- 1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
680

29f

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(4-(6- methoxypyridin-3-yl)-2-(3-methyl-1H-pyrazol-1- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
639

29g

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(4-(2- methoxypyrimidin-5-yl)-2-(3-methyl-1H-pyrazol- 1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
640

29h

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(S)-8-(6-((R)-1-(2′,4′-dimethoxy-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
668

29i

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(S)-8-(6-((R)-1-(4′-(ethoxycarbonyl)-3-(3-methyl- 1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
679

29j

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(S)-8-(6-((R)-1-(4′-(dimethylcarbamoyl)-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
678

29k

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(4-(2- methoxypyridin-3-yl)-2-(3-methyl-1H-pyrazol-1- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
639

29l

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3′- fluoro-4′-methoxy-3-(3-methyl-1H-pyrazol-1-yl)- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
655.6

29m

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(S)-8-(6-((R)-1-(3′-(dimethylcarbamoyl)-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
679

Using the generic scheme above with the biaryl coupling method B, the following examples of Table 10 were prepared.

TABLE 10

Ex. No.
Cy
CAS Name
LCMS (MH+)

29n

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(2′,4′,6′- trimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
650

29o

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(4′- isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
666

29p

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(2′-methoxy- 3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid
638

29q

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3′-methoxy- 4′-(methoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
695

29r

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(S)-8-(6-((R)-1-(4′-(tert-butyl)-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
663

29s

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(S)-8-(6-((R)-1-(4′-ethoxy-3-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2- methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
652

29t

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl- 1H-pyrazol-1-yl)-4′-(trifluoromethoxy)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
692

29u

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3′- (methoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
666

29v

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl- 1H-pyrazol-1-yl)-4-(pyrimidin-5- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
609

29w

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3′-methoxy- 3-(3-methyl-1H-pyrazol-1-yl)-1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid
637

29x

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3′-isopropyl- 3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid
650

29y

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-3- (3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid
626

29z

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl- 1H-pyrazol-1-yl)-4-(pyridin-3- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
609

29aa

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3′-methoxy- 3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid
638

29ab

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(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl- 1H-pyrazol-1-yl)-4-(pyridin-4- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
608

Example 30a
8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-phenoxypyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

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

Step 3:

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

Step 4:

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

Step 5:

To a solution of 2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (300 mg, 0.393 mmol) in 1,4-dioxane (10 mL) was added phenol (74 mg, 0.79 mmol), Cs₂CO₃(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, acidified to pH<1 with 1 N HCl, and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification on a 50 g Isco Gold RediSep reverse phase silica cartridge (H₂O:HOAc: 99:1 MeOH:HOAc 99:1) provided 2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-phenoxypyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid.

Step 6:

N-CBZ Deprotection 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 111a were prepared as described above for 8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-phenoxypyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 30a).

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TABLE 11a

Ex. No.
R
CAS Name
LCMS (MH+)

30a

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8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)-2-phenoxypyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
644

30b

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8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)-2- (cyclohexyloxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
649

TABLE 11b

NMR Data for Compounds of Table 11a

Ex.

No.
NMR

30a

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (br. s., 4 H), 2.00-2.31 (m, 2 H), 2.32 (s, 3

H), 3.06-3.28 (m, 2 H), 3.36-3.71 (m, 4 H), 4.07 (dd, J = 8.83, 7.37 Hz, 1 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, 2 H), 7.47 (d, J = 2.15 Hz, 1 H), 7.54 (dd, J = 8.54, 2.15 Hz, 1

H), 7.71 (d, J = 8.54 Hz, 1 H), 7.86 (d, J = 2.39 Hz, 1 H).

30b

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.16-1.95 (m, 14 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, 1 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)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(cyclohexylamino)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described above by replacing the alcohol in Step 5 of Example 30a with cyclohexyl amine.

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.99-1.95 (m, 14H), 2.02-2.37 (m, 2H), 2.38 (s, 3H), 3.07-3.29 (m, 2H), 3.41-3.77 (m, 5H), 4.09 (dd, J=9.10, 7.15 Hz, 1H), 5.60 (s, 1H), 6.39 (d, J=2.39 Hz, 1H), 6.87-7.21 (m, 1H), 7.49 (dtd, J=4.48, 2.26, 2.26, 2.12 Hz, 2H), 7.70 (d, J=9.03 Hz, 1H), 7.87 (d, J=2.34 Hz, 1H). LCMS (MH+): 650.

Example 32
(S)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(cyclobutanecarboxamido)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

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, MeOH-d4): δ ppm 1.66 (d, J=4.30 Hz, 4H), 1.78-1.99 (m, 2H), 2.03-2.38 (m, 6H), 2.39 (s, 3H), 3.12-3.32 (m, 2H), 3.47-3.90 (m, 5H), 4.10 (dd, J=9.10, 7.20 Hz, 1H), 6.03 (s, 1H), 6.41 (d, J=2.34 Hz, 1H), 6.82-6.98 (m, 1H), 7.45-7.57 (m, 2H), 7.73 (d, J=8.49 Hz, 1H), 7.97 (d, J=2.34 Hz, 1H). LCMS (MH+): 649.

Example 33
(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(2-oxopyrrolidin-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(5-chloro-2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)pyrrolidin-2-one.

¹H NMR (DMSO-d6): δ ppm 1.23 (m, 1H), 1.40 (m, 4H), 1.81 (dd, J=13.2, 6.9 Hz, 1H), 2.07 (m, 4H), 2.45 (d, J=8.1 Hz, 2H), 2.91 (d, J=11.5 Hz, 3H), 3.06 (d, J=11.6 Hz, 1H), 3.47 (d, J=6.9 Hz, 3H), 3.66 (m, 3H), 5.54 (s, 1H), 6.09 (s, 2H), 6.74 (q, J=6.9 Hz, 1H), 7.55 (m, 3H). LCMS (MH+): 570.

Example 34c
(S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

To a solution of (R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol (Intermediate 43) (400 mg, 1.4 mmol) in dioxane (25 mL) was added 4,6-dichloropyrimidin-2-amine (1.1 g, 7 mmol) and Cs₂CO₃(1.3 g, 4 mmol). 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 CH₂Cl₂and 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 (R)-4-(1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine as a white solid.

Step 2:

To a solution of (R)-4-(1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine (100 mg, 0.24 mmol, Step 1) in dioxane (5 mL) was added (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (100 mg, 0.29 mmol), and NaHCO₃(300 mg, 3.5 mmol). After 5 h, an additional amount of NaHCO₃(300 mg, 3.5 mmol) was added and the reaction mixture was heated to 90° C. for 36 h. The reaction was then cooled to RT and filtered. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

Step 3:

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

Step 4:

N-CBZ Deprotection was accomplished via method B to provide (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate an off-white solid.

Step 5:

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

Example 34u
(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-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-dioxaborolan-2-yl)benzenesulfonamide (195 mg, 0.7 mmol), KHCO₃(207 mg, 2.06 mmol), and PdCl₂(dppf)-CH₂Cl₂(56 mg, 0.069 mmol). The reaction was heated to 100° C. for 15 h, cooled to RT, and concentrated in vacuo. The residue was diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.

Step 2:

N-CBZ Deprotection was accomplished via method B to provide (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.

Step 3:

Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general 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)-8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 34u).

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TABLE 12a

Ex. No.
Cy
CAS Name
LCMS (MH+)

34a

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(S)-8-(2-amino-6-((R)-1-(3′,5-dichloro-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
597

34b

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-methyl-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
577

34c

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8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
563

34d

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8-(2-amino-6-((R)-1-(2′-amino-5-chloro-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
577

34e

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8-(2-amino-6-((R)-1-(5-chloro-3′-nitro-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
606

34f

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8-(2-amino-6-((R)-1-(3′-amino-5-chloro-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
577

34g

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8-(2-amino-6-((R)-1-(5-chloro-4′-nitro-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
607

34h

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8-(2-amino-6-((R)-1-(4′-amino-5-chloro-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
577

34i

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(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(6- methylpyridin-2-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
578

34j

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(ethylsulfonyl)- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
655

34k

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′- (propylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
669

34l

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(S)-8-(2-amino-6-((R)-1-(3′-(butylsulfonyl)-5-chloro- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
682

34m

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′- (hydroxymethyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
592

34n

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′- (methylsulfonamido)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
656

34o

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(2- oxopyrrolidin-1-yl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
646

34p

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(3-methyl-2- oxoimidazolidin-1-yl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
660.5

34q

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′- (trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
630

34r

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(S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
563

34s

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(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(5- chlorothiophen-2-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
604

34t

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(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(1-methyl-1H- pyrazol-3-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
566

34u

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
641

34v

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-hydroxy-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
578

34w

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′- (methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
640

34x

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-cyano-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
587

34y

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-methoxy-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
592

34z

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(S)-8-(2-amino-6-((R)-1-(3′-(aminomethyl)-5-chloro- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
591

34aa

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(S)-8-(6-((R)-1-(3′-(acrylamidomethyl)-5-chloro- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
645

34ab

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(S)-8-(2-amino-6-((R)-1-(3′-carboxy-5-chloro-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
606

34ac

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(S)-8-(2-amino-6-((R)-1-(3′-carbamoyl-5-chloro- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
605

34ad

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(S)-8-(2-amino-6-((R)-1-(5-chloro-4′- (methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
640

34ae

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(S)-8-(2-amino-6-((R)-1-(5-chloro-4′-sulfamoyl-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
641

34af

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(S)-8-(2-amino-6-((R)-1-(4′,5-dichloro-3′-fluoro- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
615

34ag

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-isopropoxy- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
621

34ah

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-ethoxy-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
607

34ai

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(S)-8-(2-amino-6-((R)-1-(3′,5-dichloro-4′-ethoxy- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
642

34aj

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(S)-8-(2-amino-6-((R)-1-(3′,5-dichloro-4′-methyl- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
611

34ak

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(S)-8-(2-amino-6-((R)-1-(3′,5-dichloro-4′- isopropoxy-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
655

34al

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-fluoro-4′- isopropoxy-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
639

34am

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(S)-8-(2-amino-6-((R)-1-(4′,5-dichloro-3′- (trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
665

34an

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(S)-8-(2-amino-6-((R)-1-(3′,5-dichloro-5′-fluoro- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
615

34ao

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(S)-8-(2-amino-6-((R)-1-(3′-(tert-butyl)-5-chloro- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
619

34ap

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(S)-8-(2-amino-6-((R)-1-(3′,5-dichloro-5′- (trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2- (trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
665

34aq

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-fluoro-5′- (trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
648

34ar

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-methoxy-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
593

34as

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-fluoro-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
580

34at

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(S)-8-(2-amino-6-((R)-1-(4′,5-dichloro-3′-methyl- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
611

34au

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′,5′-difluoro- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
598

34av

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(S)-8-(2-amino-6-((R)-1-(3′,5-dichloro-4′-fluoro- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
615

34aw

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′,4′-difluoro- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
598

34ax

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(S)-8-(2-amino-6-((R)-1-(3′,5-dichloro-4′- (trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
665

34ay

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′,4′-dimethyl- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
591

34az

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(S)-8-(2-amino-6-((R)-1-(5-chloro-4′-ethoxy-3′- fluoro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
625

34ba

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′,5′-dimethyl- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
591

34bb

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-methyl-4′- (trifluoromethoxy)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
661

34bc

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(S)-8-(2-amino-6-((R)-1-(4′,5-dichloro-3′,5′- dimethyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
625

34bd

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(S)-8-(2-amino-6-((R)-1-(5-chloro-4′-fluoro-3′- methyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
595

34be

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(S)-8-(2-amino-6-((R)-1-(3′,5-dichloro-5′-methyl- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
611

34bf

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′,4′,5′-trifluoro- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
616

34bg

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′- (trifluoromethoxy)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
696

34bh

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′,5′- bis(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
698

34bi

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(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-isopropyl-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
605

34bj

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′,5,5′- trichloro-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
631

34bk

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(S)-8-(2-amino-6-((R)-1-(5-chloro-4′-fluoro-3′- (trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
648

34bl

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-fluoro-5′- isopropoxy-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
639

34bm

embedded image

(S)-8-(2-amino-6-((R)-1-(3′-(tert-butyl)-5-chloro-5′- methyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
633

34bn

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-fluoro-4′- methyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
595

34bo

embedded image

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(pyridin-3- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
563

34bp

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-ethoxy-4′- fluoro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
625

34bq

embedded image

(S)-8-(2-amino-6-((R)-1-(3′-(tert-butyl)-5-chloro- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
619

34br

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(prop-1-en-2- yl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
603

34bs

embedded image

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(2- (dimethylamino)pyridin-4-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
603

34bt

embedded image

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(naphthalen-2- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
613

34bu

embedded image

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(2- isopropylpyridin-4-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
606

34bv

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-4′-fluoro-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
525

34bw

embedded image

(S)-8-(2-amino-6-((R)-1-(4′,5-dichloro-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
597

34bx

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-4′-methyl-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
577

34by

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-2′,3′,4′,5′- tetrahydro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
567

34bz

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-isobutoxy-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
635

34ca

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(pyrrolidine-1- carbonyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
660

34cb

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′- (cyclopentyloxy)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
647

34cc

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(((1R,4R)-4- hydroxycyclohexyl)carbamoyl)-[1,1′-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
740

34cd

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-ethyl-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
591

34ce

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-isopropyl-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
633

34cf

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-((2-(pyrrolidin- 1-yl)ethyl)carbamoyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
703

34cg

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(morpholine-4- carbonyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
676

34ch

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(4- methylpiperazine-1-carbonyl)-[1,1′-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
689

34ci

embedded image

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(2- methylthiazol-5-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
584

34cj

embedded image

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(1-methyl-2- oxo-1,2-dihydropyridin-3-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
594

34ck

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(N- methylsulfamoyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
656

34cl

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(N,N- dimethylsulfamoyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
670

34cm

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′- (methylcarbamoyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
620

34cn

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′- (dimethylcarbamoyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
634

34co

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′- (diethylcarbamoyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
662

34cp

embedded image

(S)-8-(6-((R)-1-(2-(1H-benzo[d]imidazol-4-yl)-4- chlorophenyl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
603

34cq

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(piperazine-1- carbonyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
675

34cr

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(4- cyclopropylpiperazine-1-carbonyl)-[1,1′-biphenyl]-2- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
716

34cs

embedded image

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(pyridin-2- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
564

34ct

embedded image

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(pyrimidin-2- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
564

34cu

embedded image

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(pyrazin-2- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
565

34cv

embedded image

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(2- methoxyethoxy)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
637

TABLE 12b

NMR Data for Compounds of Table 12a

Ex.

No.
NMR

34a

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (d, J = 15.3 Hz, 1H), 1.67 (d, J = 7.3 Hz,

4H), 2.10 (dd, J = 13.6, 8.1 Hz, 1H), 2.46 (m, 1H), 3.25 (t, J = 12.0 Hz, 2H), 3.52 (s, 2H),

3.63 (m, 3H), 4.45 (t, J = 8.6 Hz, 1H), 4.83 (d, J = 3.0 Hz, 1H), 6.59 (q, J = 6.5 Hz, 1H),

7.32 (q, J = 1.8 Hz, 1H), 7.39 (m, 1H), 7.52 (m, 4H), 7.70 (d, J = 8.4 Hz, 1H)

34b

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.60 (q, J = 5.6 Hz, 4H), 2.06 (dd, J = 13.4, 7.2 Hz,

1H), 2.33 (dd, J = 13.5, 9.2 Hz, 1H), 2.43 (s, 3H), 3.13 (d, J = 11.8 Hz, 1H), 3.26 (d,

J = 11.7 Hz, 1H), 3.47 (m, 2H), 3.62 (tt, J = 9.2, 4.9 Hz, 2H), 4.10 (dd, J = 9.1, 7.1 Hz,

1H), 4.61 (s, 1H), 5.48 (s, 1H), 6.66 (q, J = 6.9 Hz, 1H), 7.27 (m, 4H), 7.42 (m, 2H),

7.67 (d, J = 8.5 Hz, 1H)

34c

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H) 3.28 (d, J = 11.71 Hz,

1 H) 3.38-3.56 (m, 2 H) 3.63 (d, J = 5.66 Hz, 2 H) 4.11 (dd, J = 8.98, 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, 1 H)

34d

¹H-NMR (400 MHz, MeOH-d4): δ ppm 1.9 (m, 4H), 1.98 (m, 1H), 2.26 (m, 1H),

3.01 (m, 1H), 3.17 (m, 1H), 3.48 (m, 2H), 3.60 (m, 2H), 3.95 (m, 1H), 5.53-5.52 (d, 1H),

6.26-6.22 (q, 1H), 6.97-6.69 (m, 3H), 7.31-7.17 (m, 2H), 7.47-7.44 (m, 1H), 7.74-7.63 (m, 1H)

34e

¹H NMR (400 MHz, DMSO-d6): δ 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 = 11.8 Hz), 3.25 (d, 1 H, J = 11.8 Hz), 3.50-3.47 (m, 2 H),

3.67-3.66 (m, 2 H), 4.11-4.07 (t, 1H), 5.58 (s, 1 H), 6.58-6.53 (q, 1 H, J = 6.8 Hz), 7.36 (s, 1 H),

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 H),

8.38-8.36 (d, 1 H, J = 8.0 Hz), 8.58 (s, 1 H)

34f

¹H NMR (400 MHz, MeOH-d4): δ 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, 2H),

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, 1 H, J = 8.4 Hz), 7.66-7.64 (d, 1 H, J = 8.4 Hz)

34g

¹H-NMR 400 MHz, MeOH-d4): δ ppm 1.28 (m, 2H), 1.63 (m 4H), 2.10-2.04 (m, 1H),

2.42-2.36 (m, 1H), 3.19-3.16 (d, J = 6.0, 2H), 3.26 (s, 1H), 3.65 (m, 2H), 4.28-4.24 (t,

J = 16.0, 1H), 5.58 (s 1H), 6.62-6.57 (m, 1H), 7.37-7.36 (d, J = 4.0, 1H), 7.54-7.51 (dd,

J = 12.0, 4.0, 1H), 7.72-7.70 (d, J = 8.0, 1H), 7.78-7.76 (d, J = 8.0, 2H), 8.43-8.41 (d,

J = 8.0, 2H)

34h

¹H-NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, 2H), 1.58 (m, 4H), 2.07-2.02 (m, 1H),

2.33-2.28 (m, 1H), 3.11-3.08 (d, J = 12.0, 1H), 3.24-3.21 (d, J = 12.0, 1H), 3.48-3.41 (m, 2H),

3.60-3.55 (m, 2H), 4.08-4.04 (t, J = 16.0, 1H), 5.39 (d, J = 2.0, 1H), 6.66-6.63 (m, 1H),),

6.86-6.84 (d, J = 8.02H), 7.19-7.17 (d, J = 8.0, 2H), 7.25-7.24 (d, J = 4.0, 1H),

7.37-7.35 (dd, J = 8.0, 6.0, 1H), 7.63-7.61 (d, J = 8.0, 1H)

34i

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 5.69 (s, 1 H), 4.06 (t, J = 7.48 Hz,

2 H), 3.62 (m, 2 H), 3.48 (m, 2 H), 3.22 (d, J = 11.64 Hz, 1H), 3.09 (d, J = 11.44 Hz, 1 H),

2.61 (s, 3 H), 2.30 (m, 1 H), 2.03 (m, 1H), 1.57 (m, 4 H).

34j

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.25 (t, J = 7.4 Hz, 3H), 1.63 (m, 4H),

2.11-2.06 (m, 1H), 2.38-2.31 (m, 1H), 3.16-3.13 (m, 1H), 3.26 (m, 1H), 3.31 (m, 2H),

3.55-3.50 (m, 2H), 3.71-3.64 (m, 2H), 4.11 (M, 1H), 5.61 (s, 1H), 6.63 (m, 1H), 7.36 (s, 1H),

7.52-7.50 (m, 1H), 7.71-7.68 (m, 1H), 7.76-7.75 (m, 1H), 7.83 (t, J = 7.8 Hz, 1H), 8.04 (d, J = 7.2 Hz,

1H) 8.43 (s, 1H)

34k

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.96 (t, J = 12.0, 4H), 1.70-1.62 (m, 8H), 2.06 (s,

1H), 2.32 (s, 1H), 3.24 (d, J = 12.0, 1H), 3.50 (s, 2H), 3.67 (s, 2H), 4.07 (s, 1H), 4.63 (s,

1H), 5.61 (s, 1H), 6.62 (q, J = 8.0, 1H), 7.37 (s, 1H), 7.50 (d, 1H, J = 8.0), 7.79-7.69 (m, 2H),

7.83 (t, 1H, J = 8.0), 8.03 (d, 1H, J = 8.0), 8.45 (s, 1H)

34l

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.47 (s, 1 H), 8.03 (d, 1 H), 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 H), 3.26 (d, 1 H), 3.13 (d, 1 H), 2.35-2.32 (m, 1 H),

2.05 (m, 1 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): δ ppm 7.74-7.66 (m, 2H), 7.48-7.39 (m, 3H), 7.27 (m,

2H), 6.73-6.71 (m, 1H), 5.53 (s, 1H), 4.73 (s, 2H), 4.08 (t, J = 7.1 Hz, 1H), 3.63 (m, 2H),

3.47 (m, 2H), 3.27-3.24 (m, 1H), 3.14-3.11 (m, 1H), 2.36-2.30 (m, 1H), 2.08-2.03 (m,

1H), 1.60 (m, 4H)

34n

¹H NMR (400 MHz, MeOH-d4)δ 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)

34o

¹H-NMR (400 MHz, MeOH-d4): δ ppm 7.97 (s, 1H), 7.60-7.67 (m, 2H),

7.52-7.54 (m, 1H), 7.40-7.46 (m, 1H), 7.31-7.31 (m, 1H), 7.22-7.24 (m, 1H), 6.61-6.66 (m, 1H),

5.51 (s, 1H), 4.39-4.04 (m, 4H), 3.52-3.60 (m, 2H), 3.42-3.50 (m, 2H),

3.15-3.18 (d, 1H), 2.96-2.99 (d, 1H), 2.60-2.64 (m, 2H), 2.18-2.28 (m, 3H), 1.96-2.00 (m, 1H),

1.58-1.59 (m, 4H)

34p

¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.00 (s, 1H), 7.56-7.58 (m, 1H),

7.43-7.49 (m, 2H), 7.26-7.27 (m, 2H), 6.97-7.97 (m, 1H), 6.59-6.55 (m, 1H), 5.48 (s, 1H),

3.78-3.82 (m, 1H), 3.70-3.74 (m, 2H), 3.39-3.44 (m, 6H), 2.98-3.02 (d, 1H), 2.82-2.85 (d, 1H),

2.70 (s, 3H), 2.04-2.11 (m, 1H), 1.69-1.75 (m, 1H), 1.36-1.40 (m, 4H)

34q

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.64 (t, J = 5.8 Hz, 4H), 2.08 (dd, J = 13.5, 7.6 Hz,

1H), 2.40 (dd, J = 13.5, 9.0 Hz, 1H), 3.19 (d, J = 11.8 Hz, 1H), 3.28 (d, J = 12.2 Hz,

1H), 3.51 (m, 2H), 3.66 (m, 2H), 4.28 (t, J = 8.4 Hz, 1H), 4.87 (s, 16H), 6.53 (q, J = 6.7 Hz,

1H), 7.34 (d, J = 2.3 Hz, 1H), 7.51 (dd, J = 8.6, 2.3 Hz, 1H), 7.75 (m, 5H)

34r

¹H NMR (400 MHz, MeOH-d) δ 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, 1H) 3.28 (d, J = 11.71 Hz, 1 H)

3.38-3.56 (m, 2 H) 3.63 (d, J = 5.66 Hz, 2 H) 4.11 (dd, J = 8.98, 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, 1 H)

34s

¹H NMR (400 MHz, MeOH-d4): δ 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, 1 H) 6.74-6.89 (m, 1 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): δ ppm 1.51 (d, J = 4.69 Hz, 4 H) 1.84-2.00 (m, 1 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 = 1.95 Hz, 1 H) 7.13-7.27 (m, 1 H)

7.39 (d, J = 1.56 Hz, 1 H) 7.55 (d, J = 1.76 Hz, 1 H) 7.64 (d, J = 8.59 Hz, 1 H) 7.71 (d,

J = 1.76 Hz, 1 H)

34u

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.52-1.75 (m, 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 (m, 4 H) 4.10 (dd,

J = 9.10, 7.25 Hz, 1 H) 5.59 (s, 1 H) 6.61 (q, J = 6.59 Hz, 1 H) 7.31 (d, J = 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, 1 H) 8.32 (br. s., 1 H)

34v

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.52-1.71 (m, 4 H) 2.07 (dd, J = 13.42, 7.27 Hz,

1 H) 2.33 (dd, J = 13.47, 9.27 Hz, 1 H) 3.08-3.29 (m, 2 H) 3.36-3.76 (m, 4 H) 4.09 (dd,

J = 9.15, 7.20 Hz, 1 H) 5.48 (s, 1 H) 6.74 (q, J = 7.00 Hz, 1 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, 1 H)

7.32 (t, J = 7.88 Hz, 1 H) 7.43 (dd, J = 8.49, 2.25 Hz, 1 H) 7.67 (d, J = 8.49 Hz, 1 H)

34w

¹H NMR (400 MHz, MeOH-d4): δ 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, 1 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): δ 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, J = 6.49 Hz,

1 H) 5.84 (br. s., 1 H), 6.56 (q, J = 6.77 Hz, 1 H) 7.48 (d, J = 1.07 Hz, 1 H)

7.62-7.69 (m, 2 H) 7.75-7.82 (m, 1 H) 7.83-7.91 (m, 1 H) 7.92-8.00 (m, 2 H) 8.97 (br. s., 1 H)

10.23 (br. s., 1 H)

34y

¹H NMR (400 MHz, DMSO-d6): δ 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, 1 H) 7.57-7.70 (m, 2 H) 8.96 (d, J = 5.71 Hz, 1 H)

10.27 (br. s., 1 H)

34z

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.43-1.76 (m, 4 H) 1.92 (dd, J = 13.18, 9.32 Hz,

1 H) 2.35 (dd, J = 13.30, 8.57 Hz, 1 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, 1H) 5.93 (br. s., 1 H) 6.75 (q, J = 6.57 Hz, 1 H) 7.39 (d, J = 1.66 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., 1 H)

34aa

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.68-1.86 (m, 5 H) 2.13 (dd, J = 13.69, 8.66 Hz,

1 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 = 8.64 Hz, 1 H)

34ab

¹H NMR (400 MHz, DMSO-d6): δ 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, 1

H) 5.87 (br. s., 1 H) 6.62 (q, J = 6.78 Hz, 1 H) 7.43 (t, J = 1.22 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 (br. s., 1 H)

34ac

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.62 (d, J = 4.15 Hz, 4 H) 2.02-2.14 (m, 1 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, J = 8.98, 7.27 Hz,

1 H) 5.55 (s, 1 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, MeOH-d4): δ ppm 1.50-1.76 (m, 4 H) 2.07 (dd, J = 13.20, 7.15 Hz,

1 H) 2.34 (dd, J = 13.47, 9.27 Hz, 1 H) 3.14 (d, J = 11.71 Hz, 1 H) 3.23 (s, 3 H) 3.27 (d,

J = 11.86 Hz, 1 H) 3.40-3.76 (m, 4 H) 4.09 (dd, J = 9.03, 7.27 Hz, 1 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 = 8.49, 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): δ ppm 1.61 (q, J = 4.88 Hz, 4 H) 2.07 (dd, J = 13.37, 7.13 Hz,

1 H) 2.33 (dd, J = 13.42, 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, MeOH-d4): δ ppm 1.62 (q, J = 6.0, 5.0 Hz, 17H), 2.07 (dd, J = 13.4,

7.2 Hz, 5H), 2.33 (dd, J = 13.4, 9.2 Hz, 5H), 3.15 (d, J = 11.8 Hz, 5H), 3.27 (d, J = 11.8 Hz,

13H), 3.49 (m, 9H), 3.64 (ddt, J = 15.7, 10.7, 5.2 Hz, 9H), 4.11 (dd, J = 9.2, 7.1 Hz,

5H), 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): δ ppm 0.86 (m, 1H), 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, 1H), 2.26 (dd, J = 13.3, 9.0 Hz, 1H),

3.00 (d, J = 11.5 Hz, 1H), 3.16 (d, J = 11.5 Hz, 1H), 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, 1H), 4.69 (p, J = 6.0 Hz, 1H), 5.50 (s,

1H), 6.73 (q, J = 6.9 Hz, 1H), 6.95 (m, 1H), 7.04 (dd, J = 8.5, 2.4 Hz, 1H), 7.20 (s, 1H),

7.28 (d, J = 2.3 Hz, 1H), 7.42 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H)

34ah

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 7.3 Hz, 1H), 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, 1H), 2.35 (dd, J = 13.5, 9.1 Hz,

1H), 3.14 (d, J = 11.8 Hz, 1H), 3.26 (d, J = 11.7 Hz, 1H), 3.33 (s, 1H), 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,

1H), 6.97 (d, J = 7.6 Hz, 1H), 7.04 (dd, J = 8.3, 2.5 Hz, 1H), 7.19 (s, 1H), 7.29 (d, J = 2.2 Hz,

1H), 7.44 (m, 2H), 7.67 (d, J = 8.5 Hz, 1H)

34ai

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.48 (t, J = 7.0 Hz, 3H), 1.60 (m, 4H), 2.06 (dd, J = 13.4,

6.9 Hz, 1H), 2.33 (dd, J = 13.4, 8.9 Hz, 1H), 3.13 (d, J = 11.6 Hz, 1H), 3.25 (d, J = 11.4 Hz,

1H), 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, 1H), 4.20 (q, J = 6.9 Hz, 2H), 4.88 (s, 15H), 5.52 (s, 1H), 6.63 (q, J = 6.7 Hz,

1H), 7.24 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 7.43 (dd, J = 8.5, 2.3 Hz, 2H), 7.57 (s,

1H), 7.65 (d, J = 8.4 Hz, 1H)

34aj

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.58 (dd, J = 7.1, 4.1 Hz, 4H),

1.99 (dd, J = 13.4, 7.1 Hz, 1H), 2.29 (m, 1H), 2.46 (s, 3H), 3.02 (d, J = 11.6 Hz, 1H), 3.18 (d,

J = 11.6 Hz, 1H), 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, 1H), 5.52 (s, 1H), 6.60 (q, J = 6.6 Hz, 1H), 7.28 (m, 2H), 7.45 (dd, J = 8.3, 2.4 Hz,

2H), 7.56 (m, 1H), 7.66 (d, J = 8.5 Hz, 1H)

34ak

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 6.2 Hz, 1H), 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, 1H), 2.30 (dd, J = 13.3, 8.9 Hz,

1H), 2.81 (s, 1H), 3.07 (d, J = 11.6 Hz, 1H), 3.22 (d, J = 11.8 Hz, 1H), 3.48 (m, 2H),

3.64 (d, J = 9.7 Hz, 2H), 4.03 (t, J = 7.9 Hz, 1H), 4.75 (m, 1H), 5.53 (s, 1H), 6.63 (q, J = 6.8 Hz,

1H), 7.29 (m, 3H), 7.43 (dd, J = 8.6, 2.3 Hz, 1H), 7.58 (s, 1H), 7.65 (d, J = 8.5 Hz,

1H)

34al

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.39 (d, J = 6.0 Hz, 6H), 1.60 (m, 4H), 2.06 (dd,

J = 13.5, 7.2 Hz, 1H), 2.33 (dd, J = 13.4, 9.2 Hz, 1H), 3.13 (d, J = 11.7 Hz, 1H), 3.26 (d, J = 11.7 Hz,

1H), 3.48 (m, 2H), 3.64 (q, J = 12.4, 10.4 Hz, 2H), 4.10 (dd, J = 9.2, 7.2 Hz,

1H), 4.70 (hept, J = 5.9 Hz, 1H), 5.53 (s, 1H), 6.67 (q, J = 6.8 Hz, 1H), 7.25 (m, 4H),

7.43 (dd, J = 8.5, 2.3 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H)

34am

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.61 (q, J = 5.7 Hz, 4H), 2.06 (dd, J = 13.4,

7.1 Hz, 1H), 2.33 (dd, J = 13.4, 9.2 Hz, 1H), 3.12 (d, J = 11.7 Hz, 1H), 3.26 (d, J = 11.6 Hz,

1H), 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, 1H), 5.54 (s, 1H), 6.49 (q, J = 6.6 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H),

7.51 (dd, J = 8.5, 2.3 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.82 (td, J = 17.6, 16.6, 4.9 Hz,

3H)

34an

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.88 (d, J = 7.8 Hz, 1H), 1.29 (d, J = 6.7 Hz,

2H), 1.62 (q, J = 5.9, 5.4 Hz, 4H), 2.07 (dd, J = 13.4, 7.2 Hz, 1H), 2.33 (dd, J = 13.4, 9.2 Hz,

1H), 3.13 (d, J = 11.7 Hz, 1H), 3.26 (d, J = 11.7 Hz, 1H), 3.49 (ddd, J = 21.4, 12.5,

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, 1H), 5.55 (s,

1H), 6.59 (q, J = 6.7 Hz, 1H), 7.25 (d, J = 14.9 Hz, 1H), 7.35 (m, 2H), 7.44 (s, 1H),

7.51 (dd, J = 8.5, 2.2 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H)

34ao

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, 2H), 1.30 (d, J = 11.8 Hz, 3H), 1.36 (s,

10H), 1.60 (m, 5H), 2.34 (s, 1H), 2.81 (s, 1H), 3.14 (d, J = 11.6 Hz, 1H), 3.28 (m, 4H),

3.45 (s, 2H), 3.62 (s, 3H), 4.15 (t, J = 8.1 Hz, 1H), 4.85 (s, 38H), 6.62 (t, J = 6.7 Hz, 1H),

7.28 (m, 2H), 7.46 (m, 5H), 7.66 (d, J = 8.5 Hz, 1H)

34ap

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 7.5 Hz, 2H), 1.65 (s, 3H), 2.08 (dd, J = 13.5,

7.9 Hz, 1H), 2.44 (t, J = 11.2 Hz, 1H), 3.24 (dd, J = 14.0, 11.6 Hz, 1H), 3.61 (m,

4H), 4.41 (t, J = 8.4 Hz, 1H), 6.48 (q, J = 6.6 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.54 (dd,

J = 8.5, 2.2 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.86 (t, J = 1.5 Hz, 2H)

34aq

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (d, J = 2.2 Hz, 1H), 1.60 (s, 4H), 2.03 (d, J = 13.1 Hz,

1H), 2.30 (t, J = 11.1 Hz, 1H), 3.08 (d, J = 11.6 Hz, 1H), 3.23 (d, J = 12.3 Hz,

1H), 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, 1H),

4.58 (s, 1H), 5.55 (s, 1H), 6.52 (q, J = 6.7 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 8.5,

2.3 Hz, 1H), 7.66 (m, 4H)

34ar

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.88 (d, J = 11.4 Hz, 1H), 3.10 (d, J = 11.4 Hz,

1H), 3.45 (ddt, J = 20.3, 13.1, 6.1 Hz, 2H), 3.61 (m, 2H), 3.87 (s, 4H), 5.48 (s, 1H),

6.70 (q, J = 6.9 Hz, 1H), 7.04 (m, 2H), 7.16 (s, 1H), 7.29 (d, J = 2.2 Hz, 1H), 7.45 (m,

2H), 7.67 (d, J = 8.5 Hz, 1H)

34as

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 10.0 Hz, 2H), 1.61 (d, J = 5.6 Hz,

5H), 2.06 (dd, J = 13.4, 7.2 Hz, 1H), 2.33 (dd, J = 13.4, 9.2 Hz, 1H), 3.13 (d, J = 11.7 Hz,

1H), 3.26 (d, J = 11.7 Hz, 1H), 3.49 (dt, J = 21.9, 7.2 Hz, 3H), 3.65 (ddt, J = 15.1, 10.1,

5.2 Hz, 3H), 4.09 (dd, J = 9.2, 7.1 Hz, 1H), 4.86 (s, 26H), 5.53 (s, 1H), 6.64 (q, J = 6.8 Hz,

1H), 7.28 (m, 5H), 7.47 (dd, J = 8.5, 2.3 Hz, 1H), 7.55 (m, 1H), 7.68 (d, J = 8.5 Hz,

1H)

34at

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.35 (s, 1H), 1.60 (q, J = 5.1 Hz,

4H), 2.03 (dd, J = 13.3, 7.1 Hz, 1H), 2.30 (dd, J = 13.4, 9.1 Hz, 1H), 2.45 (s, 3H),

3.08 (d, J = 11.6 Hz, 1H), 3.23 (d, J = 11.7 Hz, 1H), 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, 2H), 4.04 (dd, J = 9.0, 7.3 Hz, 1H), 5.51 (s, 1H),

6.62 (q, J = 6.8 Hz, 1H), 7.30 (m, 3H), 7.45 (dd, J = 8.5, 2.3 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H),

7.66 (d, J = 8.5 Hz, 1H)

34au

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 6.2 Hz, 1H), 1.62 (q, J = 5.5 Hz,

4H), 2.07 (dd, J = 13.5, 7.3 Hz, 1H), 2.35 (dd, J = 13.5, 9.2 Hz, 1H), 3.15 (d, J = 11.8 Hz,

1H), 3.27 (d, J = 11.7 Hz, 1H), 3.49 (ddt, J = 21.6, 13.6, 6.3 Hz, 2H), 3.66 (ddt, J = 15.6,

10.1, 4.9 Hz, 2H), 4.14 (dd, J = 9.1, 7.3 Hz, 1H), 4.85 (d, J = 3.1 Hz, 16H), 6.63 (q, J = 6.8 Hz,

1H), 7.12 (m, 3H), 7.34 (d, J = 2.2 Hz, 1H), 7.50 (dd, J = 8.5, 2.2 Hz, 1H),

7.69 (d, J = 8.5 Hz, 1H)

34av

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.88 (m, 1H), 1.28 (s, 3H), 1.61 (q, J = 6.1 Hz,

4H), 2.07 (dd, J = 13.4, 7.1 Hz, 1H), 2.33 (dd, J = 13.5, 9.0 Hz, 1H), 3.13 (d, J = 11.6 Hz,

1H), 3.26 (d, J = 11.8 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, 1H), 4.90 (s, 1H), 5.55 (s, 1H), 6.57 (q, J = 6.8 Hz, 1H), 7.42 (m, 5H),

7.67 (d, J = 8.3 Hz, 2H)

34aw

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.30 (dd, J = 13.4, 9.0 Hz, 1H), 3.07 (d, J = 11.6 Hz,

1H), 3.22 (d, J = 11.6 Hz, 1H), 3.48 (ddt, J = 20.9, 13.3, 5.7 Hz, 2H), 3.64 (tt, J = 10.8,

5.3 Hz, 2H), 4.03 (t, J = 8.1 Hz, 1H), 4.87 (s, 17H), 5.54 (s, 1H), 6.61 (q, J = 6.7 Hz, 1H),

7.32 (t, J = 5.0 Hz, 2H), 7.46 (m, 3H), 7.54 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H)

34ax

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (dd, J = 17.9, 6.7 Hz, 2H), 1.54 (m, 4H),

1.79 (dd, J = 12.9, 7.0 Hz, 1H), 2.06 (td, J = 16.5, 14.8, 7.8 Hz, 1H), 2.66 (d, J = 11.0 Hz,

1H), 2.97 (d, J = 11.1 Hz, 1H), 3.45 (ddt, J = 20.1, 13.2, 6.0 Hz, 2H), 3.62 (m, 3H),

5.50 (d, J = 16.5 Hz, 1H), 6.54 (q, J = 6.7 Hz, 1H), 7.34 (d, J = 2.3 Hz, 1H), 7.52 (dd, J = 8.5,

2.3 Hz, 1H), 7.68 (dd, J = 24.2, 8.1 Hz, 2H), 7.84 (m, 1H), 7.97 (d, J = 8.1 Hz, 1H)

34ay

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, 2H), 1.28 (s, 2H), 1.40 (s, 10H),

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,

1H), 3.25 (d, J = 11.6 Hz, 1H), 3.47 (dq, J = 22.4, 7.8, 6.8 Hz, 2H), 3.63 (dd, J = 13.9,

7.3 Hz, 2H), 4.11 (t, J = 8.3 Hz, 1H), 6.66 (q, J = 6.8 Hz, 1H), 7.17 (d, J = 7.1 Hz,

2H), 7.26 (m, 2H), 7.41 (dd, J = 8.5, 2.2 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H)

34az

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.88 (q, J = 10.5, 8.0 Hz, 1H), 1.30 (d, J = 12.4 Hz,

4H), 1.46 (t, J = 7.0 Hz, 5H), 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, 5H), 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

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.59 (m, 4H), 2.04 (dd, J = 13.4, 7.2 Hz, 1H),

2.38 (s, 7H), 3.08 (d, J = 11.7 Hz, 1H), 3.23 (d, J = 11.7 Hz, 1H), 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, 1H), 6.67 (q, J = 6.9 Hz,

1H), 7.03 (s, 2H), 7.12 (s, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.42 (dd, J = 8.5, 2.3 Hz, 1H),

7.66 (d, J = 8.5 Hz, 1H)

34bb

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 3H), 1.58 (m, 4H), 1.98 (dd, J = 13.2, 7.1 Hz,

1H), 2.25 (dd, J = 13.3, 9.1 Hz, 1H), 2.40 (s, 3H), 2.98 (d, J = 11.5 Hz, 1H), 3.17 (d,

J = 11.5 Hz, 1H), 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, 1H), 4.89 (s, 17H), 5.52 (s, 1H), 6.61 (q, J = 6.7 Hz, 1H),

7.30 (d, J = 2.3 Hz, 1H), 7.46 (m, 4H), 7.67 (d, J = 8.4 Hz, 1H)

34bc

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.88 (d, J = 7.5 Hz, 1H), 1.28 (s, 3H), 1.60 (q, J = 5.5 Hz,

4H), 2.05 (dd, J = 13.6, 7.3 Hz, 1H), 2.30 (m, 1H), 2.44 (d, J = 2.6 Hz, 6H),

3.10 (d, J = 11.7 Hz, 1H), 3.26 (m, 2H), 3.47 (ddd, J = 16.0, 12.4, 6.6 Hz, 2H), 3.62 (d, J = 12.7 Hz,

2H), 4.06 (dd, J = 9.2, 7.2 Hz, 1H), 5.50 (d, J = 2.5 Hz, 1H), 6.64 (q, J = 6.7 Hz,

1H), 7.21 (s, 2H), 7.27 (d, J = 2.3 Hz, 1H), 7.44 (dd, J = 8.5, 2.3 Hz, 1H), 7.66 (d, J = 8.5 Hz,

1H)

34bd

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J = 7.7 Hz, 1H), 1.29 (d, J = 5.9 Hz, 5H),

1.61 (q, J = 5.6 Hz, 4H), 2.06 (dd, J = 13.5, 7.2 Hz, 1H), 2.33 (m, 4H), 2.84 (s, 1H),

3.12 (d, J = 11.7 Hz, 1H), 3.25 (d, J = 11.7 Hz, 1H), 3.48 (m, 2H), 3.64 (ddt, J = 15.0, 10.2,

5.1 Hz, 2H), 4.08 (dd, J = 9.2, 7.1 Hz, 1H), 5.52 (s, 1H), 6.63 (q, J = 6.8 Hz, 1H),

7.26 (m, 4H), 7.43 (dd, J = 8.5, 2.3 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H)

34be

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.58 (m, 4H), 1.99 (dd, J = 13.3,

7.1 Hz, 1H), 2.27 (dd, J = 13.3, 9.1 Hz, 1H), 2.42 (s, 3H), 3.01 (d, J = 11.6 Hz, 1H),

3.19 (d, J = 11.5 Hz, 1H), 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, 1H), 5.52 (s, 1H), 6.61 (q, J = 6.8 Hz, 1H), 7.18 (s, 1H),

7.31 (m, 3H), 7.46 (dd, J = 8.5, 2.3 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H)

34bf

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J = 6.6 Hz, 1H), 1.29 (d, J = 7.9 Hz, 4H),

1.62 (s, 8H), 2.09 (d, J = 6.9 Hz, 1H), 2.34 (t, J = 10.9 Hz, 2H), 3.15 (d, J = 8.2 Hz, 2H),

3.25 (m, 1H), 3.32 (s, 2H), 3.48 (s, 4H), 3.54 (s, 1H), 3.66 (s, 5H), 4.12 (s, 2H), 5.56 (s,

1H), 6.60 (q, J = 6.7 Hz, 2H), 7.34 (m, 5H), 7.50 (dd, J = 8.6, 2.2 Hz, 2H), 7.68 (d, J = 8.5 Hz,

2H)

34bg

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 3.15 (d, 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, 1H), 4.98 (s, 1H), 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, MeOH-d4): δ ppm 0.89 (t, J = 6.4 Hz, 1H), 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, 1H), 2.36 (dd, J = 13.5, 9.1 Hz,

1H), 3.15 (d, J = 11.8 Hz, 1H), 3.26 (m, 1H), 3.50 (ddd, J = 20.3, 10.5, 6.5 Hz, 2H),

3.65 (m, 2H), 4.16 (t, J = 8.2 Hz, 1H), 4.68 (s, 1H), 4.95 (t, J = 11.4 Hz, 1H), 6.40 (q, J = 6.5 Hz,

1H), 7.41 (d, J = 2.2 Hz, 1H), 7.56 (dd, J = 8.5, 2.3 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H),

8.12 (s, 3H)

34bi

¹H NMR 400 MHz, MeOH-d4): δ ppm 0.89 (d, J = 6.7 Hz, 1H), 1.15 (s, 1H), 1.28 (m,

9H), 1.57 (d, J = 6.4 Hz, 5H), 1.92 (dt, J = 13.9, 6.8 Hz, 1H), 2.21 (dd, J = 13.2, 9.1 Hz,

1H), 2.95 (m, 2H), 3.11 (d, J = 11.4 Hz, 1H), 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, 1H), 5.46 (s, 1H), 6.61 (q, J = 6.8 Hz,

1H), 7.39 (m, 6H), 7.66 (d, J = 8.5 Hz, 1H)

34bj

¹H NMR400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 5.0 Hz, 3H), 1.55 (m, 6H), 1.82 (dd, J = 12.9,

6.9 Hz, 1H), 2.10 (dd, J = 13.0, 9.0 Hz, 1H), 2.71 (d, J = 11.1 Hz, 1H), 3.00 (d, J = 11.1 Hz,

1H), 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, 17H), 5.53 (s, 2H), 6.54 (q, J = 6.6 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H),

7.51 (m, 5H), 7.59 (t, J = 1.9 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H)

34bk

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.62 (q, J = 5.5 Hz, 4H), 2.07 (dd, J = 13.5,

7.3 Hz, 1H), 2.35 (dd, J = 13.6, 9.1 Hz, 1H), 3.15 (d, J = 11.8 Hz, 1H), 3.26 (d, J = 11.7 Hz,

1H), 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,

1H), 6.49 (q, J = 6.6 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.52 (m, 2H), 7.68 (d, J = 8.5 Hz,

1H), 7.81 (s, 2H)

34bl

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.86 (d, J = 11.3 Hz, 1H),

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, 1H), 4.68 (hept, J = 6.0 Hz, 1H), 5.51 (s, 1H), 6.72 (q, J = 8.2,

7.0 Hz, 2H), 6.82 (dt, J = 11.1, 2.3 Hz, 1H), 7.02 (s, 1H), 7.28 (d, J = 2.2 Hz, 1H),

7.44 (dd, J = 8.5, 2.3 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H)

34bm

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (d, J = 18.8 Hz, 11H), 1.60 (q, J = 5.8 Hz,

4H), 2.05 (dd, J = 13.5, 7.2 Hz, 1H), 2.33 (m, 2H), 2.43 (s, 3H), 3.12 (d, J = 11.7 Hz,

1H), 3.25 (d, J = 11.7 Hz, 1H), 3.45 (ddt, J = 21.7, 13.4, 6.5 Hz, 2H), 3.62 (dq, J = 11.4,

5.5 Hz, 2H), 4.09 (dd, J = 9.2, 7.2 Hz, 1H), 6.64 (q, J = 6.8 Hz, 1H), 7.05 (s, 1H),

7.26 (m, 2H), 7.34 (d, J = 1.8 Hz, 1H), 7.42 (dd, J = 8.5, 2.3 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H)

34bm

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 2H), 1.53 (t, J = 6.1 Hz, 4H), 1.80 (dd, J = 13.0,

6.9 Hz, 1H), 2.09 (dd, J = 13.0, 8.9 Hz, 1H), 2.36 (d, J = 2.0 Hz, 3H), 2.68 (d, J = 10.8 Hz,

1H), 2.98 (d, J = 11.1 Hz, 1H), 3.42 (m, 2H), 3.63 (m, 3H), 5.49 (s, 1H),

6.64 (q, J = 6.8 Hz, 1H), 7.24 (m, 3H), 7.43 (m, 2H), 7.67 (d, J = 8.5 Hz, 1H)

34bo
1H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (d, J = 13.0 Hz, 1H), 1.53 (m, 4H),

1.79 (dd, J = 12.9, 6.9 Hz, 1H), 2.08 (dd, J = 12.9, 8.9 Hz, 1H), 2.66 (d, J = 11.1 Hz, 1H),

2.97 (d, J = 11.0 Hz, 1H), 3.42 (m, 3H), 3.62 (m, 3H), 5.50 (d, J = 15.0 Hz, 1H), 6.53 (q, J = 6.9 Hz,

1H), 7.36 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 8.4, 2.2 Hz, 1H), 7.63 (dd, J = 8.0, 5.0 Hz,

1H), 7.72 (d, J = 8.5 Hz, 1H), 7.98 (m, 1H), 8.67 (m, 1H), 8.74 (s, 1H)

34bp

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.44 (dd, J = 13.6, 8.9 Hz, 1H), 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, 1H), 6.66 (q, J = 6.7 Hz,

1H), 7.00 (s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.28 (m, 2H), 7.46 (dd, J = 8.5, 2.3 Hz, 1H),

7.67 (d, J = 8.5 Hz, 1H)

34bq

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.36 (s, 1H), 1.59 (q, J = 5.8, 4.7 Hz, 0H),

2.05 (dd, J = 13.4, 7.2 Hz, 0H), 2.31 (m, 0H), 3.12 (d, J = 11.6 Hz, 0H), 3.24 (d, J = 11.7 Hz,

0H), 3.42 (d, J = 9.4 Hz, 0H), 3.49 (m, 0H), 3.59 (d, J = 12.4 Hz, 0H), 4.09 (dd, J = 9.1,

7.1 Hz, 0H), 4.90 (s, 2H), 5.44 (s, 0H), 6.65 (q, J = 7.0 Hz, 0H), 7.27 (m, 0H), 7.45 (m,

0H), 7.54 (s, 0H), 7.69 (m, 0H)

34br

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 7.7 Hz, 3H), 1.59 (m, 6H), 2.04 (dd,

J = 13.5, 7.0 Hz, 1H), 2.19 (s, 2H), 2.31 (dd, J = 13.5, 9.2 Hz, 1H), 3.11 (d, J = 11.5 Hz,

1H), 3.24 (d, J = 11.8 Hz, 1H), 3.34 (s, 1H), 3.47 (dt, J = 24.1, 8.0 Hz, 2H), 3.63 (m, 2H),

4.07 (t, J = 7.9 Hz, 1H), 4.73 (s, 1H), 5.16 (m, 1H), 5.47 (d, J = 10.8 Hz, 2H), 6.62 (q, J = 6.8 Hz,

1H), 7.33 (m, 1H), 7.51 (m, 3H), 7.68 (d, J = 8.6 Hz, 1H)

34bs

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.60 (q, J = 5.9, 5.4 Hz, 4H),

2.04 (m, 1H), 2.31 (dd, J = 13.5, 9.2 Hz, 1H), 3.11 (s, 7H), 3.24 (d, J = 11.6 Hz, 1H), 3.47 (m,

2H), 3.63 (s, 2H), 4.06 (t, J = 8.1 Hz, 1H), 5.50 (s, 1H), 6.69 (m, 3H), 7.34 (d, J = 2.2 Hz,

1H), 7.48 (dd, J = 8.6, 2.3 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 5.2 Hz, 1H)

34bt

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.56 (t, J = 5.4 Hz, 4H), 1.99 (dd, J = 13.3, 7.0 Hz,

1H), 2.26 (dd, J = 13.3, 9.1 Hz, 1H), 3.01 (d, J = 11.5 Hz, 1H), 3.18 (d, J = 11.5 Hz,

1H), 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, 1H), 4.85 (m, 1H), 5.47 (s, 1H), 6.68 (q, J = 6.7 Hz, 1H), 7.39 (d, J = 2.3 Hz,

1H), 7.54 (m, 4H), 7.72 (d, J = 8.5 Hz, 1H), 7.97 (m, 4H)

34bu

¹H NMR (400 MHz, CDCl₃): δ ppm 1.36 (dd, J = 6.9, 3.7 Hz, 6H), 1.73 (dd, J = 13.1, 6.7 Hz,

1H), 2.05 (dd, J = 13.1, 8.8 Hz, 1H), 2.81 (d, J = 10.5 Hz, 1H), 2.94 (d, J = 10.5 Hz,

1H), 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,

1H), 4.19 (q, J = 7.1 Hz, 2H), 4.34 (s, 2H), 5.42 (s, 1H), 6.53 (q, J = 6.7 Hz, 1H),

7.25 (m, 3H), 7.42 (dd, J = 8.5, 2.2 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 8.65 (dd, J = 5.0, 0.8 Hz,

1H)

34bv

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (d, J = 13.8 Hz, 1H), 1.54 (q, J = 6.0, 5.4 Hz,

4H), 1.80 (dd, J = 13.0, 6.9 Hz, 1H), 2.08 (dd, J = 12.8, 8.9 Hz, 1H), 2.66 (d, J = 11.2 Hz,

1H), 2.97 (d, J = 11.1 Hz, 1H), 3.38 (m, 3H), 3.61 (dt, J = 13.8, 7.1 Hz, 3H), 5.49 (d,

J = 1.5 Hz, 1H), 6.60 (q, J = 6.7 Hz, 1H), 7.28 (m, 3H), 7.47 (m, 3H), 7.66 (d, J = 8.4 Hz,

1H)

34bw

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.63 (d, J = 7.6 Hz, 4H), 2.07 (dd, J = 13.4, 7.6 Hz,

1H), 2.39 (dd, J = 13.6, 9.0 Hz, 1H), 3.17 (d, J = 11.9 Hz, 1H), 3.28 (m, 2H),

3.51 (dt, J = 23.6, 8.6 Hz, 2H), 3.62 (d, J = 14.5 Hz, 2H), 4.25 (t, J = 8.4 Hz, 1H), 6.60 (q, J = 6.6 Hz,

1H), 7.29 (d, J = 2.3 Hz, 1H), 7.51 (m, 6H), 7.66 (d, J = 8.7 Hz, 1H)

34bx

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.61 (m, 4H), 2.06 (dd, J = 13.5, 7.5 Hz, 1H),

2.39 (m, 4H), 3.15 (d, J = 11.8 Hz, 1H), 3.26 (d, J = 11.7 Hz, 1H), 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, 1H), 6.64 (q, J = 6.7 Hz, 1H),

7.26 (d, J = 2.3 Hz, 1H), 7.38 (m, 4H), 7.65 (d, J = 8.5 Hz, 1H)

34by

¹H NMR (400 MHz, MeOH-d4): δ ppm: 1.30 (d, J = 17.9 Hz, 1H), 1.58 (q, J = 4.3, 2.7 Hz,

4H), 1.78 (m, 4H), 1.98 (dd, J = 13.3, 7.1 Hz, 1H), 2.24 (m, 4H), 2.41 (m, 1H),

3.02 (d, J = 11.6 Hz, 1H), 3.18 (d, J = 11.6 Hz, 1H), 3.47 (m, 2H), 3.62 (dq, J = 12.8, 5.9 Hz,

2H), 3.98 (dd, J = 9.1, 7.0 Hz, 1H), 5.49 (s, 1H), 5.75 (q, J = 2.6, 1.7 Hz, 1H), 6.94 (q, J = 6.9 Hz,

1H), 7.15 (d, J = 2.3 Hz, 1H), 7.29 (dd, J = 8.5, 2.3 Hz, 1H), 7.58 (d, J = 8.5 Hz,

1H)

34bz

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.02 (m, 7H), 1.28 (d, J = 5.2 Hz, 1H), 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, 1H), 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, 1H), 5.51 (s, 1H), 6.71 (q, J = 6.8 Hz,

1H), 7.01 (m, 2H), 7.18 (s, 1H), 7.29 (d, J = 2.1 Hz, 1H), 7.43 (m, 2H); 7.66 (d, J = 8.6 Hz,

1H)

34ca

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.00 (t, J = 7.3 Hz, 1H), 1.28 (m, 1H), 1.60 (m,

5H), 1.97 (m, 5H), 2.30 (t, J = 11.2 Hz, 1H), 2.83 (t, J = 7.4 Hz, 1H), 3.07 (d, J = 11.5 Hz,

1H), 3.22 (d, J = 11.4 Hz, 1H), 3.54 (m, 8H), 4.04 (d, J = 8.7 Hz, 1H), 5.08 (s, 1H),

5.56 (s, 1H), 6.69 (q, J = 6.6 Hz, 1H), 7.31 (d, J = 2.1 Hz, 1H), 7.48 (m, 2H), 7.65 (m,

3H), 7.93 (s, 1H)

34cb

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, 1H), 1.62 (m, 6H), 1.90 (m, 8H),

2.32 (dd, J = 13.4, 9.1 Hz, 1H), 3.11 (d, J = 11.7 Hz, 1H), 3.25 (d, J = 11.6 Hz, 1H), 3.47 (ddt,

J = 21.4, 13.3, 6.4 Hz, 2H), 3.65 (dq, J = 13.0, 6.2 Hz, 2H), 4.08 (dd, J = 9.1, 7.1 Hz,

1H), 5.51 (s, 1H), 6.72 (q, J = 6.9 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 7.02 (dd, J = 8.2, 2.6 Hz,

1H), 7.18 (s, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.42 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H)

34cc

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, 1H), 1.49 (m, 8H), 2.02 (m, 5H),

2.33 (dd, J = 13.3, 9.0 Hz, 1H), 3.13 (d, J = 11.6 Hz, 1H), 3.25 (d, J = 12.3 Hz, 1H), 3.58 (ddd,

J = 32.1, 26.0, 15.3 Hz, 5H), 3.88 (td, J = 10.6, 10.2, 3.9 Hz, 1H), 4.08 (t, J = 8.1 Hz,

1H), 5.56 (s, 1H), 6.63 (q, J = 6.7 Hz, 1H), 7.29 (d, J = 2.2 Hz, 1H), 7.56 (m, 4H),

7.89 (d, J = 7.7 Hz, 1H), 8.34 (s, 1H)

34cd

¹H NMR (400 MHz, MeOH-d4): δ^ppm1.28 (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, 1H), 2.27 (dd, J = 13.3, 9.1 Hz, 1H), 2.73 (q, J = 7.6 Hz,

2H), 3.01 (d, J = 11.5 Hz, 1H), 3.18 (d, J = 11.6 Hz, 1H), 3.45 (ddt, J = 21.2, 13.1, 5.9 Hz,

2H), 3.60 (dt, J = 12.5, 6.8 Hz, 2H), 3.98 (dd, J = 9.1, 7.1 Hz, 1H), 4.93 (s, 11H),

5.47 (s, 1H), 6.64 (q, J = 6.8 Hz, 1H), 7.30 (m, 4H), 7.43 (m, 2H), 7.66 (d, J = 8.5 Hz,

1H)

34ce

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.75 (d, J = 10.9 Hz,

1H), 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, 1H), 6.61 (q, J = 6.8 Hz, 1H), 7.32 (m, 4H),

7.44 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H)

34cf

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.09 (s, 0H), 0.89 (t, J = 6.5 Hz, 0H), 1.31 (d, J = 12.8 Hz,

1H), 1.59 (m, 0H), 1.84 (s, 0H), 2.02 (d, J = 6.4 Hz, 0H), 2.19 (t, J = 7.8 Hz,

0H), 2.65 (s, 0H), 2.76 (t, J = 6.7 Hz, 0H), 2.87 (d, J = 14.6 Hz, 0H), 3.06 (s, 0H), 3.30 (s,

1H), 3.49 (m, 0H), 3.61 (m, 0H), 3.82 (s, 0H), 4.98 (s, 0H), 5.33 (m, 0H), 5.55 (s, 0H),

7.30 (s, 0H), 7.38 (d, J = 7.9 Hz, 0H), 7.46 (t, J = 7.3 Hz, 0H), 7.54 (t, J = 7.8 Hz, 0H),

7.64 (m, 0H), 7.81 (t, J = 8.6 Hz, 0H), 7.93 (m, 0H), 8.40 (s, 0H)

34cg

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.73 (p, J = 7.2, 6.3 Hz, 4H), 2.10 (dd, J = 13.7,

8.5 Hz, 1H), 2.50 (dd, J = 13.6, 8.9 Hz, 1H), 3.26 (m, 4H), 3.61 (m, 11H), 3.78 (d, J = 16.7 Hz,

4H), 4.53 (t, J = 8.7 Hz, 1H), 6.61 (m, 1H), 7.36 (d, J = 2.2 Hz, 1H), 7.58 (m,

6H)

34ch

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.43 (m, 4H), 1.79 (dd, J = 13.3, 7.5 Hz, 1H),

2.13 (m, 1H), 2.30 (s, 3H), 2.48 (m, 3H), 2.95 (d, J = 11.8 Hz, 1H), 3.09 (m, 1H), 3.38 (s,

1H), 3.44 (s, 6H), 3.66 (s, 2H), 3.82 (t, J = 8.3 Hz, 1H), 5.54 (s, 1H), 6.57 (q, J = 6.8 Hz,

1H), 7.34 (d, J = 2.1 Hz, 1H), 7.55 (m, 6H)

34ci

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 4.2 Hz, 2H), 1.59 (m, 5H), 1.99 (dd,

J = 13.4, 6.9 Hz, 1H), 2.27 (dd, J = 13.3, 8.9 Hz, 1H), 2.80 (s, 3H), 3.01 (d, J = 11.5 Hz,

1H), 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,

1H), 5.52 (s, 1H), 6.75 (q, J = 6.7 Hz, 1H), 7.49 (m, 3H), 7.69 (d, J = 8.5 Hz, 1H),

7.76 (s, 1H)

34cj

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, 1H), 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, 1H), 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

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.62 (q, J = 6.1, 5.6 Hz, 4H), 2.06 (dd, J = 13.4,

7.2 Hz, 1H), 2.34 (dd, J = 13.5, 9.2 Hz, 1H), 2.58 (s, 3H), 3.13 (d, J = 11.7 Hz, 1H),

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, 1H), 4.87 (d, J = 7.3 Hz, 1H), 4.97 (s, 1H), 5.60 (s, 1H), 6.65 (q, J = 6.6 Hz, 1H),

7.34 (d, J = 2.3 Hz, 1H), 7.50 (dd, J = 8.6, 2.2 Hz, 1H), 7.67 (dd, J = 12.0, 8.0 Hz, 2H),

7.77 (t, J = 7.8 Hz, 1H), 7.94 (dt, J = 7.9, 1.4 Hz, 1H), 8.31 (s, 1H)

34cl

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.61 (d, J = 5.5 Hz, 5H), 2.04 (dd, J = 13.3, 7.1 Hz,

1H), 2.31 (dd, J = 13.4, 9.2 Hz, 1H), 2.73 (s, 6H), 3.08 (d, J = 11.6 Hz, 1H), 3.23 (d,

J = 11.7 Hz, 1H), 3.53 (m, 2H), 3.68 (d, J = 14.2 Hz, 2H), 4.04 (dd, J = 9.1, 7.0 Hz, 1H),

5.62 (s, 1H), 6.69 (q, J = 6.6 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.50 (dd, J = 8.5, 2.3 Hz,

1H), 7.70 (dd, J = 12.4, 7.7 Hz, 2H), 7.86 (m, 2H), 8.33 (s, 1H)

34cm

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (s, 1H), 1.57 (p, J = 7.6, 6.8 Hz, 4H),

1.86 (dd, J = 13.0, 6.9 Hz, 1H), 2.15 (dd, J = 13.2, 9.0 Hz, 1H), 2.81 (d, J = 11.2 Hz, 1H),

2.95 (s, 4H), 3.05 (d, J = 11.2 Hz, 1H), 3.32 (s, 1H), 3.46 (ddt, J = 17.4, 13.1, 5.7 Hz, 2H),

3.62 (dq, J = 11.5, 5.5 Hz, 2H), 3.76 (dd, J = 9.0, 6.9 Hz, 1H), 5.54 (s, 1H), 6.63 (q, J = 6.7 Hz,

1H), 7.29 (d, J = 2.3 Hz, 1H), 7.46 (dd, J = 8.5, 2.3 Hz, 1H), 7.62 (m, 3H),

7.89 (dt, J = 7.7, 1.5 Hz, 1H), 8.36 (s, 1H)

34cn

¹H NMR (400 MHz, MeOH-d4): δ 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,

1H), 4.97 (s, 1H), 5.56 (s, 1H), 6.71 (q, J = 6.7 Hz, 3H), 7.32 (d, J = 2.2 Hz, 3H),

7.56 (m, 15H), 7.78 (s, 3H)

34co

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.13 (t, J = 7.1 Hz, 3H), 1.26 (m, 4H), 1.61 (q, J = 6.1,

5.6 Hz, 4H), 2.05 (dd, J = 13.4, 7.2 Hz, 1H), 2.33 (dd, J = 13.4, 9.3 Hz, 1H),

3.13 (d, J = 11.7 Hz, 1H), 3.47 (m, 10H), 4.09 (t, J = 8.3 Hz, 1H), 5.55 (s, 1H), 6.74 (q, J = 6.8 Hz,

1H), 7.32 (d, J = 2.2 Hz, 1H), 7.48 (m, 3H), 7.65 (m, 3H)

34cp

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (m, 7H), 1.58 (d, J = 13.6 Hz, 14H),

2.05 (m, 3H), 2.31 (s, 4H), 2.88 (s, 1H), 3.11 (d, J = 12.1 Hz, 3H), 3.25 (d, J = 12.8 Hz, 3H),

3.38 (s, 10H), 3.48 (s, 3H), 3.63 (m, 5H), 4.09 (t, J = 8.2 Hz, 3H), 4.48 (s, 2H), 4.98 (s,

3H), 5.10 (s, 1H), 5.42 (s, 2H), 5.54 (s, 2H), 6.50 (d, J = 13.3 Hz, 2H), 6.79 (m, 1H),

7.22 (s, 2H), 7.44 (s, 5H), 7.53 (d, J = 8.4 Hz, 5H), 7.76 (s, 7H), 8.11 (m, 3H)

34cq

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (s, 3H), 1.62 (s, 8H), 2.08 (dd, J = 13.3, 7.1 Hz,

2H), 2.35 (t, J = 11.4 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, 1H), 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, MeOH-d4): δ ppm 0.46 (m, 4H), 1.28 (s, 1H), 1.58 (s, 4H), 1.69 (d,

J = 7.3 Hz, 1H), 1.97 (d, J = 9.1 Hz, 1H), 2.24 (dd, J = 13.1, 9.0 Hz, 1H), 2.58 (s, 2H),

2.73 (s, 2H), 2.96 (d, J = 11.3 Hz, 1H), 3.15 (d, J = 11.6 Hz, 1H), 3.32 (m, 1H), 3.48 (t, J = 12.1 Hz,

4H), 3.63 (s, 2H), 3.76 (s, 2H), 3.92 (t, J = 8.1 Hz, 1H), 5.55 (s, 1H), 6.71 (q, J = 6.7 Hz,

1H), 7.33 (d, J = 2.2 Hz, 1H), 7.50 (m, 3H), 7.66 (m, 2H), 7.80 (s, 1H)

34cl

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.71 (d, J = 4.7 Hz, 1H), 8.02 (t, J = 7.9 Hz, 1H),

7.72 (t, J = 7.3 Hz, 2H), 7.52 (d, J = 10.9 Hz, 3H), 6.92 (d, J = 6.7 Hz, 1H), 5.87 (s, 1H),

4.80 (s, 7H), 4.10 (d, J = 8.7 Hz, 1H), 3.66 (s, 2H), 3.50 (s, 2H), 3.30 (s, 5H), 3.25 (d, J = 11.8 Hz,

1H), 3.12 (d, J = 11.7 Hz, 1H), 2.35-2.27 (m, 1H), 2.06 (dd, J = 13.3, 7.1 Hz,

1H), 1.59 (s, 3H), 1.59 (d, J = 11.4 Hz, 1H)

34cm

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.99 (d, J = 4.9 Hz, 2H), 8.03 (s, 1H), 7.75 (d, J = 9.4 Hz,

2H), 7.60-7.49 (m, 2H), 5.71 (s, 1H), 4.10 (s, 1H), 3.59 (d, J = 18.5 Hz, 2H),

3.30 (d, J = 3.1 Hz, 9H), 3.11 (d, J = 12.0 Hz, 1H), 2.31 (t, J = 11.6 Hz, 1H), 2.06 (s, 1H),

1.57 (s, 5H), 1.28 (s, 1H)

34cu

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.96 (d, J = 1.5 Hz, 1H), 8.83-8.77 (m, 1H),

8.71 (d, J = 2.6 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.64-7.55 (m, 2H), 6.87 (q, J = 6.7 Hz,

1H), 5.64 (s, 1H), 3.99 (t, J = 8.2 Hz, 1H), 3.46 (s, 1H), 3.19 (d, J = 11.6 Hz, 1H),

3.03 (d, J = 11.6 Hz, 1H), 2.27 (dd, J = 13.3, 9.2 Hz, 1H), 2.00 (dd, J = 13.4, 7.0 Hz, 1H),

1.57 (s, 3H), 1.29 (s, 1H).

34cv

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H),

6.76 (d, J = 7.0 Hz, 2H), 4.26-4.05 (m, 5H), 3.75 (t, J = 4.7 Hz, 3H), 3.42 (s, 4H),

3.36 (s, 1H), 3.26 (d, J = 11.7 Hz, 3H), 3.13 (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, 5H).

Example 35
(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(2′-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 20) starting with (S)-8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d6): δ ppm 1.29-1.38 (m, 3H) 1.47-1.72 (m, 4H) 1.91 (dd, J=13.28, 9.18 Hz, 1H) 2.35 (dd, J=13.25, 8.61 Hz, 1H) 3.14 (br. s., 2H) 3.65 (br. s., 4H) 4.30-4.40 (m, 2H) 4.40-4.50 (m, 1H) 5.90 (br. s., 1H) 6.59 (q, J=6.67 Hz, 1H) 7.11 (br. s., 1H) 7.44 (t, J=1.22 Hz, 1H) 7.66 (s, 2H) 7.70-7.79 (m, 2H) 8.08 (dt, J=6.37, 2.14 Hz, 1H) 8.14 (br. s., 1H) 8.98 (d, J=5.61 Hz, 1H) 10.36 (d, J=5.08 Hz, 1H). LCMS (MH+): 634.

Example 36
(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(2-methoxyethoxy)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(4-bromo-2-(2-methoxyethoxy)phenyl)-2,2,2-trifluoroethanol and obtained as a white solid.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.44-1.66 (m, 4H) 1.83-1.95 (m, 1H) 2.34 (dd, J=13.08, 8.79 Hz, 1H) 3.14 (br. s., 2H) 3.33 (s, 3H) 3.42-3.65 (m, 4H) 3.67-3.79 (m, 2H) 4.19-4.27 (m, 1H) 4.27-4.36 (m, 1H) 4.48 (t, J=6.49 Hz, 1H) 5.74 (s, 1H) 6.99 (q, J=6.78 Hz, 1H) 7.07-7.16 (m, 1H) 7.27 (s, 1H) 7.43 (d, J=8.35 Hz, 1H) 8.93 (d, J=5.42 Hz, 1H) 9.81 (br. s., 1H). LCMS (MH+): 560.

Example 36b
(S)-8-(6-((R)-1-(2-(1H-benzo[d]imidazol-1-yl)-4-chlorophenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

To a solution of (R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol (1 g, 3.5 mmol) and 1H-benzo[d]imidazole (408 mg, 3.5 mmol) in toluene (24 mL) was added sequentially, CuI (131 mg, 0.69 mmol), K₂CO₃(1.19 g, 8.63 mmol), and (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (196 mg, 1.38 mmol). The reaction mixture was purged with N₂and then heated at 130° C. in a 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)-1-(2-(1H-benzo[d]imidazol-1-yl)-4-chlorophenyl)-2,2,2-trifluoroethanol as a white solid.

Steps 2-5:

The title compound was made as described for Example 10d (Steps 1-4) to provide a white solid.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.59 (m, 4H), 2.05 (dt, J=13.7, 6.9 Hz, 1H), 2.33 (dt, J=14.5, 8.5 Hz, 1H), 3.13 (dd, J=11.7, 7.6 Hz, 1H), 3.26 (m, 2H), 3.49 (m, 3H), 3.63 (m, 2H), 4.10 (q, J=7.0, 5.2 Hz, 1H), 5.48 (d, J=3.9 Hz, 1H), 6.43 (p, J=6.4 Hz, 1H), 7.22 (dd, J=7.8, 4.0 Hz, 1H), 7.38 (m, 2H), 7.61 (dd, J=5.3, 2.2 Hz, 1H), 7.81 (m, 3H), 8.54 (s, 1H). LCMS (MH⁺): 603.

Example 36c
(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(1H-indazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described for (S)-8-(6-((R)-1-(2-(1H-benzo[d]imidazol-1-yl)-4-chlorophenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 36b) starting with 1H-indazole and obtained as a white solid.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.57 (m, 5H), 2.05 (dd, J=13.4, 7.1 Hz, 1H), 2.32 (dd, J=13.5, 9.2 Hz, 1H), 3.12 (d, J=11.7 Hz, 1H), 3.24 (d, J=11.7 Hz, 1H), 3.52 (dddd, J=44.5, 25.8, 14.0, 7.1 Hz, 5H), 4.13 (dd, J=9.1, 7.1 Hz, 1H), 4.92 (s, 1H), 6.68 (q, J=6.5 Hz, 1H), 7.31 (t, J=7.4 Hz, 1H), 7.46 (m, 2H), 7.72 (m, 5H), 8.39 (s, 1H). LCMS (MH+): 603.

Example 36d
(S)-8-(2-amino-6-((R)-1-(4-bromo-2-(piperazin-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

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

Steps 3-10:

The title compound was prepared as described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 54d) following Steps 4-11.

¹H NMR (MeOH-d4): δ ppm 0.90 (dt, J=16.0, 8.0 Hz, 1H), 1.31 (s, 2H), 1.62 (t, J=5.6 Hz, 5H), 2.03 (dd, J=13.6, 6.9 Hz, 1H), 2.30 (dd, J=13.4, 9.1 Hz, 1H), 2.76 (dd, J=10.1, 6.3 Hz, 2H), 3.08 (m, 8H), 3.22 (d, J=11.6 Hz, 1H), 3.47 (s, 1H), 3.54 (m, 1H), 3.65 (dd, J=13.9, 6.8 Hz, 2H), 4.01 (t, J=8.0 Hz, 1H), 5.56 (s, 1H), 7.31 (q, J=6.9 Hz, 1H), 7.41 (dd, J=8.4, 1.9 Hz, 1H), 7.50 (m, 2H). LCMS (MH+): 615.

Example 36e
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(piperazin-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared starting with (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-(4-((benzyloxy)carbonyl)piperazin-1-yl)-4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (intermediate from Step 8, Example 36d] via a Suzuki coupling with (4-isopropoxyphenyl)boronic acid as described for example 54b.

¹H NMR (MeOH-d4): δ ppm 0.90 (m, 1H), 1.33 (m, 8H), 1.40 (s, 1H), 1.59 (q, J=5.7 Hz, 4H), 2.06 (dd, J=13.7, 7.0 Hz, 1H), 2.31 (dd, J=13.5, 9.2 Hz, 1H), 3.11 (m, 3H), 3.26 (d, J=11.7 Hz, 1H), 3.51 (m, 10H), 4.09 (dd, J=9.3, 6.8 Hz, 1H), 4.64 (p, J=6.0 Hz, 1H), 5.56 (s, 1H), 6.98 (m, 2H), 7.32 (q, J=7.0 Hz, 1H), 7.53 (m, 4H), 7.64 (d, J=8.2 Hz, 1H). LCMS (MH+): 671.

Example 36f
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-morpholino-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(piperazin-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 36e) substituting morpholine for benzyl piperazine-1-carboxylate.

¹H NMR (MeOH-d4): δ ppm 1.32 (d, J=6.0 Hz, 7H), 1.58 (d, J=6.0 Hz, 4H), 1.98 (m, 1H), 2.25 (dd, J=13.3, 9.0 Hz, 1H), 2.83 (m, 2H), 2.99 (d, J=11.5 Hz, 1H), 3.19 (m, 3H), 3.32 (s, 1H), 3.48 (ddt, J=18.5, 8.9, 5.0 Hz, 2H), 3.62 (s, 2H), 3.92 (m, 5H), 4.63 (h, J=6.0 Hz, 1H), 4.88 (m, 1H), 5.54 (s, 1H), 6.97 (m, 2H), 7.41 (m, 2H), 7.54 (m, 4H). LCMS (MH+): 672

Example 36g
(S)-8-(6-((R)-1-([1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)-2-amino pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 34u) starting with 1-(2-bromophenyl)-2,2,2-trifluoroethanone.

¹H NMR (MeOH-d4): δ ppm 1.58 (d, J=5.4 Hz, 4H), 2.00 (dd, J=13.4, 7.1 Hz, 1H), 2.27 (dd, J=13.3, 9.2 Hz, 1H), 3.02 (d, J=11.6 Hz, 1H), 3.19 (d, J=11.5 Hz, 1H), 3.30 (q, J=1.8 Hz, 3H), 3.45 (td, J=14.5, 6.3 Hz, 1H), 3.61 (m, 2H), 3.99 (m, 1H), 5.46 (s, 1H), 6.67 (q, J=6.8 Hz, 1H), 7.26 (dd, J=6.2, 2.4 Hz, 1H), 7.45 (m, 7H), 7.70 (d, J=7.3 Hz, 1H). LCMS (MH+): 528.

Example 37
(3S)-8-(6-(1-((1r,3r,5S,7S)-adamantan-2-yl)ethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

A solution of adamantan-1-yl-methanol (100 mg, 0.60 mmol) in THF (5 mL) was cooled 15 to 0° C. 15-Crown-5 ether (99 mg, 0.5 mmol) and NaH (60% in oil, 92 mg, 2.4 mmol) were added sequentially. The reaction was warmed to RT for 1 h, cooled to 0° C., and 4,6-dichloropyrimidin-2-ylamine (247 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 Na₂SO₄, filtered, and concentrated in vacuo. Purification by normal phase chromatography (EtOAc/heptane) provided 4-(adamantan-1-ylmethoxy)-6-chloro-pyrimidin-2-ylamine as a white solid.

Step 2:

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

Step 3:

N-CBZ Deprotection was accomplished via Method B to provide (S)-ethyl 8-(6-(adamantan-1-ylmethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.

Step 4:

Hydrolysis of (S)-ethyl 8-(6-(adamantan-1-ylmethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provides the title compound as a white solid.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.12 (d, J=6.25 Hz, 3H) 1.42-1.76 (m, 17H) 1.82-2.02 (m, 4H) 2.34 (dd, J=13.32, 8.59 Hz, 1H) 3.12 (br. s., 2H) 3.67 (br. s., 4H) 4.35-4.48 (m, 1H) 5.85 (br. s., 1H) 8.97 (br. s., 1H) 10.44 (br. s., 1H). LCMS (MH+): 456.

Example 38
(S)-8-(6-((1r,3r,5S,7S)-adamantan-2-ylmethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was made as described above for (3S)-8-(6-(1-((1r,3r,5S,7S)-adamantan-2-yl)ethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 37) using (1r,3r,5r,7r)-adamantan-2-ylmethanol.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.39-1.76 (m, 16H) 1.83-2.01 (m, 4H) 2.34 (dd, J=13.18, 8.44 Hz, 1H) 3.13 (br. s., 2H) 3.69 (br. s., 4H) 3.79 (s, 2H) 4.42 (br. s., 1H) 5.83 (br. s., 1H) 8.97 (br. s., 1H) 10.40 (br. s., 1H). LCMS (MH+): 442.

Example 39a
8-(4-Amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

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

Step 3:

Hydrolysis of 2-benzyl 3-ethyl 8-(4-amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate using the LiOH general method provided 8-(4-amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin-2-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic 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-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 39a).

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TABLE 13a

Ex.

LCMS

No.
A—CH(R)—NH—
CAS Name
(MH+)

39a

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8-(4-amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5- triazin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
435

39b

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8-(4-(([1,1′-biphenyl]-4-ylmethyl)amino)-6-amino- 1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
460

39c

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8-(4-amino-6-((2-(piperidin-1-yl)benzyl)amino)- 1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
467

39d

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8-(4-(([1,1′-biphenyl]-3-ylmethyl)amino)-6-amino- 1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
460

39e

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8-(4-amino-6-(((R)-1-(naphthalen-2-yl)ethyl)amino)- 1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
448

TABLE 13b

NMR Data for Compounds of Table 13a

Ex.

No.
NMR

39a
1H NMR (400 MHz, DMSO-d6): δ ppm 1.5 (br.s. 4 H),

1.6-1.8 (m, 1H), 2.1-2.2 (m, 1H), 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
1H NMR (400 MHz, MeOH-d4): δ 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 (m, 4 H)

39c
1H NMR (400 MHz, MeOH-d4): δ 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
1H NMR (400 MHz, MeOH-d4): δ ppm 1.29-1.79 (m, 4 H)

1.88-2.15 (m, 1 H) 2.25-2.54 (m, 1 H) 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 H)

39e
1H NMR (400 MHz, MeOH-d4): δ 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-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

N-CBZ Deprotection was accomplished via Method B to provide ethyl 8-(4-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.

Step 3:

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

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.55 (br. s., 4H) 1.98 (s, 1H) 2.02-2.15 (m, 1H) 2.30 (dd, J=13.42, 9.27 Hz, 1H) 2.36 (s, 3H) 3.10 (d, J=11.71 Hz, 1H) 3.23-3.28 (m, 1H) 3.40-4.01 (m, 4H) 4.08 (dd, J=9.27, 6.88 Hz, 1H) 6.39 (d, J=2.25 Hz, 1H) 7.36-7.63 (m, 3H) 7.76 (d, J=8.54 Hz, 1H) 7.91 (d, J=2.10 Hz, 1H). LCMS (MH+): 567.

Example 41a
(S)-8-(2-Amino-6-((2-(piperidin-1-yl)benzyl)amino)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

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

Step 3:

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

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

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TABLE 14a

Ex.

LCMS

No.
Ar
CAS Name
(MH+)

41a

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(S)-8-(2-amino-6-((2-(piperidin-1- yl)benzyl)amino)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
446

41b

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(S)-8-(2-amino-6-((2-phenoxy-6-(piperidin-1- yl)benzyl)amino)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
558

41c

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(3S)-8-(6-(((3S,5S)-adamantan-1-ylmethyl)amino)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
441

41d

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(3S)-8-(6-((1-((1R,3S,5S)-adamantan-1- yl)ethyl)amino)-2-aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
456

TABLE 14b

NMR Data for Compounds of Table 14a

Ex.

No.
NMR

41a

¹H NMR (400 MHz, MeOH-d4): δ 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) 2.69-2.95 (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): δ 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, J = 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) 7.03-7.09 (m, 1 H) 7.18 (s, 1 H) 7.28 (d,

J = 7.91 Hz, 2 H)

41c

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.00 (br. s., 6 H)

0.03-0.26 (m, 10 H) 0.27-0.44 (m, 9 H) 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): δ ppm 1.08 (d,

J = 6.83 Hz, 3 H) 1.52-1.71 (m, 13 H) 1.73 (br. s., 3 H) 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)-8-(2-amino-6-((R)-1-(3′-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was made as described for (S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 35) starting with (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.43 (h, J=8.5, 6.5 Hz, 4H), 1.80 (dd, J=13.3, 7.4 Hz, 1H), 2.12 (dd, J=13.2, 9.0 Hz, 1H), 2.48 (d, J=1.8 Hz, 1H), 2.95 (d, J=11.7 Hz, 1H), 3.08 (d, J=11.7 Hz, 1H), 3.37 (d, J=16.1 Hz, 1H), 3.48 (d, J=11.2 Hz, 3H), 3.79 (m, 2H), 5.57 (s, 1H), 6.62 (q, J=6.9 Hz, 1H), 7.27 (dd, J=5.8, 3.3 Hz, 1H), 7.51 (m, 7H). LCMS (MH+): 563.

Example 42b
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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¹H NMR (400 MHz, DMSO-d6): δ ppm 0.89 (m, 1H), 1.30 (d, J=16.3 Hz, 3H), 1.60 (q, J=5.9 Hz, 4H), 2.05 (dd, J=13.4, 7.2 Hz, 1H), 2.32 (dd, J=13.4, 9.1 Hz, 1H), 3.11 (d, J=11.7 Hz, 1H), 3.24 (d, J=11.7 Hz, 1H), 3.47 (ddt, J=20.6, 13.4, 6.5 Hz, 2H), 3.64 (ddt, J=15.8, 10.8, 5.2 Hz, 2H), 4.07 (dd, J=9.2, 7.1 Hz, 1H), 5.51 (s, 1H), 6.68 (q, J=6.9 Hz, 1H), 7.25 (m, 4H), 7.48 (m, 3H), 7.71 (m, 1H). LCMS (MH+): 546.

Example 43
(S)-8-(5-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazin-3-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

To (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (1.00 g, 3.44 mmol, Intermediate 3) in 1,4-dioxane (100 mL) was added 3,5-dichloropyridazine (512 mg, 3.44 mmol) and Cs₂CO₃(3.36 g, 10.3 mmol). The reaction mixture was then heated at 100° C. for 182 h. During this time, the reaction was charged with additional 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 Na₂SO₄, filtered, and concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (EtOAc/heptane) provided 3-chloro-5-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyridazine as a 3:2 mixture of (R)-3-chloro-5-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazine and (R)-5-chloro-3-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazine respectively.

Step 2:

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

Step 3:

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

Step 4:

Hydrolysis of (S)-8-(5-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazin-3-yl)-3-(ethoxycarbonyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid using the LiOH general method provided the title compound as an off-white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.66-1.80 (m, 4H), 2.11 (dd, J=13.45, 7.05 Hz, 1H), 2.30-2.40 (m, 1H), 2.36 (s, 3H), 3.16 (d, J=11.81 Hz, 1H), 3.25-3.35 (m, 1H), 3.37-3.65 (m, 4H), 4.03-4.19 (m, 1H), 6.39 (d, J=2.34 Hz, 1H), 6.63 (d, J=2.39 Hz, 1H), 6.95 (q, J=6.39 Hz, 1H), 7.43-7.57 (m, 2H), 7.76 (d, J=8.35 Hz, 1H), 8.22 (d, J=2.39 Hz, 1H), 8.63 (d, J=2.49 Hz, 1H). LCMS (MH+): 551

Example 44
(S)-8-(4-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid and
Example 45
(S)-8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

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

Step 3:

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

Step 4:

N-CBZ Deprotection was accomplished via Method A followed by normal phase silica gel purification (EtOAc:heptane) providing 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-1-(2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.52-1.76 (m, 4H) 1.95-2.15 (m, 1H) 2.23-2.37 (m, 1H) 2.39 (s, 3H) 2.87 (s, 1H) 3.05-3.16 (m, 1H) 3.19-3.27 (m, 1H) 3.38-3.72 (m, 4H) 3.77-4.13 (m, 1H) 6.39 (d, J=2.44 Hz, 1H) 6.44-6.52 (m, 1H) 6.79 (d, J=2.20 Hz, 1H) 6.83-6.97 (m, 1H) 7.43-7.51 (m, 1H) 7.54 (d, J=2.05 Hz, 1H) 7.66 (d, J=8.74 Hz, 1H) 7.81-8.00 (m, 2H). LCMS (MH+): 550.

8-(4-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.47-1.71 (m, 4H) 1.95-2.04 (m, 1H) 2.21-2.31 (m, 1H) 2.39 (s, 3H) 2.73 (s, 1H) 3.02 (d, J=11.52 Hz, 1H) 3.14-3.22 (m, 1H) 3.37-4.03 (m, 4H) 6.36 (d, J=2.34 Hz, 1H) 6.43-6.51 (m, 1H) 6.72-6.85 (m, 2H) 7.30-7.51 (m, 3H) 7.52-7.61 (m, 1H) 7.67 (d, J=7.86 Hz, 1H) 7.81 (d, J=2.34 Hz, 1H) 7.86-7.91 (m, 1H). LCMS (MH+): 516.

Example 46
8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-phenoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

To a solution of 2-benzyl 3-ethyl 8-(4-chloro-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (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 Cs₂CO₃(3.65 g, 11.2 mmol). The reaction 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 Na₂SO₄, filtered, and concentrated in vacuo. Purification on a 12 g Isco RediSep silica cartridge (EtOAc/heptane) provided 2-benzyl 3-ethyl 8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-phenoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.

Step 2:

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

Step 3:

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

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.36 (br. s., 4H), 1.90-1.99 (m, 1H), 2.11-2.21 (m, 1H), 2.26 (s, 3H), 2.92-3.17 (m, 2H), 3.24-3.60 (m, 4H), 3.96 (dd, J=9.13, 6.88 Hz, 1H), 5.44 (d, J=2.29 Hz, 1H), 6.27-6.33 (m, 1H), 7.00 (d, J=8.00 Hz, 2H), 7.08-7.16 (m, 1H), 7.24-7.32 (m, 2H), 7.38 (dd, J=8.44, 1.90 Hz, 1H), 7.44 (d, J=2.00 Hz, 1H), 7.54-7.62 (m, 1H), 7.64 (d, J=8.49 Hz, 1H), 7.81 (d, J=2.25 Hz, 1H). LCMS (MH+): 642.

Example 47
(3S)-8-(2-Amino-6-(1-(2,6-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, 1H), 1.62 (q, J=5.7 Hz, 4H), 2.06 (m, 1H), 2.33 (dd, J=13.5, 9.2 Hz, 1H), 3.13 (d, J=11.7 Hz, 1H), 3.26 (d, J=11.7 Hz, 1H), 3.49 (m, 2H), 3.65 (dq, J=10.7, 5.4 Hz, 2H), 4.09 (dd, J=9.2, 7.2 Hz, 1H), 5.56 (s, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.28 (q, J=8.0 Hz, 1H), 7.69 (m, 2H). LCMS (MH+): 611.

Example 48
(S)-8-(2-Amino-6-((R)-1-(2,5-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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¹H NMR (400 MHz, MeOH-d4): δ ppm 1.62 (q, J=5.8, 5.2 Hz, 4H), 2.06 (dd, J=13.5, 7.2 Hz, 1H), 2.34 (dd, J=13.4, 9.2 Hz, 1H), 3.13 (d, J=11.7 Hz, 1H), 3.26 (d, J=11.8 Hz, 1H), 3.50 (m, 2H), 3.66 (ddt, J=15.0, 10.7, 5.2 Hz, 2H), 4.09 (dd, J=9.2, 7.2 Hz, 1H), 4.83 (s, 1H), 5.58 (s, 1H), 6.97 (q, J=6.6 Hz, 1H), 7.47 (dd, J=8.6, 2.4 Hz, 1H), 7.58 (d, J=8.6 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H). LCMS (MH+): 611.

Example 49
(S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(4-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (500 mg, 0.65 mmol) in DMF (10 mL) was added tributyl(prop-1-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 130° C. in a sealed tube for 3 h, then cooled to RT. The reaction mixture was partitioned between water and CH₂Cl₂, and extracted. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-(prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

Step 3:

To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-(prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (200 mg, 0.26 mmol) in EtOH (10 mL) was added 10% Pd/C (200 mg) and the reaction mixture was stirred under 1 atm H₂for 12 h. The solids were filtered and the filtrate was concentrated to afford (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid that is used directly without further purification.

Step 4:

To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate in CH₂Cl₂(4 mL) 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 saturated aqueous NaHCO₃solution. The aqueous layer was extracted with CH₂Cl₂. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (CH₂Cl₂/MeOH) provided the title compound as a white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.41 (m, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H), 7.73-7.71 (m, 1H), 7.53 (s, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 6.61 (q, J=6.7 Hz, 1H), 5.61 (s, 1H), 4.10 (t, J=8.4 Hz, 1H), 3.72-3.63 (m, 2H), 3.55-3.46 (m, 2H), 3.26 (m, 1H), 3.21 (s, 3H), 3.16-3.13 (m, 1H), 2.66 (t, J=7.6 Hz, 2H), 2.38-2.32 (m, 1H), 2.10-2.05 (m, 2H), 1.65-1.60 (m, 3H). LCMS (MH+): 649.

Example 50
(S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-((E)-prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described for (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-(prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (Example 49) by omitting the olefin hydrogenation reaction of Step 3.

¹H NMR (400 MHz, CD₃OD-d4): δ ppm 8.46-8.42 (m, 1H), 8.06-8.03 (m, 1H), 7.82-7.71 (m, 2H), 7.64 (s, 1H), 7.45 (dd, J1=8.2 Hz, J2=33.2 Hz, 1H), 7.25 (dd, J1=7.9 Hz, J2=23.9 Hz, 1H), 6.64-6.62 (m, 1H), 6.49-6.45 (m, 1H), 6.39-5.86 (m, 1H), 5.62 (d, J=5.3 Hz, 1H), 4.12-4.08 (m, 1H), 3.70-3.62 (m, 2H), 3.54-3.45 (m, 2H), 3.29-3.26 (m, 1H), 3.22-3.21 (m, 3H), 3.16-3.13 (m, 1H), 2.37-2.31 (m, 1H), 2.10-2.05 (m, 1H), 1.91-1.87 (m, 3H), 1.62 (m, 4H). LCMS (MH+): 647.

Example 51a
(S)-8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

To a solution of (S)-2-tert-butyl 3-ethyl 8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (550 mg, 0.75 mmol) in CH₂Cl₂(4 mL) was added TFA (2.0 mL) dropwise at 0° C. The reaction mixture was stirred at RT for 2 h, and concentrated in vacuo. The pH was adjusted to 7-8 with a saturated aqueous NaHCO₃solution. The aqueous layer was extracted with CH₂Cl₂. The organic layer is washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (CH₂Cl₂/MeOH) provided (S)-ethyl 8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.

Step 3:

Hydrolysis of (S)-ethyl 8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as a white solid.

¹H NMR (400 MHz, CD₃OD-d4): δ ppm 7.91 (s, 1H), 7.70 (dd, J1=6.08 Hz, J=1.88 Hz, 1H), 7.62 (m, 2H), 7.56-7.44 (m, 7H), 7.39-7.35 (m, 2H), 6.72 (q, J=6.52 Hz, 1H), 5.48 (s, 1H), 4.18 (q, J=6.96 Hz, 2H), 3.67 (m, 1H), 3.58 (m, 2H), 3.41 (m, 2H), 2.98 (d, J=10.96 Hz, 1H), 2.69 (d, J=11.24 Hz, 1H), 2.12-2.06 (m, 1H), 1.83-1.78 (m, 1H), 1.52 (m, 4H). LCMS (MH+): 604.5

Example 51b
(S)-8-(6-((R)-1-([1,1′:3′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described for (S)-8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 51a) starting with (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(2,6-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (product of Step 4, example 63ao).

¹H NMR (400 MHz, CD₃OD-d4): δ ppm 1.32 (dd, J=15.5, 7.9 Hz, 1H), 1.70 (dd, J=7.9, 4.3 Hz, 5H), 2.12 (m, 1H), 2.49 (ddd, J=12.3, 9.0, 2.6 Hz, 1H), 3.25 (dd, J=11.9, 2.2 Hz, 1H), 3.60 (s, 9H), 4.48 (t, J=8.6 Hz, 1H), 6.89 (q, J=7.8 Hz, 1H), 7.21 (d, J=7.6 Hz, 2H), 7.42 (m, 14H). LCMS (MH+): 604.

Example 52a
(S)-8-(2-Amino-6-((R)-1-(3,4-dimethyl-3″-(methylsulfonyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (product of Step 1, Example 34w) (273 mg, 0.34 mmol) in 1,4-dioxane (5 mL) was added (3,4-dimethylphenyl)boronic acid (77 mg, 0.51 mmol), KHCO₃(341 mg, 3.40 mmol), and Pd(PCy₃)₂(34 mg, 0.051 mmol). The reaction was heated 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 Na₂SO₄, filtered, and concentrated in vacuo. Purification on a 12 g Isco RediSep silica cartridge (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(3,4-dimethyl-3″-(methylsulfonyl)-[1,1′:3,1″-terphenyl]-4′-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an white solid.

Step 2:

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

Step 3:

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

Using the generic scheme below, the following examples of Table 16a were prepared as described above for (S)-8-(2-amino-6-((R)-1-(3,4-dimethyl-3″-(methylsulfonyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 52a).

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TABLE 16a

Ex.

LCMS

No.
Cy
CAS Name
(MH+)

52a

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(S)-8-(2-amino-6-((R)-1-(3,4-dimethyl-3″-(methylsulfonyl)- [1,1′:3′,1″-terphenyl]-4′-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
710

52b

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)- 5-(quinolin-6-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
733

TABLE 16b

NMR Data for Compounds of Table 16a

Ex.

No.
NMR

52a

¹H NMR (400 MHz, MeOH-d4): δ ppm 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, 1 H) 3.14 (d, J = 11.76 Hz, 1 H) 3.22 (s, 3 H)

3.27 (d, J = 11.76 Hz, 1 H) 3.40-3.77 (m, 4 H) 4.09 (dd, J = 9.08,

7.27 Hz, 1 H) 5.62 (s, 1 H) 6.63 (q, J = 6.64 Hz, 1 H) 7.18 (d,

J = 7.96 Hz, 1 H) 7.35 (dd, J = 7.81, 1.81 Hz, 1 H) 7.40 (s,

1 H) 7.47 (d, J = 1.85 Hz, 1 H) 7.63-7.72 (m, 1 H)

7.72-7.77 (m, 1 H) 7.80-7.85 (m, 2 H) 8.07 (dt, J = 6.97,

1.96 Hz, 1 H) 8.48 (br. s., 1 H)

52b

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.59 (t,

J = 5.54 Hz, 4 H) 1.92 (dd, J = 13.13, 7.03 Hz,

1 H) 2.20 (dd, J = 13.15, 9.10 Hz, 1 H) 2.81-3.17 (m, 2 H)

3.24 (s, 3 H) 3.38-3.74 (m, 4 H) 3.84 (dd, J = 8.96, 7.05 Hz,

1 H) 5.64 (s, 1 H) 6.67 (q, J = 6.64 Hz, 1 H) 7.55 (dd,

J = 8.35, 4.34 Hz, 1 H) 7.67 (d, J = 1.61 Hz, 1 H)

7.78-7.92 (m, 4 H) 8.04-8.15 (m, 3 H) 8.21 (s, 1 H) 8.41 (dd,

J = 8.40, 1.56 Hz, 1 H) 8.54 (br. s., 1 H) 8.84 (dd,

J = 4.32, 1.68 Hz, 1 H)

Example 53
(S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-((E)-prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

To a solution (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (500 mg, 0.65 mmol) in DMF (10 mL) was added tributyl(prop-1-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 130° C. in a sealed tube for 3 h, then cooled to RT, and partitioned between water and CH₂Cl₂. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-((E)-prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

Step 3:

To a solution of(S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-((E)-prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate in CH₂Cl₂(4 mL) was added TFA (2.0 mL) dropwise at 0° C. The reaction mixture was stirred at RT for 2 h, then concentrated in vacuo. The pH was adjusted to 7-8 with a saturated aqueous NaHCO₃solution. The aqueous layer was extracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (CH₂Cl₂/MeOH) provided (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-((E)-prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.

Step 4:

Hydrolysis of (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-((E)-prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid using the LiOH general method provided the title compound as an off-white solid.

¹H NMR (400 MHz, CD₃OD-d4): δ ppm 8.40 (s, 1H), 8.02 (d, 1H, J=7.4 Hz), 7.50 (m, 3H), 7.40 (m, 1H), 7.20 (m, 1H), 6.58 (m, 1H), 5.58 (m, 1H), 4.09 (m, 1H), 3.55 (m, 2H), 3.48 (m, 2H), 3.21 (m, 4H), 3.10 (m, 1H), 2.59 (m, 2H), 2.29 (m, 1H), 1.95 (m, 1H), 1.86 (m, 3H), 1.30 (m, 4H). LCMS (MH+): 646.

Example 54a
(S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-((E)-prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (product from Step 2, Example 53) (200 mg, 0.26 mmol) in EtOH (10 mL) is added 10% Pd/C (200 mg), and the reaction mixture was stirred under 1 atm H₂for 12 h. The solids were filtered and the filtrate was concentrated in vacuo to provide (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid that is used directly without further purification.

Step 2:

To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate in CH₂Cl₂(4 mL) 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 saturated aqueous NaHCO₃solution. The aqueous layer was extracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (CH₂Cl₂/MeOH) provided (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.

Step 3:

Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provides the title compound as an off-white solid.

¹H NMR (400 MHz, CD₃OD-d4): 5 ppm 8.40 (s, 1H), 8.02 (d, 1H, J=7.8 Hz), 7.60 (m, 3H), 7.29 (m, 1H), 7.08 (s, 1H), 6.58 (m, 1H), 5.56 (s, 1H), 4.00 (m, 1H), 3.55 (m, 2H), 3.48 (m, 2H), 3.31 (m, 4H), 3.30 (m, 1H), 2.59 (m, 2H), 2.29 (m, 1H), 1.95 (m, 1H), 1.54 (m, 6H), 0.95 (m, 3H). LCMS (MH+): 649.

Example 54b
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

To a solution of (S)-ethyl 8-(2-amino-6-((R)-1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (350 mg, 0.56 mmol) in CH₂Cl₂(20 mL) was added Boc₂O (436 mg, 2.0 mmol) and Et₃N (306 mg, 3.03 mmol) at 0° 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 (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a yellow solid.

Step 2:

A solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (150 mg, 0.2 mmol), 4-isopropoxyphenyl boronic acid (44 mg, 0.25 mmol) and Pd(dppf)Cl₂(15 mg, 0.02 mmol) in dioxane (3.0 mL)/aqueous Na₂CO₃solution (3.0 mL, 2.0 M, aq.) was stirred at 90° C. for 2 h. The aqueous layer was extracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/Hex=10 to 50%) to (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.

Step 3:

To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (130 mg, 0.164 mmol) in CH₂Cl₂(4 mL) 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 NaHCO₃. The aqueous layer was extracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to provide (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a light yellow solid that is used without further purification.

Step 4:

Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (d, J=6.0 Hz, 6H), 1.58 (m, 4H), 2.04 (dd, J=13.4, 7.2 Hz, 1H), 2.32 (dd, J=13.4, 9.2 Hz, 1H), 3.11 (d, J=11.7 Hz, 1H), 3.24 (d, J=11.7 Hz, 1H), 3.45 (ddd, J=21.2, 10.1, 6.4 Hz, 2H), 3.60 (td, J=12.4, 11.2, 6.0 Hz, 2H), 4.08 (dd, J=9.1, 7.1 Hz, 1H), 4.62 (p, J=6.1 Hz, 1H), 6.67 (q, J=6.8 Hz, 1H), 6.95 (m, 2H), 7.54 (m, 9H), 7.72 (d, J=8.3 Hz, 1H). LCMS (MH+): 663.

Example 54c
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-propoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 54b) by substituting 4-propoxyphenyl boronic acid for 4-isopropoxyphenyl boronic acid in Step 2.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.04 (t, J=7.4 Hz, 3H), 1.57 (m, 4H), 1.80 (h, J=6.7 Hz, 2H), 1.99 (dd, J=13.3, 7.3 Hz, 1H), 2.27 (dd, J=13.3, 9.1 Hz, 1H), 3.02 (d, J=11.6 Hz, 1H), 3.18 (d, J=11.5 Hz, 1H), 3.30 (d, J=3.2 Hz, 1H), 3.45 (q, J=15.9, 11.4 Hz, 2H), 3.60 (s, 2H), 3.97 (dt, J=13.1, 7.3 Hz, 3H), 4.88 (m, 1H), 5.47 (s, 1H), 6.66 (q, J=6.9 Hz, 1H), 6.97 (d, J=8.3 Hz, 2H), 7.54 (m, 9H), 7.72 (m, 1H). LCMS (MH+): 662.

Example 54d
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

To a mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (5 g, 21.3 mmol) in anhydrous methanol (100 mL) was added concentrated sulfuric acid (0.5 mL). The resulting solution was stirred for 18 h at reflux. Upon cooling, the mixture was concentrated under reduced pressure, dissolved in CH₂Cl₂and washed with NaHCO₃solution and brine. The organic phase was dried over sodium sulfate and concentrated to afford methyl 2-chloro-4-(methylsulfonyl)benzoate as a white solid.

Step 2:

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

Step 3:

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

Step 4:

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

Step 5:

To a solution of 5-(methylsulfonyl)-[1,1′-biphenyl]-2-carbaldehyde (1 g, 3.8 mmol) was added TMS-CF₃(1.0 g, 7.7 mmol) in THF (10 mL). The reaction was cooled to 0° C. to and TBAF (0.57 mL, 0.57 mmol) was added dropwise. The reaction mixture was stirred 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 acetate, washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification on normal phase silica gel provided 2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)ethanol as a white solid.

Step 6:

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

Step 7:

Chiral reduction of 2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)ethanone using the Iridium complex-catalyzed hydrogenation as described for Intermediate 1, (R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol, provided (R)-2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)ethanol as a white solid.

Steps 8-11:

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.63 (q, J=5.7, 4.9 Hz, 4H), 2.10 (m, 1H), 2.36 (dd, J=13.5, 9.2 Hz, 1H), 3.23 (d, J=31.0 Hz, 5H), 3.50 (dddd, J=18.0, 13.4, 9.5, 5.1 Hz, 2H), 3.66 (ddt, J=15.9, 10.6, 4.6 Hz, 2H), 4.16 (dd, J=9.2, 7.2 Hz, 1H), 6.78 (q, J=6.7 Hz, 1H), 7.57 (m, 5H), 7.86 (d, J=1.9 Hz, 1H), 8.01 (m, 2H), 8.17 (s, 1H). LCMS (MH+): 607.

Example 54e
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-fluoro-4-propoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 54b) by replacing the 4-isopropoxyphenyl boronic acid in Step 2 with (3-fluoro-4-propoxyphenyl)boronic acid (CAS#192376-68-4).

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.86 (m, 1H), 1.05 (t, J=7.4 Hz, 3H), 1.26 (s, 1H), 1.59 (s, 4H), 1.83 (h, J=7.1 Hz, 2H), 2.06 (dd, J=13.4, 7.2 Hz, 1H), 2.33 (m, 1H), 3.10 (d, J=11.9 Hz, 1H), 3.23 (d, J=12.0 Hz, 1H), 3.43 (s, 2H), 3.60 (s, 2H), 4.02 (t, J=6.5 Hz, 2H), 4.12 (s, 1H), 6.62 (d, J=6.8 Hz, 1H), 7.09 (t, J=8.7 Hz, 1H), 7.34 (s, 1H), 7.43 (m, 4H), 7.50 (s, 3H), 7.60 (m, 1H), 7.76 (m, 2H). LCMS (MH+): 681.

Example 54f
(S)-8-(2-amino-6-((R)-1-(3,4-dimethyl-[1,1′:3′,1″-terphenyl]-4′-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 54b) by replacing the 4-isopropoxyphenyl boronic acid in Step 2 with 3,4-dimethylphenyl boronic acid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.62 (s, 4H), 2.06 (dd, J=13.5, 7.6 Hz, 1H), 2.29 (d, J=9.7 Hz, 5H), 2.37 (m, 1H), 3.17 (d, J=11.8 Hz, 1H), 3.26 (d, J=11.7 Hz, 1H), 3.63 (d, J=14.2 Hz, 2H), 4.27 (t, J=8.3 Hz, 1H), 6.66 (q, J=6.8 Hz, 1H), 7.18 (d, J=7.9 Hz, 1H), 7.36 (m, 2H), 7.49 (m, 5H), 7.64 (dd, J=8.2, 2.0 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H). LCMS (MH+): 633.

Example 54g
(S)-8-(6-((R)-1-([1,1′:3′,1″-terphenyl]-4′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 54b) by substituting phenyl boronic acid for 4-isopropoxyphenyl boronic acid in Step 2.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.62 (s, 4H), 2.06 (dd, J=13.5, 7.7 Hz, 1H), 2.38 (dd, J=13.5, 9.1 Hz, 1H), 3.16 (d, J=11.8 Hz, 1H), 3.26 (d, J=11.8 Hz, 1H), 3.47 (s, 2H), 3.62 (s, 2H), 4.26 (t, J=8.4 Hz, 1H), 6.68 (q, J=6.9 Hz, 1H), 7.35 (m, 1H), 7.47 (m, 4H), 7.53 (s, 3H), 7.66 (m, 3H), 7.77 (d, J=8.2 Hz, 1H). LCMS (MH+): 604.

Example 54h
(R)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 34c) by using (R)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.59 (d, J=5.5 Hz, 4H), 2.03 (dd, J=13.4, 7.1 Hz, 1H), 2.31 (dd, J=13.4, 9.2 Hz, 1H), 3.09 (d, J=11.8 Hz, 1H), 3.23 (d, J=11.6 Hz, 1H), 3.46 (dt, J=15.3, 8.2 Hz, 2H), 3.62 (s, 2H), 4.06 (dd, J=9.1, 7.1 Hz, 1H), 5.49 (s, 1H), 6.64 (q, J=6.9 Hz, 1H), 7.28 (d, J=2.2 Hz, 1H), 7.46 (m, 5H), 7.53 (s, 1H), 7.67 (d, J=8.5 Hz, 1H). LCMS (MH+): 562.

Example 54i
(R)-8-(2-amino-6-((S)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 34c) by using (R)-2-benzyl 3-ethyl 8-(2-amino-6-((S)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.70 (d, J=8.5 Hz, 1H), 7.59-7.44 (m, 4H), 7.47-7.40 (m, 2H), 7.32 (d, J=2.2 Hz, 1H), 6.61 (q, J=6.5 Hz, 1H), 4.51 (t, J=8.7 Hz, 1H), 3.72-3.59 (m, 1H), 3.56 (s, 1H), 3.28 (s, 1H), 2.49 (dd, J=13.6, 8.9 Hz, 1H), 2.10 (dd, J=13.6, 8.4 Hz, 1H), 1.71 (dt, J=16.0, 6.6 Hz, 4H), 1.28 (s, 0H). LCMS (MH+): 562.

Example 54j
(S)-8-(2-amino-6-((S)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 34c) by using (S)-2-benzyl 3-ethyl 8-(2-amino-6-((S)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.70 (d, J=8.5 Hz, 1H), 7.61-7.42 (m, 6H), 7.32 (d, J=2.3 Hz, 1H), 6.66 (q, J=6.7 Hz, 1H), 4.25 (dd, J=9.0, 7.6 Hz, 1H), 3.72-3.60 (m, 1H), 3.29 (d, J=11.7 Hz, 1H), 3.18 (d, J=11.8 Hz, 1H), 2.40 (dd, J=13.5, 9.2 Hz, 1H), 2.09 (dd, J=13.5, 7.6 Hz, 1H), 1.64 (s, 2H). LCMS (MH+): 562.

Example 54k
(S)-8-(2-amino-6-((S)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 1m) by using (S)-2-benzyl 3-ethyl 8-(2-amino-6-((S)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.58 (s, 6H), 2.04 (dd, J=13.4, 7.2 Hz, 1H), 2.30 (d, J=11.1 Hz, 9H), 2.40 (s, 3H), 3.10 (d, J=11.8 Hz, 1H), 3.23 (d, J=11.7 Hz, 1H), 3.48 (s, 2H), 3.66 (d, J=15.7 Hz, 3H), 4.08 (t, J=8.2 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 6.77 (q, J=6.5 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.73 (m, 2H), 7.97 (d, J=2.4 Hz, 1H). LCMS (MH+): 635.

Example 54l
(R)-8-(2-amino-6-((S)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described above for (R)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 1m) by using (R)-2-benzyl 3-ethyl 8-(2-amino-6-((S)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.97 (d, J=2.3 Hz, 0H), 7.79-7.69 (m, 0H), 7.61 (d, J=1.6 Hz, 0H), 7.45 (s, 0H), 7.42-7.35 (m, 0H), 7.21 (d, J=7.9 Hz, 0H), 6.77 (q, J=6.5 Hz, 0H), 6.41 (d, J=2.3 Hz, 0H), 4.10 (t, J=8.2 Hz, 0H), 3.68 (dd, J=13.9, 6.3 Hz, 0H), 3.58-3.43 (m, 0H), 3.24 (d, J=11.7 Hz, 0H), 3.11 (d, J=11.8 Hz, 0H), 2.42-2.27 (m, 1H), 2.05 (dd, J=13.5, 7.2 Hz, 0H), 1.59 (d, J=11.4 Hz, 0H), 1.59 (s, 0H). LCMS (MH+): 635.

Example 54m
(R)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was prepared as described above for (R)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (Example 1m) by using (R)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.97 (d, J=2.4 Hz, 1H), 7.79-7.68 (m, 2H), 7.60 (d, J=1.7 Hz, 1H), 7.44 (s, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 6.76 (q, J=6.7 Hz, 1H), 6.41 (d, J=2.3 Hz, 1H), 5.75 (s, 1H), 3.98 (t, J=8.1 Hz, 1H), 3.64 (d, J=15.5 Hz, 3H), 3.47 (s, 2H), 3.33-3.27 (m, 6H), 3.17 (d, J=11.6 Hz, 1H), 3.01 (d, J=11.6 Hz, 1H), 2.39 (s, 3H), 2.34-2.18 (m, 8H), 1.99 (dd, J=13.4, 7.1 Hz, 1H), 1.56 (s, 5H). LCMS (MH+): 635.

Example 55an
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

To a solution of (R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol (150 mg, 0.60 mmol) in dioxane (10 mL) was added 4,6-dichloropyrimidin-2-amine (120 mg g, 0.71 mmol) and Cs₂CO₃(290 mg, 0.88 mmol), and the reaction mixture was heated 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 Na₂SO₄, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (R)-4-(1-(4-bromophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine as a colorless oil.

Step 2:

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

Step 3:

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

Step 4:

To a solution of (S)-8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (80 mg, 0.12 mmol) in dioxane (1 mL)/Na₂CO₃(1.0 mL, 2 M, aq) were added (3-methoxyphenyl)boronic acid (22 mg, 0.14 mmol) and Pd(dppf)₂(8 mg, 0.01 mmol). The reaction flask was degassed and refilled with argon via balloon 3 times, and the reaction mixture was refluxed for 4 h. Then the reaction was cooled to RT, concentrated in vacuo, and extracted with EtOAc. The combined organic layers were are washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by reverse phase silica gel column (H₂O/NH₄OH/MeOH) provided (S)-8-(2-amino-6-((S)-2,2,2-trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethoxy)-4-yl)ethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic 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 described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 55an) using the appropriate boronic acid or boronate In some cases, the Cy coupling reaction was performed prior to ethyl ester and N—CBz removal (see alternative Steps 3a and 4a) as noted in the scheme. In the cases of example 55al and 55 am, racemic 1-(4-bromophenyl)-2,2,2-trifluoroethanol was used as opposed to (R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol for all other examples.

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TABLE 17a

Ex.

No.
Cy
CAS Name
LCMS (MH+)

55a

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(S)-8-(6-((R)-1-([1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
529

55b

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1- methyl-1H-indazol-5- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
583

55c

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1- methyl-1H-benzo[d]imidazol-5- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
583

55d

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(S)-8-(6-((R)-1-(4-(1H-benzo[d]imidazol-5- yl)phenyl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid
569

55e

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(S)-8-(2-ammo-6-((R)-2,2,2-trifluoro-1-(3′- fluoro-4-methoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
577

55f

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(S)-8-(2-amino-6-((R)-1-(4-(benzo[d]isothiazol- 6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
586

55g

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(S)-8-(2-amino-6-((R)-1-(4-(benzo[d]isoxazol-6- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
570

55h

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(S)-8-(6-((R)-1-(4-(1H-indazol-6-yl)phenyl)- 2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
569

55i

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1- methyl-1H-indazol-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro)[4.5]decane-3-carboxylic acid
583

55j

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(S)-8-(2-amino-6-((R)-1-(4-(benzo[d]isothiazol- 5-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
586

55k

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(S)-8-(2-amino-6-((R)-1-(4-(benzo[d]thiazol-6- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
586

55l

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(S)-8-(6-((R)-1-(4-([1,2,4]triazolo[1,5-a]pyridin- 6-yl)phenyl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid
570

55m

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4- (naphthalen-2-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
579

55n

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- methoxy-4′-methyl-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
573

55o

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- methoxy-5′-methyl-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
573

55p

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(5′- methoxy-2′-methyl-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
573

55q

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(S)-8-(2-amino-6-((R)-1-(3′,4′-dimethoxy-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
589

55r

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- methoxy-4′-(pyrrolidine-1-carbonyl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
656

55s

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1- oxo-1,3-dihydroisobenzofuran-5- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
585

55t

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2- oxo-1,2-dihydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
596

55u

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1- methyl-2-oxo-1,2-dihydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
610

55v

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2- oxo-1,2,3,4-tetrahydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
598

55w

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(S)-8-(6-((R)-1-(4-(1H-indazol-5-yl)phenyl)- 2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
569

55x

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(S)-8-(2-amino-6-((R)-1-(4-(1,3-dimethyl-1H- indazol-5-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
597

55y

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(S)-8-(2-amino-6-((R)-1-(4-(1,3-dimethyl-1H- indol-5-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
596

55z

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- methoxy-5′-(trifluoromethyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
627

55aa

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(S)-8-(2-amino-6-((R)-1-(3′-cyano-5′-methoxy- [1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
584

55ab

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2- oxo-2,3-dihydrobenzo[d]oxazol-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
586

55ac

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3- methyl-1H-indol-5-yl)phenyl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
1

55ad

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(S)-8-(6-((R)-1-(3′-acetoxy-4′- (methoxycarbonyl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
645

55ae

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2- oxo-2H-chromen-7-yl)phenyl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
596

55af

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1- methyl-6-oxo-1,6-dihydropyridin-3- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
560

55ag

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(S)-8-(2-amino-6-((R)-1-(4′-carboxy-3′-hydroxy- [1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
588

55ah

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2- methoxyquinolin-6-yl)phenyl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
610

55ai

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2- (methylthio)quinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
626

55aj

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1- methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
612

55ak

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(3S)-8-(2-amino-6-(2,2,2-trifluoro-1-(3′-fluoro- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
547

55al

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(3S)-8-(2-amino-6-(2,2,2-trifluoro-1-(3′-methoxy- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
559

55am

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- fluoro-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
547

55an

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- methoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
559

55ao

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- fluoro-5′-methoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
577

55ap

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(S)-8-(2-amino-6-((R)-1-(3′,5′-difluoro-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
565

55aq

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- methoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
559

55ar

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2′- methoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
559

55as

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- (trifluoromethyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
597

55at

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- (trifluoromethoxy)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
613

55au

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(S)-8-(2-amino-6-((R)-1-(3′-ethoxy-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
573

55av

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- isopropoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
587

55aw

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4- (pyridin-3-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
530

55ax

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4- (pyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
530

55ay

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4- (pyrimidin-5-yl)phenyl)ethoxy)pyrimidin-4-yl) 2,8-diazaspiro[4.5]decane-3-carboxylic acid
531

55az

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3- methyl-1H-indazol-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
583

55ba

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(S)-8-(2-amino-6-((R)-1-(4-(1,3-dimethyl-1H- indazol-6-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
597

55bb

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S)-8-(2-amino-6-((R)-1-(4-(2,3-dimethyl-2H- indazol-6-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
597

55bc

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1- oxo-1,2,3,4-tetrahydroisoquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
598

55bd

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4- (isoquinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
580

55be

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4- (isoquinolin-7-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
580

55bf

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(S)-8-(2-amino-6-((R)-1-(4′- ((dimethylamino)methyl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
586

55bg

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4- (quinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
580

55bh

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4- (quinolin-7-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
580

55bi

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4- (quinoxalin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
581

55bj

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2- methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
612

55bk

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4- (quinazolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
581

55bl

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- fluoro-2′-methoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
577

55bm

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2′- fluoro-3′-methoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
577

55bn

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2′- fluoro-5′-methoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
577

55bo

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(6- methylpyridin-3-yl)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
544

55bp

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- (pyrrolidine-1-carbonyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
626

55bq

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(S)-8-(2-amino-6-((R)-1-(3′-carboxy-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
573

55br

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(S)-8-(2-amino-6-((R)-1-(4′-carboxy-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
573

55bs

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- propyl-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
571

55bt

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- (hydroxymethyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
559

55bu

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2′- (hydroxymethyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
559

55bv

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- isopropoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
587

55bw

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(S)-8-(2-amino-6-((R)-1-(4′- (dimethylcarbamoyl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
600

55bx

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- (piperidine-1-carbonyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
640

55by

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(S)-8-(2-amino-6-((R)-1-(2′- ((dimethylamino)methyl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
586

55bz

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(S)-8-(2-amino-6-((R)-1-(4′-ethyl-[1,1′-biphenyl]- 4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
557

55ca

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- hydroxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
545

55cb

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- hydroxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
545

55cc

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(S)-8-(2-amino-6-((R)-1-(2′,4′-dimethoxy-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
589

55cd

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- (trifluoromethyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
597

55ce

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2′- (trifluoromethyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
597

55cf

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(S)-8-(2-amino-6-((R)-1-(2′,6′-difluoro-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
565

55cg

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(S)-8-(2-amino-6-((R)-1-(2′,6′-dimethyl-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
557

55ch

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(S)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
557

55ci

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(S)-8-(2-amino-6-((R)-1-(4′-(tert-butyl)-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
585

55cj

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- isopropyl-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
571

55ck

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- isopropyl-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
571

55cl

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(S)-8-(2-amino-6-((R)-1-(3′,4′-dichloro-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
597

55cm

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- (trifluoromethoxy)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
613

55cn

embedded image

(S)-8-(2-amino-6-((R)-1-(2′,3′-dimethyl-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
557

55co

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′,4′,5′- trifluoro-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
583

55cp

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(S)-8-(2-amino-6-((R)-1-(4′-chloro-2′-methyl- [1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
577

55cq

embedded image

(S)-8-(2-amino-6-((R)-1-(3′,5′-dimethyl-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
557

55cr

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(S)-8-(2-amino-6-((R)-1-(3′,4′-difluoro-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
565

55cs

embedded image

(S)-8-(2-amino-6-((R)-1-(2′,5′-dimethyl-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
557

55ct

embedded image

(S)-8-(2-amino-6-((R)-1-(4′-butyl-[1,1′-biphenyl]- 4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
585

55cu

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- fluoro-4′-methyl-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
561

55cv

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- (methylsulfonyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
607

55cw

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- methyl-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
543

55cx

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- methyl-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
543

55cy

embedded image

(S)-8-(2-amino-6-((R)-1-(4′-chloro-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
563

55cz

embedded image

(S)-8-(2-amino-6-((R)-1-(4-(benzofuran-3- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
569

55da

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(5′- fluoro-2′-methoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
577

55db

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2- oxochroman-7-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
599

55dc

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trfluoro-1-(4-(3- fluoroquinolin-6-yl)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
597

55dd

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- propoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
587

55de

embedded image

(S)-8-(2-amino-6-((R)-1-(4′-(diethylcarbamoyl)- [1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
628

55df

embedded image

(S)-8-(2-amino-6-((R)-1-(4′-carbamoyl-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
572

55dg

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- (methylcarbamoyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
585

55dh

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-((2- morpholinoethyl)carbamoyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
685

55di

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- (methylsulfonyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
606

55dj

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- sulfamoyl-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
607

55dk

embedded image

(S)-8-(2-amino-6-((R)-1-(4′- (dimethylcarbamoyl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
600

55dl

embedded image

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′- (piperazine-1-carbonyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
641

55dm

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(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- fluoro-4′-propoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
605

55dn

embedded image

(S)-8-(2-amino-6-((R)-1-(4′-ethoxy-3-fluoro- [1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
591

55do

embedded image

(S)-8-(2-amino-6-((R)-1-(4′-ethoxy-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
573

55dp

embedded image

(S)-8-(2-amino-6-((R)-1-(4-(cinnolin-6- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
580

55dq

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(S)-8-(2-amino-6-((R)-1-(4-(chroman-6- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
584

TABLE 17b

NMR Data for Compounds of Table 17a

Ex.

No.
NMR

55a

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.66-7.58 (m, 6H), 7.45-7.41 (m, 2H),

7.36-7.32 (m, 1H), 6.64 (q, J = 6.8 Hz, 1H), 5.56 (s, 1H), 4.00 (m, 1H), 3.67-3.60 (m, 2H),

3.52-3.44 (m, 2H), 3.20-3.02 (m, 2H), 2.31-2.25 (m, 1H), 2.01 (m, 1H), 1.58 (s, 4H)

55b

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.02 (s, 1 H), 7.92 (s, 1 H), 7.67-7.65 (m, 3 H),

7.61-7.55 (m, 4H), 6.60 (m, 1 H), 5.47 (s, 1 H), 3.97 (s, 4 H), 3.53 (m, 2 H), 3.35 (m, 2

H), 3.15-3.12 (m, 1 H), 3.13-3.00 (m, 1 H), 2.21 (m, 1 H), 1.95 (m, 1H), 1.50 (m, 4H)

55c

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.16 (s, 1 H), 7.89 (s, 1 H), 7.71-7.69 (d, 2 H),

7.63-7.60 (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),

1.54 (m, 4 H), 1.23 (m, 3 H).

55d

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.56 (s, 1H), 7.90 (s, 1H), 7.76-7.61 (m, 6H),

6.66 (q, J = 6.6 Hz, 1H), 5.59 (s, 1H), 4.17-4.13 (m, 1H), 3.69-3.57 (m, 2H),

3.52-3.43 (m, 2H), 3.27-3.24 (m, 1H), 3.16-3.13 (m, 1H), 2.37-2.31 (m, 1H), 2.09-2.04 (m, 5H),

1.61 (m, 4H)

55e

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.62-7.56 (m, 4 H), 7.40 (m, 2 H), 7.15 (m, 1

H), 6.61 (m, 1 H), 5.56 (m, 1 H), 4.07 (m, 1 H), 3.90 (s, 3 H), 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 (m, 1 H), 1.60 (s, 4 H)

55f

¹H NMR (400 MHz, DMSO-d6): δ 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, 1H), 5.57 (s.1H), 3.45 (m, 4H),

2.99 (m, 2 H), 2.10 (m, 1 H), 1.79 (m, 1 H), 1.42 (m, 4 H).

55g

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.66-7.56 (m, 6H), 7.19-7.17 (m, 2H), 6.66 (q,

J = 6.7 Hz, 1H), 5.56-5.55 (m, 1H), 4.08 (m, 1H), 3.64-3.59 (m, 2H), 3.53-3.43 (m, 2H),

3.23-3.13 (m, 1H), 2.98-2.92 (m, 1H), 2.35-2.19 (m, 1H), 2.08-2.03 (m, 1H), 1.59 (m,

4H).

55h

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.06 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.73 (d,

J = 7.7 Hz, 3H), 7.62 (d, J = 7.5 Hz, 2H), 7.44 (d, J = 8.6 Hz, 1H), 6.67 (q, J = 7.4 Hz,

1H), 5.58 (s, 1H), 4.08 (m, 1H), 3.69-3.61 (m, 2H), 3.52-3.43 (m, 2H), 3.23-3.10 (m,

2H), 2.35-2.30 (m, 1H), 2.08-2.03 (m, 1H), 1.60 (s, 4H).

55i

¹H NMR (400 MHz, DMSO-d6): δ ppm 8.03 (s, 1 H), 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, 1 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): δ ppm 8.96 (s, 1 H), 8.33 (s, 1 H), 8.09-8.07 (d, 1 H,

J = 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, J = 8.0 Hz), 6.63-6.58 (q, 1 H), 5.51 (s.1H), 4.00-3.96 (m, 1 H), 3.57 (m, 2 H),

3.40 (m, 2 H), 3.17-3.14 (d, 1 H, J = 11.7 Hz), 3.13-3.00 (d, 1 H, J = 11.7 Hz), 2.23-2.21 (m, 1

H), 1.99-1.94 (m, 1 H), 1.53 (m, 5 H).

55k

¹H NMR (400 MHz, MeOH-d4): δ ppm 9.26 (S, 1 H), 8.33 (s, 1 H), 8.13-8.11 (d, 1 H,

J = 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), 6.67-6.65 (q, 1 H, J = 7.2 Hz), 4.15-4.11 (m, 1 H), 3.53 (m, 2 H), 3.49 (m,

2 H), 3.27-3.24 (d, 1 H, J = 11.7 Hz), 3.15-3.12 (d, 1 H, J = 11.7 Hz), 3.33-2.31 (m, 1 H),

2.07-2.03 (m, 1 H), 1.61 (m, 5 H).

55l

¹H-NMR (400 MHz, MeOH-d4): δ ppm 9.08 9 (s, 1H), 8.44 (s, 1H),

8.02-8.03 (m, 1H), 7.83-7.86 (m, 2H), 7.66-7.75 (m, 2H), 6.66-6.69 (m, 1H), 5.50 (s, 1H),

4.07-4.07 (m, 1H), 3.64-3.66 (m, 2H), 3.44-3.48 (m, 2H), 3.19-3.24 (m, 1H),

3.16-3.46 (m, 1H), 2.29-2.55 (m, 1H), 2.03-2.08 (m, 1H), 1.60-1.61 (m, 4H)

55m

¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.19 (s, 1H), 7.84-7.97 (m, 6H),

7.63-7.82 (m, 2H), 7.50-7.61 (m, 2H), 6.70-6.76 (m, 1H), 5.58 (s, 1H), 3.38-3.47 (S, 1H),

3.00-3.00 (m, 1H), 2.91-2.94 (m, 1H), 2.06-2.13 (m, 1H), 1.74-1.78 (m, 1H),

1.37-1.44 (m, 4H)

55n

¹H-NMR (400 MHz, MeOH-d4): δ ppm 7.63-7.65 (m, 2H), 7.56-7.58 (m, 2H),

7.15-7.20 (m, 1H), 7.07-7.09 (m, 2H), 6.60-6.65 (m, 1H), 4.11-4.16 (m, 1H), 3.87 (s, 3H),

3.48-3.66 (m, 4H), 3.23-3.26 (m, 1H), 3.11-3.16 (m, 1H), 2.31-3.41 (m, 1H),

2.20 (s, 3H), 2.02-2.10 (m, 1H), 1.59-1.61 (m, 4H), 1.27-1.31 (m, 1H)

55o

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.62-7.56 (m, 4H), 7.00 (s, 1H), 6.93 (s, 1H),

6.74 (s, 1H), 6.64 (q, 1H, J = 8.0), 5.56 (d, 1H, J = 4.0), 4.08-4.04 (m, 1H), 3.80 (s, 3H),

3.63 (s, 2H), 3.47 (s, 2H) 3.23 (d, 1H, J = 16.0), 3.10 (d, 1H, J = 12.0 Hz), 2.36 (s, 3H),

2.04 (s, 1H), 1.59 (s, 1H), 1.28 (s, 1H)

55p

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, 1H), 1.30 (d, J = 15.5 Hz, 3H),

1.62 (d, J = 5.7 Hz, 5H), 2.06 (m, 1H), 2.14 (s, 3H), 2.33 (dd, J = 13.5, 9.2 Hz, 1H), 3.13 (d,

J = 11.7 Hz, 1H), 3.25 (d, J = 11.3 Hz, 1H), 3.51 (dt, J = 20.9, 6.7 Hz, 2H), 3.66 (d, J = 13.3 Hz,

2H), 3.76 (s, 3H), 4.09 (t, J = 8.2 Hz, 1H), 5.57 (s, 1H), 6.69 (m, 2H),

6.81 (dd, J = 8.4, 2.8 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.35 (m, 2H), 7.57 (d, J = 7.9 Hz,

2H)

55q

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 4.01-3.97 (m, 1H),

3.31-3.23 (m, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.67-3.60 (m, 2H), 3.49-3.43 (m, 2H)

3.19 (d, 1H, J = 12.0), 3.02 (d, 1H, J = 12.0 Hz), 2.27 (dd, 1H, J = 12.0, 8.0), 2.00 (dd, 1H, J = 14.0,

4.0), 1.58 (s, 1H), 1.28 (s, 1H)

55r

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.70-7.61 (m, 4H), 7.28 (m, 3H), 6.67 (q, J = 7.6 Hz,

1H), 5.56 (s, 1H), 4.08 (m, 1H), 3.91 (s, 3H), 3.63-3.46 (m, 8H), 3.13 (m, 1H),

2.35-2.29 (m, 1H), 2.01-1.99 (m, 1H), 1.97-1.87 (m, 5H), 1.59 (m, 4H).

55s

¹H-NMR (400 MHz, MeOH-d4): δ ppm 1.74-1.73 (m, 4H), 2.13-2.07 (m, 1H),

2.52-2.46 (m, 1H), 3.60-3.55 (m, 1H), 3.70-3.66 (m, 2H), 4.55-4.50 (m, 1H), 5.44 (s, 2H),

6.66-6.63 (m, 1H), 7.74-7.69 (m, 2H), 7.88-7.80 (m, 4H), 7.96-7.92 (m, 1H)

55t

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.03-8.05 (m, 1H), 7.95 (s, 1H),

7.84-7.86 (m, 1H), 7.71-7.73 (m, 2H), 7.60-7.62 (m, 2H), 7.43-7.45 (m, 1H), 6.62-6.65 (m, 2H),

5.57 (s, 1H), 4.05-4.10 (m, 1H), 3.61-3.70 (m, 3H), 3.42-3.52 (m, 3H), 3.09-3.12 (m,

1H), 2.29-2.36 (m, 1H), 2.02-2.07 (m, 1H), 1.60 (m, 4H)

55u

¹H NMR (400 MHz, DMSO-d6): δ ppm 8.02 (s, 1H), 7.93-7.98 (m, 2H),

7.76-7.78 (m, 2H), 7.59-7.63 (m, 3H), 6.63-6.73 (m, 2H), 5.55 (s, 1H), 3.74-3.79 (m, 1H),

3.61 (s, 3H), 3.32-3.47 (m, 5H), 2.89-3.07 (m, 2H), 2.08-2.14 (m, 1H), 1.73-1.80 (m, 1H),

1.41 (m, 4H).

55v

¹H NMR (400 MHz, MeOH-d4): δ 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), 5.56 (s, 1H), 4.07 (t, 1H, J = 8.0),

3.64δ3.58 (m, 2H), 3.52-3.45 (m, 2H), 3.24 (d, 1H, J = 12.0), 3.11 (d, 1H, J = 8.0 Hz),

3.01 (t, 2H, J = 8.0), 2.59-2.57 (m, 2H), 2.32 (dd, 1H, J = 12.0, 8.0), 2.05 (dd, 1H, J = 12.0,

8.0), 1.58 (s, 4H), 1.28 (s, 1H)

55w

¹H NMR (400 MHz, DMSO-d6): δ 1.59 (m, 4 H), 2.05-2.01 (m, 1 H, J = 11.6 Hz),

2.32-2.28 (m, 1 H, J = 11.6 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),

7.61-7.60 (m, 3 H, J = 8.6 Hz), 7.71-7.69 (m, 3 H, J = 8.6 Hz), 8.01 (s, 1 H)

55x

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.61 (d, J = 5.7 Hz, 4H), 2.06 (dd, J = 13.5, 7.3 Hz,

1H), 2.35 (dd, J = 13.5, 9.2 Hz, 1H), 2.56 (s, 3H), 3.15 (d, J = 11.8 Hz, 1H),

3.25 (d, J = 11.7 Hz, 1H), 3.54 (m, 5H), 3.99 (s, 3H), 4.17 (t, J = 8.3 Hz, 1H), 5.00 (s, 1H),

6.66 (q, J = 7.1 Hz, 1H), 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, MeOH-d4): δ ppm 1.54 (m, 4 H), 2.10 (m, 1 H), 2.26 (m, 4 H),

3.04 (m, 1 H), 3.17 (m, 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), 7.45-7.42 (m, 1 H),

7.57-7.55 (m, 2 H), 7.72-7.68 (m, 3 H)

55z

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.72-7.63 (m, 4H), 7.45 (s, 1H), 7.40 (s, 1H),

7.18 (s, 1H), 6.66 (q, 1H, J = 8.0), 4.30 (d, 1H, J = 8.0), 3.91 (s, 3H), 3.66 (s, 2H), 3.55 (s, 2H),

3.26 (s, 1H), 3.19 (d, 1H, J = 12.0 Hz), 2.43-2.37 (m, 1H), 2.10-2.05 (m, 1H), 1.65 (s,

5H), 1.28 (s, 1H)

55aa

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H),

3.09 (s, 1H), 2.75 (t, 2H, J = 8.0), 2.46 (d, 1H, J = 16.0), 2.38 (s, 3H), 2.22 (dd, 1H, J = 16.0,

8.0), 1.23-1.19 (m, 3H)

55ab

¹H NMR (400 MHz, MeOH-d4): δ 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 = 11.9 Hz), 3.26-3.23 (d, 1 H, J = 11.9 Hz), 3.52-3.47 (m, 2

H), 3.65-3.54 (m, 2 H), 4.10-4.06 (m, 1H), 5.57 (s, 1 H), 6.65-6.64 (q, 1 H),

7.16-7.14 (d, 2 H, J = 8.2 Hz), 7.51-7.44 (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): δ 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

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.08 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.2 Hz,

2H), 7.67-7.65 (m, 3H), 7.46 (m, 1H), 6.67-6.61 (m, 1H), 4.47 (m, 1H), 3.87 (s, 3H),

3.73-3.52 (m, 4H), 3.27-3.22 (m, 2H), 2.50-2.44 (m, 1H), 2.33 (s, 3H), 2.12-2.06 (m,

1H), 1.68 (m, 4H).

55ae

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.22 (d, J = 5.3 Hz, 2H), 1.42 (m, 4H), 1.82 (d,

J = 13.2 Hz, 1H), 1.98 (dd, J = 17.4, 8.5 Hz, 1H), 2.91 (m, 1H), 3.03 (d, J = 11.0 Hz,

1H), 3.55 (s, 1H), 3.68 (s, 1H), 3.80 (s, 1H), 5.62 (s, 1H), 6.13 (s, 2H), 6.49 (d, J = 9.6 Hz,

1H), 6.75 (q, J = 7.3 Hz, 1H), 7.67 (m, 4H), 7.83 (dd, J = 22.1, 8.1 Hz, 3H),

8.09 (d, J = 9.5 Hz, 1H)

55af

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.01 (d, J = 2.6 Hz, 1H), 7.89 (dd, J = 2.72, 6.8 Hz,

1H), 7.58 (m, 4H), 6.64 (m, 2H), 5.56 (s, 1H), 4.08 (m, 1H), 3.64 (s, 3H), 3.53 (m,

4H), 3.12 (m, 2H), 2.33 (m, 1H), 2.06 (m, 1H), 1.60 (m, 4H).

55ag

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.92 (d, J = 8.8 Hz, 1H), 7.65 (dd, J1 = 8.4 Hz,

J2 = 31.9 Hz, 4H), 7.17-7.14 (m, 2H), 6.66-6.63 (m, 1H), 4.14-4.10 (m, 1H),

3.66-3.59 (m, 2H), 3.54-3.43 (m, 2H), 3.26-3.24 (m, 1H), 3.15-3.12 (m, 1H), 2.37-2.32 (m, 1H),

2.08-2.03 (m, 1H), 1.61 (m, 4H)

55ah

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.16 (d, J = 8.92 Hz, 1H), 8.02 (d, J = 1.56 Hz,

1H), 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,

1H), 6.66 (q, J = 7.12 Hz, 1H), 5.57 (s, 1H), 4.06 (s, 3H), 3.97 (m, 1H), 3.64 (m, 2H),

3.47 (m, 2H), 3.17 (d, J = 10.92 Hz, 1H), 3.00 (d, J = 12.04 Hz, 1H), 2.26 (m, 1H), 2.01 (m,

1H), 1.58 (s, 4H)

55ai

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.06 (d, J = 8.76 Hz, 1H), 8.01 (s, 1H), 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, 1H),

6.68 (q, J = 8.48 Hz, 1H), 5.58 (s, 1H), 4.08 (m, 1H), 3.63-3.50 (m, 4H), 3.24 (d, J = 11.64 Hz,

1H), 3.12 (d, J = 11.64 Hz, 1H), 2.68 (s, 3H), 2.31 (m, 1H), 2.05 (m, 1H),

1.59 (m, 4H).

55aj

¹H NMR (400 MHz, MeOH-d4): δ ppm 67.67 (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, 1H, J = 12.0), 3.67δ3.58 (m,

2H), 3.53-3.48 (m, 2H), 3.38 (s, 3H), 3.27 (d, 1H, J = 12.0), 3.19 (d, 1H, J = 8.0 Hz),

2.99-2.95 (m, 2H), 2.65-2.63 (m, 2H), 2.40 (dd, 1H, J = 12.0, 8.0), 2.09 (dd, 1H, J = 12.0,

8.0), 1.66 (s, 5H), 1.31 (s, 2H)

55ak

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.52-1.67 (m, 4 H) 2.05 (dd, J = 13.42, 7.13 Hz,

1 H) 2.32 (dd, J = 13.54, 9.30 Hz, 1 H) 3.07-3.16 (m, 1 H) 3.24 (d, J = 11.76 Hz, 1

H) 3.38-3.55 (m, 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): δ 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,

1 H) 7.46-7.68 (m, 4 H)

55am

¹H NMR (400 MHz, MeOH-d4): δ 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 = 11.71 Hz,

1 H) 3.40-3.58 (m, 2 H) 3.59-3.80 (m, 2 H) 4.11 (t, J = 7.96 Hz, 1 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 = 10.35 Hz, 1 H)

7.42-7.52 (m, 2 H) 7.56-7.79 (m, 4 H)

55an

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.48-1.66 (m, 4 H) 2.01 (dd, J = 13.37, 7.17 Hz,

1 H) 2.28 (dd, J = 13.35, 9.20 Hz, 1 H) 3.06 (d, J = 11.71 Hz, 1 H) 3.20 (d, J = 11.67 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, 1 H) 7.47-7.68 (m, 4 H)

55ao

¹H NMR (400 MHz, MeOH-d4): δ 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 = 10.75, 2.26 Hz, 1 H)

6.90-7.02 (m, 2 H) 7.51-7.80 (m, 4 H).

55ap

¹H NMR (400 MHz, MeOH-d4): δ 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)

5.93 (s, 1 H) 6.63 (q, J = 6.61 Hz, 1 H) 6.96 (tt, J = 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): δ ppm 1.60-1.87 (m, 4 H) 2.09 (dd, J = 13.64, 8.76 Hz,

1 H) 2.50 (dd, J = 13.59, 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): δ 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, 1 H) 6.59 (q, J = 6.22 Hz, 1 H) 7.00 (td, J = 7.46, 0.95 Hz, 1 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 MHz, MeOH-d4): δ 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)

5.93 (s, 0 H) 6.64 (q, J = 6.65 Hz, 1 H) 7.61-7.72 (m, 4 H) 7.73-7.80 (m, 2 H)

7.84-7.94 (m, 2 H)

55at

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.67-1.84 (m, 4 H) 2.10 (dd, J = 13.67, 8.69 Hz,

1 H) 2.51 (dd, J = 13.69, 8.81 Hz, 1 H) 3.55-3.82 (m, 4 H) 4.56 (t, J = 8.76 Hz, 1 H)

5.95 (s, 1 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, MeOH-d4): δ ppm 1.39 (t, J = 7.00 Hz, 3 H) 1.65-1.86 (m, 4 H)

2.09 (dd, J = 13.64, 8.76 Hz, 1 H) 2.50 (dd, J = 13.62, 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, 1 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, MeOH-d4): δ ppm 1.32 (d, J = 6.05 Hz, 6 H) 1.65-1.86 (m, 4 H)

2.09 (dd, J = 13.67, 8.69 Hz, 1 H) 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 = 12.08, 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, 1 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): δ 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, J = 8.27, 1.72 Hz, 1 H) 9.24 (d, J = 2.00 Hz, 1 H)

55ax

¹H NMR (400 MHz, MeOH-d4): δ 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): δ 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): δ ppm 1.60 (t, J = 5.08 Hz, 4 H) 2.00 (s, 2 H)

2.03-2.13 (m, 1 H) 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 = 11.71 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

H)

55ba

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.47-1.74 (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 (m, 1 H) 3.21 3.29 (m, 1H) 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): δ 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): δ ppm 1.62 (br. s., 4 H) 1.97-2.09 (m, 1 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): δ ppm 1.50-1.68 (m, 4 H) 1.86-2.01 (m, 1 H)

2.11-2.28 (m, 1 H) 2.77-2.91 (m, 1 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 H) 7.99-8.09 (m, 1 H) 8.16-8.27 (m, 2 H) 8.41-8.53 (m, 1 H)

9.21-9.33 (m, 1 H)

55be

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.50-1.65 (m, 4 H) 1.92-2.00 (m, 1 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, 1 H) 8.10-8.20 (m, 1 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): δ ppm 1.61 (br. s., 4 H) 1.94-2.04 (m, 1 H) 2.28 (s, 7

H) 2.92-3.06 (m, 1 H) 3.11-3.23 (m, 1 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): δ ppm 1.56 (d, J = 4.69 Hz, 4 H) 1.78-1.95 (m, 1 H)

2.07-2.22 (m, 1 H) 2.69-2.83 (m, 1 H) 2.96-3.09 (m, 1 H) 3.38-3.54 (m, 2 H)

3.56-3.69 (m, 2 H) 3.70-3.79 (m, 1 H) 5.57 (s, 1 H) 6.59-6.77 (m, 1 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, 1 H) 8.77-8.92 (m, 1 H)

55bh

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (br. s., 4 H) 1.84-2.03 (m, 1 H)

2.12-2.29 (m, 1 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 = 1.17 Hz, 1 H) 8.02 (d, J = 8.59 Hz,

1 H) 8.25 (s, 1 H) 8.37 (s, 1 H) 8.87 (d, J = 2.93 Hz, 1 H)

55bi

¹H NMR (400 MHz, MeOH-d 4): δ ppm 1.56 (d, J = 5.08 Hz, 4 H) 1.76-1.88 (m, 1 H)

2.05-2.20 (m, 1 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, 1H) 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, 1 H) 8.89 (dd, J = 12.98, 1.66 Hz, 2 H)

55bj

¹H NMR (400 MHz, MeOH-d4): δ 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, 1 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

¹H NMR (400 MHz, MeOH-d4): δ 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, 1 H)

55bp

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.60 (q, J = 5.9, 5.2 Hz, 4H), 1.98 (m, 5H),

2.32 (dd, J = 13.4, 9.3 Hz, 1H), 3.12 (d, J = 11.8 Hz, 1H), 3.25 (d, J = 11.7 Hz, 1H),

3.50 (m, 4H), 3.61 (m, 4H), 4.08 (dd, J = 9.2, 7.2 Hz, 1H), 5.57 (s, 1H), 6.67 (q, J = 7.1 Hz,

1H), 7.61 (ddd, J = 356.8, 7.9, 5.7 Hz, 4H), 7.71 (m, 4H)

55cc

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.09 (d, J = 1.2 Hz, 0H), 1.28 (s, 0H), 1.61 (q,

J = 5.3 Hz, 0H), 1.92 (m, 0H), 2.05 (dd, J = 13.3, 7.3 Hz, 0H), 2.32 (m, 0H), 3.10 (s,

0H), 3.29 (s, 2H), 3.53 (s, 0H), 3.65 (s, 1H), 3.80 (dd, J = 16.8, 1.2 Hz, 0H), 4.07 (t, J = 8.2 Hz,

0H), 4.89 (d, J = 3.8 Hz, 0H), 5.56 (d, J = 1.2 Hz, 0H), 5.99 (m, 0H), 6.60 (m,

0H), 7.21 (dd, J = 8.4, 1.2 Hz, 0H), 7.48 (d, J = 1.2 Hz, 1H)

55ce

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.58 (q, J = 6.7, 6.1 Hz, 4H), 1.94 (dd, J = 13.2,

9.1 Hz, 1H), 2.39 (dd, J = 13.3, 8.6 Hz, 1H), 3.20 (s, 2H), 3.80 (m, 3H), 4.54 (t, J = 8.4 Hz,

1H), 5.74 (s, 1H), 6.31 (s, 2H), 6.90 (q, J = 7.2 Hz, 1H), 7.49 (t, J = 6.5 Hz,

3H), 7.76 (m, 6H), 9.01 (dt, J = 21.8, 11.9 Hz, 1H), 9.74 (d, J = 11.9 Hz, 1H)

55cg

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.59 (m, 4H), 2.00 (s, 7H), 2.41 (m, 1H),

3.20 (s, 2H), 3.60 (m, 4H), 3.83 (m, 1H), 4.53 (d, J = 8.7 Hz, 1H), 5.74 (s, 1H), 6.34 (dd, J = 28.1,

14.7 Hz, 2H), 6.91 (q, J = 7.4 Hz, 1H), 7.24 (m, 5H), 7.67 (d, J = 7.8 Hz, 2H),

8.99 (s, 1H), 9.77 (d, J = 8.4 Hz, 1H)

55cj

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.29 (d, J = 6.8 Hz, 6H), 1.58 (m, 4H),

1.94 (dd, J = 13.2, 9.2 Hz, 1H), 2.39 (dd, J = 13.4, 8.6 Hz, 1H), 2.99 (hept, J = 7.1 Hz, 1H),

3.19 (s, 2H), 3.59 (m, 4H), 4.55 (d, J = 9.2 Hz, 1H), 5.73 (s, 1H), 6.28 (m, 2H), 6.81 (q,

J = 7.4 Hz, 1H), 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, 1H), 9.76 (s, 1H)

55ck

¹H NMR (400 MHz, DMSO-d6): δ ppm 0.99 (s, 1H), 1.31 (d, J = 6.9 Hz, 7H), 1.58 (m,

4H), 1.94 (dd, J = 13.2, 9.2 Hz, 1H), 2.39 (dd, J = 13.4, 8.6 Hz, 1H), 3.02 (hept, J = 7.2 Hz,

1H), 3.19 (s, 2H), 3.55 (ddd, J = 19.7, 12.2, 5.9 Hz, 2H), 3.86 (s, 2H), 4.05 (s, 1H),

4.54 (q, J = 8.9, 6.7 Hz, 1H), 5.73 (s, 1H), 6.31 (m, 2H), 6.81 (q, J = 7.3 Hz, 1H),

7.46 (m, 5H), 7.65 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 8.96 (dt, J = 20.8, 8.6 Hz,

1H), 9.77 (d, J = 8.5 Hz, 1H)

55cp

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.29 (s, 1H), 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, 1H),

3.19 (s, 7H), 3.59 (m, 13H), 4.15 (s, 1H), 4.55 (d, J = 8.4 Hz, 4H), 5.75 (s, 3H),

6.38 (m, 5H), 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): δ ppm 1.60 (m, 4H), 2.05 (m, 1H), 2.34 (s, 7H),

3.12 (d, J = 11.5 Hz, 1H), 3.24 (d, J = 11.5 Hz, 1H), 3.49 (m, 2H), 3.64 (dq, J = 12.6, 6.5,

4.7 Hz, 2H), 4.08 (t, J = 8.2 Hz, 1H), 5.56 (s, 1H), 6.64 (q, J = 7.1 Hz, 1H), 6.99 (s,

1H), 7.21 (s, 2H), 7.59 (m, 5H)

55cr

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.29 (s, 1H), 1.58 (dq, J = 11.6, 7.5, 7.1 Hz,

11H), 1.94 (dd, J = 13.3, 9.1 Hz, 3H), 2.15 (s, 0H), 2.39 (dd, J = 13.3, 8.6 Hz, 3H),

2.61 (d, J = 8.8 Hz, 3H), 3.05 (s, 0H), 3.19 (s, 6H), 3.40 (s, 1H), 3.54 (h, J = 6.4 Hz, 3H),

3.81 (m, 4H), 4.01 (dd, J = 19.9, 11.7 Hz, 1H), 4.16 (s, 1H), 4.54 (t, J = 8.6 Hz, 3H),

5.73 (s, 3H), 6.28 (d, J = 15.5 Hz, 5H), 6.81 (q, J = 7.3 Hz, 3H), 7.63 (m, 11H),

7.86 (dd, J = 17.4, 7.8 Hz, 8H), 8.99 (dq, J = 23.7, 15.7, 12.4 Hz, 2H), 9.72 (s, 3H)

55cs

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.57 (m, J = 8.0, 6.2 Hz, 8H), 1.94 (dd, J = 13.2,

9.2 Hz, 2H), 2.23 (s, 6H), 2.34 (s, 8H), 3.20 (s, 5H), 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, 1H), 6.45 (s, 1H),

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): δ ppm 0.97 (t, J = 7.3 Hz, 3H), 1.50 (m, 9H),

1.94 (dd, J = 13.3, 9.2 Hz, 1H), 2.39 (dd, J = 13.3, 8.6 Hz, 1H), 2.67 (q, J = 6.9, 6.2 Hz, 2H),

3.19 (s, 2H), 3.57 (m, 5H), 3.85 (m, 1H), 4.06 (d, J = 16.1 Hz, 1H), 4.54 (m, 1H),

5.74 (s, 1H), 6.31 (s, 2H), 6.81 (q, J = 7.3 Hz, 1H), 7.35 (d, J = 7.8 Hz, 2H), 7.64 (d, J = 7.8 Hz,

4H), 7.78 (d, J = 8.0 Hz, 2H), 8.96 (m, 1H), 9.73 (d, J = 8.2 Hz, 1H)

55cv

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.29 (s, 1H), 1.38 (s, 1H), 1.58 (qd, J = 12.6,

8.1, 7.6 Hz, 11H), 1.95 (m, 8H), 2.43 (m, 5H), 2.94 (t, J = 10.0 Hz, 1H), 3.08 (dd, J = 16.3,

7.0 Hz, 1H), 3.19 (s, 6H), 3.33 (s, 8H), 3.52 (m, 4H), 3.82 (m, 5H), 4.11 (m, 4H),

4.53 (dt, J = 12.6, 6.0 Hz, 3H), 5.75 (s, 2H), 6.20 (s, 1H), 6.28 (d, J = 9.3 Hz, 2H),

6.48 (s, 3H), 6.84 (q, J = 7.3 Hz, 2H), 7.56 (s, 1H), 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): δ ppm 1.29 (s, 1H), 1.58 (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, 0H), 2.40 (s, 8H), 2.49 (d, J = 9.3 Hz,

0H), 3.03 (m, 1H), 3.19 (s, 5H), 3.55 (m, 3H), 3.81 (t, J = 8.1 Hz, 0H), 4.00 (m,

8H), 4.24 (m, 0H), 4.35 (m, 1H), 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, 2H), 9.74 (s, 2H)

55cx

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.29 (s, 1H), 1.59 (m, 11H), 1.94 (dd, J = 13.3,

9.1 Hz, 3H), 2.43 (s, 11H), 2.61 (d, J = 9.0 Hz, 1H), 3.19 (s, 6H), 3.58 (m, 11H),

4.13 (s, 1H), 4.54 (m, 6H), 5.75 (s, 2H), 6.26 (s, 1H), 6.34 (s, 1H), 6.42 (s, 2H), 6.81 (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,

3H)

55db

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H)

55dc

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.58 (t, J = 5.4 Hz, 4H), 2.02 (dd, J = 13.4, 7.0 Hz,

1H), 2.29 (dd, J = 13.4, 9.1 Hz, 1H), 3.08 (d, J = 11.6 Hz, 1H), 3.21 (d, J = 11.5 Hz,

1H), 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,

1H), 4.94 (s, 10H), 5.58 (s, 1H), 6.69 (q, J = 7.2 Hz, 1H), 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, 1H), 8.12 (m, 3H), 8.79 (d, J = 2.7 Hz,

1H)

55dd

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.05 (t, J = 7.4 Hz, 3H), 1.29 (d, J = 5.8 Hz,

1H), 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,

1H), 2.32 (dd, J = 13.4, 9.2 Hz, 1H), 3.11 (d, J = 11.8 Hz, 1H), 3.23 (d, J = 12.0 Hz,

1H), 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, 1H), 5.55 (s, 1H), 6.62 (q, J = 7.1 Hz, 1H), 6.97 (m, 2H), 7.56 (m,

6H)

55de

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.32 (dd, J = 13.4,

9.2 Hz, 1H), 3.11 (d, J = 11.8 Hz, 1H), 3.24 (d, J = 11.6 Hz, 1H), 3.35 (m, 3H),

3.56 (dddd, J = 47.5, 27.9, 14.5, 7.8 Hz, 6H), 4.07 (dd, J = 9.2, 7.1 Hz, 1H), 4.92 (s, 17H),

5.57 (s, 1H), 6.66 (q, J = 7.1 Hz, 1H), 7.46 (m, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.71 (m,

4H)

55df

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.64 (m, 4H), 2.07 (dd, J = 13.5,

7.6 Hz, 1H), 2.39 (dd, J = 13.5, 9.0 Hz, 1H), 3.17 (d, J = 11.7 Hz, 1H), 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,

1H), 4.87 (m, 3H), 6.66 (q, J = 7.0 Hz, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.74 (m,

4H), 7.96 (m, 2H)

55dg

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (dd, J = 17.3, 3.8 Hz, 2H), 1.62 (m, 4H),

2.06 (dd, J = 13.5, 7.4 Hz, 1H), 2.36 (dd, J = 13.5, 9.1 Hz, 1H), 2.93 (s, 3H), 3.15 (d, J = 11.9 Hz,

1H), 3.26 (d, J = 11.6 Hz, 1H), 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, 1H), 4.93 (d, J = 1.7 Hz, 19H), 6.66 (q, J = 7.1 Hz, 1H),

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): δ ppm 1.60 (q, J = 6.0, 5.0 Hz, 4H), 2.03 (dd, J = 13.4,

7.2 Hz, 1H), 2.31 (dd, J = 13.4, 9.2 Hz, 1H), 2.59 (dt, J = 24.2, 5.7 Hz, 6H),

3.10 (d, J = 11.7 Hz, 1H), 3.23 (d, J = 11.9 Hz, 1H), 3.62 (m, 10H), 4.06 (dd, J = 9.2, 7.2 Hz,

1H), 4.87 (s, 1H), 5.57 (s, 1H), 6.66 (q, J = 7.1 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H),

7.72 (m, 4H), 7.91 (m, 2H)

55di

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.61 (d, J = 5.5 Hz, 4H), 2.05 (dd, J = 13.4, 7.1 Hz,

1H), 2.32 (dd, J = 13.4, 9.3 Hz, 1H), 3.15 (s, 4H), 3.25 (d, J = 11.6 Hz, 1H),

3.50 (dt, J = 20.2, 7.0 Hz, 2H), 3.64 (m, 2H), 4.09 (dd, J = 9.2, 7.1 Hz, 1H), 5.58 (s, 1H),

6.68 (q, J = 7.2 Hz, 1H), 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

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.60 (q, J = 6.4, 5.0 Hz, 4H),

2.03 (dd, J = 13.4, 7.1 Hz, 1H), 2.31 (dd, J = 13.4, 9.2 Hz, 1H), 3.10 (d, J = 11.7 Hz, 1H),

3.23 (d, J = 11.8 Hz, 1H), 3.48 (m, 2H), 3.63 (m, 2H), 4.06 (dd, J = 9.2, 7.1 Hz, 1H),

5.57 (s, 1H), 6.67 (q, J = 7.1 Hz, 1H), 7.68 (m, 4H), 7.79 (m, 2H), 7.96 (m, 2H)

55dk

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 3.6 Hz, 1H), 1.63 (q, J = 5.8 Hz,

5H), 2.07 (dd, J = 13.5, 7.5 Hz, 1H), 2.37 (dd, J = 13.5, 9.0 Hz, 1H), 3.04 (s, 3H),

3.15 (d, J = 24.6 Hz, 6H), 3.27 (m, 1H), 3.52 (dt, J = 24.6, 8.3 Hz, 2H), 3.65 (m, 2H),

4.23 (t, J = 8.1 Hz, 1H), 6.66 (q, J = 7.0 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.68 (m, 6H)

55dl

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, 3H), 1.60 (q, J = 6.1, 4.7 Hz, 4H),

2.05 (dd, J = 13.2, 7.0 Hz, 1H), 2.32 (dd, J = 13.5, 9.2 Hz, 1H), 3.13 (d, J = 11.6 Hz,

1H), 3.26 (m, 5H), 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, 1H), 3.90 (m, 3H), 4.10 (dd, J = 9.2, 7.1 Hz, 1H), 4.95 (s, 13H),

5.56 (s, 1H), 6.67 (q, J = 7.0 Hz, 1H), 7.67 (m, 7H)

55dm

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.06 (t, J = 7.4 Hz, 4H), 1.59 (d, J = 6.1 Hz,

5H), 1.82 (dq, J = 14.1, 6.6 Hz, 2H), 2.02 (dd, J = 13.4, 7.2 Hz, 1H), 2.30 (dd, J = 13.5,

9.2 Hz, 1H), 3.07 (d, J = 11.6 Hz, 1H), 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, 1H),

6.63 (q, J = 7.2 Hz, 1H), 7.13 (t, J = 8.7 Hz, 1H), 7.38 (m, 2H), 7.59 (q, J = 8.4 Hz, 4H)

55dn

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (d, J = 2.6 Hz, 1H), 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, 1H), 2.33 (dd, J = 13.4, 9.0 Hz,

1H), 3.12 (d, J = 11.4 Hz, 1H), 3.25 (d, J = 11.4 Hz, 1H), 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, 1H), 6.63 (q, J = 7.0 Hz,

1H), 7.13 (t, J = 8.6 Hz, 1H), 7.38 (m, 2H), 7.59 (q, J = 8.1 Hz, 4H)

55do

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.33 (dd, J = 13.4, 9.2 Hz, 1H), 3.12 (d, J = 11.7 Hz,

1H), 3.24 (d, J = 11.7 Hz, 1H), 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, 1H), 6.62 (q, J = 7.1 Hz, 1H), 6.97 (m, 2H),

7.57 (m, 6H)

55dp

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.64 (d, J = 6.8 Hz, 5H), 2.07 (dd,

J = 13.5, 7.6 Hz, 1H), 2.38 (dd, J = 13.5, 9.1 Hz, 1H), 3.17 (d, J = 11.8 Hz, 1H),

3.27 (d, J = 11.8 Hz, 1H), 3.52 (m, 1H), 3.66 (m, 1H), 4.24 (t, J = 8.3 Hz, 1H), 6.70 (p, J = 7.2 Hz,

1H), 7.72 (d, J = 8.1 Hz, 3H), 7.90 (m, 3H), 8.28 (m, 3H), 8.53 (m, 1H),

9.31 (d, J = 5.9 Hz, 1H)

55dq

¹NMR (400 MHz, MeOH-d4): δ ppm 7.62-7.49 (m, 4H), 7.33-7.24 (m, 2H),

6.76 (d, J = 8.3 Hz, 1H), 6.62 (q, J = 7.2 Hz, 1H), 5.53 (s, 1H), 4.19-4.12 (m, 2H),

4.08 (dd, J = 9.1, 7.3 Hz, 1H), 3.61 (s, 2H), 3.44 (ddt, J = 20.8, 13.4, 6.0 Hz, 2H), 3.22 (d, J = 11.7 Hz,

1H), 3.10 (d, J = 11.7 Hz, 1H), 2.80 (t, J = 6.5 Hz, 2H), 2.30 (dd, J = 13.5,

9.2 Hz, 1H), 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, 1H)

Example 56
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(1,2,3,4-tetrahydroquinoxalin-6-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (a by-product from the N-CBZ deprotection of Example 55bi) using the LiOH general method provided the title compound as an off-white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.54-1.72 (m, 4H) 2.07-2.14 (m, 1H) 2.29-2.41 (m, 1H) 3.09-3.18 (m, 1H) 3.22-3.29 (m, 1H) 3.36-3.42 (m, 4H) 3.43-3.58 (m, 2H) 3.60-3.80 (m, 2H) 4.03-4.17 (m, 1H) 5.49-5.65 (m, 1H) 6.50-6.67 (m, 2H) 6.77-6.92 (m, 2H) 7.43-7.63 (m, 4H). LCMS (MH+): 585.

Example 57
(S)-8-(2-amino-6-((R)-1-(3,4-dihydroquinazolin-6-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(3,4-dihydroquinazolin-6-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (a by-product from the N-CBZ deprotection of Example 55bk) using the LiOH general method provided the title compound as an off-white solid.

¹H NMR (400 MHz, MeOH-d4) δ ppm 1.54-1.66 (m, 4H) 1.98-2.08 (m, 1H) 2.23-2.34 (m, 1H) 3.02-3.11 (m, 1H) 3.17-3.25 (m, 1H) 3.37-3.54 (m, 2H) 3.55-3.72 (m, 2H) 3.97-4.08 (m, 1H) 4.62-4.70 (m, 2H) 5.50-5.58 (m, 1H) 6.56-6.66 (m, 1H) 6.86-6.93 (m, 1H) 7.19-7.24 (m, 1H) 7.25-7.31 (m, 1H) 7.38-7.44 (m, 1H) 7.51-7.57 (m, 2H) 7.57-7.64 (m, 2H). LCMS (MH+): 583

Example 58
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(1,2,3,4-tetrahydroquinazolin-6-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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¹H NMR (400 MHz, MeOH-d4) δ ppm 1.57-1.68 (m, 4H) 1.93-2.03 (m, 1H) 2.18-2.30 (m, 1H) 2.90-3.01 (m, 1H) 3.12-3.19 (m, 1H) 3.43-3.75 (m, 4H) 3.86-3.95 (m, 1H) 4.00-4.07 (m, 2H) 4.15-4.23 (m, 2H) 5.45-5.64 (m, 1H) 6.56-6.67 (m, 2H) 7.17-7.23 (m, 1H) 7.27-7.33 (m, 1H) 7.49-7.55 (m, 2H) 7.55-7.62 (m, 2H). LCMS (MH+): 585.

Example 59a
(S)-8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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N-CBZ Deprotection was carried out using Method B with (S)-8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-(benzyloxycarbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (75 mg, product of Step 3, Example 55an) providing the title compound as a white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.50-1.68 (m, 4H) 1.96 (s, 2H) 2.04 (dd, J=13.35, 7.20 Hz, 1H) 2.31 (dd, J=13.35, 9.10 Hz, 1H) 3.07-3.26 (m, 2H) 3.35-3.55 (m, 2H) 3.55-3.73 (m, 2H), 4.06 (dd, J=9.13, 7.17 Hz, 1H) 5.52 (s, 1H) 6.57 (q, J=7.11 Hz, 1H) 7.41 (d, J=8.44 Hz, 2H) 7.51-7.58 (m, 2H); LCMS (MH+): 531.

Example 59b
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(naphthalen-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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The title compound was made as described for Example 10e, starting with (R)-2,2,2-trifluoro-1-(naphthalen-2-yl)ethanol.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.20 (dt, J=12.5, 5.3 Hz, 2H), 1.47 (m, 3H), 1.88 (dd, J=12.4, 8.0 Hz, 1H), 2.57 (s, 1H), 2.69 (s, 1H), 2.80 (d, J=12.4 Hz, 1H), 3.36 (m, 3H), 3.97 (dt, J=12.3, 5.2 Hz, 2H), 6.05 (s, 1H), 6.37 (m, 3H), 7.53 (m, 2H), 7.77 (dd, J=7.5, 1.5 Hz, 1H), 7.93 (m, 4H); LCMS (MH+): 562.

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

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Step 1:

To a solution of 4-bromo-2-methylbenzoic acid (5.0 g, 23.2 mmol) in DMF (50 mL) was added potassium carbonate (6.4 g, 46.4 mmol) and iodomethane (6.6 g, 46.479 mmol). The mixture was stirred at RT for 12 h then diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄and concentrated in vacuo. Purification by normal phase silica gel column provided methyl 4-bromo-2-methylbenzoate as a colorless oil.

Step 2:

To a solution of methyl 4-bromo-2-methylbenzoate (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 (1.0M, 10 mL) and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄and concentrated in vacuo. Purification by normal phase silica gel column provided (4-bromo-2-methylphenyl)methanol as a colorless oil.

Step 3:

To the solution of (4-bromo-2-methylphenyl)methanol (1.8 g, 8.1 mmol) in CH₂Cl₂(20 mL) was added Dess-Martin Periodinane (5.1 g, 12.1 mmol) at 0° C. The mixture was stirred at RT for 1 h, then diluted with water, and the solid was removed by filtration. The filtrate was extracted with CH₂Cl₂. The combined organic layer was washed with brine, dried over Na₂SO₄and concentrated in vacuo. Purification by normal phase silica gel column provided 4-bromo-2-methylbenzaldehyde as a yellow oil.

Step 4:

To a solution of 4-bromo-2-methylbenzaldehyde (1.5 g, 7.5 mmol) in THF (20 mL) was added TMSCF₃(2.2 g, 15.5 mmol) at 0° C. and then TBAF (1.1 mL, 1.0 M in THF). The mixture was stirred at RT for 1 h, then diluted with HCl (3.0 M, 10 mL), stirred at RT for 1 h and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄and concentrated in vacuo. Purification by normal phase silica gel column provided 1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanol as an off-white solid.

Step 5:

To a solution of 1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanol (1.8 g, 6.7 mmol) in CH₂Cl₂(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 (10 mL) and filtered. The filtrate was extracted with CH₂Cl₂. The combined organic layer was washed with brine, dried over Na₂SO₄and concentrated in vacuo. Purification by normal phase silica gel column provided 1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanone as a yellow oil.

Step 6:

Chiral reduction of 1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanone using the Iridium complex-catalyzed hydrogenation as described for Intermediate 1, (R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol provides (R)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanol.

Steps 7:

The title compound was prepared as described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 55an) Steps 4-5. 3-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolone was used as the Suzuki coupling partner (CAS#1251731-31-3).

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.59 (s, 4H), 2.04 (dd, J=13.5, 7.0 Hz, 1H), 2.31 (dd, J=13.3, 9.3 Hz, 1H), 2.65 (s, 3H), 3.10 (d, J=11.7 Hz, 1H), 3.23 (d, J=11.5 Hz, 1H), 3.47 (t, J=14.3 Hz, 2H), 3.63 (t, J=13.8 Hz, 2H), 4.07 (t, J=8.1 Hz, 1H), 5.56 (s, 1H), 6.87 (q, J=7.0 Hz, 1H), 7.63 (d, J=4.6 Hz, 3H), 8.01 (d, J=8.9 Hz, 1H), 8.12 (m, 3H), 8.80 (m, 1H). LCMS (MH+): 611.

Example 59d
(S)-8-(2-amino-6-((R)-1-(2-ethyl-4-(3-fluoroquinolin-6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

To a 0° C. solution of LDA (10.7 mL, 21.39 mmol) in THF (20 mL) was added 4-bromo-2-methylbenzoic acid (2 g, 9.3 mmol) in THF (5 mL). The mixture was stirred at 0° C. for 1 h, cooled to −70° C., and then MeI (2.3 mL, 37.20 mmol) was added dropwise. The mixture was allowed to warm up to 0° C., stirred for 3 h, then quenched with H₂O, 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 Na₂SO₄and concentrated in vacuo. Purification by normal phase silica gel column provided 4-bromo-2-ethylbenzoic acid as a white solid.

Step 2:

The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-fluoroquinolin-6-yl)-2-methylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 59c) starting with 4-bromo-2-ethylbenzoic acid in place of 4-bromo-2-methylbenzoic acid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, 1H), 1.41 (t, J=7.5 Hz, 3H), 1.59 (q, J=6.1, 5.6 Hz, 4H), 2.04 (dd, J=13.5, 7.1 Hz, 1H), 2.32 (dd, J=13.4, 9.1 Hz, 1H), 3.01 (dt, J=12.1, 7.0 Hz, 2H), 3.12 (d, J=11.6 Hz, 1H), 3.24 (d, J=11.8 Hz, 1H), 3.48 (dt, J=21.5, 6.9 Hz, 2H), 3.62 (m, 2H), 4.08 (dd, J=9.1, 7.0 Hz, 1H), 4.94 (s, 15H), 5.56 (s, 1H), 7.00 (q, J=6.9 Hz, 1H), 7.67 (m, 3H), 8.11 (m, 5H), 8.80 (d, J=2.8 Hz, 1H). LCMS (MH+): 626.

Example 60
9-(2-Amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-3,9-diazaspiro[5.5]undecane-2-carboxylic acid

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Step 1:

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

Step 2:

Hydrolysis of methyl 9-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-3,9-diazaspiro[5.5]undecane-2-carboxylate using the LiOH general method provides the title compound as an off-white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.22-1.37 (m, 1H) 1.30-1.30 (m, 1H) 1.46-1.68 (m, 4H) 1.68-1.90 (m, 2H) 2.29 (dd, J=12.59, 6.83 Hz, 1H) 2.37 (d, J=1.90 Hz, 3H) 3.07-3.24 (m, 2H) 3.59-3.90 (m, 4H) 4.03-4.19 (m, 1H) 6.29-6.38 (m, 1H) 6.40 (d, J=2.29 Hz, 1H), 6.88-7.02 (m, 1H) 7.52-7.61 (m, 2H) 7.65-7.74 (m, 1H) 7.89 (d, J=2.34 Hz, 1H). LCMS (MH+): 581.

Example 61
(S)-8-(2-Amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

A mixture of 4-bromophenol (173 mg, 1.00 mmol), 4-chloro-6-(chloromethyl)pyrimidin-2-amine (CAS#: 92311-35-8) (178 mg, 1.16 mmol) and K₂CO₃(175 mg, 1.00 mmol) in DMF (5 mL) was heated to 100° C. for 12 h. The reaction was cooled to RT, concentrated in vacuo, and the residue taken up in and EtOAc. The organic layer was washed with brine, dried over Na₂SO₄and concentrated in vacuo. Purification on normal phase silica gel (EtOAc/petroleum ether) provided 4-((4-bromophenoxy)methyl)-6-chloropyrimidin-2-amine as a white solid.

Step 2:

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

Step 3:

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

Step 4:

A mixture of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((4-bromophenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (350 mg, 0.56 mmol), 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (285 mg, 1.1 mmol) and Pd(dppf)Cl₂(62 mg, 0.09 mmol) in dioxane (5 mL)/aq. Na₂CO₃solution (2.0 M, 5 mL) was heated to 90° C. for 4 h. The reaction was cooled to RT, the solids filtered away, and the solution concentrated in vacuo. Purification on normal phase silica gel (CH₂Cl₂/MeOH) provided (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a brown solid.

Step 5:

To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (150 mg, 0.19 mmol) in CH₂Cl₂(5 mL) was added TFA (3 mL), and the resulting mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo, and the resulting material partitioned between CH₂Cl₂and saturated NaHCO₃, and extracted. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by prep-TLC (CH₂Cl₂/MeOH) provided (S)-ethyl 8-(2-amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a brown solid.

Step 6:

To a solution of (S)-ethyl 8-(2-amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (70 mg, 0.11 mmol) in MeOH (3 mL) is added 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.

¹H NMR (400 MHz, DMSO-d6): δ ppm 7.72-7.70 (d, 1H), 7.61-7.59 (d, 3H), 7.31-7.30 (d, 1H), 7.06-7.04 (d, 2H), 6.14 (s, 1H), 4.76 (s, 2H), 3.87-3.83 (q, 1H), 3.46-3.41 (m, 4H), 3.08-3.06 (d, 1H), 2.98-2.95 (d, 1H), 2.43 (s, 1H), 2.16-2.13 (m, 1H), 1.82-1.80 (m, 1H), 1.44 (m, 4H). LCMS (MH+): 514.

Example 62
(S)-8-(2-amino-6-((5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

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Step 1:

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

Step 2:

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

Step 3:

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

Step 4:

A mixture of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((2-bromo-4-chlorobenzyl)oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (300 mg, 0.4 mmol), (3-(methylsulfonyl)phenyl)boronic acid (280 mg, 1 mmol), and Pd(dppf)Cl₂(62 mg, 0.09 mmol) in dioxane (5 mL)/aq. Na₂CO₃solution (2.0 M, 5 mL) was heated to 90° C. for 4 h. The reaction was then cooled to RT, the solids filtered away, and the filtrate concentrated in vacuo. Purification on normal phase silica gel (CH₂Cl₂/MeOH) provided (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.

Step 5:

To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (200 mg, 0.25 mmol) in CH₂Cl₂(5 ml) was added TFA (3 mL), and the resulting mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between CH₂Cl₂and saturated NaHCO₃. The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by prep-TLC (CH₂Cl₂/MeOH) provided (S)-ethyl 8-(2-amino-6-((5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as an off-white solid.

Step 6:

To a solution (S)-ethyl 8-(2-amino-6-((5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (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 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, 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.

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.94 (m, 2H), 7.59-7.57 (m, 3H), 7.44-7.40 (m, 1H), 7.33 (m, 1H), 5.33 (m, 1H), 4.07 (m, 1H), 3.59 (m, 2H), 3.45 (m, 2H), 3.30 (m, 1H), 3.15 (m, 1H), 2.32 (m, 1H), 2.06 (m, 1H), 1.61 (s, 4H). LCMS (MH+): 573.

The following esters were isolated as either a TFA or HCl salt formed during the HPLC purification procedure used to isolate the final compounds.

Example 63bd
(S)-ethyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

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A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (from Step 3, Example 1m, 220 mg, 0.3 mmol) in EtOAc (5 mL) was hydrogenated using Method A by 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-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.

Example 63kp
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

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

Example 63i
(S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

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A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[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.

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TABLE 18a

Ex.

Method

LCMS

No.
Ar
A or B
CAS Name
(MH+)

63a

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4- (benzo[d]thiazol-6-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
613

63b

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A
(S)-ethyl 8-(6-((R)-1-(4-(1H- indazol-5-yl)phenyl)-2,2,2- trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
596

63c

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-methoxy-4′- (pyrrolidine-1-carbonyl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
683

63d

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-4′-nitro-[1,1′-biphenyl]-2- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
631

63e

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- (benzo[d]isothiazol-5-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
613

63f

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4- (benzo[d]isothiazol-6-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
616

63g

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A
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,4′-dimethoxy-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
616

63h

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(1-methyl-2-oxo- 1,2-dihydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
637

63i

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
591

63j

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- amino-5-chloro-[1,1′-biphenyl]-2- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
606

63k

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-(methylsulfonyl)-5- propyl-[1,1′-biphenyl]-2- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
676

63l

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4- (1,3-dimethyl-1H-indol-5- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
622

63m

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A
(S)-ethyl 8-(6-((R)-1-(3′- acrylamido-5-chloro-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
659.1

63n

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-4′-methoxy- [1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
604

63o

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(1-methyl-6-oxo- 1,6-dihydropyridin-3- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
587

63p

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(2-oxo-1,2,3,4- tetrahydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
626

63q

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(2-oxo-1,2- dihydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
623

63r

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B
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-l-(3′-(methylsulfonyl)-5- ((E)-prop-1-en-1-yl)-[1,1′- biphenyl]-2-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
674

63s

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-3- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
583

63t

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- chloro-4-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
671

63u

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-(methylsulfonyl)-4- propyl-[1,1′-biphenyl]-2- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
677

63v

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B
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-(methylsulfonyl)-4- ((E)-prop-1-en-1-yl)-[1,1′- biphenyl]-2-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
675

63w

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(ethylsulfonyl)-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
683

63x

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3-(propylsulfonyl)-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
697

63y

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(butylsulfonyl)-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
711

63z

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(1-oxo-1,3- dihydroisobenzofuran-5- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
612

63aa

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(2-methoxyquinolin- 6-yl)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
638

63ab

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(hydroxymethyl)-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
621

63ac

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(2-oxopyrrolidin-1-yl)- [1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
673

63ad

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(3-methyl-2- oxoimidazolidin-1-yl)-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
688

63ae

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-3′-(methylsulfonyl)-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
668

63af

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(methylsulfonamido)- [1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
683

63ag

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(2- bromo-5-chlorophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
593

63ah

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(1-methyl-2-oxo- 1,2,3,4-tetrahydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate (
595

63ai

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(2- (methylthio)quinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
554

63aj

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (2,5-dibromophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
638

63ak

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A
(S)-ethyl 8-(6-((R)-1-([1,1′:4′,1″- terphenyl]-2′-yl)-2,2,2- trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
633

63al

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(2′- (ethoxycarbonyl)-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
708

63am

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- (ethoxycarbonyl)-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
708

63an

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- (ethoxycarbonyl)-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
708

63ao

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (2,6-dibromophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
638

63ap

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,5-dichloro-[1,1′-biphenyl]-2- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
625

63aq

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-methyl-[1,1′-biphenyl]- 2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
605

63ar

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(trifluoromethyl)-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
659

63as

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H- pyrazol-1-yl)-4′-(methylthio)- [1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
583

63at

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
591

63au

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-methyl-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
651

63av

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-methyl-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
651

63aw

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,4′-dichloro-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
705

63ax

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(2-oxopyrrolidin-1- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
598

63ay

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B
ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
594

63az

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
594

63ba

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-methoxy-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
587

63bb

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-methoxy-2-(3- methyl-1H-pyrazol-1- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
591

63bc

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
575

63bd

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A
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,4′-dimethyl-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
665

63be

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4- ethyl-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
589

63bf

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H- pyrazol-1-yl)-4- propylphenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
603

63bg

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4- butyl-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
617

63bh

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(5- (ethoxycarbonyl)-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
633

63bi

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4- (ethoxycarbonyl)-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
632

63bj

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(5- ((E)-3-ethoxy-3-oxoprop-1-en-1- yl)-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
559

63bk

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(5- (3-ethoxy-3-oxopropyl)-2-(3- methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
588

63bl

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(6-methyl-2-(3-methyl- 1H-pyrazol-1-yl)pyridin-3- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
618

63bm

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B
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H- pyrazol-1-yl)-5-((E)-prop-1-en-1- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
600

63bn

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A
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,4′-dimethyl-4-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-3- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
664

63bo

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H- pyrazol-1-yl)-5- propylphenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
602

63bp

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(5- ethyl-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
588

63bq

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(5- butyl-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
616

63br

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B
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H- pyrazol-1-yl)-5- vinylphenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
586

63bs

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- ((E)-but-1-en-1-yl)-2-(3-methyl- 1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
614

63bt

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(1-methyl-1H-pyrazol-3- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
594

63bu

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(1-methyl-1H- pyrazol-3- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
560

63bv

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4- (1,3-dimethyl-1H-indazol-6- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
624

63bw

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4- (2,3-dimethyl-2H-indazol-6- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
624

63bx

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(1-oxo-1,2,3,4- tetrahydroisoquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
625

63by

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(isoquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
607

63bz

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4- (3-ethoxy-3-oxopropyl)-2-(3- methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
660

63ca

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(isoquinolin-7- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
607

63cb

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(5- (4-ethoxy-4-oxobutyl)-2-(3- methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
674

63cc

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4- (4-ethoxy-4-oxobutyl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
594

63cd

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4- (4-ethoxy-4-oxobutyl)-2-(3- methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
674

63ce

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- cyano-3-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
661

63cf

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-cyano-[1,1′-biphenyl]-2- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
615

63cg

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-methoxy-[1,1′-biphenyl]- 2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
620

63ch

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-sulfamoyl-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
669

63ci

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-hydroxy-[1,1′-biphenyl]- 2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
606

63cj

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(methylsulfonyl)-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
668

63ck

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- (aminomethyl)-5-chloro-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
619

63cl

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(quinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
608

63cm

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(quinolin-7- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
608

63cn

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-isopropoxy-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
694

63co

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(quinoxalin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
608

63cp

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A
(S)-ethyl 8-(6-((R)-1-(4′- (acetamidomethyl)-3-(3-methyl- 1H-pyrazol-1-yl)-[1,1′-biphenyl]- 4-yl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
707

63cq

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A
(S)-ethyl 8-(6-((R)-1-(4′-(2- acetamidoethyl)-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
721

63cr

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H- pyrazol-1-yl)-4-(quinolin-7- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
687

63cs

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(2-methoxypyridin- 4-yl)-2-(3-methyl-1H-pyrazol-1- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
666

63ct

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A
(S)-ethyl 8-(6-((R)-1-(4-(1H- indol-6-yl)-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
595

63cu

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(ethoxycarbonyl)-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
662

63cv

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B
2′-((R)-1-((2-amino-6-((S)-3- (ethoxycarbonyl)-2,8- diazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)oxy)-2,2,2- trifluoroethyl)-5′-chloro-[1,1′- biphcnyl]-3-carboxylic acid
634

63cw

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B
(S)-ethyl 8-(6-((R)-1-(3′- (acrylamidomethyl)-5-chloro- [1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
673

63cx

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- carbamoyl-5-chloro-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
633

63cy

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-4′-(methylsulfonyl)-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
668

63cz

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-4′-sulfamoyl-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylale
669

63da

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(2′- (ethoxycarbonyl)-4-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-3- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
708

63db

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- (ethoxycarbonyl)-4-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-3- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
708

63dc

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- (ethoxycarbonyl)-4-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-3- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
708

63dd

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A
(3S)-ethyl 8-(2-amino-6-((1R)-1- (4-(1,2-dihydroxyethyl)-2-(3- methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
620

63de

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- (aminomethyl)-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
666

63df

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- ((R)-3-ethoxy-3-oxoprop-1-en-1- yl)-4-(3-methyl-1H-pyrazol-1-yl)- [1,1′-biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
734

63dg

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- ((E)-3-ethoxy-3-oxoprop-1-en-1- yl)-4-(3-methyl-1H-pyrazol-1-yl)- [1,1′-biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
734

63dh

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- (3-ethoxy-3-oxopropyl)-4-(3- methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
736

63di

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- (3-ethoxy-3-oxopropyl)-4-(3- methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
736

63dj

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-3-(3-methyl- 1H-pyrazol-1-yl)-[1,1′-biphenyl]- 4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
654

63dk

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H- pyrazol-1-yl)-4-(quinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
687

63dl

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A
(3S)-ethyl 8-(2-amino-6-((1R)- 2,2,2-trifluoro-1-(2-(3-methyl-1H- pyrazol-1-yl)-4-(2-oxo-1,3- dioxolan-4- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
646

63dm

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(2-methyl-1-oxo- 1,2,3,4-tetrahydroisoquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
639

63dn

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A
(S)-ethyl 8-(6-((R)-1-(4- (acetamidomethyl)-2-(3-methyl- 1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
631

63do

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A
(3S)-ethyl 8-(2-amino-6-((1R)- 2,2,2-trifluoro-1-(3-(3-methyl-1H- pyrazol-1-yl)-4′-((2-((2- oxotetrahydrofuran-3- yl)thio)ethyl)carbamoyl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
823

63dp

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A
(S)-ethyl 8-(2-amino-6-((R)-1- (3,4-dimethyl-3″- (methylsulfonyl)-[1,1′:3′,1″- terphenyl]-4′-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
738

63dq

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-(methylsulfonyl)-5- (quinolin-6-yl)-[1,1′-biphenyl]-2- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
761

63dr

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-(hydroxymethyl)-3′- methyl-4-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-3- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
680

63ds

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-(hydroxymethyl)-4′- methyl-4-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-3- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
680

63dt

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-(methoxycarbonyl)- 4-(3-methyl-1H-pyrazol-1-yl)- [1,1′-biphenyl]-3- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
694

63du

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A
3′-((S)-1-((2-amino-6-((R)-3- (ethoxycarbonyl)-2,8- diazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)oxy)-2,2,2- trifluoroethyl)-4′-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- carboxylic acid
680

63dv

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H- pyrazol-1-yl)-4-(1-oxo-1,3- dihydroisobenzofuran-5- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
693

63dw

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(quinazolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
608

63dx

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H- pyrazol-1-yl)-4-(pyrimidin-5- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
638

63dy

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A
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,4′-difluoro-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
672

63dz

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- chloro-3-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
671

63ea

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
591

63eb

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A
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,4′-difluoro-4-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-3- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
672

63ed

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-3- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
636

63ee

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,4′-dichloro-4-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-3- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
705

63ef

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-[1,1′- biphenyl]-2-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
574

63eg

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H- pyrazol-1-yl)-5-(pyrimidin-5- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
638

63eh

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (4′,5-dichloro-3′-fluoro-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
643

63ei

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-ethoxy-[1,1′-biphenyl]- 2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
635

63ej

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,5-dichloro-4′-ethoxy-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
669

63ek

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,5-dichloro-5′-fluoro-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
643

63el

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- (tert-butyl)-5-chloro-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
647

63em

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,5-dichloro-5′-(trifluoromethyl)- [1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
693

63en

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-fluoro-5′- (trifluoromethyl)-[1,1′-biphenyl]- 2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
677

63eo

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
591

63ep

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-methoxy-[1,1′-biphenyl]- 2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
621

63eq

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-isopropoxy-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
649

63er

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,5-dichloro-4′-methyl-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
639

63es

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,5-dichloro-4′-isopropoxy-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
683

63et

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-fluoro-4′-isopropoxy- [1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
667

63eu

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (4′,5-dichloro-3′-(trifluoromethyl)- [1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
693

63ev

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-fluoro-[1,1′-biphenyl]-2- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
609

63ew

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (4′,5-dichloro-3′-methyl-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
639

63ex

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,5-dichloro-4′-(trifluoromethyl)- [1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
693

63ey

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′,5′-difluoro-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate

63ez

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,5-dichloro-4′-fluoro-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate

63fa

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′,4′-difluoro-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate

63fb

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′,4′-dimethyl-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
619

63fc

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (4′,5-dichloro-3′,5′-dimethyl-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
653

63fd

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-4′-ethoxy-3′-fluoro-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
653

63fe

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′,5′-dimethyl-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
619

63ff

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,5-dichloro-5′-methyl-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
639

63fg

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(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-4′-fluoro-3′-methyl-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
623

63fh

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-methyl-4′- (trifluoromethoxy)-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
689

63fi

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(trifluoromethoxy)-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
675

63fj

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-isopropyl-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
633

63fk

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′,5′-bis(trifluoromethyl)- [1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
727

63fl

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-fluoro-4′-methyl-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
623

63fm

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B
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′,5,5′-trichloro-[1,1′- biphenyl]-2-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
659

63fn

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-4′-fluoro-3′- (trifluoromethyl)-[1,1′-biphenyl]- 2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
677

63fo

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(pyridin-3-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
592

63fp

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-fluoro-5′-isopropoxy- [1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
667

63fq

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-ethoxy-5′-fluoro-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
653

63fr

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- (tert-butyl)-5-chloro-5′-methyl- [1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
661

63fs

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-cyano-[1,1′-biphenyl]-2- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
616

63ft

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- ethoxy-5′-fluoro-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
698

63fv

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- chloro-3-fluoro-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
689

63fw

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-4′-ethoxy-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
715

63fx

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- ethoxy-3-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylale
680

63fy

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A
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,5′-difluoro-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
672

63fz

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H- pyrazol-1-yl)-3′-(trifluoromethyl)- [1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
704

63ga

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-ethoxy-4′-fluoro-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
653

63gb

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-4′- isopropoxy-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
712

63gc

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A
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,5′-dimethyl-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
664

63gd

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-5′-methyl-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
685

63ge

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-4′-methyl-3- (3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
678

63gf

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- (tert-butyl)-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
692

63gg

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-3-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
671

63gh

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-4′-fluoro-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
689

63gi

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-fluoro-3-(3-methyl- 1H-pyrazol-1-yl)-3′- (trifluoromethyl)-[1,1′-biphenyl]- 4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
722

63gk

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-3-(3-methyl-1H-pyrazol-1- yl)-5′-(trifluoromethyl)-[1,1′- biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
739

63gl

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H- pyrazol-1-yl)-3′- (trifluoromethoxy)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
720

63gm

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- (tert-butyl)-5′-methyl-3-(3-methyl- 1H-pyrazol-1-yl)-[1,1′-biphenyl]- 4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
706

63gn

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- chloro-3′-methyl-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
685

63go

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- chloro-3′,5′-dimethyl-3-(3-methyl- 1H-pyrazol-1-yl)-[1,1′-biphenyl]- 4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
699

63gp

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-fluoro-3′-methyl-3- (3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
668

63gq

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- ethoxy-3′-fluoro-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
698

63gr

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,5′-dichloro-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
705

63gs

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-isopropyl-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
678

63gt

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- chloro-3-(3-methyl-1H-pyrazol-1- yl)-3′-(trifluoromethyl)-[1,1′- biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
739

63gu

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-3-(3-methyl-1H-pyrazol-1- yl)-4′-(trifluoromethyl)-[1,1′- biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
738

63gv

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- carbamoyl-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
679

63gw

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H- pyrazol-1-yl)-3′,5′- bis(trifluoromethyl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
772

63gx

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-isopropoxy-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
694

63gy

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- ethoxy-4′-fluoro-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
698

63gz

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-5′- isopropoxy-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
712

63ha

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-methoxy-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
666

63hb

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- ethoxy-3-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
680

63hc

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′,4′,5′-trifluoro-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
690

63hd

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(1-methyl-2-oxo-1,2- dihydropyridin-4-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
622

63he

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-methyl-3-(3- methyl-1H-pyrazol-1-yl)-4′- (trifluoromethoxy)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
734

63hf

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-4′-methyl-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
685

63hg

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-3-(3-methyl- 1H-pyrazol-1-yl)-5′- (trifluoromethyl)-[1,1′-biphenyl]- 4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
722

63hh

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-5′-fluoro-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
689

63hi

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-cyclopropyl-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
631

63hj

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-4′-isopropoxy-3-(3-methyl- 1H-pyrazol-1-yl)-[1,1′-biphenyl]- 4-yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
729

63hk

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(2- (benzo[d]thiazol-5-yl)-4- chlorophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
648

63hl

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(2- (dimethylamino)pyridin-4- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
635

63hm

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(naphthalen-2- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
641

63hn

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(3′- (tert-butyl)-5-chloro-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
647

63ho

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B
(S)-ethyl 8-(6-((R)-1-(2-(1H- benzo[d]imidazol-1-yl)-4- chlorophenyl)-2,2,2- trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
631

63hp

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(1H-indazol-1- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
631

63hq

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(2-isopropylpyridin-4- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
634

63hr

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-4′-fluoro-[1,1′-biphenyl]-2- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
609

63hs

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B
(S)-ethyl 8-(2-amino-6-((R)-1- (4′,5-dichloro-[1,1′-biphenyl]-2- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
625

63ht

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-4′-methyl-[1,1′-biphenyl]- 2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
605

63hu

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H- pyrazol-1-yl)-4-(naphthalen-2- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
687

63hv

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-2′,3′,4′,5′-tetrahydro-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
595

63hw

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- (benzyloxy)-3′-fluoro-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
761

63hx

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-isopropoxy-3′- methyl-3-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
709

63hy

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-isobutoxy-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
663

63hz

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-isopropoxy- [1,1′:3′,1″-terphenyl]-4′- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
690

63ia

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(3-fluoroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
626

63ib

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-3-(3-methyl- 1H-pyrazol-1-yl)-4′-propoxy-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
713

63ic

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- butoxy-3′-fluoro-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
727

63id

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-4′-(5-methyl- 1,3,4-oxadiazol-2-yl)-3-(3-methyl- 1H-pyrazol-1-yl)-[1,1′-biphenyl]- 4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
734

63ie

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(pyrrolidine-1-carbonyl)- [1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
688

63if

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(cyclopentyloxy)-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
675

63ig

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(morpholine-4- carbonyl)-[1,1′-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
704

63ih

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(((1R,4R)-4- hydroxycyclohexyl)carbamoyl)- [1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
732

63ii

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-ethyl-[1,1′-biphenyl]-2- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
619

63ij

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-isopropyl-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
633

63ik

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-propoxy-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
614

63il

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(2- ethyl-4-(3-fluoroquinolin-6- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
654

63im

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(4-methylpiperazine-1- carbonyl)-[1,1′-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy) pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
717

63in

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(3-fluoroquinolin-6- yl)-2- methylphenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
640

63io

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- (diethylcarbamoyl)-[1,1′- biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
656

63ip

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- carbamoyl-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
600

63iq

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(2-methylthiazol-5- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
612

63ir

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-propoxy-[1,1′:3′,1″- terphenyl]-4′-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
691

63is

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(5-chlorothiophen-2- yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
631

63it

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-(methylsulfonyl)- [1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
635

63iu

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H- pyrazol-1-yl)-4′-(methylsulfonyl)- [1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
715

63iv

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H- pyrazol-1-yl)-4′-propoxy-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
695

63ix

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- (diethylcarbamoyl)-3-(3-methyl- 1H-pyrazol-1-yl)-[1,1′-biphenyl]- 4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
736

63iy

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-(methylcarbamoyl)- [1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
613

63iz

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H- pyrazol-1-yl)-4′-sulfamoyl-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
715

63ja

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-sulfamoyl-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
635

63jb

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-((2- morpholinoethyl)carbamoyl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
712

63jc

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H- pyrazol-1-yl)-4′-((2- morpholinoethyl)carbamoyl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
792

63jd

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- (dimethylcarbamoyl)-[1,1′- biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
628

63je

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-(piperazine-1- carbonyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
669

63jf

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H- pyrazol-1-yl)-4′-(piperazine-1- carbonyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
749

63jg

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(1-methyl-2-oxo-1,2- dihydropyridin-3-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
622

63jh

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- (dimethylcarbamoyl)-3-(3-methyl- 1H-pyrazol-1-yl)-[1,1′-biphenyl]- 4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
708

63ji

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-4′-methoxy- 3-(3-methyl-1H-pyrazol-1-yl)- [1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
685

63jj

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-4′-propoxy- [1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
633

63jk

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H- pyrazol-1-yl)-4′- (methylcarbamoyl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
694

63jl

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(N-methylsulfamoyl)- [1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
684

63jm

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(N,N- dimethylsulfamoyl)-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
698

63jn

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-isopropoxy-3- morpholino-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
700

63jo

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(methylcarbamoyl)-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
648

63jp

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(dimethylcarbamoyl)- [1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
662

63jq

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- ethoxy-3′-fluoro-[1,1′-biphenyl]-4- yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
618

63jr

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4′- ethoxy-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
601

63js

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(5-(methylsulfonyl)- [1,1′-biphenyl]-2- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
635

63jt

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(diethylcarbamoyl)-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
690

63ju

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-isobutoxy-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
709

63jv

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H- pyrazol-1-yl)-4′-(neopentyloxy)- [1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
723

63jw

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B
(S)-ethyl 8-(6-((R)-1-(2-(1H- benzo[d]imidazol-4-yl)-4- chlorophenyl)-2,2,2- trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
631

63jx

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4- (chroman-6-yl)-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
693

63jy

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(piperazine-1-carbonyl)- [1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
703

63jz

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(4- cyclopropylpiperazine-1- carbonyl)-[1,1′-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
743

63ka

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4- (cinnolin-6-yl)-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
689

63kb

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(3-(trifluoromethyl)-1H- pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
649

63kc

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(2- (3-(tert-butyl)-1H-pyrazol-1-yl)-4- chlorophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
637

63kd

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(3-isopropyl-1H-pyrazol- 1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
624

63ke

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(3-cyclopropyl-1H- pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
622

63kf

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A
(S)-ethyl 8-(2-amino-6-((R)-1- (3′,4′-dimethyl-3-(3- (trifluoromethyl)-1H-pyrazol-1- yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
719

63kg

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A
(S)-ethyl 8-(2-amino-6-((R)- 2,2,2-trifluoro-1-(3-fluoro-4- propoxy-[1,1′:3′,1″-terphenyl]-4′- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
660

63kh

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A
(S)-ethyl 8-(2-amino-6-((R)-1- (3,4-dimethyl-[1,1′:3′,1″- terphenyl]-4′-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
708

63ki

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A
(S)-ethyl 8-(6-((R)-1-([1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
556

63kj

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A
(S)-ethyl 8-(6-((R)-1-([1,1′:3′,1″- terphenyl]-4′-yl)-2,2,2- trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
633

63kl

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-(hydroxymethyl)-4- (3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-3-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
667

63km

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4- (chroman-6-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
612

63kn

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(pyridin-2-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
592

63ko

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(pyrimidin-2-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
593

63kp

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-(hydroxymethyl)-4′- methyl-3-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
681

63kq

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-(hydroxymethyl)-3′- methyl-3-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
681

63kr

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(4- (6-ethoxypyridin-3-yl)-2-(3- methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
681

63ks

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A
(S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(6-methoxypyridin- 3-yl)-2-(3-methyl-1H-pyrazol-1- yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
668

63kt

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A
(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(2-methoxyethoxy)- [1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
665

63ku

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B
(S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(pyrazin-2-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
594

63kv

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B
(S)-ethyl 8-(2-amino-6-((S)-1- (3′,4′-bis(hydroxymethyl)-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
697

TABLE 18b

NMR Data for Compounds of Table 18a

Ex.

No.
NMR

63a

¹H NMR (400 MHz, MeOH-d4): δ PPM 1.26 (t, J = 7.1 Hz, 3H), 1.50 (m, 5H),

1.63 (s, 1H), 1.73 (dd, J = 13.0, 7.2 Hz, 1H), 2.07 (dd, J = 13.0, 8.7 Hz, 1H), 2.74 (d, J = 11.0 Hz,

1H), 2.88 (d, J = 11.0 Hz, 1H), 3.50 (pd, J = 13.6, 5.4 Hz, 5H), 3.81 (t, J = 8.0 Hz,

1H), 4.17 (qd, J = 7.0, 1.6 Hz, 2H), 4.92 (s, 6H), 5.55 (s, 1H), 6.66 (q, J = 7.2 Hz,

1H), 7.63 (d, J = 8.0 Hz, 2H), 7.77 (m, 4H), 8.10 (d, J = 8.6 Hz, 1H), 8.29 (d, J = 1.8 Hz,

1H), 9.24 (s, 1H)

63b

¹H NMR (400 MHz, CDCl3): δ ppm 1.28 (m, 5H), 1.59 (t, J = 5.6 Hz, 2H), 1.77 (dd, J = 13.1,

6.8 Hz, 1H), 2.09 (m, 1H), 2.87 (d, J = 10.6 Hz, 1H), 2.98 (d, J = 10.6 Hz, 1H),

3.51 (dt, J = 14.9, 5.0 Hz, 4H), 3.92 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.62 (s, 2H),

5.54 (s, 1H), 6.63 (q, J = 7.0 Hz, 1H), 7.40 (dd, J = 8.5, 1.4 Hz, 1H), 7.62 (q, J = 8.3 Hz,

6H), 7.81 (d, J = 8.5 Hz, 1H), 8.11 (s, 1H)

63c

¹H NMR (400 MHz, CDCl3): δ ppm 0.87 (dd, J = 7.5, 3.2 Hz, 1H), 1.28 (dd, J = 14.0,

6.9 Hz, 7H), 1.57 (dt, J = 17.4, 5.6 Hz, 4H), 1.87 (m, 5H), 2.11 (dd, J = 13.1, 8.8 Hz,

1H), 2.89 (d, J = 10.6 Hz, 1H), 2.99 (d, J = 10.6 Hz, 1H), 3.28 (t, J = 6.7 Hz, 2H),

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),

5.53 (s, 1H), 6.61 (q, J = 7.1 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 7.17 (dd, J = 7.7, 1.5 Hz,

1H), 7.33 (d, J = 7.8 Hz, 1H), 7.58 (s, 4H)

63d

¹H-NMR (400 MHz, MeOH-d4): δ ppm 1.62 (m, 4H), 2.09-2.04 (m, 1H),

2.40-2.35 (m, 1H), 3.14 (m, 1H), 3.25 (m, 1H), 3.47 (m, 2H), 3.31-3.30 (m, 2H),

4.22-4.20 (m, 1H), 5.49 (s, 1H), 5.83-5.80 (m, 1H), 6.52-6.38 (m, 2H), 6.65 (m, 1H),

7.31 (d, J = 2.0, 1H), 7.45-7.43 (d, J = 8.0, 3H), 7.68-7.66 (d, J = 8.0, 1H), 7.80-7.78 (d,

J = 8.0, 2H)

63e

¹H NMR (400 MHz, CDCl3): δ ppm 0.07 (s, 1H), 0.87 (dd, J = 17.8, 8.8 Hz, 2H),

1.12 (s, 3H), 1.29 (m, 18H), 1.51 (s, 1H), 1.63 (dq, J = 29.6, 7.7, 6.6 Hz, 10H), 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, 1H), 4.20 (dq, J = 33.0, 7.5 Hz, 8H), 4.35 (s, 1H), 4.60 (m, 5H), 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, 1H),

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): δ 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, 1H), 2.12 (dd, J = 13.1, 8.9 Hz, 1H), 2.90 (d,

J = 10.7 Hz, 1H), 3.00 (d, J = 10.6 Hz, 1H), 3.52 (dt, J = 11.4, 5.4 Hz, 7H), 3.96 (t, J = 7.8 Hz,

1H), 4.21 (q, J = 7.2 Hz, 2H), 4.61 (s, 2H), 5.54 (s, 1H), 6.64 (q, J = 7.1 Hz,

1H), 7.66 (q, J = 8.4 Hz, 5H), 8.12 (t, J = 4.2 Hz, 2H), 8.94 (s, 1H)

63g

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.49 (dd, J = 13.6, 8.7 Hz, 1H), 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,

1H), 6.62 (q, J = 7.1 Hz, 1H), 7.03 (m, 1H), 7.19 (m, 2H), 7.57 (d, J = 8.2 Hz, 2H),

7.64 (m, 2H)

63h

¹H NMR (400 MHz, CDCl3): δ ppm 7.769-7.796 (m, 1H), 7.707-7.740 (m, 2H),

7.585-7.636 (m, 4H), 7.422-7.444 (m, 1H), 6.738-6.762 (m, 1H), 6.579-6.658-6.537 (m,

1H), 5.521 (s, 1H), 4.612 (s, 2H), 4.200-4.253 (q, 2H), 4.114-4.154 (t, 1H), 3.747 (s, 3H),

3.475-3.523 (m, 4H), 3.047-3.160 (m, 2H), 2.171-2.726 (m, 1H), 1.840-1.891 (m, 1H),

1.543-1.649 (m, 4H), 1.209-1.305 (t, 3H)

63i

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.25 (t, J = 7.10 Hz, 3 H) 1.42-1.69 (m, 4 H)

1.92 (dd, J = 13.25, 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, 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)

63j

¹H NMR (400 MHz, CD3OD): δ 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), 6.82-6.68 (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 = 10.9 Hz),

2.77-2.75 (d, 1 H, J = 10.9 Hz), 2.11-2.07 (m, 1 H), 2.12-2.10 (m, 1 H), 1.53-1.51 (m, 4 H),

1.28-1.25 (t, 3 H, J = 7.0 Hz Hz)

63k

¹H NMR (400 MHz, MeOH-d4): δ 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, 1 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 (m, 3 H)

63l

¹H NMR (400 MHz, CD3OD-d4): δ ppm 1.28-1.24 (m, 4H), 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, 1 H), 6.93 (s, 1 H), 7.37-7.34 (m, 1 H), 7.45-7.42 (m, 1 H), 7.57-7.55 (m, 2 H)

63m

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.19 (s, 1 H), 7.64 (d, 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), 5.80-5.77 (d, 1 H),

5.50 (s, 1 H), 4.21-4.18 (m, 2 H), 3.97 (t, 1 H), 3.49 (m, 4 H), 2.98-2.95 (d, 1 H),

2.86-2.83 (d, 1 H), 2.16-2.14 (m, 1 H), 1.80-1.76 (m, 1 H), 1.54 (m, 4 H), 1.19-1.16 (t, 3 H)

63n

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (q, J = 7.1, 6.1 Hz, 4H), 1.52 (dt, J = 10.4,

5.7 Hz, 4H), 1.74 (dd, J = 13.0, 7.2 Hz, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, 1H),

2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.52 (tq, J = 14.5, 8.2 Hz, 4H),

3.82 (dd, J = 8.8, 7.2 Hz, 1H), 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, J = 18.8 Hz, 2H), 6.62 (q, J = 7.1 Hz, 1H), 7.15 (t, J = 8.6 Hz,

1H), 7.39 (m, 2H), 7.59 (m, 4H)

63o

¹H-NMR (400 MHz, MeOH-d4): δ ppm δ8.00 (d, J = 2.36 Hz, 1H), 7.88 (dd, J = 2.6, 6.76 Hz,

1H), 7.58 (m, 4H), 6.62 (m, 2H), 5.55 (s, 1H), 4.22 (m, 3H), 3.64 (s, 3H), 3.52 (m,

4H), 3.02 (m, 2H), 2.27 (m, 1H), 1.89 (m, 1H), 1.59 (m, 4H), 1.29 (t, J = 7.16 Hz, 3H).

63p

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 4.21 (t, 2H,

J = 4.0), 3.99 (t, 1H, J = 4.0), 3.56δ3.49 (m, 4H), 3.00 (dd, 3H, J = 20.0, 8.0), 2.86 (d, 1H, J = 8.0),

2.59-2.57 (m, 2H), 2.18 (dd, 2H, J = 12.0, 8.0), 1.80 (dd, 2H, J = 8.0, 4.0),

1.54 (m, 5), 1.28 (t, 4H, J = 8.0)

63q

¹H-NMR (400 MHz, CDCl3): δ ppm 11.76 (m, 1H), 7.84-7.86 (m, 1H),

7.70-7.73 (m, 2H), 7.59 (m, 4H), 7.43-7.45 (m, 1H), 6.73-6.75 (m, 1H), 6.57-6.63 (q, 1H),

5.53 (s, 1H), 4.61 (s, 2H), 4.17-4.23 (q, 2H), 3.90-3.94 (t, 1H), 3.48-3.51 (m, 4H),

2.86-2.99 (m, 2H), 2.07-2.12 (m, 2H), 1.74-1.79 (m, 1H), 1.53-1.59 (m, 4H), 1.24-1.29 (t,

3H).

63r

¹H NMR (400 MHz, CD3OD-d4): δ ppm 8.42 (s, 1 H), 8.04 (d, 1 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

H), 3.83 (m, 1 H), 3.50 (m, 4 H), 3.21 (s, 3 H), 2.90 (m, 1 H), 2.78 (m, 1 H), 2.14 (m, 1

H), 1.86 (m, 3 H), 1.76 (m, 1 H), 1.54 (m, 4 H), 1.26 (m, 3 H)

63s

¹H NMR (MeOH-d4): δ ppm 0.90 (t, J = 6.9 Hz, 1H), 1.17 (p, J = 6.3 Hz, 3H), 1.29 (s,

2H), 1.56 (m, 4H), 1.80 (s, 1H), 2.29 (s, 1H), 2.41 (s, 3H), 2.80 (m, 4H), 3.26 (d, J = 11.3 Hz,

1H), 3.44 (s, 1H), 4.09 (tdd, J = 14.2, 7.9, 4.6 Hz, 2H), 4.48 (s, 1H), 4.87 (s,

2H), 5.56 (s, 1H), 6.42 (t, J = 2.2 Hz, 1H), 6.93 (m, 1H), 7.46 (m, 4H), 7.61 (m, 2H),

7.80 (dd, J = 8.3, 2.2 Hz, 1H), 7.93 (dd, J = 5.2, 2.5 Hz, 2H)

63t

¹H NMR (MeOH-d4): δ ppm 0.91 (dd, J = 12.4, 6.3 Hz, 2H), 1.17 (q, J = 7.4 Hz, 3H),

1.31 (d, J = 16.3 Hz, 3H), 1.65 (m, 4H), 1.83 (s, 1H), 2.32 (s, 2H), 2.41 (s, 3H),

2.92 (ddt, J = 18.2, 14.3, 9.1 Hz, 5H), 3.28 (s, 1H), 4.11 (dtt, J = 10.7, 7.1, 3.9 Hz, 2H),

4.48 (s, 1H), 4.95 (d, J = 11.7 Hz, 1H), 6.43 (d, J = 2.2 Hz, 1H), 6.94 (q, J = 6.5 Hz,

1H), 7.50 (m, 3H), 7.61 (dd, J = 8.6, 2.1 Hz, 2H), 7.79 (dt, J = 8.3, 1.4 Hz, 1H),

7.93 (dd, J = 10.2, 3.2 Hz, 2H)

63u

¹H NMR (400 MHz, CDCl₃-d): δ ppm 8.50 (s, 1H), 7.99-7.96 (m, 1H), 7.69-7.63 (m,

2H), 7.51 (s, 1H), 7.25-7.23 (m, 1H), 7.11 (d, J = 7.8 Hz, 1H), 6.57 (q, J = 6.6 Hz,

1H), 5.51 (s, 1H), 5.18 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.93-3.89 (m, 1H),

3.53-3.48 (m, 4H), 3.14 (s, 3H), 2.93 (dd, J1 = 10.6 Hz, J2 = 42.0 Hz, 2H), 2.66-2.62 (m, 2H),

2.12-2.07 (m, 1H), 1.79-1.74 (m, 1H), 1.69-1.63 (m, 2H), 1.61-1.58 (m, 2H),

1.55-1.52 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H)

63v

¹H NMR (400 MHz, CDCl₃): δ ppm 8.52 (d, J = 9.5 Hz, 1H), 7.99-7.97 (m, 1H),

7.69-7.62 (m, 3H), 7.38 (dd, J1 = 7.9 Hz, J2 = 20.6 Hz, 1H), 7.15 (dd, J1 = 7.9 Hz, J2 = 17.0 Hz,

1H), 6.57 (m, 1H), 6.46-6.42 (m, 1H), 6.34-5.84 (m, 1H), 5.51-5.50 (m,

1H), 5.18 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.87 (t, J = 7.6 Hz, 1H), 3.52-3.50 (m, 4H),

3.15-3.14 (m, 3H), 2.90 (dd, J1 = 10.2 Hz, J2 = 47.8 Hz, 2H), 2.10-2.05 (m, 1H),

1.91 (d, J = 6.4 Hz, 3H), 1.78-1.73 (m, 1H), 1.58-1.53 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H)

63w

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.49 (s, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.71 (t,

J = 7.8 Hz, 1H), 7.65-7.63 (m, 2H), 7.42-7.40 (m, 1H), 7.23 (d, J = 1.9 Hz, 1H),

6.53 (q, J = 6.8 Hz, 1H), 5.48 (s, 1H), 5.26 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 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, J1 = 10.9 Hz, J2 = 34.9 Hz,

2H), 2.18-2.12 (m, 1H), 1.85-1.80 (m, 1H), 1.62-1.61 (m, 2H), 1.56-1.55 (m, 2H),

1.31-1.28 (m, 6H)

63x
1H NMR (400 MHz, MeOH-d4): δ 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),

5.61 (s, 1H), 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, 1H, J = 12.0, 8.0), 1.98 (dd, 1H, J = 12.0, 8.0), 1.70-1.62 (m,

7H), 1.31 (dd, 5H, J = 12.0, 8.0) 0.96 (t, 4H, J = 8.0)

63y

¹H NMR (400 MHz, MeOH-d4): δ 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), 0.84-0.81 (t,

3 H)

63z

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.09 (dd, J = 4.2, 2.0 Hz, 1H), 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,

1H), 2.03 (s, 1H), 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, 1H), 3.53 (td, J = 13.8, 13.4, 6.0 Hz, 6H), 3.86 (dd, J = 8.8, 7.3 Hz,

1H), 4.20 (m, 3H), 5.46 (d, J = 22.4 Hz, 3H), 5.56 (s, 1H), 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): δ ppm: 8.16 (d, J = 8.84 Hz, 1H), 8.03 (d, J = 1.84 Hz,

1H), 7.94-7.81 (m, 2H), 7.77 (d, J = 8.32 Hz, 2H), 7.64 (d, J = 8.24 Hz, 2H), 6.96 (d, J = 8.88 Hz,

1H), 6.65 (q, J = 7.08 Hz, 1H), 5.56 (s, 1H), 4.18 (m, 2H), 4.06 (s, 3H), 3.82 (m,

1H), 3.53 (m, 4H), 2.90 (d, J = 11.0 Hz, 1H), 2.76 (d, J = 11.0 Hz, 1H), 2.09 (m, 1H),

1.75 (m, 1H), 1.53 (s, 4H), 1.27 (t, J = 7.12 Hz, 3H)

63ab

¹H NMR (400 MHz, CDCl3): δ ppm 7.76 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.43 (t, J = 7.6 Hz,

1H), 7.37 (dd, J1 = 2.2 Hz, J2 = 8.5 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H),

7.28 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 2.2 Hz, 1H), 6.63 (q, J = 6.7 Hz, 1H), 5.41 (s, 1H),

5.02 (s, 2H), 4.80 (m, 2H), 4.21 (q, J = 7.1 Hz, 2H), 4.05-4.01 (m, 1H), 3.48-3.46 (m,

4H), 3.01 (dd, J1 = 10.9 Hz, J2 = 31.0 Hz, 2H), 2.17-2.11 (m, 1H), 1.83-1.78 (m, 1H),

1.59-1.50 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H)

63ac

¹H-NMR (400 MHz, MeOH-d4): δ ppm 7.97 (s, 1H), 7.60-7.67 (m, 2H),

7.52-7.56 (m, 1H), 7.43-7.45 (m, 1H), 7.31-7.31 (m, 1H), 7.22-7.24 (m, 1H), 6.621-6.663 (m,

1H), 5.498 (s, 1H), 4.16-4.22 (m, 2H), 4.92-4.03 (m, 2H), 3.83-3.87 (m, 1h),

3.46-3.53 (m, 4H), 2.90-2.92 (d, 1H), 2.76-2.78 (d, 1H), 2.59-2.63 (m, 2H), 2.10-2.22 (m,

3H), 1.71-1.78 (m, 1H), 1.52-1.55 (m, 4H), 1.25-1.28 (m, 3H)

63ad

¹H-NMR (400 MHz, MeOH-d4) δ ppm: 7.98 (s, 1H), 7.63-7.65 (m, 1H),

7.42-7.50 (m, 3H), 7.30-7.30 (m, 1H), 7.05-7.07 (m, 1H), 6.62-6.67 (m, 1H), 5.49 (s, 1H),

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, 1H), 2.07-2.13 (d, 1H), 1.73-1.78 (m, 1H), 1.49-1.57 (m, 4H), 1.25-1.29 (m, 3H)

63ae

¹H NMR (400 MHz, DMSO-d6) δ ppm: 1.25 (t, J = 7.10 Hz, 3 H) 1.42-1.69 (m, 4 H)

1.92 (dd, J = 13.25, 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, 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)

63af

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.66 (d, 1 H, J = 8.4 Hz), 7.50 (m, 3 H),

7.31 (d, 2 H, J = 8.7 Hz), 7.24 (d, 1 H, J = 7.2 Hz), 6.64 (m, 1 H), 5.50 (m, 1 H), 4.21 (m, 1

H), 3.87 (m, 1 H), 3.53 (m, 4 H), 3.01 (s, 3 H), 3.18 (m, 1 H), 2.90 (m, 3 H), 2.79 (m,

1 H), 2.07 (m, 1 H), 1.74 (m, 1 H), 1.53 (m, 4 H), 1.27 (m, 3 H)

63ag

¹H NMR (400 MHz, CDCl3): δ ppm 7.54 (d, J = 2.2 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H),

7.19 (dd, J1 = 2.6 Hz, J2 = 8.6 Hz, 1H), 6.85 (q, J = 6.6 Hz, 1H), 5.49 (s, 1H), 4.56 (s,

2H), 4.20 (q, J = 7.2 Hz, 2H), 3.90-3.86 (m, 1H), 3.53-3.47 (m, 4H), 2.90 (dd, J1 = 10.4 Hz,

J2 = 47.6 Hz, 2H), 2.13-2.05 (m, 1H), 1.78-1.73 (m, 1H), 1.59-1.56 (m, 2H),

1.54-1.51 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H)

63ah

¹H NMR (400 MHz, CDCl3): δ ppm 7.54 (d, J = 2.2 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H),

7.19 (dd, J1 = 2.6 Hz, J2 = 8.6 Hz, 1H), 6.85 (q, J = 6.6 Hz, 1H), 5.49 (s, 1H), 4.56 (s,

2H), 4.20 (q, J = 7.2 Hz, 2H), 3.90-3.86 (m, 1H), 3.53-3.47 (m, 4H), 2.90 (dd, J1 = 10.4 Hz,

J2 = 47.6 Hz, 2H), 2.13-2.05 (m, 1H), 1.78-1.73 (m, 1H), 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): δ ppm 8.06 (d, J = 8.72 Hz, 1H), 8.01 (s, 1H), 7.94 (s,

2H), 7.76 (d, J = 8.28 Hz, 2H), 7.64 (d, J = 8.16 Hz, 2H), 7.31 (d, J = 8.68 Hz, 1H),

6.66 (q, J = 7.32 Hz, 1H), 5.56 (s, 1H), 4.18 (q, J = 7.04 Hz, 2H), 3.84-3.80 (m, 1H),

3.51 (m, 4H), 2.89 (d, J = 10.96 Hz, 1H), 2.75 (d, J = 11 Hz, 1H), 2.68 (s, 3H),

2.10-2.01 (m, 1H), 1.76-1.71 (m, 1H), 1.54-1.49 (m, 4H), 1.25 (t, J = 7.12 Hz, 3H)

63aj

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.69 (d, J = 1.8 Hz, 1H), 7.60-7.57 (d, 1H),

7.48 (dd, J1 = 2.44, J2 = 8.6 Hz, 1H), 6.96 (q, J = 7.32 Hz, 1H), 5.56 (s, 1H), 4.19 (q, J = 7.12 Hz,

2H), 3.86-3.82 (m, 1H), 3.54 (m, 4H), 2.91 (d, J = 11 Hz, 1H), 2.77 (d, J = 11 Hz,

1H), 2.14-2.08 (m, 1H), 1.79-1.73 (m, 1H), 1.55 (m, 4H), 1.27 (t, J = 7.12 Hz,

3H)

63ak

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.91 (s, 1H), 7.71 (dd, J1 = 6.12 Hz, J2 = 1.96 Hz,

1H), 7.63 (m, 2H), 7.56-7.49 (m, 7H), 7.39-7.35 (m, 2H), 6.74 (q, J = 6.88 Hz, 1H),

5.50 (s, 1H), 4.18 (q, J = 6.96 Hz, 2H), 3.83 (m, 1H), 3.50 (m, 4H), 2.89 (d, J = 11.04 Hz,

1H), 2.75 (d, J = 11 Hz, 1H), 2.12-2.06 (m, 1H), 1.76-1.71 (m, 1H), 1.54-1.49 (m,

4H), 1.27 (t, J = 7.12 Hz, 3H)

63al

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.84 (t, J = 7.1 Hz, 8H), 1.26 (t, J = 7.1 Hz,

8H), 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, 1H), 2.38 (s, 3H), 2.73 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H),

3.51 (m, 4H), 3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.00 (qd, J = 7.1, 4.5 Hz, 2H), 4.17 (qd, J = 7.1,

1.5 Hz, 2H), 5.74 (s, 1H), 6.39 (d, J = 2.3 Hz, 1H), 6.85 (q, J = 6.7 Hz, 1H),

7.45 (m, 5H), 7.80 (m, 2H), 7.90 (d, J = 2.4 Hz, 1H)

63am

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, 1H), 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, 1H), 2.05 (m, 1H), 2.40 (s, 3H),

2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.53 (m, 4H), 3.81 (dd, J = 8.8,

7.1 Hz, 1H), 4.18 (qd, J = 7.1, 2.5 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 5.73 (s, 1H),

6.43 (d, J = 2.4 Hz, 1H), 6.82 (q, J = 6.6 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.68 (d, J = 1.9 Hz,

1H), 7.79 (m, 2H), 7.90 (dt, J = 8.0, 1.4 Hz, 1H), 8.02 (m, 2H), 8.28 (d, J = 1.9 Hz,

1H)

63an

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.33 (dt, J = 54.3, 7.1 Hz, 6H), 1.50 (dt, J = 10.8,

5.8 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H),

2.40 (s, 3H), 2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H),

3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.5 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H),

5.74 (s, 1H), 6.43 (d, J = 2.3 Hz, 1H), 6.84 (q, J = 6.6 Hz, 1H), 7.77 (m, 5H), 8.00 (d, J = 2.3 Hz,

1H), 8.09 (m, 2H)

63ao

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 3H), 1.54 (m, 4H),

1.76 (dd, J = 13.1, 7.2 Hz, 1H), 2.11 (dd, J = 13.1, 8.7 Hz, 1H), 2.77 (dd, J = 11.0, 1.1 Hz,

1H), 2.91 (d, J = 11.0 Hz, 1H), 3.53 (td, J = 11.9, 11.4, 4.9 Hz, 4H), 3.84 (dd, J = 8.7,

7.2 Hz, 1H), 4.19 (qd, J = 7.2, 1.6 Hz, 2H), 5.53 (s, 1H), 7.15 (t, J = 8.0 Hz, 1H),

7.27 (q, J = 8.0 Hz, 1H), 7.69 (m, 2H)

63ap

¹H NMR (400 MHz, CDCl3): δ 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, 1H), 2.12 (m, 1H), 2.90 (d, J = 10.7 Hz, 1H), 2.99 (d, J = 10.6 Hz,

1H), 3.49 (dt, J = 11.5, 5.7 Hz, 4H), 3.94 (dd, J = 8.8, 6.9 Hz, 1H), 4.21 (q,

J = 7.1 Hz, 2H), 4.58 (s, 2H), 5.43 (s, 1H), 6.55 (q, J = 6.8 Hz, 1H), 7.24 (m, 3H),

7.41 (m, 3H), 7.65 (m, 2H)

63aq

¹H NMR (400 MHz, CDCl3): δ ppm 0.84 (m, 2H), 1.14 (s, 1H), 1.28 (t, J = 7.1 Hz,

3H), 1.53 (m, 4H), 1.74 (dd, J = 13.1, 6.8 Hz, 1H), 2.05 (m, 1H), 2.43 (s, 3H), 2.82 (d,

J = 10.5 Hz, 1H), 2.94 (d, J = 10.5 Hz, 1H), 3.46 (dt, J = 14.0, 5.8 Hz, 4H), 3.86 (dd, J = 8.8,

6.7 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 4.35 (s, 2H), 5.40 (s, 1H), 6.61 (q, J = 6.8 Hz,

1H), 7.33 (m, 5H), 7.65 (d, J = 8.5 Hz, 1H)

63ar

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.12 (m, 1H), 2.78 (m, 1H), 2.90 (m, 1H),

3.52 (m, 4H), 3.85 (td, J = 9.2, 8.8, 7.3 Hz, 1H), 4.19 (qd, J = 7.1, 1.6 Hz, 2H),

4.86 (d, J = 0.8 Hz, 11H), 5.51 (d, J = 13.8 Hz, 1H), 6.52 (q, J = 6.7 Hz, 1H), 7.34 (d, J = 2.2 Hz,

1H), 7.51 (dd, J = 8.5, 2.2 Hz, 1H), 7.75 (m, 5H)

63as

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (t, J = 7.1 Hz, 3H), 1.67 (m, 4H),

2.05 (dd, J = 13.6, 8.8 Hz, 1H), 2.46 (d, J = 45.5 Hz, 7H), 2.66 (s, 1H), 3.28 (s, 2H),

3.69 (m, 4H), 4.32 (qd, J = 7.1, 2.3 Hz, 2H), 4.58 (t, J = 8.7 Hz, 1H), 6.43 (d, J = 2.4 Hz,

1H), 6.85 (q, J = 6.3 Hz, 1H), 7.37 (m, 2H), 7.66 (m, 3H), 7.79 (m, 2H), 7.97 (d, J = 2.4 Hz,

1H)

63at

¹H NMR (MeOH-d4): δ ppm 1.28 (m, 15H), 1.53 (m, 13H), 1.76 (dd, J = 13.1, 7.3 Hz,

3H), 1.86 (s, 1H), 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, 1H),

3.87 (m, 3H), 4.19 (qd, J = 7.1, 1.6 Hz, 5H), 5.51 (s, 3H), 6.68 (q, J = 6.7 Hz, 3H), 7.29 (m,

6H), 7.47 (m, 19H), 7.65 (m, 5H)

63au

¹H NMR (MeOH-d4): δ ppm 1.13 (s, 2H), 1.26 (t, J = 7.3 Hz, 4H), 1.49 (m, 6H),

1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.06 (dd, J = 13.1, 8.7 Hz, 1H), 2.38 (d, J = 12.1 Hz, 7H),

2.73 (d, J = 11.0 Hz, 1H), 2.87 (d, J = 11.0 Hz, 1H), 3.53 (tt, J = 14.1, 5.1 Hz, 5H),

3.81 (m, 1H), 4.18 (tt, J = 7.8, 3.6 Hz, 2H), 4.81 (s, 2H), 4.97 (d, J = 15.9 Hz, 1H),

5.74 (s, 1H), 6.41 (d, J = 2.1 Hz, 1H), 6.78 (q, J = 6.7 Hz, 1H), 7.26 (d, J = 7.9 Hz,

2H), 7.57 (m, 5H), 7.73 (m, 2H), 7.96 (d, J = 2.3 Hz, 1H)

63av

¹H NMR (MeOH-d4): δ ppm 1.26 (m, 3H), 1.51 (dt, J = 10.6, 5.6 Hz, 4H), 1.74 (dd, J = 13.1,

7.2 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s, 7H), 2.74 (d, J = 10.9 Hz,

1H), 2.88 (d, J = 11.0 Hz, 1H), 3.54 (m, 4H), 3.81 (dd, J = 8.8, 7.1 Hz, 1H), 4.18 (qd, J = 7.1,

1.6 Hz, 2H), 5.74 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.79 (q, J = 6.6 Hz, 1H),

7.21 (d, J = 7.5 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.46 (m, 2H), 7.62 (d, J = 1.9 Hz,

1H), 7.75 (m, 2H), 7.98 (d, J = 2.4 Hz, 1H)

63aw

¹H NMR (MeOH-d4): δ ppm 0.90 (m, 1H), 1.27 (m, 5H), 1.51 (dt, J = 10.5, 5.6 Hz,

4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.09 (dd, J = 13.1, 8.7 Hz, 1H), 2.40 (s, 3H),

2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.54 (m, 4H), 3.84 (dd, J = 8.7, 7.2 Hz,

1H), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.73 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.84 (q, J = 6.5 Hz,

1H), 7.64 (m, 3H), 7.80 (m, 3H), 8.01 (d, J = 2.4 Hz, 1H)

63ax

¹H NMR (400 MHz, Chloroform-d): δ ppm 1.27 (m, 9H), 1.52 (dt, J = 22.3, 5.4 Hz,

4H), 1.72 (d, J = 13.1 Hz, 1H), 2.05 (m, 1H), 2.25 (ddd, J = 18.1, 13.9, 8.2 Hz, 2H),

2.63 (m, 2H), 2.82 (d, J = 10.5 Hz, 1H), 2.94 (d, J = 10.4 Hz, 1H), 3.48 (dd, J = 13.6,

7.4 Hz, 5H), 3.63 (m, 1H), 3.81 (m, 4H), 4.19 (q, J = 7.1 Hz, 2H), 4.86 (s, 2H),

5.46 (s, 1H), 6.46 (m, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.34 (dd, J = 8.5, 2.2 Hz, 1H), 7.59 (d,

J = 8.5 Hz, 1H)

63ay

¹H NMR (400 MHz, MeOH-d4): δ 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 = 1.27 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, 1 H) 6.45 (s, 1 H) 6.90-7.04 (m, 1 H) 7.61 (s, 2

H) 7.68-7.79 (m, 1 H) 7.88-8.00 (m, 1 H)

63az

¹H NMR (400 MHz, MeOH-d4): δ 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 = 13.08, 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 H) 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

¹H NMR (400 MHz, MeOH-d4): δ 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, 1 H),

5.60 (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 H), 7.54-7.61 (m, 2 H),

7.62-7.70 (m, 2 H)

63bb

¹H NMR (400 MHz, dichloromethane-d2): δ ppm 1.29 (t, J = 7.15 Hz, 3 H)

1.47-1.85 (m, 4 H) 2.01 (dd, J = 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 (br. s, 2H) 5.49 (s, 1 H) 6.31 (d, J = 2.25 Hz, 1 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, MeOH-d4): δ 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): δ 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 = 12.89 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, 1 H) 7.26 (d, J = 7.81 Hz, 1 H) 7.40-7.47 (m,

1 H) 7.50 (s, 1 H) 7.68 (d, J = 1.37 Hz, 1 H) 7.78 (s, 1 H) 7.82 (d, J = 1.37 Hz, 1 H) 7.98;

(d, J = 2.15 Hz, 1 H)

63be

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (m, 6 H) 1.59 (m, 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, J = 2.20 Hz, 1

H) 6.71 (m, 1 H) 7.25 (d, J = 1.56 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

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.96 (t, J = 7.35 Hz, 2 H) 1.32 (t, J = 7.15 Hz, 4

H) 1.63 (m, 6 H) 2.00 (dd, J = 13.59, 8.61 Hz, 1 H) 2.37 (s, 3 H) 2.42 (m, 1 H) 2.66 (m,

2 H) 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) 6.71 (q, J = 6.67 Hz, 1 H) 7.23 (d, J = 1.66 Hz, 1 H) 7.34 (dd,

J = 8.10, 1.66 Hz, 1 H) 7.63 (d, J = 8.10 Hz, 1 H) 7.85 (d, J = 2.29 Hz,

1 H)

63bg

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.95 (t, J = 7.35 Hz, 3 H) 1.32 (t, J = 7.15 Hz, 4

H) 1.63 (m, 6 H) 2.02 (m, 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 H) 5.72 (s, 1 H)

6.38 (d, J = 2.29 Hz, 1 H)

6.71 (m, 1 H) 7.23 (d, J = 1.61 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, 1 H)

63bh

¹H NMR (400 MHz, CHLOROFORM-d): δ 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., 1 H) 6.36 (s, 1 H) 6.59 (br. s., 1 H) 7.48 (d, J = 7.96 Hz,

1 H) 7.61 (br. s., 1 H) 8.16 (d, J = 8.05 Hz, 1 H) 8.34 (br. s., 1 H)

63bi

¹H NMR (400 MHz, MeOH-d4): δ ppm 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 = 1.61 Hz, 1 H) 8.08 (dd, J = 8.27, 1.64 Hz, 1 H)

63bj

¹H NMR (400 MHz, MeOH-d4): δ 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 = 13.59, 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 = 8.30 Hz, 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, 1 H)

63bk

¹H NMR (400 MHz, MeOH-d4): δ 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, 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) 3.06-3.29 (m, 2 H)

3.41-3.76 (m, 4 H) 4.08 (dd, J = 9.20, 7.25 Hz, 1 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

¹H NMR (400 MHz, DMSO-d6): δ 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 (br. s., 4 H) 4.33-4.52 (m, 1 H) 6.14 (br. s.,

1 H) 6.38 (d, J = 2.29 Hz, 1 H) 7.05 (br. s., 1 H) 7.37-7.52 (m, 3 H) 7.76 (br. s., 1 H)

8.02 (d, J = 2.29 Hz, 1 H) 8.97 (d, J = 5.32 Hz, 1 H) 10.42 (br. s., 1 H)

63bm

¹H NMR (400 MHz, MeOH-d4): δ 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, 8.44 Hz, 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, 1 H)

5.75 (s, 1 H) 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, 1 H) 7.83 (d, J = 2.29 Hz, 1 H)

63bn

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (t, J = 7.15 Hz, 3 H) 1.49-1.70 (m, 4 H)

2.01 (dd, J = 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, 1 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): δ ppm 0.92 (t, J = 7.35 Hz, 3 H) 1.32 (t, J = 7.13 Hz, 3

H) 1.49-1.76 (m, 6 H) 1.94-2.06 (m, 1 H) 2.37 (s, 3 H) 2.43 (dd, J = 13.57, 8.79 Hz,

1 H) 2.66 (t, J = 7.52 Hz, 2 H) 3.13-3.28 (m, 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

H)

63bp

¹H NMR (400 MHz, MeOH-d4): δ 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, J = 13.93, 8.52 Hz, 1 H) 2.37 (s, 3 H) 2.47 (dd,

J = 13.62, 8.74 Hz, 1 H) 2.72 (q, J = 7.61 Hz, 2 H) 3.26 (d, J = 1.51 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, 1 H)

7.81 (d, J = 2.29 Hz, 1 H)

63bq

¹H NMR (400 MHz, MeOH-d4): δ 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 = 13.57, 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)

63br

¹H NMR (400 MHz, MeOH-d4): δ 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, J = 13.62, 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 = 11.08 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)

63bs

¹H NMR (400 MHz, MeOH-d4): δ 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 (m, 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, 1

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,

J = 2.34 Hz, 1 H)

63bt

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (t, J = 7.13 Hz, 3 H) 1.45-1.65 (m, 4 H)

1.79-1.91 (m, 1 H) 2.16-2.32 (m, 1 H) 3.03 (s, 2 H) 3.51 (br. 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

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (t, J = 7.13 Hz, 3 H) 1.40-1.61 (m, 4 H)

1.71-1.86 (m, 1 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 = 1.17 Hz, 1 H) 7.72 (d,

J = 2.34 Hz, 2 H)

63bv

¹H NMR (400 MHz, MeOH-d4): δ 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,

J = 8.49, 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): δ ppm 1.35 (t, J = 7.13 Hz, 3 H) 1.67-1.90 (m, 4 H)

2.03-2.18 (m, 1 H) 2.47-2.61 (m, 1 H) 2.72 (s, 3 H) 3.34 (br. 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)

63bx

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.35 (t, J = 7.13 Hz, 3 H) 1.77 (br. 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 (m, 2 H) 4.57-4.69 (m, 1H) 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)

63by

¹H NMR (400 MHz, MeOH-d4): δ 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): δ 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 = 13.15, 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 H) 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 = 1.56 Hz, 1 H) 7.35 (dd, J = 8.13, 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, MeOH-d4): δ 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)

63cb

¹H NMR (400 MHz, DMSO-d6): δ 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 = 13.28, 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, J = 8.49 Hz, 1 H) 5.72 (br. s., 1 H)

6.01 (br. s., 2 H) 6.37 (d, J = 2.15 Hz, 1 H) 6.99 (q, J = 6.87 Hz, 1 H) 7.33-7.44 (m, 2 H)

7.47 (s, 1 H) 8.01 (d, J = 2.25 Hz, 1 H) 9.20 (br. s., 1 H) 10.39 (br. s., 1 H)

63cc

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.10-1.20 (m, 3 H) 1.25 (t, J = 7.10 Hz, 3 H)

1.44-1.63 (m, 4 H) 1.82 (quin, J = 7.53 Hz, 2 H) 1.91 (dd, J = 13.28, 9.37 Hz, 1 H)

2.19-2.40 (m, 3 H) 2.60 (t, J = 7.71 Hz, 2 H) 3.13 (br. s., 2 H) 3.40-3.68 (m, 4 H) 4.02 (q,

J = 7.09 Hz, 2 H) 4.13-4.33 (m, 2 H) 4.53 (br. s., 1 H) 5.70 (br. s., 1 H) 6.29 (br. s, 2

H) 6.62-6.76 (m, 1 H) 7.28 (d, J = 8.20 Hz, 2 H) 7.43 (d, J = 8.10 Hz, 2 H) 9.21 (br. s.,

1 H) 10.43 (br. s., 1 H)

63cd

¹H NMR (400 MHz, DMSO-d6): δ 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) 4.15-4.31 (m, 2 H)

4.52 (hr. 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 = 1.51 Hz, 1 H) 7.33-7.41 (m, 1 H) 7.59 (d, J = 8.05 Hz, 1 H)

8.04 (d, J = 2.29 Hz, 1 H) 9.20 (br. s., 1 H) 10.38 (br. s., 1 H)

63ce

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.22-1.30 (m, 3 H) 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, J = 2.39 Hz, 1 H) 6.81-6.88 (m, 1 H) 7.61-7.66 (m, 1 H)

7.71 (d, J = 1.76 Hz, 1 H) 7.73-7.86 (m, 3 H) 7.97-8.02 (m, 2 H) 8.08 (s, 1 H)

63cf

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.25 (t, J = 7.13 Hz, 3 H) 1.45-1.66 (m, 4 H)

1.92 (dd, J = 13.18, 9.42 Hz, 1 H) 2.35 (dd, J = 13.28, 8.54 Hz, 1 H) 3.14 (br. s., 2 H)

3.60 (br. s., 4 H) 4.14-4.31 (m, 2H) 4.54 (br. s., 1 H) 5.75 (br. s., 1 H) 6.56 (q, J = 6.72 Hz,

1 H) 7.47 (t, J = 1.27 Hz, 1 H) 7.65 (s, 2 H) 7.75-7.84 (m, 1 H) 7.89 (d, J = 7.81 Hz,

1 H) 7.93-8.01 (m, 2 H) 9.21 (br. s., 1 H) 10.36 (br. s., 1 H)

63cg

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.25 (t, J = 7.10 Hz, 3 H) 1.57 (d, J = 5.37 Hz, 4

H) 1.83-1.99 (m, 1 H) 2.28-2.40 (m, 1 H) 3.14 (br. s., 2 H) 3.58 (br. 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, 1 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

¹H NMR (400 MHz, MeOH-d4): δ 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

¹H NMR (400 MHz, MeOH-d4): δ 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, 1 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

¹H NMR (400 MHz, MeOH-d4): δ 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 = 13.42, 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, 1 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 = 0.73 Hz, 1 H)

63ck

¹H NMR (400 MHz, DMSO-d6): δ 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 (br. s., 1 H) 10.62 (br. s., 1 H)

63cl

¹H NMR (400 MHz, MeOH-d4): δ 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, 1 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 = 1.56 Hz,

1 H) 9.21 (s, 2 H)

63cm

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.35 (t, J = 6.93 Hz, 5 H) 1.83 (br. s., 4 H)

2.04-2.22 (m, 1 H) 2.47-2.65 (m, 1 H) 3.36 (br. s., 2 H) 4.35 (d, J = 6.64 Hz, 2 H)

4.57-4.71 (m, 1 H) 6.64-6.85 (m, 1 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

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.24-1.45 (m, 10 H) 1.75 (d, J = 18.55 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 = 5.86 Hz, 2 H) 4.54-4.75 (m, 2 H) 6.44 (d, J = 1.95 Hz, 1 H) 6.89 (d, J = 5.66 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 = 1.76 Hz,

1 H)

63co

¹H NMR (400 MHz, MeOH-d4): δ 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, MeOH-d4): δ 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 H) 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,

J = 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, J = 2.29 Hz, 1 H)

63cq

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.10-1.20 (m, 3 H) 1.25 (t, J = 7.10 Hz, 3 H)

1.44-1.63 (m, 4 H) 1H NMR (400 MHz, MeOH-d4): δ ppm 1.21-1.31 (m, 3 H)

1.52 (dt, J = 10.53, 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, 1 H)

4.12-4.25 (m, 2 H) 5.72 (s, 1 H) 6.40 (d, J = 2.29 Hz, 1 H) 6.77 (q, J = 6.74 Hz, 1 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, MeOH-d4): δ 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,

J = 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, 1 H)

6.84 (q, J = 6.69 Hz, 1 H) 7.55 (dd, J = 8.30, 4.34 Hz, 1 H) 7.83 (d, J = 1.76 Hz, 1 H)

7.85-7.99 (m, 3 H) 8.00-8.07 (m, 2 H) 8.30 (d, J = 1.51 Hz, 1 H) 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): δ 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 = 11.71 Hz, 1 H) 3.41-3.78 (m, 4 H) 4.02-4.17 (m, 1 H) 4.66 (s, 1 H) 5.78 (s, 1 H)

6.43 (d, J = 2.15 Hz, 1 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, MeOH-d4): δ 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, 1 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, 1 H), 5.61-5.77 (m, 1 H) 6.42-6.53 (m, 1 H) 6.59-6.70 (m,

1 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): δ ppm 1.25 (t, J = 7.10 Hz, 3 H) 1.33 (t, J = 7.10 Hz, 3

H) 1.44-1.64 (m, 4 H) 1.92 (dd, J = 13.28, 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., 1 H) 10.41 (br. s, 1 H)

63cv

¹H NMR (400 MHz, MeOH-d4): δ 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, J = 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, 1 H) 6.55-6.67 (m,

1 H) 7.37 (d, J = 2.20 Hz, 1 H) 7.54 (dd, J = 8.52, 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): δ 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, 1 H) 5.87 (br. s., 1 H) 6.62 (q, J = 6.78 Hz, 1 H) 7.43 (t, J = 1.22 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 (br. s., 1 H)

63cx

¹H NMR (400 MHz, MeOH-d4): δ 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 = 13.54, 8.76 Hz, 1 H) 3.26 (s, 2 H)

3.44-3.73 (m, 4 H) 4.25-4.41 (m, 2 H) 4.56 (t, J = 8.74 Hz, 1 H) 5.57 (s, 1 H) 6.63 (q,

J = 6.80 Hz, 1 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 H)

63cy

¹H NMR (400 MHz, MeOH-d4): δ 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 = 1.22 Hz, 2 H) 3.42-3.79 (m, 4 H) 4.22-4.42 (m, 2 H) 4.57 (t, J = 8.79 Hz, 1 H)

5.54 (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

¹H NMR (400 MHz, MeOH-d4): δ 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

¹H NMR (400 MHz, MeOH-d4): δ 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, J = 13.64, 8.86 Hz, 1 H) 2.41 (s, 3 H) 2.50 (dd,

J = 13.67, 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, J = 2.34 Hz, 1 H)

63db

¹H NMR (400 MHz, MeOH-d4): δ 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 = 13.64, 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, J = 6.62 Hz, 1 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 (m, 2 H) 8.03 (dt, J = 7.79, 1.33 Hz, 1 H) 8.21 (t, J = 1.61 Hz, 1

H)

63dc

¹H NMR (400 MHz, MeOH-d4): δ 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,

J = 13.57, 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, 1 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 = 1.51 Hz, 1 H)

8.08-8.18 (m, 2 H)

63dd

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (t, J = 7.15 Hz, 3 H) 1.50-1.71 (m, 4 H)

2.00 (dd, J = 13.54, 8.61 Hz, 1 H) 2.38 (s, 3 H) 2.42 (dd, J = 13.59, 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, 1 H) 6.39 (d, J = 2.29 Hz, 1 H) 6.77 (q, J = 6.54 Hz, 1

H) 7.45 (d, J = 1.56 Hz, 1 H) 7.52 (dd, J = 8.20, 1.56 Hz, 1H) 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): δ ppm 1.22-1.29 (m, 3 H) 1.51 (dt, J = 11.74, 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 = 13.13, 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 = 1.71 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): δ ppm 1.33 (dt, J = 10.30, 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 H) 3.44-3.74 (m, 4 H) 4.21-4.36 (m, 4 H) 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, J = 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, J = 8.27, 2.17 Hz,

1 H) 7.94 (dd, J = 6.39, 1.85 Hz, 2 H)

63dg

¹H NMR (400 MHz, MeOH-d4): δ 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 (m, 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, 1

H) 6.42 (d, J = 2.20 Hz, 1 H) 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 = 1.27 Hz, 1 H)

63dh

¹H NMR (400 MHz, MeOH-d4): δ 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 = 13.62, 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, J = 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, MeOH-d4): δ ppm 1.22 (t, J = 7.13 Hz, 3 H) 1.32 (t, J = 7.15 Hz, 3

H) 1.53-1.72 (m, 4 H) 2.03 (dd, J = 13.62, 8.83 Hz, 1 H) 2.40 (s, 3 H) 2.47 (dd,

J = 13.59, 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, 1 H) 6.87 (q, J = 6.57 Hz, 1 H)

7.34 (d, J = 8.25 Hz, 2 H) 7.49 (d, J = 8.30 Hz, 1 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): δ 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 = 10.93 Hz, 1 H) 2.89 (d,

J = 10.93 Hz, 1 H) 3.55 (d, J = 5.86 Hz, 4 H) 3.82 (s, 1 H) 4.20 (dd, J = 7.13, 1.27 Hz, 2

H) 5.74 (s, 1 H) 6.44 (d, J = 2.15 Hz, 1 H) 6.85 (d, J = 6.64 Hz, 1 H) 7.04-7.24 (m, 1 H)

7.39-7.53 (m, 3 H) 7.67 (d, J = 1.56 Hz, 1 H) 7.76 (d, J = 1.76 Hz, 1 H) 7.79-7.88 (m,

1 H) 8.01 (d, J = 2.15 Hz, 1 H)

63dk

¹H NMR (400 MHz, MeOH-d4): δ 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 H) 8.40-8.52 (m, 1 H)

8.80-8.96 (m, 1 H)

63dl

¹H NMR (400 MHz, MeOH-d4): δ 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, 1 H) 3.15-3.27 (m, 2

H) 3.43-3.72 (m, 4 H) 4.26-4.36 (m, 2 H) 4.39-4.45 (m, 1 H) 4.49 (t, J = 8.69 Hz, 1

H) 4.90 (t, J = 8.44 Hz, 1 H) 5.70 (d, J = 2.83 Hz, 1 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 = 1.85 Hz, 1 H) 7.58 (dt, J = 8.20,

2.17 Hz, 1 H) 7.82 (dd, J = 8.27, 1.54 Hz, 1 H) 7.95 (dd, J = 3.44, 2.61 Hz, 1 H)

63dm

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (t, J = 7.13 Hz, 3 H) 1.43-1.62 (m, 4 H)

1.70-1.83 (m, 1 H) 2.03-2.18 (m, 1 H) 2.79 (s, 1 H) 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, J = 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, 1 H)

63dn

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (t, J = 7.13 Hz, 3 H) 1.55 (dt, J = 11.03,

5.37 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,

J = 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

¹H NMR (400 MHz, MeOH-d4): δ 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, J = 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 = 1.76 Hz, 2 H) 3.45-3.76 (m, 6

H) 3.81 (dd, J = 8.52, 5.88 Hz, 1 H) 4.25-4.45 (m, 4 H) 4.55 (t, J = 8.79 Hz, 1 H)

5.81 (s, 1 H) 6.41 (d, J = 2.29 Hz, 1 H) 6.82 (q, J = 6.65 Hz, 1 H) 7.71 (s, 1 H) 7.77-7.84 (m,

4 H) 7.90-8.01 (m, 3 H)

63dp

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.33 (t, J = 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 (t, J = 8.69 Hz, 1 H) 5.63 (s, 1 H) 6.63 (q, J = 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 = 1.81 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): δ 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, 1 H) 3.11-3.23 (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 δ 8.12 (m, 3 H) 8.23 (s, 1 H), 8.42 (dd, J = 8.44, 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): δ 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, 1 H)

3.25 (d, J = 1.07 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): δ 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 = 13.62, 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, 1 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 = 1.81 Hz, 1 H) 7.85 (dd, J = 8.27, 2.12 Hz, 1 H) 7.88-7.96 (m, 2 H)

63dt

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (t, J = 7.13 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 = 1.61 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)

5.78 (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 = 1.37 Hz, 1 H) 8.07-8.16 (m, 2 H)

63du

¹H NMR (400 MHz, MeOH-d4): δ ppm 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, J = 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, J = 2.29 Hz, 1 H) 7.96 (s, 1 H) 8.07 (d, J = 8.30 Hz,

2 H)

63dv

¹H NMR (400 MHz, MeOH-d4): δ 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 (m, 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, 1 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, 1 H)

63dw

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (t, J = 7.13 Hz, 3 H) 1.55 (br. 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

¹H NMR (400 MHz, Chloroform-d): δ ppm 1.27 (m, 7H), 1.55 (m, 3H), 1.77 (dd, J = 13.1,

7.0 Hz, 1H), 2.11 (dd, J = 13.1, 8.9 Hz, 1H), 2.42 (s, 3H), 2.96 (m, 2H), 3.47 (dt,

J = 11.6, 5.7 Hz, 4H), 3.98 (dd, J = 8.8, 6.9 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.73 (s,

2H), 5.49 (s, 1H), 5.99 (m, 1H), 6.35 (d, J = 2.3 Hz, 1H), 6.63 (q, J = 6.7 Hz, 1H),

7.61 (m, 2H), 7.73 (d, J = 2.3 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 8.96 (s, 2H), 9.24 (s,

1H)

63dy

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 8H), 1.51 (dt, J = 10.8, 5.6 Hz, 8H),

1.74 (dd, J = 13.1, 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 (m,

8H), 8.00 (d, J = 2.4 Hz, 2H)

63dz

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.50 (dt, J = 10.6, 5.6 Hz,

4H), 1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H),

2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.52 (dq, J = 23.8, 7.6, 6.5 Hz,

4H), 3.81 (dd, J = 8.8, 7.1 Hz, 1H), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 5.73 (s, 1H),

6.41 (d, J = 2.4 Hz, 1H), 6.80 (q, J = 6.5 Hz, 1H), 7.46 (m, 2H), 7.71 (m, 5H), 7.98 (d, J = 2.3 Hz,

1H)

63ea

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.25 (t, J = 7.10 Hz, 3 H) 1.42-1.69 (m, 4 H)

1.92 (dd, J = 13.25, 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, 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): δ ppm 1.25 (t, J = 7.1 Hz, 4H), 1.49 (dt, J = 10.6,

5.6 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.06 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s,

3H), 2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.50 (m, 4H), 3.82 (dd, J = 8.7,

7.2 Hz, 1H), 4.17 (qd, J = 7.1, 1.5 Hz, 2H), 5.76 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H),

6.89 (q, J = 6.6 Hz, 1H), 7.51 (m, 6H), 7.76 (dd, J = 8.3, 2.2 Hz, 1H), 7.92 (t, J = 2.2 Hz,

2H)

63ec

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 5H), 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, 1H), 2.39 (s, 3H),

2.80 (d, J = 11.1 Hz, 1H), 2.93 (d, J = 11.1 Hz, 1H), 3.53 (m, 4H), 3.91 (t, J = 8.0 Hz,

1H), 4.19 (qd, J = 7.2, 1.7 Hz, 2H), 5.77 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.91 (q, J = 6.6 Hz,

1H), 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,

1H), 7.91 (dd, J = 9.9, 2.4 Hz, 2H)

63ed

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 6H), 1.50 (dt, J = 10.4, 5.4 Hz, 5H),

1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.06 (m, 1H), 2.39 (s, 3H), 2.74 (d, J = 11.0 Hz, 1H),

2.88 (d, J = 11.0 Hz, 1H), 3.53 (m, 5H), 3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.17 (qd, J = 7.1,

1.5 Hz, 2H), 5.77 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.87 (q, J = 6.7 Hz, 1H),

7.44 (m, 4H), 7.60 (m, 3H), 7.78 (dd, J = 8.3, 2.1 Hz, 1H), 7.92 (t, J = 2.6 Hz, 2H)

63ee

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (q, J = 8.3, 7.1 Hz, 6H), 1.49 (m, 4H),

1.72 (dd, J = 13.1, 7.2 Hz, 1H), 2.06 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.74 (d, J = 11.0 Hz,

1H), 2.88 (d, J = 11.0 Hz, 1H), 3.50 (m, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, 1H),

4.18 (qd, J = 7.1, 1.5 Hz, 2H), 5.77 (s, 1H), 6.41 (d, J = 2.5 Hz, 1H), 6.93 (q, J = 6.6 Hz,

1H), 7.50 (m, 2H), 7.59 (d, J = 8.3 Hz, 1H), 7.73 (m, 2H), 7.92 (dd, J = 7.7, 2.3 Hz,

2H)

63ef

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (t, J = 7.1 Hz, 5H), 1.54 (tt, J = 7.3, 4.4 Hz,

4H), 1.80 (dd, J = 13.2, 7.6 Hz, 1H), 2.17 (dd, J = 13.2, 8.8 Hz, 1H), 2.85 (d, J = 11.2 Hz,

1H), 2.97 (d, J = 11.2 Hz, 1H), 3.52 (ddt, J = 28.3, 12.4, 8.0 Hz, 4H),

3.97 (dd, J = 8.8, 7.5 Hz, 1H), 4.21 (qd, J = 7.1, 1.7 Hz, 2H), 5.50 (s, 1H), 6.68 (q, J = 6.9 Hz,

1H), 7.25 (m, 4H), 7.48 (m, 3H), 7.71 (m, 1H)

63eg

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.3 Hz, 4H), 1.51 (dt, J = 11.2, 5.5 Hz,

4H), 1.75 (dd, J = 13.1, 7.3 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s, 3H),

2.78 (d, J = 11.1 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.53 (m, 5H), 3.86 (dd, J = 8.6,

7.4 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.77 (s, 1H), 6.44 (d, J = 2.4 Hz, 1H),

7.00 (q, J = 6.7 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.97 (m, 3H), 9.06 (s, 2H), 9.17 (s, 1H)

63eh

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, 1H),

2.75 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.51 (m, 4H), 3.82 (dd, J = 8.7, 7.1 Hz,

1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.52 (s, 1H), 6.61 (q, J = 6.7 Hz, 1H), 7.33 (m,

2H), 7.47 (m, 2H), 7.66 (m, 2H)

63ei

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H),

2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.77 (d, J = 10.9 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H),

3.29 (s, 1H), 3.51 (dq, J = 18.9, 6.1 Hz, 4H), 3.84 (m, 1H), 4.16 (m, 3H), 5.48 (d, J = 2.0 Hz,

1H), 6.73 (q, J = 6.8 Hz, 1H), 7.02 (m, 2H), 7.20 (s, 1H), 7.28 (d, J = 2.2 Hz,

1H), 7.43 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H)

63ej

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 4H), 1.50 (dt, J = 22.1, 6.5 Hz, 7H),

1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.08 (dd, J = 13.1, 8.8 Hz, 1H), 2.75 (d, J = 11.0 Hz,

1H), 2.90 (d, J = 11.0 Hz, 1H), 3.31 (d, J = 1.8 Hz, 1H), 3.49 (dq, J = 25.8, 7.5, 6.6 Hz,

4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (m, 4H), 5.49 (s, 1H), 6.62 (q, J = 6.8 Hz,

1H), 7.20 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 2.2 Hz, 1H), 7.34 (m, 1H), 7.42 (dd, J = 8.5,

2.2 Hz, 1H), 7.58 (m, 1H), 7.65 (d, J = 8.5 Hz, 1H)

63ek

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.0 Hz, 4H), 1.53 (m, 4H),

1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.7 Hz, 1H), 2.76 (d, J = 10.9 Hz, 1H),

2.90 (d, J = 11.0 Hz, 1H), 3.51 (dq, J = 26.1, 7.5, 6.6 Hz, 4H), 3.83 (dd, J = 8.8, 7.2 Hz,

1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.53 (s, 1H), 6.59 (q, J = 6.7 Hz, 1H), 7.27 (d,

J = 8.8 Hz, 1H), 7.34 (m, 2H), 7.49 (m, 2H), 7.69 (d, J = 8.5 Hz, 1H)

63el

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, 1H), 2.75 (d, J = 11.0 Hz,

1H), 2.89 (d, J = 11.0 Hz, 1H), 3.49 (ddt, J = 17.6, 11.8, 6.7 Hz, 4H),

3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.2, 1.5 Hz, 2H), 5.44 (s, 1H), 6.60 (q, J = 6.8 Hz,

1H), 7.28 (m, 2H), 7.47 (m, 4H), 7.67 (d, J = 8.5 Hz, 1H)

63em

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 6H), 1.53 (m, 4H), 1.75 (dd, J = 13.1,

7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.7 Hz, 1H), 2.76 (d, J = 10.9 Hz, 1H), 2.91 (d, J = 11.0 Hz,

1H), 3.52 (m, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.7 Hz,

2H), 5.53 (s, 1H), 6.47 (q, J = 6.7 Hz, 1H), 7.36 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 8.6,

2.3 Hz, 1H), 7.72 (m, 2H), 7.85 (m, 2H)

63en

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (t, J = 7.1 Hz, 7H), 1.59 (dt, J = 11.5, 5.7 Hz,

8H), 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, 1H), 4.28 (m, 6H), 5.55 (s, 1H), 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, MeOH-d4): δ ppm 1.26 (td, J = 7.0, 0.7 Hz, 4H), 1.53 (m, 4H),

1.75 (dd, J = 13.1, 7.3 Hz, 1H), 2.09 (dd, J = 13.1, 8.7 Hz, 1H), 2.76 (d, J = 11.0 Hz,

1H), 2.90 (d, J = 11.0 Hz, 1H), 3.30 (m, 1H), 3.51 (dtd, J = 19.2, 13.4, 7.5 Hz, 4H),

3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (m, 2H), 5.50 (s, 1H), 6.63 (q, J = 6.9 Hz, 1H),

7.25 (m, 1H), 7.47 (m, 6H), 7.71 (m, 1H)

63ep

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.33 (t, J = 7.1 Hz, 4H), 1.65 (m, 5H),

2.06 (dd, J = 13.6, 8.9 Hz, 1H), 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, 1H), 6.68 (q, J = 6.7 Hz,

1H), 6.98 (d, J = 7.5 Hz, 1H), 7.07 (m, 2H), 7.32 (d, J = 2.2 Hz, 1H), 7.46 (m,

2H), 7.68 (d, J = 8.5 Hz, 1H)

63eq

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (m, 10H), 1.52 (m, 4H), 1.74 (dd, J = 13.1,

7.2 Hz, 1H), 2.09 (dd, J = 13.1, 8.7 Hz, 1H), 2.75 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz,

1H), 3.50 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.5 Hz,

2H), 4.70 (h, J = 6.1 Hz, 1H), 5.48 (s, 1H), 6.73 (q, J = 6.9 Hz, 1H), 6.95 (d, J = 7.6 Hz,

1H), 7.04 (m, 1H), 7.21 (s, 1H), 7.27 (d, J = 2.3 Hz, 1H), 7.42 (m, 2H), 7.66 (d, J = 8.5 Hz,

1H)

63er

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (td, J = 7.1, 1.4 Hz, 3H), 1.54 (m, 4H),

1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.7 Hz, 1H), 2.46 (s, 3H), 2.76 (d, J = 10.9 Hz,

1H), 2.91 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H),

4.18 (qd, J = 7.2, 1.6 Hz, 2H), 5.50 (d, J = 1.5 Hz, 1H), 6.60 (q, J = 6.8 Hz, 1H),

7.29 (m, 2H), 7.45 (m, 2H), 7.57 (s, 1H), 7.67 (m, 1H)

63es

¹H NMR (400 MHz, MeOH-d4): δ ppm: 1.19 (s, 2H), 1.34 (m, 11H), 1.53 (m, 4H),

1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.76 (d, J = 11.0 Hz,

1H), 2.91 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H), 3.83 (m, 1H), 4.18 (m, 2H), 4.73 (h, J = 6.1 Hz,

1H), 5.50 (s, 1H), 6.62 (q, J = 6.6 Hz, 1H), 7.28 (m, 3H), 7.43 (dd, J = 8.5, 2.3 Hz,

1H), 7.59 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H)

63et

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.88 (d, J = 8.3 Hz, 1H), 1.30 (m, 11H),

1.53 (m, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.76 (d, J = 11.0 Hz,

1H), 2.91 (d, J = 11.0 Hz, 1H), 3.52 (m, 5H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H),

4.18 (qd, J = 7.1, 1.6 Hz, 2H), 4.71 (h, J = 6.2 Hz, 1H), 5.49 (s, 1H), 6.66 (q, J = 6.8 Hz,

1H), 7.27 (m, 4H), 7.43 (dd, J = 8.5, 2.3 Hz, 1H), 7.65 (m, 1H)

63eu

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (m, 4H), 1.60 (tt, J = 9.2, 4.2 Hz, 4H),

1.97 (m, 1H), 2.37 (dd, J = 13.6, 8.8 Hz, 1H), 3.14 (q, J = 11.6 Hz, 2H), 3.56 (m, 4H),

4.31 (m, 3H), 4.87 (d, J = 1.7 Hz, 18H), 5.54 (s, 1H), 6.49 (q, J = 6.6 Hz, 1H), 7.35 (d,

J = 2.2 Hz, 1H), 7.51 (dd, J = 8.5, 2.2 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.82 (m, 3H)

63ev

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 4H), 1.54 (m, 4H), 1.78 (dd, J = 13.1,

7.4 Hz, 1H), 2.13 (dd, J = 13.1, 8.8 Hz, 1H), 2.81 (d, J = 11.1 Hz, 1H), 2.93 (d, J = 11.0 Hz,

1H), 3.53 (dq, J = 13.2, 6.0 Hz, 4H), 3.89 (dd, J = 8.8, 7.3 Hz, 1H),

4.20 (qd, J = 7.1, 1.7 Hz, 2H), 5.51 (s, 1H), 6.63 (q, J = 6.7 Hz, 1H), 7.28 (m, 4H), 7.52 (m,

2H), 7.68 (d, J = 8.5 Hz, 1H)

63ew

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.90 (d, J = 8.0 Hz, 1H), 1.27 (m, 5H),

1.53 (dt, J = 7.7, 4.7 Hz, 4H), 1.76 (dd, J = 13.1, 7.2 Hz, 1H), 2.11 (dd, J = 13.1, 8.8 Hz,

1H), 2.45 (s, 3H), 2.78 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.31 (s, 3H),

3.50 (dq, J = 27.7, 7.7, 6.6 Hz, 4H), 3.85 (t, J = 8.0 Hz, 1H), 4.19 (m, 2H), 5.49 (s,

1H), 6.61 (q, J = 6.8 Hz, 1H), 7.32 (m, 3H), 7.45 (dd, J = 8.6, 2.3 Hz, 1H), 7.52 (d, J = 8.1 Hz,

1H), 7.67 (d, J = 8.5 Hz, 1H)

63ex

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 4H), 1.54 (m, 4H),

1.76 (dd, J = 13.1, 7.2 Hz, 1H), 2.11 (dd, J = 13.1, 8.8 Hz, 1H), 2.77 (d, J = 11.0 Hz, 1H),

2.91 (d, J = 11.0 Hz, 1H), 3.54 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.19 (qd, J = 7.1,

1.7 Hz, 2H), 5.53 (s, 1H), 6.54 (q, J = 6.7 Hz, 1H), 7.36 (d, J = 2.2 Hz, 1H),

7.53 (dd, J = 8.6, 2.2 Hz, 1H), 7.68 (dd, J = 23.2, 8.4 Hz, 2H), 7.84 (s, 1H), 7.97 (d, J = 8.1 Hz,

1H)

63ey

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.11 (dd, J = 13.1, 8.7 Hz, 1H),

2.77 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.52 (dq, J = 26.9, 7.7, 6.7 Hz, 4H),

3.84 (dd, J = 8.7, 7.2 Hz, 1H), 4.19 (qd, J = 7.2, 1.6 Hz, 2H), 5.53 (s, 1H), 6.63 (q, J = 6.7 Hz,

1H), 7.10 (tt, J = 9.2, 2.4 Hz, 1H), 7.19 (s, 2H), 7.34 (d, J = 2.2 Hz, 1H),

7.50 (dd, J = 8.6, 2.2 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H)

63ez

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.07 (d, J = 1.0 Hz, 1H), 0.88 (dd, J = 14.3,

7.9 Hz, 1H), 1.28 (m, 6H), 1.56 (m, 3H), 1.75 (dd, J = 13.1, 6.7 Hz, 1H), 2.07 (dd, J = 13.1,

8.8 Hz, 2H), 2.84 (d, J = 10.5 Hz, 1H), 2.96 (d, J = 10.5 Hz, 1H), 3.49 (m, 4H),

3.88 (m, 1H), 4.20 (m, 2H), 4.56 (s, 2H), 5.44 (d, J = 1.0 Hz, 1H), 6.52 (q, J = 6.7 Hz,

1H), 7.23 (m, 3H), 7.40 (m, 1H), 7.66 (m, 2H)

63fa

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 3H), 1.53 (m, 4H),

1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.76 (d, J = 11.0 Hz, 1H),

2.90 (d, J = 10.9 Hz, 1H), 3.52 (m, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.2,

1.6 Hz, 2H), 5.52 (s, 1H), 6.60 (q, J = 6.8 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H),

7.45 (m, 3H), 7.67 (d, J = 8.5 Hz, 1H)

63fb

¹H NMR (400 MHz, MeOH-d₄): δ ppm 0.89 (dd, J = 10.8, 3.8 Hz, 1H), 1.27 (t, J = 7.1 Hz,

4H), 1.53 (m, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.7 Hz, 1H),

2.25 (s, 1H), 2.35 (d, J = 3.2 Hz, 6H), 2.77 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz,

1H), 3.50 (m, 4H), 3.85 (dd, J = 8.7, 7.2 Hz, 1H), 4.19 (qd, J = 7.2, 1.6 Hz, 2H),

4.87 (d, J = 5.2 Hz, 13H), 5.44 (s, 1H), 6.64 (q, J = 6.8 Hz, 1H), 7.18 (d, J = 7.7 Hz, 2H),

7.26 (m, 2H), 7.41 (dd, J = 8.5, 2.3 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H)

63fc

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J = 6.7 Hz, 1H), 1.30 (m, 11H),

1.59 (dt, J = 7.7, 4.0 Hz, 9H), 1.94 (dd, J = 13.4, 8.3 Hz, 2H), 2.45 (s, 15H), 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): δ ppm 0.08 (dd, J = 4.2, 1.7 Hz, 1H), 0.90 (q, J = 7.7 Hz,

1H), 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, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.76 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz,

1H), 3.50 (dq, J = 24.8, 7.5, 6.5 Hz, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H),

4.19 (ttd, J = 7.1, 4.5, 2.1 Hz, 4H), 5.49 (s, 1H), 6.66 (q, J = 6.8 Hz, 1H), 7.27 (m, 4H),

7.43 (dd, J = 8.5, 2.3 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H)

63fe

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.09 (dd, J = 13.2, 8.7 Hz, 1H),

2.38 (s, 6H), 2.75 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.50 (m, 5H),

3.82 (t, J = 8.0 Hz, 1H), 4.18 (m, 2H), 5.45 (s, 1H), 6.66 (q, J = 6.8 Hz, 1H), 7.04 (s, 2H),

7.12 (d, J = 1.8 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.41 (m, 1H), 7.66 (d, J = 8.5 Hz,

1H)

63ff

¹H NMR (400 MHz, MeOH-d4): δ ppm1.27 (t, J = 7.1 Hz, 3H), 1.54 (m, 4H),

1.76 (dd, J = 13.1, 7.3 Hz, 1H), 2.11 (dd, J = 13.1, 8.7 Hz, 1H), 2.43 (s, 3H), 2.78 (d, J = 11.0 Hz,

1H), 2.92 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H), 3.86 (dd, J = 8.7, 7.3 Hz, 1H),

4.19 (qd, J = 7.1, 1.6 Hz, 2H), 5.50 (s, 1H), 6.61 (q, J = 6.8 Hz, 1H), 7.18 (s, 1H),

7.31 (m, 2H), 7.39 (s, 1H), 7.46 (dd, J = 8.5, 2.3 Hz, 1H), 7.68 (m, 1H)

63fg

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J = 6.9 Hz, 1H), 1.27 (m, 6H),

1.53 (dt, J = 7.9, 4.6 Hz, 4H), 1.76 (dd, J = 13.1, 7.3 Hz, 1H), 2.11 (m, 1H), 2.35 (d, J = 1.9 Hz,

3H), 2.77 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.49 (dp, J = 25.1, 5.9 Hz,

4H), 3.84 (dd, J = 8.7, 7.2 Hz, 1H), 4.19 (qd, J = 7.1, 1.6 Hz, 2H), 4.87 (s, 13H),

5.49 (s, 1H), 6.62 (q, J = 6.8 Hz, 1H), 7.26 (m, 4H), 7.43 (dd, J = 8.6, 2.3 Hz, 1H),

7.66 (d, J = 8.5 Hz, 1H)

63fh

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.10 (dd, J = 13.1, 8.7 Hz, 1H), 2.40 (s,

3H), 2.77 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.51 (m, 4H), 3.84 (dd, J = 8.7,

7.2 Hz, 1H), 4.19 (qd, J = 7.1, 1.6 Hz, 2H), 5.50 (s, 1H), 6.61 (q, J = 6.7 Hz, 1H),

7.30 (d, J = 2.3 Hz, 1H), 7.45 (m, 4H), 7.67 (d, J = 8.5 Hz, 1H)

63fi

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 5H), 1.53 (m, 4H),

1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.09 (dd, J = 13.1, 8.7 Hz, 1H), 2.76 (d, J = 11.0 Hz, 1H),

2.90 (d, J = 11.0 Hz, 1H), 3.51 (dtt, J = 18.9, 13.4, 7.4 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz,

1H), 4.18 (qd, J = 7.2, 1.6 Hz, 2H), 5.50 (d, J = 10.3 Hz, 1H), 6.58 (q, J = 6.7 Hz,

1H), 7.32 (d, J = 2.2 Hz, 1H), 7.47 (m, 4H), 7.67 (m, 2H)

63fj

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.87 (dd, J = 11.5, 4.7 Hz, 1H), 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, 1H), 2.05 (m, 1H),

2.74 (d, J = 11.0 Hz, 1H), 2.93 (m, 2H), 3.45 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H),

4.17 (qd, J = 7.1, 1.4 Hz, 2H), 5.44 (s, 1H), 6.63 (q, J = 6.8 Hz, 1H), 7.34 (m, 7H),

7.66 (d, J = 8.5 Hz, 1H)

63fk

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.88 (d, J = 7.9 Hz, 1H), 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, 1H),

2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 10.9 Hz, 1H),

3.51 (m, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 4.87 (s, 7H),

5.52 (s, 1H), 6.40 (q, J = 6.6 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.55 (dd, J = 8.5, 2.3 Hz,

1H), 7.71 (d, J = 8.5 Hz, 1H), 8.11 (s, 2H)

63fl

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 6H), 1.54 (m, 7H), 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, 5H), 2.79 (d, J = 11.1 Hz, 2H), 2.93 (d, J = 11.0 Hz, 2H), 3.30 (d, J = 9.7 Hz,

1H), 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): δ ppm1.30 (m, 5H), 1.61 (m, 4H), 1.96 (dd, J = 13.4,

8.4 Hz, 1H), 2.37 (dd, J = 13.4, 8.7 Hz, 1H), 2.81 (s, 1H), 3.13 (q, J = 11.6 Hz, 2H),

3.57 (m, 4H), 4.30 (m, 3H), 5.56 (s, 1H), 6.55 (q, J = 6.7 Hz, 1H), 7.34 (d, J = 2.2 Hz,

1H), 7.55 (m, 5H), 7.69 (d, J = 8.5 Hz, 1H)

63fn

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 4H), 1.53 (m, 4H), 1.75 (dd, J = 13.1,

7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.76 (d, J = 10.9 Hz, 1H), 2.90 (d, J = 11.0 Hz,

1H), 3.51 (m, 4H), 3.82 (dd, J = 8.8, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz,

2H), 5.53 (s, 1H), 6.49 (q, J = 6.7 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.52 (m, 2H),

7.68 (d, J = 8.6 Hz, 1H), 7.81 (s, 2H)

63fo

¹H NMR (400 MHz, MeOH-d4): δ ppm1.27 (t, J = 7.1 Hz, 4H), 1.54 (m, 4H),

1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.77 (d, J = 11.0 Hz, 1H),

2.83 (s, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.53 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H),

4.19 (qd, J = 7.2, 1.6 Hz, 2H), 5.53 (s, 1H), 6.53 (q, J = 6.8 Hz, 1H), 7.37 (d, J = 2.2 Hz,

1H), 7.53 (dd, J = 8.5, 2.2 Hz, 1H), 7.62 (ddd, J = 7.9, 5.0, 0.9 Hz, 1H), 7.72 (d, J = 8.6 Hz,

1H), 7.98 (m, 1H), 8.67 (dd, J = 5.0, 1.6 Hz, 1H), 8.75 (d, J = 2.2 Hz, 1H)

63fp

¹H NMR (400 MHz, MeOH-d4): δ ppm1.31 (m, 10H), 1.54 (m, 4H), 1.75 (dd, J = 13.1,

7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.77 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz,

1H), 3.53 (m, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, 1H), 4.19 (qd, J = 7.1, 1.6 Hz,

2H), 4.69 (p, J = 6.1 Hz, 1H), 5.51 (s, 1H), 6.72 (q, J = 7.0 Hz, 1H), 6.83 (dt, J = 11.3,

2.3 Hz, 1H), 7.03 (m, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.46 (dd, J = 8.5, 2.3 Hz, 1H),

7.67 (d, J = 8.5 Hz, 1H)

63fq

¹H NMR (400 MHz, MeOH-d4): δ ppm0.88 (m, 1H), 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): δ ppm1.32 (m, 15H), 1.52 (m, 4H), 1.74 (dd, J = 13.1,

7.2 Hz, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, 1H), 2.32 (d, J = 0.7 Hz, 1H), 2.43 (d, J = 0.8 Hz,

3H), 2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.48 (m, 4H),

3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.2, 1.5 Hz, 2H), 5.43 (s, 1H), 6.63 (q, J = 6.8 Hz,

1H), 7.06 (s, 1H), 7.26 (m, 2H), 7.34 (q, J = 1.3 Hz, 1H), 7.42 (dd, J = 8.5, 2.3 Hz,

1H), 7.66 (d, J = 8.5 Hz, 1H)

63fs

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.79 (d, J = 11.0 Hz, 1H),

2.92 (d, J = 11.0 Hz, 1H), 3.53 (m, 4H), 3.86 (dd, J = 8.7, 7.3 Hz, 1H), 4.19 (qd, J = 7.1,

1.7 Hz, 2H), 4.86 (s, 3H), 5.53 (s, 1H), 6.57 (q, J = 6.8 Hz, 1H), 7.34 (d, J = 2.2 Hz,

1H), 7.51 (dd, J = 8.5, 2.3 Hz, 1H), 7.72 (m, 2H), 7.84 (m, 2H), 7.92 (s, 1H)

63ft

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.08 (ddd,

J = 11.4, 8.7, 2.6 Hz, 1H), 2.39 (s, 3H), 2.76 (d, J = 11.1 Hz, 1H), 2.88 (dd, J = 11.0,

5.7 Hz, 1H), 3.58 (m, 4H), 3.85 (m, 1H), 4.13 (m, 4H), 5.73 (s, 1H), 6.42 (d, J = 2.4 Hz,

1H), 6.70 (dt, J = 10.7, 2.2 Hz, 1H), 6.80 (p, J = 6.5 Hz, 1H), 7.01 (m, 2H),

7.63 (d, J = 1.9 Hz, 1H), 7.76 (m, 2H), 8.00 (d, J = 2.4 Hz, 1H)

63fu

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.07 (dd, J = 13.1, 8.7 Hz, 1H), 2.22 (s, 1H),

2.29 (d, J = 10.3 Hz, 6H), 2.39 (s, 3H), 2.75 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz,

1H), 3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H),

5.74 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.75 (m, 1H), 7.19 (d, J = 7.9 Hz, 1H), 7.39 (m, 2H),

7.59 (d, J = 1.8 Hz, 1H), 7.72 (m, 2H), 7.96 (d, J = 2.3 Hz, 1H)

63fv

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 4H), 1.51 (dt, J = 10.6, 5.6 Hz, 4H),

1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.08 (dd, J = 13.1, 8.7 Hz, 1H), 2.39 (s, 1H), 2.76 (d, J = 11.0 Hz,

1H), 2.89 (d, J = 11.0 Hz, 1H), 3.53 (m, 4H), 3.83 (m, 1H), 4.18 (m, 2H),

4.85 (d, J = 10.8 Hz, 1H), 5.73 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.83 (q, J = 6.6 Hz,

1H), 7.60 (m, 4H), 7.79 (m, 2H), 8.00 (d, J = 2.4 Hz, 1H)

63fw

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.25 (t, J = 7.1 Hz, 3H), 1.46 (m, 7H),

1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.06 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.73 (d, J = 11.0 Hz,

1H), 2.87 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H), 3.80 (dd, J = 8.7, 7.1 Hz, 1H),

4.16 (m, 4H), 5.73 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78 (q, J = 6.6 Hz, 1H), 7.11 (d, J = 8.6 Hz,

1H), 7.57 (m, 1H), 7.71 (m, 3H), 7.98 (d, J = 2.4 Hz, 1H)

63fx

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.07 (dd, J = 13.0, 8.8 Hz,

1H), 2.39 (s, 3H), 2.74 (d, J = 10.9 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.53 (m, 4H),

3.81 (dd, J = 8.8, 7.1 Hz, 1H), 4.13 (m, 4H), 4.87 (s, 13H), 5.74 (s, 1H), 6.41 (d, J = 2.4 Hz,

1H), 6.78 (q, J = 7.6, 7.0 Hz, 1H), 6.93 (m, 1H), 7.20 (m, 2H), 7.34 (t, J = 7.9 Hz,

1H), 7.62 (d, J = 1.8 Hz, 1H), 7.75 (m, 2H), 7.98 (d, J = 2.4 Hz, 1H)

63fy

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 3H), 1.50 (dt, J = 10.5, 5.8 Hz, 4H),

1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.0, 8.8 Hz, 1H), 2.39 (s, 3H), 2.74 (d, J = 11.0 Hz,

1H), 2.88 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H), 3.80 (m, 1H), 4.17 (qd, J = 7.1,

1.6 Hz, 2H), 5.73 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.84 (q, J = 6.6 Hz, 1H),

6.99 (tt, J = 9.1, 2.4 Hz, 1H), 7.34 (m, 2H), 7.68 (d, J = 1.9 Hz, 1H), 7.79 (m, 2H), 8.01 (d,

J = 2.4 Hz, 1H)

63fz

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 3H), 1.51 (dt, J = 10.6, 5.6 Hz, 4H),

1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s, 3H), 2.74 (d, J = 11.0 Hz,

1H), 2.88 (d, J = 11.0 Hz, 1H), 3.52 (dq, J = 25.8, 8.1, 6.9 Hz, 4H),

3.81 (dd, J = 8.8, 7.1 Hz, 1H), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 5.73 (s, 1H), 6.43 (d, J = 2.4 Hz,

1H), 6.83 (q, J = 6.6 Hz, 1H), 7.69 (m, 3H), 7.82 (m, 2H), 7.98 (m, 3H)

63ga

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.11 (m, 1H), 2.77 (d, J = 11.0 Hz,

1H), 2.91 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.17 (m,

4H), 5.49 (s, 1H), 6.66 (q, J = 6.8 Hz, 1H), 7.02 (s, 1H), 7.27 (m, 3H), 7.45 (dd, J = 8.5,

2.3 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H)

63gb

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.88 (m, 2H), 1.17 (t, J = 7.0 Hz, 1H),

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, 1H),

2.08 (ddd, J = 11.9, 8.8, 2.8 Hz, 1H), 2.39 (s, 3H), 2.76 (d, J = 11.0 Hz, 1H), 2.89 (dd, J = 11.0,

5.9 Hz, 1H), 3.57 (m, 5H), 3.84 (dt, J = 8.6, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.7 Hz,

1H), 4.64 (p, J = 6.1 Hz, 1H), 5.74 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78 (q, J = 6.5 Hz,

1H), 7.16 (t, J = 8.6 Hz, 1H), 7.44 (m, 2H), 7.61 (d, J = 1.9 Hz, 1H), 7.73 (m,

2H), 7.98 (d, J = 2.4 Hz, 1H)

63gc

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 4H), 1.51 (dt, J = 10.6, 5.7 Hz, 4H),

1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.28 (s, 1H), 2.37 (d, J = 16.9 Hz,

9H), 2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.53 (dt, J = 22.1,

6.0 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.74 (s,

1H), 6.41 (d, J = 2.3 Hz, 1H), 6.77 (q, J = 6.6 Hz, 1H), 7.03 (m, 1H), 7.27 (d, J = 1.5 Hz,

2H), 7.60 (d, J = 1.8 Hz, 1H), 7.74 (m, 2H), 7.97 (d, J = 2.4 Hz, 1H)

63gd

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (q, J = 7.1, 6.4 Hz, 4H), 1.50 (dt, J = 10.3,

5.6 Hz, 4H), 1.73 (dd, J = 13.0, 7.2 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H),

2.39 (d, J = 3.0 Hz, 6H), 2.74 (d, J = 10.9 Hz, 1H), 2.88 (d, J = 10.9 Hz, 1H), 3.52 (dt,

J = 22.1, 6.1 Hz, 4H), 3.81 (dd, J = 8.8, 7.1 Hz, 1H), 4.17 (qd, J = 7.1, 1.6 Hz, 2H),

4.87 (s, 9H), 5.73 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.81 (q, J = 6.6 Hz, 1H), 7.23 (s,

1H), 7.42 (s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 1.9 Hz, 1H), 7.71 (dd, J = 8.1,

1.9 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H)

63ge

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J = 7.0 Hz, 1H), 1.26 (m, 5H),

1.50 (dt, J = 10.5, 5.4 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz,

1H), 2.29 (d, J = 1.9 Hz, 1H), 2.39 (s, 3H), 2.74 (d, J = 10.9 Hz, 1H), 2.88 (d, J = 11.0 Hz,

1H), 3.52 (m, 4H), 3.81 (dd, J = 8.8, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H),

5.73 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.79 (q, J = 6.6 Hz, 1H), 7.37 (m, 1H), 7.63 (d, J = 1.9 Hz,

1H), 7.76 (m, 2H), 7.98 (d, J = 2.4 Hz, 1H)

63gf

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.08 (m, 1H), 1.26 (m, 4H), 1.36 (s, 9H),

1.51 (dt, J = 10.5, 5.5 Hz, 5H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.08 (dd, J = 13.1, 8.8 Hz,

1H), 2.40 (s, 3H), 2.74 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 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, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.76 (q, J = 6.6 Hz, 1H), 7.43 (m, 3H), 7.61 (d, J = 1.9 Hz,

1H), 7.73 (m, 3H), 7.99 (d, J = 2.4 Hz, 1H)

63gg

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.3 Hz, 6H), 1.50 (dt, J = 10.5,

5.6 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.08 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s,

3H), 2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H), 3.83 (dd, J = 8.7,

7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.73 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H),

6.82 (q, J = 6.6 Hz, 1H), 7.41 (m, 2H), 7.61 (m, 2H), 7.74 (m, 3H), 8.00 (d, J = 2.4 Hz,

1H)

63gh

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.2 Hz, 3H), 1.51 (dt, J = 10.4, 5.5 Hz,

4H), 1.75 (dd, J = 13.1, 7.3 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 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,

1H), 4.18 (qd, J = 7.2, 1.6 Hz, 2H), 5.73 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.82 (q, J = 6.6 Hz,

1H), 7.33 (t, J = 8.8 Hz, 1H), 7.63 (m, 2H), 7.73 (dd, J = 8.3, 1.9 Hz, 1H),

7.82 (m, 2H), 8.00 (d, J = 2.3 Hz, 1H)

63gi

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (m, 4H), 1.53 (dt, J = 10.2, 5.5 Hz, 4H),

1.82 (dd, J = 13.2, 7.7 Hz, 1H), 2.19 (m, 1H), 2.39 (s, 3H), 2.88 (d, J = 11.2 Hz, 1H),

2.99 (d, J = 11.2 Hz, 1H), 3.55 (m, 4H), 4.02 (t, J = 8.2 Hz, 1H), 4.22 (qd, J = 7.1, 1.9 Hz,

2H), 5.74 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.82 (m, 1H), 7.35 (dt, J = 10.4, 8.4 Hz,

1H), 7.50 (ddt, J = 7.9, 3.8, 1.8 Hz, 1H), 7.72 (m, 4H), 8.00 (d, J = 2.4 Hz, 1H)

63gj

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (m, 3H), 1.65 (dt, J = 12.8, 6.2 Hz, 4H),

2.03 (m, 1H), 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, 1H), 4.85 (m, 1H), 6.43 (d, J = 2.5 Hz, 1H), 6.89 (q, J = 6.4 Hz,

1H), 7.45 (m, 1H), 7.72 (d, J = 1.8 Hz, 1H), 7.81 (m, 2H), 8.00 (m, 3H)

63gk

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.44 (m, 4H), 2.80 (s, 1H), 3.25 (m, 2H),

3.56 (m, 1H), 3.70 (d, J = 5.7 Hz, 2H), 4.32 (qd, J = 7.1, 2.5 Hz, 2H), 4.57 (t, J = 8.8 Hz,

1H), 6.44 (d, J = 2.4 Hz, 1H), 6.90 (q, J = 6.5 Hz, 1H), 7.76 (q, J = 1.5, 1.0 Hz,

2H), 7.85 (m, 2H), 7.95 (m, 1H), 8.04 (m, 2H)

63gl

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.08 (dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s, 3H),

2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H), 3.83 (dd, J = 8.7,

7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.73 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H),

6.82 (q, J = 6.6 Hz, 1H), 7.31 (ddt, J = 8.1, 2.3, 1.1 Hz, 1H), 7.57 (dd, J = 15.9, 7.9 Hz,

2H), 7.74 (m, 4H), 8.01 (d, J = 2.4 Hz, 1H)

63gm

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (d, J = 34.9 Hz, 12H), 1.51 (dt, J = 10.4,

5.7 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.06 (m, 1H), 2.39 (d, J = 3.3 Hz, 6H),

2.74 (d, J = 11.0 Hz, 2H), 2.89 (d, J = 11.0 Hz, 1H), 3.53 (m, 5H), 3.81 (dd, J = 8.7,

7.1 Hz, 1H), 4.17 (qd, J = 7.2, 1.6 Hz, 2H), 4.87 (s, 3H), 5.73 (s, 1H), 6.41 (d, J = 2.4 Hz,

1H), 6.75 (q, J = 6.8 Hz, 1H), 7.28 (d, J = 9.0 Hz, 2H), 7.46 (t, J = 1.6 Hz, 1H),

7.59 (d, J = 1.8 Hz, 1H), 7.75 (m, 2H), 7.98 (d, J = 2.3 Hz, 1H)

63gn

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.41 (d, J = 11.8 Hz,

6H), 2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.52 (dq, J = 24.2,

7.6, 6.3 Hz, 4H), 3.81 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.73 (s,

1H), 6.41 (d, J = 2.4 Hz, 1H), 6.79 (m, 1H), 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, 1H)

63go

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.88 (d, J = 7.9 Hz, 1H), 1.26 (t, J = 7.1 Hz,

7H), 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, 1H), 2.40 (d, J = 9.3 Hz, 16H), 2.75 (d, J = 11.0 Hz,

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, 4H), 7.62 (d, J = 1.8 Hz, 2H), 7.74 (m, 4H), 7.98 (d, J = 2.4 Hz,

2H)

63gp

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (q, J = 7.1, 5.7 Hz, 7H), 1.51 (dt, J = 10.7,

5.5 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.06 (td, J = 15.3, 14.1, 7.4 Hz,

1H), 2.32 (d, J = 2.1 Hz, 3H), 2.39 (s, 2H), 2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz,

1H), 3.53 (dt, J = 22.2, 6.1 Hz, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, 1H), 4.18 (m, 2H),

5.74 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.78 (q, J = 6.5 Hz, 1H), 7.10 (t, J = 9.0 Hz,

1H), 7.56 (m, 3H), 7.74 (m, 2H), 7.98 (d, J = 2.4 Hz, 1H)

63gq

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, 1H), 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, 1H), 2.09 (m, 1H), 2.39 (s, 3H), 2.75 (d,

J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.53 (m, 4H), 3.82 (dd, J = 8.7, 7.2 Hz,

1H), 4.16 (m, 4H), 5.74 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78 (q, J = 6.5 Hz, 1H),

7.15 (t, J = 8.6 Hz, 1H), 7.47 (m, 4H), 7.73 (m, 2H), 7.97 (d, J = 2.3 Hz, 1H)

63gr

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.52 (t, J = 8.0 Hz,

5H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.08 (dd, J = 13.0, 8.7 Hz, 1H), 2.40 (s, 3H),

2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 10.9 Hz, 1H), 3.25 (p, J = 1.7 Hz, 1H), 3.53 (m, 5H),

3.81 (dd, J = 8.8, 7.1 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 4.82 (s, 1H), 5.73 (s,

1H), 6.00 (m, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.85 (d, J = 6.6 Hz, 1H), 7.48 (t, J = 1.9 Hz,

1H), 7.69 (m, 3H), 7.80 (m, 3H), 8.03 (d, J = 2.4 Hz, 1H)

63gs

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 10H), 1.50 (dt, J = 10.3, 5.6 Hz, 4H),

1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.74 (d, J = 11.0 Hz,

1H), 2.93 (m, 2H), 3.52 (m, 5H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4.17 (qd, J = 7.1,

1.5 Hz, 2H), 5.74 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78 (q, J = 6.6 Hz, 1H),

7.26 (dt, J = 7.6, 1.4 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.47 (m, 2H), 7.61 (d, J = 1.9 Hz,

1H), 7.75 (m, 2H), 7.98 (d, J = 2.4 Hz, 1H)

63gt

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 4H), 1.51 (dt, J = 11.0, 5.6 Hz, 4H),

1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.2, 8.8 Hz, 1H), 2.40 (s, 2H), 2.75 (d, J = 10.9 Hz,

1H), 2.89 (d, J = 11.0 Hz, 1H), 3.53 (m, 4H), 3.82 (dd, J = 8.8, 7.2 Hz, 1H),

4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.72 (s, 1H), 6.00 (m, 1H), 6.43 (d, J = 2.4 Hz, 1H),

6.84 (q, J = 6.5 Hz, 1H), 7.71 (m, 2H), 7.82 (m, 2H), 7.92 (dd, J = 8.4, 2.3 Hz, 1H),

8.05 (dd, J = 15.9, 2.3 Hz, 2H)

63gu

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s, 3H),

2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.53 (dt, J = 22.4, 6.0 Hz, 4H),

3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 5.73 (s, 1H), 6.43 (d, J = 2.4 Hz,

1H), 6.86 (q, J = 6.6 Hz, 1H), 7.81 (m, 5H), 7.97 (m, 1H), 8.03 (d, J = 2.4 Hz,

1H)

63gv

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.08 (m, 1H), 1.26 (m, 4H), 1.51 (dt, J = 10.7,

5.5 Hz, 5H), 1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.06 (m, 1H), 2.40 (s, 3H), 2.74 (d, J = 11.0 Hz,

1H), 2.88 (d, J = 11.0 Hz, 1H), 3.26 (s, 1H), 3.53 (dt, J = 22.3, 6.1 Hz, 5H),

3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 5.74 (s, 1H), 6.42 (dd, J = 2.4,

0.6 Hz, 1H), 6.83 (q, J = 6.6 Hz, 1H), 7.57 (dd, J = 8.1, 7.5 Hz, 1H), 7.74 (t, J = 1.1 Hz,

1H), 7.87 (m, 4H), 8.00 (d, J = 2.4 Hz, 1H), 8.19 (m, 1H)

63gw

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.41 (s, 3H),

2.76 (d, J = 11.0 Hz, 1H), 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, 1H), 4.18 (qd, J = 7.2, 1.7 Hz, 2H), 5.72 (s, 1H), 6.44 (d, J = 2.4 Hz,

1H), 6.87 (q, J = 6.6 Hz, 1H), 7.80 (d, J = 1.6 Hz, 1H), 7.89 (m, 2H), 8.00 (s,

1H), 8.07 (d, J = 2.4 Hz, 1H), 8.30 (d, J = 1.5 Hz, 2H)

63gx

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (m, 10H), 1.50 (dt, J = 10.2, 5.5 Hz, 4H),

1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.06 (m, 1H), 2.39 (s, 3H), 2.74 (d, J = 11.0 Hz, 1H),

2.88 (d, J = 10.9 Hz, 1H), 3.53 (m, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4.17 (qd, J = 7.2,

1.6 Hz, 2H), 4.65 (h, J = 5.9 Hz, 1H), 5.73 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H),

6.78 (q, J = 6.6 Hz, 1H), 6.92 (m, 1H), 7.19 (m, 2H), 7.33 (t, J = 7.9 Hz, 1H), 7.60 (d, J = 1.8 Hz,

1H), 7.74 (m, 2H), 7.98 (d, J = 2.3 Hz, 1H)

63gy

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.2 Hz, 4H), 1.46 (m, 7H),

1.75 (dd, J = 13.1, 7.3 Hz, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.76 (d, J = 11.0 Hz,

1H), 2.90 (d, J = 11.0 Hz, 1H), 3.52 (dq, J = 24.9, 7.0, 6.0 Hz, 4H), 3.84 (dd,

J = 8.7, 7.2 Hz, 1H), 4.18 (ttd, J = 7.0, 5.2, 2.5 Hz, 4H), 5.74 (s, 1H), 6.41 (d, J = 2.3 Hz,

1H), 6.78 (q, J = 6.5 Hz, 1H), 7.18 (m, 2H), 7.35 (dd, J = 8.0, 2.1 Hz, 1H),

7.62 (d, J = 1.8 Hz, 1H), 7.74 (m, 2H), 7.99 (d, J = 2.3 Hz, 1H)

63gz

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, 9H), 1.51 (dt, J = 10.4, 5.6 Hz, 4H),

1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.0, 8.7 Hz, 1H), 2.39 (s, 3H), 2.74 (d, J = 11.0 Hz,

1H), 2.88 (d, J = 11.0 Hz, 1H), 3.53 (m, 4H), 3.81 (dd, J = 8.7, 7.1 Hz, 1H),

4.17 (qd, J = 7.1, 1.6 Hz, 2H), 4.66 (h, J = 6.1 Hz, 1H), 5.73 (s, 1H), 6.41 (d, J = 2.4 Hz,

1H), 6.70 (dt, J = 10.8, 2.2 Hz, 1H), 6.81 (q, J = 6.6 Hz, 1H), 6.99 (m, 2H),

7.62 (d, J = 1.8 Hz, 1H), 7.72 (dd, J = 8.3, 1.9 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 2.3 Hz,

1H)

63ha

¹H NMR (400 MHz, MeOH-d4): δ 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, J = 7.03, 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): δ 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 = 5.17, 3.61 Hz, 3 H), 7.72-7.85 (m, 2 H), 7.93-8.02 (m, 1 H)

63hc

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.2 Hz, 3H), 1.51 (dt, J = 11.0, 5.6 Hz,

4H), 1.74 (dd, J = 13.1, 7.3 Hz, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H),

2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H), 3.84 (dd, J = 8.7,

7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 4.88 (s, 7H), 5.72 (s, 1H), 6.42 (d, J = 2.4 Hz,

1H), 6.84 (q, J = 6.5 Hz, 1H), 7.52 (m, 2H), 7.67 (d, J = 1.9 Hz, 1H), 7.74 (dd, J = 8.3,

1.9 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 2.4 Hz, 1H)

63hd

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.77 (d, J = 10.9 Hz,

1H), 2.91 (d, J = 10.9 Hz, 1H), 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, 1H), 4.19 (qd, J = 7.2, 1.6 Hz, 2H), 5.51 (d, J = 18.6 Hz, 1H),

6.49 (dd, J = 6.9, 2.0 Hz, 1H), 6.81 (q, J = 6.8 Hz, 1H), 6.91 (s, 1H), 7.35 (d, J = 2.2 Hz,

1H), 7.51 (dd, J = 8.5, 2.2 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 6.8 Hz,

1H)

63he

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 4H), 1.51 (dt, J = 10.8, 5.6 Hz,

5H), 1.74 (dd, J = 13.1, 7.1 Hz, 1H), 2.07 (dd, J = 13.0, 8.7 Hz, 1H), 2.38 (d, J = 9.6 Hz,

6H), 2.74 (d, J = 10.9 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.53 (dt, J = 21.9,

6.3 Hz, 5H), 3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 4.88 (s,

15H), 5.74 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.81 (q, J = 6.6 Hz, 1H), 7.33 (m, 1H),

7.58 (m, 1H), 7.66 (t, J = 2.6 Hz, 2H), 7.77 (m, 2H), 7.99 (d, J = 2.4 Hz, 1H)

63hf

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.08 (m, 1H), 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, 1H), 2.11 (dd, J = 13.2, 8.8 Hz,

1H), 2.39 (s, 7H), 2.79 (d, J = 11.0 Hz, 1H), 2.92 (d, J = 11.1 Hz, 1H), 3.52 (dq, J = 29.5,

7.4, 6.4 Hz, 5H), 3.89 (dd, J = 8.7, 7.4 Hz, 1H), 4.19 (qd, J = 7.2, 1.7 Hz, 2H),

5.73 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.80 (q, J = 6.6 Hz, 1H), 7.37 (d, J = 7.9 Hz,

1H), 7.51 (dd, J = 7.9, 1.9 Hz, 1H), 7.62 (d, J = 1.9 Hz, 1H), 7.73 (m, 3H), 7.99 (d, J = 2.4 Hz,

1H)

63hg

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.51 (dt, J = 10.5, 5.6 Hz,

4H), 1.75 (dd, J = 13.1, 7.3 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s, 3H),

2.77 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.53 (m, 4H), 3.85 (dd, J = 8.7,

7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 5.73 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H),

6.86 (q, J = 6.6 Hz, 1H), 7.50 (dd, J = 8.4, 2.1 Hz, 1H), 7.79 (m, 6H), 8.04 (d, J = 2.4 Hz,

1H)

63hh

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.93 (m, 2H), 1.36 (m, 11H), 1.69 (td, J = 13.3,

6.6 Hz, 1H), 2.04 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.72 (d, J = 11.0 Hz,

1H), 2.86 (d, J = 11.0 Hz, 1H), 3.50 (m, 4H), 3.80 (t, J = 7.9 Hz, 1H), 4.17 (m, 2H),

5.71 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.85 (q, J = 6.6 Hz, 1H), 7.20 (dt, J = 8.5, 2.1 Hz,

1H), 7.39 (dt, J = 9.7, 2.0 Hz, 1H), 7.52 (t, J = 1.6 Hz, 1H), 7.67 (m, 2H), 7.80 (d,

J = 8.3 Hz, 1H), 8.01 (d, J = 2.3 Hz, 1H)

63hi

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.75 (m, 2H), 1.01 (dq, J = 8.4, 2.4 Hz, 2H),

1.19 (s, 1H), 1.26 (t, J = 7.1 Hz, 4H), 1.52 (m, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H),

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, 1H), 4.18 (qd, J = 7.1, 1.5 Hz, 2H), 5.44 (s, 1H), 6.60 (q, J = 6.9 Hz,

1H), 7.20 (m, 4H), 7.41 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H)

63hj

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.05 (dd, J = 13.1,

8.8 Hz, 1H), 2.39 (s, 3H), 2.72 (d, J = 11.0 Hz, 1H), 2.87 (d, J = 11.0 Hz, 1H),

3.51 (m, 4H), 3.80 (dd, J = 8.7, 7.1 Hz, 1H), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 4.67 (hept,

J = 6.1 Hz, 1H), 5.73 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.78 (q, J = 6.6 Hz, 1H),

7.12 (d, J = 8.6 Hz, 1H), 7.54 (m, 2H), 7.67 (m, 2H), 7.75 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 2.4 Hz,

1H)

63hk

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 4H), 1.54 (m, 4H), 1.75 (dd, J = 13.1,

7.2 Hz, 1H), 2.11 (dd, J = 13.1, 8.8 Hz, 1H), 2.77 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz,

1H), 3.52 (dq, J = 27.4, 7.7, 6.5 Hz, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H),

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, 1H),

7.40 (d, J = 2.2 Hz, 1H), 7.52 (m, 2H), 7.73 (d, J = 8.5 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H),

8.47 (s, 1H), 9.34 (s, 1H)

63hl

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.07 (dd, J = 13.1, 8.7 Hz, 1H), 2.74 (d, J = 10.9 Hz,

1H), 2.88 (d, J = 10.9 Hz, 1H), 3.10 (s, 6H), 3.49 (m, 4H), 3.81 (dd, J = 8.7,

7.2 Hz, 1H), 4.17 (qd, J = 7.1, 1.3 Hz, 2H), 5.47 (s, 1H), 6.69 (m, 3H), 7.32 (d, J = 2.2 Hz,

1H), 7.45 (dd, J = 8.5, 2.2 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 8.18 (d, J = 5.2 Hz,

1H)

63hm

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.03 (dd, J = 13.1, 8.7 Hz, 1H), 2.70 (d, J = 11.0 Hz,

1H), 2.85 (d, J = 11.0 Hz, 1H), 3.40 (m, 4H), 3.79 (t, J = 7.9 Hz, 1H),

4.16 (q, J = 7.1 Hz, 2H), 5.45 (d, J = 17.0 Hz, 1H), 6.68 (q, J = 6.8 Hz, 1H), 7.37 (d, J = 2.3 Hz,

1H), 7.44 (dd, J = 8.6, 2.2 Hz, 1H), 7.56 (m, 3H), 7.71 (d, J = 8.5 Hz, 1H),

7.94 (m, 4H)

63hn

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 3H), 1.36 (s, 9H), 1.52 (m,

4H), 1.77 (dd, J = 13.1, 7.4 Hz, 1H), 2.13 (dd, J = 13.1, 8.7 Hz, 1H), 2.80 (d, J = 11.1 Hz,

1H), 2.93 (d, J = 11.1 Hz, 1H), 3.48 (m, 4H), 3.91 (dd, J = 8.7, 7.4 Hz, 1H),

4.20 (qd, J = 7.2, 1.7 Hz, 2H), 5.41 (s, 1H), 6.64 (q, J = 6.9 Hz, 1H), 7.27 (m, 2H), 7.44 (m,

5H), 7.69 (d, J = 7.3 Hz, 1H)

63ho

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.09 (m, 1H), 2.75 (dd, J = 10.9, 7.2 Hz,

1H), 2.90 (dd, J = 11.0, 6.6 Hz, 1H), 3.29 (s, 1H), 3.52 (m, 4H), 3.83 (td, J = 8.2,

4.3 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 5.47 (m, 1H), 6.43 (dt, J = 11.2, 5.6 Hz, 1H),

7.22 (m, 1H), 7.38 (m, 2H), 7.61 (dd, J = 5.0, 2.2 Hz, 1H), 7.81 (m, 3H)

63hp

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 4H), 1.51 (dt, J = 10.0, 5.2 Hz,

4H), 1.80 (m, 1H), 2.17 (dd, J = 13.3, 8.8 Hz, 1H), 2.86 (d, J = 11.2 Hz, 1H),

2.97 (d, J = 11.2 Hz, 1H), 3.50 (m, 4H), 4.01 (t, J = 8.2 Hz, 1H), 4.21 (qd, J = 7.1, 1.9 Hz,

2H), 5.63 (s, 1H), 6.69 (q, J = 6.6 Hz, 1H), 7.30 (ddd, J = 7.9, 6.9, 0.9 Hz, 1H),

7.46 (m, 2H), 7.75 (m, 4H), 8.39 (d, J = 1.0 Hz, 1H)

63hq

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.05 (dd, J = 13.1, 8.8 Hz, 1H),

2.81 (d, J = 10.5 Hz, 1H), 2.94 (d, J = 10.5 Hz, 1H), 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, 1H), 4.19 (q, J = 7.1 Hz, 2H), 4.34 (s,

2H), 5.42 (s, 1H), 6.53 (q, J = 6.7 Hz, 1H), 7.25 (m, 3H), 7.42 (dd, J = 8.5, 2.2 Hz,

1H), 7.68 (d, J = 8.5 Hz, 1H), 8.65 (dd, J = 5.0, 0.8 Hz, 1H)

63hr

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.77 (d, J = 11.0 Hz, 1H),

2.91 (d, J = 11.0 Hz, 1H), 3.51 (dq, J = 17.7, 6.1 Hz, 4H), 3.84 (dd, J = 8.7, 7.3 Hz,

1H), 4.19 (qd, J = 7.1, 1.6 Hz, 2H), 5.50 (s, 1H), 6.60 (q, J = 6.7 Hz, 1H), 7.28 (m,

3H), 7.48 (ddd, J = 25.4, 8.2, 3.7 Hz, 3H), 7.66 (d, J = 8.5 Hz, 1H)

63hs

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.52 (m, 4H),

1.75 (dd, J = 13.1, 7.3 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.77 (d, J = 11.0 Hz, 1H),

2.91 (d, J = 11.0 Hz, 1H), 3.50 (dq, J = 25.8, 7.7, 6.9 Hz, 4H), 3.85 (dd, J = 8.7, 7.3 Hz,

1H), 4.19 (qd, J = 7.1, 1.5 Hz, 2H), 5.50 (s, 1H), 6.60 (q, J = 6.7 Hz, 1H), 7.28 (d,

J = 2.2 Hz, 1H), 7.52 (m, 6H)

63ht

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.25 (dd, J = 13.3, 8.7 Hz, 1H), 2.44 (s, 3H),

2.96 (d, J = 11.4 Hz, 1H), 3.05 (d, J = 11.3 Hz, 1H), 3.54 (m, 3H), 3.75 (s, 1H),

4.13 (t, J = 8.3 Hz, 1H), 4.24 (qd, J = 7.2, 2.0 Hz, 2H), 5.48 (s, 1H), 6.64 (q, J = 6.8 Hz,

1H), 7.26 (d, J = 2.3 Hz, 1H), 7.35 (s, 4H), 7.42 (dd, J = 8.5, 2.3 Hz, 1H), 7.65 (d, J = 8.5 Hz,

1H)

63hu

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.24 (m, 3H), 1.49 (dt, J = 10.2, 5.7 Hz, 4H),

1.72 (m, 1H), 2.04 (m, 1H), 2.41 (s, 2H), 2.72 (d, J = 10.9 Hz, 1H), 2.86 (d, J = 10.9 Hz,

1H), 3.52 (m, 4H), 3.79 (dd, J = 8.8, 7.1 Hz, 1H), 4.16 (qd, J = 7.1, 1.6 Hz, 2H),

5.76 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.82 (q, J = 6.7 Hz, 1H), 7.49 (m, 2H), 7.84 (m,

7H), 8.01 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 1.9 Hz, 1H)

63hv

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.53 (m, 4H),

1.78 (m, 5H), 2.11 (m, 2H), 2.25 (dt, J = 7.9, 4.0 Hz, 2H), 2.41 (d, J = 18.1 Hz, 1H),

2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 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, 1H), 5.76 (h, J = 2.0 Hz,

1H), 6.93 (q, J = 6.9 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.30 (dd, J = 8.5, 2.3 Hz,

1H), 7.58 (d, J = 8.5 Hz, 1H)

63hw

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.17 (dd, J = 13.3, 8.8 Hz, 1H), 2.39 (s, 3H),

2.88 (d, J = 11.3 Hz, 1H), 2.98 (d, J = 11.3 Hz, 1H), 3.53 (m, 4H), 4.04 (t, J = 8.2 Hz,

1H), 4.21 (qd, J = 7.2, 1.8 Hz, 2H), 4.90 (d, J = 1.1 Hz, 5H), 5.74 (s, 1H), 6.41 (d, J = 2.3 Hz,

1H), 6.78 (q, J = 6.6 Hz, 1H), 7.17 (t, J = 8.6 Hz, 1H), 7.40 (m, 7H), 7.62 (m,

2H), 7.74 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 2.3 Hz, 1H)

63hx

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (m, 9H), 1.55 (dt, J = 10.7, 5.8 Hz, 4H),

1.87 (dd, J = 13.3, 8.0 Hz, 1H), 2.24 (m, 4H), 2.39 (s, 3H), 2.98 (d, J = 11.4 Hz, 1H),

3.06 (d, J = 11.4 Hz, 1H), 3.58 (m, 4H), 4.22 (m, 3H), 4.63 (p, J = 6.0 Hz, 1H),

5.76 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.75 (q, J = 6.6 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H),

7.45 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 1.7 Hz, 1H), 7.71 (m, 2H), 7.96 (d, J = 2.3 Hz,

1H)

63hy

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.08 (m, 2H), 2.75 (d, J = 11.0 Hz, 1H),

2.90 (d, J = 11.0 Hz, 1H), 3.50 (m, 4H), 3.80 (m, 3H), 4.18 (qd, J = 7.1, 1.4 Hz, 2H),

5.48 (s, 1H), 6.70 (q, J = 6.9 Hz, 1H), 7.02 (m, 2H), 7.19 (s, 2H), 7.28 (d, J = 2.3 Hz, 1H),

7.42 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H)

63hz

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.33 (t, J = 6.3 Hz, 9H), 1.68 (m, 4H),

2.04 (m, 1H), 2.50 (dd, J = 13.6, 8.7 Hz, 1H), 3.28 (s, 2H), 3.56 (m, 5H), 4.32 (qd, J = 7.2,

2.2 Hz, 2H), 4.62 (m, 2H), 6.59 (m, 1H), 6.97 (m, 2H), 7.53 (m, 9H), 7.66 (dd, J = 8.3,

2.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H)

63ia

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, 1H), 2.75 (d, J = 11.0 Hz,

1H), 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, 1H), 4.18 (qd, J = 7.1, 1.5 Hz, 2H), 5.56 (s, 1H), 6.68 (q, J = 7.2 Hz,

1H), 7.67 (d, J = 8.1 Hz, 2H), 7.82 (m, 2H), 8.03 (dd, J = 8.9, 2.0 Hz, 1H), 8.15 (m,

3H), 8.81 (dd, J = 2.9, 0.9 Hz, 1H)

63ib

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.06 (t, J = 7.4 Hz, 3H), 1.24 (m, 3H),

1.50 (dt, J = 10.7, 5.6 Hz, 4H), 1.79 (m, 3H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H),

2.74 (d, J = 10.9 Hz, 1H), 2.87 (m, 1H), 3.55 (m, 5H), 3.81 (dd, J = 8.8, 7.2 Hz, 1H),

4.04 (t, J = 6.4 Hz, 2H), 4.17 (qd, J = 7.2, 1.7 Hz, 2H), 5.75 (s, 1H), 6.41 (d, J = 2.4 Hz,

1H), 6.78 (q, J = 6.6 Hz, 1H), 7.15 (t, J = 8.6 Hz, 1H), 7.45 (m, 2H), 7.60 (d, J = 1.8 Hz,

1H), 7.73 (m, 2H), 7.98 (d, J = 2.4 Hz, 1H)

63ic

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.39 (s, 3H), 2.74 (d,

J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.53 (qd, J = 13.9, 7.7 Hz, 4H), 3.81 (dd, J = 8.7,

7.2 Hz, 1H), 4.14 (m, 4H), 5.74 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78 (q, J = 6.6 Hz,

1H), 7.15 (m, 1H), 7.46 (m, 2H), 7.61 (d, J = 1.7 Hz, 1H), 7.73 (m, 2H),

7.98 (d, J = 2.4 Hz, 1H)

63id

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.25 (t, J = 7.1 Hz, 3H), 1.51 (m, 4H),

1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.0, 8.8 Hz, 1H), 2.40 (s, 3H), 2.64 (s, 3H),

2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H), 3.81 (dd, J = 8.7,

7.2 Hz, 1H), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 5.74 (s, 1H), 6.44 (d, J = 2.3 Hz, 1H),

6.86 (q, J = 6.6 Hz, 1H), 7.76 (m, 3H), 7.85 (d, J = 1.2 Hz, 2H), 8.08 (m, 2H)

63ie

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (d, J = 6.7 Hz, 2H), 1.27 (t, J = 7.1 Hz,

3H), 1.53 (m, 4H), 1.72 (ddd, J = 23.9, 13.2, 7.0 Hz, 1H), 1.94 (m, 4H), 2.11 (dd, J = 13.1,

8.8 Hz, 1H), 2.77 (d, J = 10.9 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.55 (m, 9H),

3.85 (dd, J = 8.7, 7.3 Hz, 1H), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.53 (s, 1H), 6.69 (q, J = 6.7 Hz,

1H), 7.31 (d, J = 2.2 Hz, 1H), 7.48 (m, 2H), 7.64 (m, 3H), 7.93 (s, 1H)

63if

¹H NMR (400 MHz, MeOH-d4): δ 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 = 13.1, 8.8 Hz, 1H), 2.77 (d,

J = 11.0 Hz, 1H), 2.91 (d, J = 10.9 Hz, 1H), 3.31 (m, 3H), 3.51 (dq, J = 19.6, 6.3 Hz,

4H), 3.84 (dd, J = 8.7, 7.3 Hz, 1H), 4.19 (m, 2H), 5.48 (s, 1H), 6.71 (q, J = 6.9 Hz,

1H), 6.94 (d, J = 7.6 Hz, 1H), 7.02 (dd, J = 8.4, 2.6 Hz, 1H), 7.18 (s, 1H), 7.28 (d, J = 2.2 Hz,

1H), 7.43 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H)

63ig

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (dd, J = 6.7, 0.7 Hz, 1H), 1.27 (td, J = 7.1,

0.7 Hz, 3H), 1.53 (m, 4H), 1.75 (dd, J = 13.1, 7.3 Hz, 1H), 2.11 (m, 1H), 2.76 (d,

J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.30 (dq, J = 3.5, 1.8 Hz, 5H), 3.54 (m,

10H), 3.82 (m, 5H), 4.18 (qd, J = 7.2, 1.6 Hz, 2H), 5.53 (s, 1H), 6.70 (q, J = 6.7 Hz,

1H), 6.84 (m, 1H), 7.30 (m, 1H), 7.51 (m, 3H), 7.66 (m, 2H), 7.79 (s, 1H)

63ih

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.39 (m, 12H), 1.84 (dd, J = 13.2, 7.8 Hz,

1H), 1.98 (m, 5H), 2.24 (m, 1H), 2.92 (d, J = 11.3 Hz, 1H), 3.02 (d, J = 11.2 Hz, 1H),

3.54 (ddq, J = 27.6, 15.0, 7.8, 7.4 Hz, 6H), 3.89 (s, 1H), 4.07 (t, J = 8.2 Hz, 1H),

4.23 (qd, J = 7.1, 2.0 Hz, 2H), 4.93 (d, J = 1.4 Hz, 11H), 5.55 (s, 1H), 6.63 (q, J = 6.7 Hz,

1H), 7.30 (d, J = 2.2 Hz, 1H), 7.46 (dd, J = 8.5, 2.3 Hz, 1H), 7.63 (m, 3H), 7.89 (dt, J = 7.7,

1.6 Hz, 1H), 8.35 (s, 1H)

63ii

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H),

2.74 (m, 3H), 2.90 (d, J = 11.0 Hz, 1H), 3.30 (d, J = 9.9 Hz, 1H), 3.49 (m, 4H), 3.83 (dd, J = 8.7,

7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.5 Hz, 2H), 5.46 (s, 1H), 6.64 (q, J = 6.8 Hz,

1H), 7.30 (m, 4H), 7.43 (m, 2H), 7.67 (d, J = 8.5 Hz, 1H)

63ij

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.30 (dd, J = 13.4, 9.2 Hz, 1H), 3.03 (m, 2H),

3.22 (d, J = 11.7 Hz, 1H), 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, 1H), 5.48 (s, 1H), 6.62 (q, J = 6.7 Hz, 1H), 7.31 (m, 4H), 7.44 (m,

2H), 7.66 (d, J = 8.5 Hz, 1H)

63ik

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H),

3.30 (p, J = 1.6 Hz, 5H), 3.51 (m, 4H), 3.81 (dd, J = 8.7, 7.2 Hz, 1H), 3.95 (t, J = 6.5 Hz,

2H), 4.18 (qd, J = 7.1, 1.5 Hz, 2H), 5.53 (s, 1H), 6.61 (q, J = 7.2 Hz, 1H), 6.97 (m,

2H), 7.56 (m, 6H)

63il

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 4H), 1.46 (m, 8H),

1.73 (dd, J = 13.0, 7.3 Hz, 1H), 2.08 (m, 1H), 2.74 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz,

1H), 3.02 (m, 2H), 3.50 (dd, J = 17.6, 11.2 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H),

4.18 (qd, J = 7.2, 1.5 Hz, 2H), 5.53 (s, 1H), 6.99 (q, J = 6.9 Hz, 1H), 7.67 (m, 3H),

8.03 (dd, J = 8.9, 2.1 Hz, 1H), 8.14 (m, 3H), 8.80 (dd, J = 2.8, 0.9 Hz, 1H)

63im

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 5H), 1.53 (td, J = 7.3, 6.9,

4.5 Hz, 4H), 1.75 (dd, J = 13.1, 7.3 Hz, 1H), 2.10 (m, 1H), 2.29 (s, 3H), 2.39 (s, 3H),

2.53 (s, 2H), 2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.52 (m, 6H),

3.83 (m, 3H), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 5.51 (d, J = 15.3 Hz, 1H), 6.71 (q, J = 6.6 Hz,

1H), 7.32 (d, J = 2.3 Hz, 1H), 7.50 (m, 3H), 7.66 (m, 2H), 7.80 (s, 1H)

63in

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.25 (m, 4H), 1.54 (m, 4H), 1.75 (dd, J = 13.1,

7.3 Hz, 1H), 2.10 (dd, J = 12.8, 8.5 Hz, 1H), 2.66 (s, 3H), 2.76 (d, J = 11.0 Hz,

1H), 2.90 (d, J = 11.0 Hz, 1H), 3.52 (dd, J = 14.8, 8.9 Hz, 5H), 3.83 (dd, J = 8.7, 7.3 Hz,

1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.54 (s, 1H), 6.85 (t, J = 7.0 Hz, 1H), 7.65 (d,

J = 2.9 Hz, 3H), 8.04 (dd, J = 8.9, 2.0 Hz, 1H), 8.15 (m, 3H), 8.81 (d, J = 2.8 Hz, 1H)

63io

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.10 (dd, J = 13.1,

8.7 Hz, 1H), 2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.36 (d, J = 7.7 Hz,

1H), 3.54 (m, 6H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.2, 1.6 Hz, 2H),

5.55 (s, 1H), 6.65 (q, J = 7.1 Hz, 1H), 7.46 (m, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.72 (m, 4H)

63ip

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 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, 4H), 7.72 (m, 8H), 7.95 (m, 4H)

63iq

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 6H), 1.54 (m, 4H), 1.78 (dd, J = 13.1,

7.4 Hz, 1H), 2.14 (dd, J = 13.2, 8.8 Hz, 1H), 2.81 (d, J = 13.9 Hz, 4H), 2.94 (d, J = 11.0 Hz,

1H), 3.22 (s, 2H), 3.52 (ddt, J = 19.7, 11.9, 6.0 Hz, 4H), 3.92 (t, J = 8.0 Hz,

1H), 4.21 (qd, J = 7.8, 6.4, 4.7 Hz, 2H), 4.88 (s, 1H), 5.51 (s, 1H), 6.75 (q, J = 6.7 Hz,

1H), 7.49 (m, 2H), 7.72 (m, 2H)

63ir

¹H NMR (400 MHz, MeOH-d4): δ 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,

1H), 2.74 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.47 (dq, J = 26.7, 7.9, 6.9 Hz,

4H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 3.95 (t, J = 6.5 Hz, 2H), 4.18 (m, 2H), 5.45 (s,

1H), 6.66 (q, J = 6.9 Hz, 1H), 6.97 (m, 2H), 7.55 (m, 9H), 7.73 (d, J = 8.3 Hz, 1H)

63is

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (t, J = 7.1 Hz, 4H), 1.54 (m, 4H),

1.81 (dd, J = 13.2, 7.6 Hz, 1H), 2.18 (dd, J = 13.3, 8.8 Hz, 1H), 2.87 (d, J = 11.2 Hz, 1H),

2.98 (d, J = 11.1 Hz, 1H), 3.51 (m, 4H), 4.00 (t, J = 8.1 Hz, 1H), 4.21 (qd, J = 7.1, 1.8 Hz,

2H), 5.49 (d, J = 2.0 Hz, 1H), 6.82 (q, J = 6.7 Hz, 1H), 7.13 (m, 2H), 7.46 (m,

2H), 7.67 (d, J = 8.5 Hz, 1H)

63it

¹H NMR (400 MHz, MeOH-d4): δ 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 = 13.1, 8.7 Hz, 1H), 2.76 (d, J = 11.0 Hz,

1H), 2.90 (d, J = 11.0 Hz, 1H), 3.15 (s, 3H), 3.53 (m, 4H), 3.83 (dd, J = 8.8,

7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.56 (s, 1H), 6.67 (q, J = 7.1 Hz, 1H),

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): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.51 (dt, J = 10.8,

5.6 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.08 (dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s,

3H), 2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.15 (s, 3H), 3.53 (m, 4H),

3.81 (dd, J = 8.8, 7.2 Hz, 1H), 4.18 (qd, J = 7.2, 1.7 Hz, 2H), 5.74 (s, 1H), 6.43 (d, J = 2.4 Hz,

1H), 6.85 (q, J = 6.6 Hz, 1H), 7.76 (dd, J = 1.7, 0.6 Hz, 1H), 7.83 (m, 2H),

7.95 (m, 2H), 8.03 (m, 3H)

63iv

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.05 (t, J = 7.4 Hz, 3H), 1.26 (m, 3H),

1.49 (dt, J = 10.7, 5.7 Hz, 4H), 1.78 (m, 3H), 2.08 (dd, J = 13.1, 8.8 Hz, 1H), 2.25 (d, J = 14.0 Hz,

1H), 2.39 (s, 3H), 2.75 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H),

3.53 (m, 4H), 3.83 (t, J = 8.0 Hz, 1H), 3.95 (t, J = 6.4 Hz, 2H), 4.18 (qd, J = 7.1, 1.6 Hz,

2H), 5.76 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.75 (t, J = 6.7 Hz, 1H), 6.98 (m, 2H),

7.58 (m, 3H), 7.71 (m, 2H), 7.96 (d, J = 2.4 Hz, 1H)

63ix

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.08 (dd, J = 13.0,

8.8 Hz, 1H), 2.39 (d, J = 1.7 Hz, 3H), 2.74 (d, J = 10.9 Hz, 1H), 2.88 (d, J = 11.0 Hz,

1H), 3.31 (d, J = 16.3 Hz, 3H), 3.56 (s, 6H), 3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.18 (m,

2H), 5.75 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.82 (q, J = 6.5 Hz, 1H), 7.47 (dd, J = 8.3,

2.0 Hz, 2H), 7.70 (d, J = 1.8 Hz, 1H), 7.79 (m, 4H), 8.01 (d, J = 2.4 Hz, 1H)

63iy

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 5H), 1.53 (dt, J = 9.7, 5.4 Hz,

8H), 1.74 (dd, J = 13.0, 7.3 Hz, 2H), 2.09 (dd, J = 13.1, 8.8 Hz, 2H), 2.76 (d, J = 11.0 Hz,

2H), 2.91 (d, J = 19.4 Hz, 7H), 3.36 (s, 1H), 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, 1H), 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): δ ppm 1.26 (t, J = 7.1 Hz, 4H), 1.51 (dt, J = 10.6, 5.5 Hz,

4H), 1.76 (dd, J = 13.1, 7.3 Hz, 1H), 2.11 (dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s, 3H),

2.78 (d, J = 11.1 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.54 (qq, J = 14.0, 7.5, 6.5 Hz,

4H), 3.88 (dd, J = 8.7, 7.4 Hz, 1H), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.75 (s, 1H),

6.43 (d, J = 2.4 Hz, 1H), 6.83 (q, J = 6.6 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.84 (m, 4H),

7.99 (m, 3H)

63ja

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 7H), 1.53 (dt, J = 9.9, 5.5 Hz, 8H),

1.77 (dd, J = 13.1, 7.4 Hz, 2H), 2.17 (m, 2H), 2.81 (d, J = 11.1 Hz, 2H), 2.93 (d, J = 11.1 Hz,

2H), 3.33 (d, J = 12.6 Hz, 1H), 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): δ ppm 1.27 (t, J = 7.1 Hz, 5H), 1.53 (dt, J = 9.6, 5.3 Hz,

5H), 1.76 (dd, J = 13.1, 7.3 Hz, 1H), 2.11 (dd, J = 13.1, 8.7 Hz, 1H), 2.61 (m, 7H),

2.77 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.56 (m, 8H), 3.71 (t, J = 4.7 Hz,

5H), 3.85 (dd, J = 8.7, 7.2 Hz, 1H), 4.19 (qd, J = 7.1, 1.6 Hz, 2H), 5.55 (s, 1H),

6.66 (q, J = 7.2 Hz, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.73 (m, 4H), 7.91 (m, 2H)

63jc

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.21 (dt, J = 33.8, 7.2 Hz, 4H), 1.51 (dt, J = 10.8,

5.4 Hz, 4H), 1.74 (dd, J = 13.1, 7.3 Hz, 1H), 2.08 (m, 1H), 2.40 (s, 3H), 2.58 (dt,

J = 23.6, 5.8 Hz, 6H), 2.75 (d, J = 11.0 Hz, 1H), 2.88 (dd, J = 11.0, 5.9 Hz, 1H),

3.32 (s, 1H), 3.57 (m, 6H), 3.70 (t, J = 4.7 Hz, 4H), 3.82 (m, 1H), 4.18 (qd, J = 7.1, 1.7 Hz,

2H), 5.75 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.82 (q, J = 6.6 Hz, 1H), 7.72 (d, J = 1.5 Hz,

1H), 7.81 (m, 4H), 7.96 (m, 4H)

63jd

¹H NMR (400 MHz, MeOH-d4): δ 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 = 13.1, 7.2 Hz, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, 1H),

2.75 (d, J = 11.1 Hz, 1H), 2.89 (d, J = 10.9 Hz, 1H), 3.04 (d, J = 1.3 Hz, 3H), 3.11 (s, 3H),

3.52 (m, 4H), 3.82 (m, 1H), 4.18 (qt, J = 7.1, 1.4 Hz, 2H), 5.55 (d, J = 1.3 Hz, 1H),

6.66 (q, J = 7.1 Hz, 1H), 7.51 (m, 2H), 7.68 (m, 6H)

63je

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.11 (dd, J = 13.1, 8.8 Hz, 1H), 2.78 (t, J = 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, 1H), 4.19 (qd, J = 7.2, 1.6 Hz, 2H), 5.55 (s, 1H), 6.66 (q, J = 7.0 Hz, 1H),

7.51 (m, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.72 (m, 4H)

63jf

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (td, J = 7.4, 1.9 Hz, 8H), 1.50 (dt, J = 10.8,

5.8 Hz, 5H), 1.75 (dd, J = 13.1, 7.4 Hz, 1H), 2.10 (dd, J = 13.2, 8.9 Hz, 1H),

2.39 (s, 3H), 2.86 (m, 8H), 3.26 (s, 1H), 3.52 (m, 8H), 3.76 (s, 2H), 3.88 (dd, J = 8.8,

7.3 Hz, 1H), 4.18 (ddtd, J = 7.7, 5.3, 3.6, 2.0 Hz, 2H), 4.93 (s, 2H), 5.74 (s, 1H),

6.43 (d, J = 2.4 Hz, 1H), 6.82 (q, J = 6.6 Hz, 1H), 7.51 (dd, J = 8.3, 2.0 Hz, 2H), 7.75 (m,

7H), 8.01 (d, J = 2.4 Hz, 1H)

63jg

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (t, J = 7.2 Hz, 8H), 1.57 (s, 10H),

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, 15H),

4.31 (m, 6H), 5.49 (s, 1H), 5.62 (s, 1H), 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): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.50 (dt, J = 10.4, 5.5 Hz,

4H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.08 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H),

2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.53 (m, 4H), 3.83 (m, 1H),

3.90 (s, 3H), 4.18 (qd, J = 7.2, 1.6 Hz, 2H), 5.75 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.78 (q, J = 6.7 Hz,

1H), 7.17 (t, J = 8.9 Hz, 1H), 7.48 (m, 2H), 7.61 (d, J = 1.8 Hz, 1H),

7.73 (m, 2H), 7.99 (d, J = 2.4 Hz, 1H)

63ji

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (d, J = 11.1 Hz, 1H), 1.51 (q, J = 6.8, 6.0 Hz,

4H), 1.78 (dd, J = 13.0, 7.0 Hz, 1H), 1.89 (s, 2H), 2.07 (dd, J = 13.1, 9.1 Hz, 1H),

2.40 (s, 3H), 2.68 (d, J = 11.1 Hz, 1H), 2.95 (d, J = 11.1 Hz, 1H), 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, 1H), 6.43 (d, J = 2.4 Hz,

1H), 6.82 (q, J = 6.6 Hz, 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.70 (m, 1H), 7.80 (m,

4H), 8.01 (d, J = 2.5 Hz, 1H)

63jj

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 3.09 (m, 3H), 3.54 (m, 4H), 4.03 (t, J = 6.4 Hz,

2H), 4.27 (m, 3H), 5.55 (s, 1H), 6.64 (q, J = 7.2 Hz, 1H), 7.12 (t, J = 8.8 Hz,

1H), 7.37 (m, 2H), 7.58 (q, J = 8.4 Hz, 4H)

63jk

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 5H), 1.50 (dt, J = 10.2, 5.2 Hz,

4H), 1.75 (dd, J = 13.1, 7.4 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s, 3H),

2.78 (d, J = 11.1 Hz, 1H), 2.91 (d, J = 13.6 Hz, 4H), 3.52 (m, 4H), 3.88 (dd, J = 8.7,

7.3 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.75 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H),

6.82 (q, J = 6.5 Hz, 1H), 7.70 (d, J = 1.7 Hz, 1H), 7.78 (m, 4H), 7.90 (m, 2H), 8.01 (d, J = 2.4 Hz,

1H)

63jl

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.25 (m, 5H), 1.54 (dt, J = 11.2, 6.0 Hz, 4H),

1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.11 (dd, J = 13.1, 8.8 Hz, 1H), 2.58 (s, 3H), 2.77 (d, J = 11.0 Hz,

1H), 2.91 (d, J = 11.0 Hz, 1H), 3.55 (h, J = 7.5 Hz, 4H), 3.84 (dd, J = 8.7,

7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 5.58 (s, 1H), 6.65 (q, J = 6.6 Hz, 1H),

7.34 (d, J = 2.2 Hz, 1H), 7.49 (dd, J = 8.5, 2.3 Hz, 1H), 7.73 (m, 3H), 7.94 (ddd, J = 7.9,

1.8, 1.1 Hz, 1H), 8.32 (s, 1H)

63jm

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.11 (dd, J = 13.1, 8.8 Hz, 1H), 2.73 (s, 7H),

2.91 (d, J = 10.9 Hz, 1H), 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, 1H), 6.69 (q, J = 6.4 Hz, 1H), 7.36 (d,

J = 2.2 Hz, 1H), 7.50 (dd, J = 8.5, 2.2 Hz, 1H), 7.70 (dd, J = 13.1, 8.0 Hz, 2H),

7.85 (m, 2H), 8.34 (s, 1H)

63jn

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (m, 10H), 1.52 (dt, J = 10.2, 5.7 Hz, 4H),

1.74 (dd, J = 13.1, 7.3 Hz, 1H), 2.08 (m, 1H), 2.83 (m, 4H), 3.20 (ddd, J = 11.9, 6.2,

3.0 Hz, 2H), 3.31 (s, 1H), 3.49 (ddd, J = 30.2, 13.4, 6.0 Hz, 4H), 3.90 (dddd, J = 32.2,

15.9, 7.4, 5.0 Hz, 5H), 4.18 (qd, J = 7.2, 1.5 Hz, 2H), 4.64 (p, J = 6.0 Hz, 1H), 5.52 (s,

1H), 6.96 (m, 2H), 7.40 (m, 2H), 7.54 (m, 4H)

63jo

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 4H), 1.54 (dt, J = 7.6, 4.8 Hz, 5H),

1.76 (dd, J = 13.1, 7.3 Hz, 1H), 2.11 (dd, J = 13.1, 8.8 Hz, 1H), 2.77 (d, J = 11.0 Hz,

1H), 2.92 (d, J = 18.5 Hz, 3H), 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, 1H), 6.63 (q, J = 6.7 Hz, 1H),

7.29 (d, J = 2.2 Hz, 1H), 7.46 (dd, J = 8.5, 2.3 Hz, 1H), 7.62 (m, 3H), 7.88 (dt, J = 7.7,

1.6 Hz, 1H), 8.37 (s, 1H)

63jp

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.76 (d, J = 11.0 Hz,

1H), 2.90 (d, J = 11.0 Hz, 1H), 3.06 (s, 3H), 3.12 (s, 3H), 3.51 (m, 4H),

3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.53 (s, 1H), 6.70 (q, J = 6.7 Hz,

1H), 7.32 (d, J = 2.2 Hz, 1H), 7.56 (m, 5H), 7.79 (s, 1H)

63jq

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 5H), 1.46 (m, 7H),

1.74 (dd, J = 13.1, 7.3 Hz, 1H), 2.09 (dd, J = 13.1, 8.7 Hz, 1H), 2.75 (d, J = 11.0 Hz, 1H),

2.89 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4.15 (m, 4H),

5.53 (s, 1H), 6.62 (q, J = 7.1 Hz, 1H), 7.12 (t, J = 8.7 Hz, 1H), 7.38 (m, 2H), 7.58 (q, J = 8.4 Hz,

4H)

63jr

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.08 (dd, J = 13.1, 8.8 Hz, 1H),

2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.49 (dtt, J = 19.6, 13.1, 6.9 Hz,

4H), 3.82 (dd, J = 8.8, 7.3 Hz, 1H), 4.05 (q, J = 7.0 Hz, 2H), 4.18 (qd, J = 7.1, 1.5 Hz,

2H), 5.53 (s, 1H), 6.61 (q, J = 7.1 Hz, 1H), 6.96 (m, 2H), 7.55 (m, 6H)

63js

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.52 (m, 4H),

1.75 (dd, J = 13.1, 7.3 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.76 (d, J = 11.0 Hz, 1H),

2.90 (d, J = 11.0 Hz, 1H), 3.16 (s, 3H), 3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.3 Hz, 1H),

4.18 (qd, J = 7.2, 1.5 Hz, 2H), 5.53 (s, 1H), 6.75 (q, J = 6.7 Hz, 1H), 7.56 (m, 5H),

7.84 (d, J = 1.9 Hz, 1H), 7.99 (m, 2H)

63jt

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.18 (dd, J = 13.2, 8.7 Hz, 1H),

2.86 (d, J = 11.2 Hz, 1H), 2.98 (d, J = 11.2 Hz, 1H), 3.36 (q, J = 7.1 Hz, 2H), 3.56 (m,

6H), 3.98 (t, J = 8.1 Hz, 1H), 4.21 (qd, J = 7.2, 1.8 Hz, 2H), 5.54 (s, 1H), 6.74 (q, J = 6.8 Hz,

1H), 7.32 (d, J = 2.2 Hz, 1H), 7.49 (m, 3H), 7.65 (m, 3H)

63ju

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.07 (ddd, J = 13.0,

7.7, 4.9 Hz, 2H), 2.39 (s, 2H), 2.74 (d, J = 10.9 Hz, 1H), 2.88 (d, J = 11.0 Hz,

1H), 3.49 (d, J = 7.5 Hz, 1H), 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, 1H), 6.41 (d, J = 2.4 Hz, 1H), 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, 1H)

63jv

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.05 (dd, J = 13.1, 8.8 Hz, 1H),

2.39 (s, 3H), 2.72 (d, J = 11.0 Hz, 1H), 2.86 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H),

3.64 (s, 2H), 3.80 (dd, J = 8.7, 7.1 Hz, 1H), 4.17 (qd, J = 7.1, 1.5 Hz, 2H), 5.75 (s, 1H),

6.41 (d, J = 2.3 Hz, 1H), 6.76 (q, J = 6.6 Hz, 1H), 6.98 (m, 2H), 7.57 (m, 3H), 7.70 (m,

2H), 7.96 (d, J = 2.4 Hz, 1H)

63jw

¹H NMR (400 MHz, MeOH-d4): δ ppm

1H NMR (MeOH-d4) δ: 1.29 (t, J = 7.1 Hz, 7H), 1.53 (s, 8H), 1.79 (s, 2H), 2.14 (s,

2H), 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, 1H), 6.51 (s, 1H), 6.85 (s, 1H),

7.25 (s, 1H), 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, MeOH-d4): δ 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, 1H), 2.03 (m, 3H), 2.39 (s, 3H), 2.73 (d, J = 11.0 Hz,

1H), 2.85 (m, 3H), 3.53 (m, 4H), 3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.17 (m, 4H),

5.75 (s, 1H), 6.40 (d, J = 2.3 Hz, 1H), 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, 1H), 7.69 (m, 2H), 7.96 (d, J = 2.3 Hz, 1H)

63jy

¹H NMR (400 MHz, MeOH-d4): δ 1.27 (dd, J = 7.9, 6.4 Hz, 4H), 1.54 (dt, J = 10.7,

5.6 Hz, 4H), 1.76 (dd, J = 13.2, 7.4 Hz, 1H), 2.12 (dd, J = 13.1, 8.8 Hz, 1H), 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, 1H), 4.19 (qd,

J = 7.1, 1.7 Hz, 2H), 5.51 (d, J = 15.6 Hz, 1H), 6.72 (q, J = 6.6 Hz, 1H), 7.33 (d, J = 2.2 Hz,

1H), 7.51 (m, 3H), 7.66 (m, 2H), 7.79 (s, 1H)

63jz

¹H NMR (400 MHz, MeOH-d4): δ 0.46 (m, 4H), 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, 1H), 2.58 (s, 2H), 2.73 (s, 2H),

2.80 (d, J = 11.1 Hz, 1H), 2.93 (d, J = 11.0 Hz, 1H), 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, 1H), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.52 (d, J = 17.0 Hz,

1H), 6.71 (q, J = 6.7 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.57 (m, 5H), 7.80 (s,

1H)

63ka

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.25 (t, J = 7.1 Hz, 3H), 1.50 (dt, J = 10.3, 5.3 Hz,

4H), 1.73 (dd, J = 13.1, 7.3 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.41 (s, 3H),

2.75 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.51 (m, 4H), 3.82 (dd, J = 8.8,

7.2 Hz, 1H), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 5.76 (s, 1H), 6.45 (d, J = 2.4 Hz, 1H),

6.88 (q, J = 6.6 Hz, 1H), 7.92 (m, 3H), 8.07 (d, J = 2.4 Hz, 1H), 8.29 (m, 3H), 8.52 (d, J = 8.9 Hz,

1H), 9.32 (d, J = 5.9 Hz, 1H)

63kb

¹H NMR (400 MHz, MeOH-d4): δ 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 = 13.67, 8.79 Hz, 1 H) 3.35 (s, 2 H)

3.56-3.91 (m, 4 H) 4.35 (qd, J = 7.06, 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, 1H) 7.69-7.78 (m, 2 H) 7.79-7.88 (m, 1 H) 8.29 (d,

J = 1.37 Hz, 1 H)

63kc

¹H NMR (400 MHz, MeOH-d4): δ 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 H) 2.43-2.61 (m, 1H)

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, 1 H) 7.53-7.61 (m, 1 H)

7.69 (d, J = 1.95 Hz, 2 H) 8.01 (d, J = 2.54 Hz, 1 H)

63kd

¹H NMR (400 MHz, MeOH-d4): δ 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 H) 3.09 (s, 1 H) 3.21 (d, J = 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): δ 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 (m, 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 MHz, MeOH-d4): δ ppm 1.35 (t, J = 7.13 Hz, 4 H) 1.74 (br. s., 4 H)

2.04-2.15 (m, 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 H) 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, 1 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): δ ppm 1.29 (t, J = 7.1 Hz, 3H), 1.55 (s, 3H), 1.58 (d,

J = 5.8 Hz, 1H), 1.88 (m, 1H), 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, 1H), 7.17 (d, J = 7.9 Hz, 1H), 7.36 (m, 2H), 7.45 (m,

1H), 7.52 (s, 2H), 7.53 (d, J = 2.8 Hz, 1H), 7.63 (dd, J = 8.2, 2.0 Hz, 1H), 7.73 (d, J = 8.2 Hz,

1H)

63kh

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 1.79 (m, 3H), 2.09 (dd, J = 13.1, 8.8 Hz,

1H), 2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.50 (s, 3H), 3.83 (dd, J = 8.8,

7.2 Hz, 1H), 4.02 (t, J = 6.5 Hz, 2H), 4.17 (m, 2H), 5.46 (s, 1H), 6.67 (q, J = 6.7 Hz,

1H), 7.12 (t, J = 8.6 Hz, 1H), 7.40 (m, 4H), 7.52 (s, 4H), 7.54 (s, 1H), 7.62 (dd, J = 8.2,

2.1 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H)

63ki

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 3H), 1.53 (dd, J = 11.2,

5.2 Hz, 5H), 1.75 (dd, J = 13.1, 7.3 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.76 (d, J = 11.0 Hz,

1H), 2.90 (d, J = 11.0 Hz, 1H), 3.49 (m, 2H), 3.51 (s, 3H), 3.84 (dd, J = 8.7,

7.3 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.44 (s, 1H), 6.66 (q, J = 6.9 Hz, 1H),

7.26 (m, 1H), 7.45 (m, 8H), 7.70 (d, J = 7.2 Hz, 1H)

63kj

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 3H), 1.53 (dd, J = 11.0,

5.2 Hz, 4H), 1.77 (dd, J = 13.2, 7.4 Hz, 1H), 2.13 (dd, J = 13.1, 8.8 Hz, 1H), 2.80 (d, J = 11.1 Hz,

1H), 2.93 (d, J = 11.1 Hz, 1H), 3.46 (m, 1H), 3.53 (m, 2H), 3.91 (t, J = 8.1 Hz,

1H), 4.19 (qd, J = 7.1, 1.4 Hz, 2H), 5.47 (s, 1H), 6.69 (q, J = 6.9 Hz, 1H), 7.35 (m,

1H), 7.45 (m, 4H), 7.54 (d, J = 4.6 Hz, 4H), 7.65 (m, 3H), 7.77 (d, J = 8.2 Hz, 1H)

63kk

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.25 (t, J = 7.1 Hz, 3H), 1.51 (m, 4H),

1.74 (dd, J = 13.1, 7.4 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.29 (d, J = 9.9 Hz, 6H),

2.39 (s, 3H), 2.77 (d, J = 11.1 Hz, 1H), 2.90 (d, J = 11.1 Hz, 1H), 3.54 (tq, J = 14.0,

7.9, 6.7 Hz, 4H), 3.88 (dd, J = 8.7, 7.4 Hz, 1H), 4.17 (m, 2H), 5.74 (s, 1H), 6.41 (d, J = 2.3 Hz,

1H), 6.77 (q, J = 6.6 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.36 (dd, J = 7.6, 2.1 Hz,

1H), 7.42 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 1.9 Hz, 1H), 7.72 (m, 2H), 7.97 (d, J = 2.4 Hz,

1H)

63kl

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.51 (dd, J = 11.1,

5.8 Hz, 5H), 1.74 (dd, J = 13.1, 7.3 Hz, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s,

3H), 2.76 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.55 (d, J = 5.0 Hz, 4H),

3.85 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (m, 2H), 4.65 (s, 2H), 5.78 (s, 1H), 6.41 (d, J = 2.4 Hz,

1H), 6.87 (q, J = 6.5 Hz, 1H), 7.47 (dd, J = 10.9, 8.2 Hz, 3H), 7.59 (m, 2H),

7.79 (dd, J = 8.3, 2.1 Hz, 1H), 7.93 (d, J = 2.3 Hz, 2H)

63km

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.61-7.49 (m, 4H), 7.35-7.27 (m, 2H),

6.77 (dd, J = 8.4, 1.8 Hz, 1H), 6.60 (q, J = 7.3 Hz, 1H), 5.55-5.46 (m, 1H),

4.24-4.13 (m, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, 1H), 2.93-2.71 (m, 4H), 2.14-1.94 (m, 3H),

1.74 (dd, J = 13.1, 7.3 Hz, 1H), 1.56-1.48 (m, 1H), 1.51 (s, 3H), 1.27 (td, J = 7.1, 2.0 Hz,

3H).

63kn

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.71 (d, J = 5.2 Hz, 2H), 8.02 (td, J = 7.7, 1.7 Hz,

1H), 7.78-7.68 (m, 3H), 7.51 (tt, J = 7.9, 3.3 Hz, 5H), 6.92 (d, J = 6.5 Hz, 1H),

5.81 (d, J = 3.8 Hz, 2H), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 3.83 (s, 1H), 3.56 (s, 6H),

3.57-3.46 (m, 1H), 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, 1H), 1.74 (dd, J = 13.1, 7.3 Hz, 1H), 1.52 (dd, J = 10.9, 5.5 Hz, 5H),

1.31-1.22 (m, 6H)

63ko

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.99 (d, J = 4.9 Hz, 2H), 8.03 (s, 1H),

7.73 (dd, J = 15.2, 7.7 Hz, 2H), 7.60-7.48 (m, 2H), 5.69 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H),

3.83 (t, J = 8.1 Hz, 1H), 3.54-3.43 (m, 4H), 2.89 (d, J = 11.1 Hz, 1H), 2.75 (d, J = 11.0 Hz,

1H), 2.14-2.04 (m, 1H), 1.74 (dd, J = 13.0, 7.4 Hz, 1H), 1.50 (dd, J = 10.6,

5.5 Hz, 5H), 1.26 (t, J = 7.2 Hz, 4H)

63kp

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.97 (s, 1H), 7.76 (s, 2H), 7.66 (d, J = 16.1 Hz,

2H), 7.49 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 6.77 (d, J = 7.1 Hz, 1H),

6.41 (s, 1H), 5.74 (d, J = 2.7 Hz, 1H), 4.68 (s, 2H), 4.18 (d, J = 7.6 Hz, 2H), 3.84 (t, J = 8.1 Hz,

1H), 3.56 (s, 3H), 3.49 (s, 1H), 3.30 (d, J = 3.4 Hz, 9H), 2.89 (d, J = 11.1 Hz,

1H), 2.76 (d, J = 11.0 Hz, 1H), 2.37 (d, J = 14.1 Hz, 5H), 1.79-1.69 (m, 1H),

1.51 (d, J = 8.8 Hz, 4H), 1.30-1.21 (m, 3H)

63kq

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.98 (s, 1H), 7.76 (d, J = 5.1 Hz, 2H), 7.63 (s,

1H), 7.48 (d, J = 13.3 Hz, 3H), 6.77 (d, J = 6.8 Hz, 1H), 6.41 (s, 1H), 5.74 (s, 1H),

4.66 (s, 2H), 4.18 (d, J = 7.4 Hz, 2H), 3.82 (t, J = 8.2 Hz, 1H), 3.56 (s, 3H), 3.50 (s,

1H), 2.89 (d, J = 11.0 Hz, 1H), 2.75 (d, J = 11.1 Hz, 1H), 2.39 (s, 6H), 1.74 (dd, J = 13.0,

7.2 Hz, 1H), 1.51 (s, 4H), 1.30-1.22 (m, 3H)

63kr

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.43 (d, J = 2.5 Hz, 1H), 7.98 (d, J = 10.3 Hz,

2H), 7.79 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 6.83 (dd, J = 19.6,

7.7 Hz, 2H), 6.42 (d, J = 2.3 Hz, 1H), 5.74 (s, 1H), 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, 1H), 2.88 (d, J = 11.0 Hz, 1H),

2.74 (d, J = 11.0 Hz, 1H), 2.39 (s, 3H), 2.07 (dd, J = 13.0, 8.9 Hz, 1H), 1.73 (dd, J = 13.0,

7.2 Hz, 1H), 1.50 (d, J = 8.3 Hz, 4H), 1.38 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H).

63ks

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.46 (s, 1H), 7.99 (s, 2H), 7.83-7.69 (m,

2H), 7.64 (s, 1H), 6.80 (d, J = 5.3 Hz, 1H), 6.42 (s, 1H), 5.74 (s, 1H), 4.18 (d, J = 7.3 Hz,

2H), 3.94 (d, J = 2.7 Hz, 3H), 3.86 (t, J = 8.1 Hz, 1H), 3.56 (s, 3H), 3.50 (s, 1H),

2.91 (d, J = 11.0 Hz, 1H), 2.77 (d, J = 11.6 Hz, 1H), 2.39 (d, J = 2.7 Hz, 3H), 2.10 (t, J = 10.9 Hz,

1H), 1.80-1.70 (m, 1H), 1.51 (s, 4H), 1.26 (dd, J = 8.3, 5.7 Hz, 3H).

63kt

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.67 (d, J = 8.5 Hz, 1H), 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, 1H), 6.99 (d, J = 7.6 Hz,

1H), 6.76 (q, J = 6.9 Hz, 1H), 5.51 (s, 1H), 4.27 (dd, J = 7.0, 2.0 Hz, 1H),

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, 1H), 2.99 (d, J = 11.4 Hz, 1H), 2.28 (dd, J = 13.3, 8.7 Hz, 1H),

1.88 (dd, J = 13.3, 8.0 Hz, 1H), 1.57 (p, J = 5.4 Hz, 4H), 1.29 (t, J = 7.1 Hz, 3H)

63ku

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.97 (d, J = 1.5 Hz, 1H), 8.80 (dd, J = 2.6, 1.5 Hz,

1H), 8.71 (d, J = 2.6 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.64-7.55 (m, 1H),

6.87 (q, J = 6.7 Hz, 1H), 5.62 (s, 1H), 4.23-4.13 (m, 2H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H),

3.60-3.42 (m, 3H), 2.89 (d, J = 11.0 Hz, 1H), 2.75 (d, J = 11.0 Hz, 1H), 2.09 (dd, J = 13.1,

8.7 Hz, 1H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 1.51 (dt, J = 10.9, 5.6 Hz, 3H),

1.26 (t, J = 7.1 Hz, 2H)

Example 64a
(S)-Octyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

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To a flask equipped with a Dean Stark trap were added (2S)-8-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]-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 (CH₂Cl₂/MeOH/NH₄OH) provided the title compound as a white solid.

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

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TABLE 19a

Ex.

LCMS

No.
R
CAS Name
(MH+)

64a

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(S)-Octyl 8-(2-amino-6-((R)-1-(4- chloro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro [4.5]decane-3-carboxylate
679.2

64b

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(S)-cyclopentyl 8-(2-amino-6-((R)- 1-(4-chloro-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylate
635.1

64c

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(S)-pentyl 8-(2-amino-6-((R)-1- (4-chloro-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
637

64d

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(S)-cyclohexyl 8-(2-amino-6- ((R)-1-(4-chloro-2-(3-methyl- 1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5] decane-3-carboxylate
648

64e

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(S)-propyl 8-(2-amino-6-((R)- 1-(4-chloro-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane- 3-carboxylate
608

64f

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(S)-neopentyl 8-(2-amino-6- ((R)-1-(4-chloro-2-(3-methyl- 1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylate
636

64g

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(S)-butyl 8-(2-amino-6-((R)-1- (4-chloro-2-(3-methyl-1H- pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane- 3-carboxylate
622

64h

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(S)-isopropyl 8-(2-amino-6- ((R)-1-(4-chloro-2-(3-methyl- 1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylate
622

TABLE 19b

NMR Data for Compounds of Table 19a

Ex.

No.
NMR

64a

¹H NMR (400 MHz, MeOH-d4): δ 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, J = 8.8 Hz, 1 H),

5.81 (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): δ 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, 1 H), 5.74 (s, 1 H), 6.42 (d, J = 2.3 Hz, 1 H), 6.83 (q, J = 6.6 Hz, 1 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 (400 MHz, MeOH-d4): δ ppm 0.94 (t, J = 7.2 Hz, 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, 1H), 2.08-2.14 (m, 1H), 2.40 (s, 3 H),

2.77 (d, J = 10.8 Hz, 1H), 2.92 (d, J = 10.8 Hz, 1H), 3.48-3.58 (m, 4 H), 3.83-3.87 (m, 1H),

4.13-4.18 (m, 2H), 5.69 (s, 1 H), 6.43 (d, J = 2.0 Hz, 1H), 6.81-6.86 (m, 1H),

7.51-7.55 (m, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H)

64d

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.31-1.56 (m, 10H), 1.75-1.80 (m, 3H),

1.85-1.89 (m, 2H), 2.08-2.13 (m, 1H), 2.39 (s, 3H), 2.76 (d, J = 10.8 Hz, 1 H), 2.93 (d, J = 10.8 Hz,

1H), 3.50-3.58 (m, 4H), 3.81-3.84 (m, 1H), 4.77-4.83 (m, 1H), 5.69 (s, 1 H), 6.42 (d,

J = 2.0 Hz, 1H), 6.81-6.86 (m, 1H), 7.51-7.55 (m, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.95 (d,

J = 2.4 Hz, 1H)

64e

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.98 (t, J = 7.6 Hz, 3H), 1.54-1.59 (m, 4 H),

1.66 (m, 2H), 1.81-1.86 (m, 1H), 2.17-2.23 (m, 1H), 2.40 (s, 3H), 2.89 (d, J = 11.2 Hz, 1H),

3.00 (d, J = 11.2 Hz, 1H), 3.47-3.62 (m, 4H), 4.03 (t, J = 8.0 Hz, 1H), 4.11-4.18 (m, 2H),

5.70 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.84 (q, 1H), 7.51-7.55 (m, 2H), 7.73 (d, J = 8.4 Hz,

1H), 7.95 (d, J = 2.4 Hz, 1H)

64f

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.98 (s, 9H), 1.50-1.58 (m, 4 H), 1.77-1.82 (m,

1H), 2.12-2.17 (m, 1H), 2.40 (s, 3H), 2.79 (d, J = 11.2 Hz, 1H), 2.94 (d, J = 11.2 Hz, 1H),

3.52-3.58 (m, 4H), 3.83-3.93 (m, 3H), 5.70 (s, 1 H), 6.43 (d, J = 2.4 Hz, 1H),

6.81-6.86 (m, 1H), 7.52-7.55 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H)

64g

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.95 (t, J = 7.6 Hz, 3H), 1.37-1.43 (m, 2H),

1.50-1.54 (m, 4H), 1.60-1.67 (m, 2H), 1.72-1.77 (m, 1H), 2.06-2.12 (m, 1H), 2.38 (s, 3 H),

2.75 (d, J = 11.2 Hz, 1 H), 2.90 (d, J = 11.2 Hz, 1H), 3.45-3.58 (m, 4 H), 3.83-3.86 (m, 1H),

4.10-4.20 (m, 2H), 5.67 (s, 1H), 6.40 (d, J = 2.4 Hz, 1H), 6.80-6.85 (m, 1 H),

7.50-7.53 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H)

64h

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.85 (d, J = 6.8 Hz, 6H), 1.42-1.47 (m, 4H),

1.68-1.73 (m, 1H), 1.82-1.89 (m, 1H), 2.05-2.10 (m, 1H), 2.28 (s, 3H), 2.74 (d, J = 11.2 Hz, 1

H), 2.87 (d, J = 11.2 Hz, 1H), 3.37-3.48 (m, 4H), 3.81-3.91 (m, 3H), 5.58 (s, 1H), 6.30 (d,

J = 2.0 Hz, 1H), 6.70-6.75 (m, 1 H), 7.40-7.43 (m, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.83 (d,

J = 2.4 Hz, 1H)

Example 65a
(S)-Tert-butyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

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Step 1:

To a mixture of (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (2.8 g, 4.1 mmol) in t-BuOH (50 mL) were added BOC₂O (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 concentrated in vacuo. Purification on a 220 g Isco RediSep silica cartridge (EtOAc/heptane) provided (S)-2-benzyl 3-tert-butyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.

Step 2:

To a solution of (S)-2-benzyl 3-tert-butyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (1.35 g, 1.7 mmol) in EtOAc (130 mL) was added 5% (w/w) Pd/C (130 mg). The solution was degassed, charged with 1 atm H₂(balloon), and stirred at RT for 3.5 h. Then the solids were filtered through celite, washed with EtOAc/methanol, and the filtrate was concentrated in vacuo. Purification on a 220 g Isco RediSep silica cartridge (CH₂Cl₂/MeOH/NH₄OH) provided the title compound as an off-white solid.

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

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TABLE 20a

Ex.

LCMS

No.
Ar
CAS Name
(MH+)

65a

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(S)-tert-butyl 8-(2- amino-6-((R)-1-(4- chloro-2-(3-methyl- 1H-pyrazol-1-yl) phenyl)-2,2,2- trifluoroethoxy) pyrimidin-4-yl)- 2,8-diazaspiro[4.5] decane-3- carboxylate
623

65b

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(S)-tert-butyl 8-(2- amino-6-((R)-2,2,2- trifluoro-1-(2-(3- methyl-1H-pyrazol- 1-yl)-4- propylphenyl) ethoxy)pyrimidin-4- yl)-2,8-diazaspiro [4.5]decane-3- carboxylate
630

65c

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(S)-tert-butyl 8-(2- amino-6-((R)-1-(3′, 4′-dimethyl-3-(3- methyl-1H-pyrazol- 1-yl)-[1,1′- biphenyl]-4-yl)- 2,2,2- trifluoroethoxy) pyrimidin-4-yl)-2,8- diazaspiro[4.5] decane-3-carboxylate
693

65d

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(S)-tert-butyl 8-(2- amino-6-((R)-2,2,2- trifluoro-1-(4′- isopropoxy-3-(3- methyl-1H-pyrazol- 1-yl)-[1,1′-biphenyl]- 4-yl)ethoxy) pyrimidin-4-yl)-2,8- diazaspiro[4.5] decane-3-carboxylate
722

TABLE 20b

NMR Data for Compounds of Table 20a

Ex.

No.
NMR

65a

¹H NMR (400 MHz, MeOH-d4): δ 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, 1 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): δ 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, J = 2.29 Hz, 1 H) 6.72 (q, J = 6.74 Hz, 1 H) 7.23 (d, J = 1.61 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, J = 2.34 Hz, 1 H)

65c

¹H NMR (400 MHz, MeOH-d4): δ 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 (m, 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, 1 H) 6.39 (d,

J = 2.29 Hz, 1 H) 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

H)

65d

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (d, J = 6.05 Hz, 6 H) 1.50 (s, 4 H)

1.51 (s, 5 H) 1.55-1.70 (m, 4 H) 1.92-2.06 (m, 1 H) 2.38 (s, 3 H) 2.39-2.48 (m, 1 H)

3.16-3.27 (m, 2 H) 3.47-3.75 (m, 4 H) 4.46 (t, J = 8.64 Hz, 1 H) 4.63 (dt, J = 12.10,

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

H)

Example 66a
(S)-2-(Dimethylamino)ethyl 8-(2-amino-6-((R)-1-(4-chlor-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

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Step 1:

To a mixture of (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (85 mg, 0.16 mmol) in THF (10 mL) was added BOC₂O (4 g, 18.6 mmol) in THF (10 mL), and the reaction mixture was stirred at RT for 16 h. Then the reaction was diluted with CH₂Cl₂, cooled to 0° C., and the pH adjusted to 2 with 2 N HCl. The reaction mixture was then extracted CH₂Cl₂and concentrated in vacuo to provide (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid that was used directly without further purification.

Step 2:

To a solution of (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (1.6 g, 2.45 mmol) in DMF (24 mL) were added (2-chloro-ethyl)-dimethyl-amine hydrochloride (535 mg, 3.7 mmol) and K₂CO₃(1.0 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 extracted. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification via prep-HPLC column chromatography (CH₂Cl₂/MeOH/NH₄OH) provided (S)-2-tert-butyl 3-(2-(dimethylamino)ethyl) 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.

Step 3:

To a solution of (S)-2-tert-butyl 3-(2-(dimethylamino)ethyl) 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (1.4 g, 1.86 mmol) in CH₂Cl₂(9 mL) was added TFA (4.5 mL), and the reaction was stirred at RT for 2 h. Then the reaction was concentrated in vacuo and the residue was partitioned between CH₂Cl₂and aqueous NaHCO₃, and extracted. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Purification via prep-HPLC column chromatography (CH₂Cl₂/EtOH/NH₄OH) provided the title compound as an off-white solid.

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

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TABLE 21a

Ex.

LCMS

No.
R^X
R^Y
R^Z
CAS Name
(MH+)

66a
H

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H
(S)-2- (dimethylamino) ethyl 8-(2- amino-6-((R)- 1-(4-chloro- 2-(3-methyl- 1H-pyrazol- 1-yl)phenyl)- 2,2,2- trifluoroethoxy) pyrimidin-4-yl)- 2,8-diazaspiro [4.5]decane-3- carboxylate
638

66b
H

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(S)-2- (dimethylamino)- 2-oxoethyl 8-(2- amino-6-((R)-1- (4-chloro-2-(3- methyl-1H- pyrazol-1-yl) phenyl)-2,2,2- trifluoroethoxy) pyrimidin-4-yl)- 2,8-diazaspiro [4.5]decane-3- carboxylate
652

66c
H

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H
(S)-2- (((R)-2-amino-3- methylbutanoyl) oxy)ethyl 8-(2- amino-6-((R)-1- (4-chloro-2-(3- methyl-1H- pyrazol-1-yl) phenyl)-2,2,2- trifluoroethoxy) pyrimidin-4-yl)- 2,8-diazaspiro [4.5]decane-3- carboxylate
710

66d
H

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H
(S)-2- (pivaloyloxy) ethyl 8-(2- amino-6-((R)- 1-(4-chloro- 2-(3-methyl- 1H-pyrazol- 1-yl)phenyl)- 2,2,2- trifluoroethoxy) pyrimidin-4-yl)- 2,8-diazaspiro [4.5]decane-3- carboxylate
695

TABLE 21b

NMR Data for Compounds of Table 21a

Ex.

No.
NMR

66a

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.59 (d, J = 5.08 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.,

2 H) 3.60 (br. s., 2 H) 4.45 (dd, J = 5.71, 3.90 Hz, 1 H) 4.49-4.68 (m, 2 H) 5.90 (br. s., 1

H) 6.39 (d, J = 2.39 Hz, 1 H) 7.15 (d, J = 5.86 Hz, 1 H) 7.53-7.73 (m, 3 H) 8.14 (d,

J = 2.39 Hz, 1 H) 9.65 (br. s., 1 H) 10.59 (br. s., 1 H), 10.80 (br. s., 1 H).

66b

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.46-1.77 (m, 4 H) 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 H) 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

H).

66c

¹H NMR (400 MHz, DMSO-d6): δ 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., 1 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)

10.52-10.84 (m, 1 H).

66d

¹H NMR (400 MHz, DMSO-d6): δ 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 H) 2.22-2.43 (m, 4 H) 3.15 (d, J = 3.56 Hz, 2 H)

3.58-3.80 (m, 4 H) 4.60 (d, J = 5.71 Hz, 1 H) 6.06 (br. s., 1 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, 1 H)

10.74 (br. s., 1 H).

Example 67a
(S)-isopropyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

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To a solution of the compound of Example 1m (400 mg, 0.53 mmol) in propan-2-ol (5 mL) was added thionyl chloride (2 drops) at 0° C. The mixture was warmed to RT and then heated to reflux for 2 h. Then the reaction mixture was cooled to RT, concentrated and neutralized with saturated aqueous NaHCO₃solution to pH 7-8. The aqueous layer was extracted with CH₂Cl₂. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, concentrated in vacuo and purified by flash column (0˜10% MeOH in DCM) on silica gel to afford the title compound as a white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.96 (d, J=2.3 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.70 (dd, J=8.2, 1.8 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.43 (s, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 6.76 (q, J=6.8 Hz, 1H), 6.41 (d, J=2.3 Hz, 1H), 5.74 (s, 1H), 5.01 (m, 1H), 3.76 (dd, J=8.7, 7.0 Hz, 1H), 3.61-3.42 (m, 4H), 2.88 (d, J=11.1 Hz, 1H), 2.72 (d, J=11.0 Hz, 1H), 2.39 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H), 2.05 (dd, J=13.1, 8.9 Hz, 1H), 1.71 (dd, J=13.0, 7.0 Hz, 1H), 1.50 (m, 4H), 1.24 (dd, J=6.2, 3.9 Hz, 6H). LCMS (MH+): 679.

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

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TABLE 22a

Ex.

LCMS

No.
R¹
CAS Name
(MH+)

67b

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(S)-cyclopentyl 8-(2-amino-6-((R)- 1-(3′,4′-dimethyl-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
705

67c
CH₃
(S)-methyl 8-(2-amino-6-((R)-1- (3′,4′-dimethyl-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro [4.5]decane-3-carboxylate
650

67d

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(S)-propyl 8-(2-amino-6-((R)-1- (3′,4′-dimethyl-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro [4.5]decane-3-carboxylate
679

TABLE 22b

NMR Data for Compounds of Table 22

Ex.

No.
NMR

67b

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.96 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 8.2 Hz,

1H), 7.71 (dd, J = 8.2, 1.8 Hz, 1H), 7.60 (d, J = 1.7 Hz, 1H), 7.44 (s, 1H), 7.37 (dd, J = 7.9,

1.9 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6.76 (q, J = 6.9 Hz, 1H), 6.41 (d, J = 2.3 Hz,

1H), 5.74 (s, 1H), 5.21-5.14 (m, 1H), 3.76 (dd, J = 8.8, 6.9 Hz, 1H), 3.61-3.42 (m,

4H), 2.88 (d, J = 11.0 Hz, 1H), 2.72 (d, J = 11.0 Hz, 1H), 2.39 (s, 3H), 2.31 (s, 3H),

2.28 (s, 3H), 2.04 (dd, J = 13.1, 8.8 Hz, 1H), 1.87 (d, J = 7.3 Hz, 2H), 1.77-1.56 (m, 7H),

1.50-1.45 (m, 4H)

67c

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.96 (d, J = 2.3 Hz, 1H), 7.76 (d, J = 8.3 Hz,

1H), 7.71 (dd, J = 8.2, 1.6 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.44 (s, 1H), 7.37 (dd, J = 7.8,

1.6 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 6.76 (q, J = 6.5 Hz, 1H), 6.41 (d, J = 2.3 Hz,

1H), 5.74 (s, 1H), 3.83 (t, J = 8.0 Hz, 1H), 3.71 (s, 3H), 3.61-3.41 (m, 4H), 2.86 (d, J = 11.0 Hz,

1H), 2.74 (d, J = 11.0 Hz, 1H), 2.39 (s, 3H), 2.31 (s, 3H), 2.28 (s, 3H),

2.06 (dd, J = 13.0, 8.7 Hz, 1H), 1.72 (dd, J = 13.0, 7.2 Hz, 1H), 1.55-1.43 (m, 4H)

67d

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.95 (m, 3H), 1.49 (dt, J = 12.0, 6.0 Hz, 4H),

1.69 (m, 3H), 2.06 (dd, J = 13.1, 8.8 Hz, 1H), 2.29 (d, J = 10.3 Hz, 6H), 2.39 (s, 3H),

2.73 (d, J = 11.0 Hz, 1H), 2.87 (d, J = 11.0 Hz, 1H), 3.30 (m, 4H), 3.51 (dt, J = 27.9, 6.6 Hz,

4H), 3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.08 (m, 2H), 5.74 (s, 1H), 6.41 (d, J = 2.3 Hz,

1H), 6.76 (q, J = 6.7 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 7.40 (m, 2H), 7.59 (d, J = 1.8 Hz,

1H), 7.72 (m, 2H), 7.96 (d, J = 2.4 Hz, 1H)

Example 68a
(S)-isopropyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

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The title compound was prepared as described for (S)-isopropyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (Example 67a) starting with (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic 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-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (Example 68a), using the appropriate alcohol.

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TABLE 23a

Ex.

LCMS

No.
R¹
CAS Name
(MH+)

68a

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(S)-isopropyl 8-(2-amino-6-((R)- 2,2,2-trifluoro-1-(4′-isopropoxy- 3-(3-methyl-1H-pyrazol-1-yl)- [1,1′-biphenyl]-4-yl)ethoxy) pyrimidin-4-yl)-2,8-diazaspiro [4.5]decane-3-carboxylate
709

68b

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(S)-cyclopentyl 8-(2-amino-6- ((R)-2,2,2-trifluoro-1-(4′- isopropoxy-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]- 4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
735

68c

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(S)-propyl 8-(2-amino-6-((R)- 2,2,2-trifluoro-1-(4′- isopropoxy-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]- 4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5] decane-3-carboxylate
709

TABLE 23b

NMR Data for Compounds of Table 23

Ex.

No.
NMR

68a

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 14H), 1.49 (dt, J = 10.9, 5.2 Hz, 4H),

1.72 (dd, J = 13.1, 7.0 Hz, 1H), 2.05 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.72 (d, J = 11.0 Hz,

1H), 2.89 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H), 3.77 (dd, J = 8.8, 7.0 Hz, 1H),

4.63 (hept, J = 6.0 Hz, 1H), 5.01 (p, J = 6.2 Hz, 1H), 5.74 (s, 1H), 6.40 (d, J = 2.3 Hz,

1H), 6.76 (q, J = 6.6 Hz, 1H), 6.96 (m, 2H), 7.57 (m, 3H), 7.70 (m, 2H), 7.95 (d, J = 2.3 Hz,

1H)

68b

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.39 (s,

3H), 2.73 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.52 (dt, J = 21.1, 6.5 Hz, 4H),

3.78 (dd, J = 8.8, 7.0 Hz, 1H), 4.64 (p, J = 6.0 Hz, 1H), 5.18 (td, J = 5.9, 2.7 Hz, 1H),

5.75 (s, 1H), 6.40 (d, J = 2.4 Hz, 1H), 6.75 (q, J = 6.6 Hz, 1H), 6.97 (m, 2H), 7.59 (m,

3H), 7.71 (m, 2H), 7.95 (d, J = 2.4 Hz, 1H)

68c

¹H NMR (400 MHz, MeOH-d4): δ 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 (m, 3H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H),

2.39 (s, 3H), 2.73 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.52 (dp, J = 20.9, 7.5 Hz,

4H), 3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.09 (m, 2H), 4.64 (h, J = 6.0 Hz, 1H), 5.74 (s, 1H),

6.40 (d, J = 2.4 Hz, 1H), 6.76 (q, J = 6.7 Hz, 1H), 6.96 (m, 2H), 7.58 (m, 3H), 7.71 (m,

2H), 7.95 (d, J = 2.4 Hz, 1H)

Example 69a
(S)-isopropyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

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

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

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TABLE 24a

Ex.

LCMS

No.
R¹
CAS Name
(MH+)

69a

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(S)-isopropyl 8-(2-amino-6-((R)-1-(5- chloro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate
605

69b

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(S)-cyclopentyl 8-(2-amino-6-((R)-1- (4′-chloro-3-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate
735

69c

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(S)-propyl 8-(2-amino-6-((R)-1-(5- chloro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
605

69d

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(S)-tetrahydro-2H-pyran-4-yl 8-(2- amino-6-((R)-1-(5-chloro-[1,1′- biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
645

TABLE 24b

NMR Data for Compounds of Table 24

Ex.

No.
NMR

69a

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.25 (dd, J = 6.3, 3.2 Hz, 6H), 1.52 (m, 4H),

1.74 (dd, J = 13.1, 7.1 Hz, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, 1H), 2.75 (d, J = 11.0 Hz,

1H), 2.91 (d, J = 11.0 Hz, 1H), 3.49 (m, 4H), 3.80 (dd, J = 8.8, 7.1 Hz, 1H), 5.02 (hept, J = 6.2 Hz,

1H), 5.47 (d, J = 7.8 Hz, 1H), 6.63 (q, J = 6.8 Hz, 1H), 7.28 (d, J = 2.2 Hz,

1H), 7.48 (m, 6H), 7.67 (d, J = 8.5 Hz, 1H)

69b

¹H NMR (400 MHz, MeOH-d4): δ 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, 1H), 2.39 (s,

3H), 2.73 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.52 (dt, J = 21.1, 6.5 Hz, 4H),

3.78 (dd, J = 8.8, 7.0 Hz, 1H), 4.64 (q, J = 6.0 Hz, 1H), 5.18 (td, J = 5.9, 2.7 Hz, 1H),

5.75 (s, 1H), 6.40 (d, J = 2.4 Hz, 1H), 6.75 (q, J = 6.6 Hz, 1H), 6.97 (m, 2H), 7.59 (m,

3H), 7.71 (m, 2H), 7.95 (d, J = 2.4 Hz, 1H)

69c

¹H NMR (MeOH-d4): δ ppm 0.95 (t, J = 7.4 Hz, 3H), 1.52 (dt, J = 14.2, 4.9 Hz, 4H),

1.71 (ddd, J = 31.8, 13.7, 7.1 Hz, 3H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.76 (d, J = 11.0 Hz,

1H), 2.91 (d, J = 11.0 Hz, 1H), 3.50 (ddd, J = 19.5, 7.9, 4.8 Hz, 4H), 3.84 (dd, J = 8.7,

7.2 Hz, 1H), 4.10 (m, 2H), 4.88 (s, 8H), 5.48 (d, J = 7.9 Hz, 1H), 6.63 (q, J = 6.9 Hz,

1H), 7.28 (d, J = 2.2 Hz, 1H), 7.47 (m, 6H), 7.67 (d, J = 8.6 Hz, 1H)

69d

¹H NMR (MeOH-d4): δ ppm 1.61 (m, 6H), 1.82 (dd, J = 13.2, 7.5 Hz, 1H), 1.93 (dd, J = 11.6,

6.1 Hz, 2H), 2.03 (s, 1H), 2.20 (dd, J = 13.2, 8.8 Hz, 1H), 2.89 (d, J = 11.2 Hz,

1H), 2.99 (d, J = 11.2 Hz, 1H), 3.54 (m, 6H), 3.89 (dq, J = 12.1, 3.9 Hz, 2H), 4.04 (dd, J = 8.7,

7.5 Hz, 1H), 5.01 (tt, J = 8.3, 4.0 Hz, 1H), 5.48 (s, 1H), 6.64 (q, J = 6.9 Hz, 1H),

7.28 (d, J = 2.2 Hz, 1H), 7.47 (m, 6H), 7.67 (d, J = 8.5 Hz, 1H)

Example 70
(S)-methyl 8-(2-amino-6-((R)-1-(5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

embedded image

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

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.51 (q, J=7.1, 6.7 Hz, 6H), 1.72 (dd, J=13.0, 7.3 Hz, 1H), 2.07 (dd, J=13.2, 8.7 Hz, 1H), 2.75 (d, J=11.0 Hz, 1H), 2.87 (d, J=11.0 Hz, 1H), 3.21 (s, 4H), 3.50 (tdt, J=20.3, 13.5, 7.0 Hz, 4H), 3.71 (s, 2H), 3.84 (t, J=8.0 Hz, 1H), 4.87 (m, 1H), 5.57 (s, 1H), 6.57 (q, J=6.6 Hz, 1H), 7.33 (d, J=2.3 Hz, 1H), 7.41 (s, 2H), 7.48 (dd, J=8.5, 2.2 Hz, 1H), 7.75 (m, 3H), 8.07 (d, J=7.8 Hz, 1H), 8.43 (s, 1H). LCMS (MH+): 655.

Example 71
(S)-methyl 8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

embedded image

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

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.54 (dt, J=8.9, 6.0 Hz, 5H), 1.75 (dd, J=13.1, 7.4 Hz, 1H), 2.10 (dd, J=13.1, 8.7 Hz, 1H), 2.77 (d, J=11.0 Hz, 1H), 2.89 (d, J=11.0 Hz, 1H), 3.53 (qt, J=14.0, 7.8 Hz, 4H), 3.72 (s, 3H), 3.86 (dd, J=8.7, 7.3 Hz, 1H), 4.91 (s, 13H), 5.57 (s, 1H), 6.60 (q, J=6.5 Hz, 1H), 7.31 (d, J=2.2 Hz, 1H), 7.49 (dd, J=8.5, 2.3 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.71 (m, 2H), 8.02 (ddd, J=7.9, 1.9, 1.1 Hz, 1H), 8.33 (s, 1H). LCMS (MH+): 656. LCMS (MH+): 656.

Example A
In Vitro Inhibition Assays

TPH1 and TPH2 Assays

Recombinant human TPH1 (rTPH1 GenBank TM accession no. NP_—004179) was expressed by cloning full length human TPH1 cDNA in to a bacterial pMAL-c5E expression vector to produce maltose-binding protein (MBP) TPH1 fusion proteins. E. coli BL21 (DE3) containing pMAL-c5E-TPH1 was used for protein generation and the recombinant protein was purified utilizing standard column chromatography techniques. The MBP tagged TPH1 (MBP-TPH1) was used directly to screen compounds as described below. Recombinant human TPH2 (rTPH2 GenBank TM accession no. 173353), PheOH (rPheOH GenBank TM accession no. K03020) and TH (rTH GenBank TM accession no. L20679) with an MBP tag were produced similarly.

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

Kinetic assay data for compounds at specific 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 1%. Typically, in the absence of enzyme, reaction slopes were ˜0. IC₅₀'s were determined using Graphpad Prism.

Compounds having an IC₅₀of 10,000 nM or less were considered active.

Inhibition of TPH2 activity by the compounds of the invention was measured similarly. In some instances, compounds of the invention showed dual inhibition of both TPH1 and TPH2.

Data related to TPH1 inhibition activity of the compounds of the invention is provided below in Table 25. Compounds that inhibit TPH1 with an IC₅₀from 3,000 nM to 10,000 nM are indicated by +. Compounds that inhibit TPH1 with an IC₅₀of less than 3,000 nM but more than 300 nM are indicated by ++. Compounds that inhibit TPH1 from 50 nM to 300 nM are indicated by +++. Compounds that inhibit TPH1 with an IC₅₀less than 50 nM are indicated by ++++. Ester prodrugs listed, for example, in Tables 18a, 19a, 20a, and 21a-24a, as well as in Examples 70 and 71, are not expected to be active in this in vitro assay.

TABLE 25

TPH1 Inhibition Data

TPH1

Ex. No.
Range

1a
++++

1b
++++

1c
++++

1d
++++

1e
++++

1f
+++

1g
++++

1h
++++

1i
+++

1j
+++

1k
++++

1l
++++

1m
++++

1n
++++

1o
++++

1p
++++

1q
++++

1r
++++

1s
++++

1u
++++

1v
++++

1w
++++

1x
++++

1y
++++

1z
++++

1aa
++++

1ab
++++

1ac
++++

1ad
++++

1ae
++++

1af
++++

1ag
++++

1ah
++++

1ai
++++

1aj
++++

1ak
+++

1al
++++

1am
++++

1an
++++

1ao
++++

1ap
++++

1aq
+++

1ar
+++

1as
++++

1at
++++

1au
+++

1av
++++

1aw
+++

1ax
++++

1ay
+++

1az
+++

1ba
++++

1bb
++++

1bc
++++

1bd
++++

1be
+++

1bf
+++

1bg
++++

1bh
++++

1bi
++++

1bj
+++

1bk
++++

1bl
++++

1bm
++++

1bn
++++

1bo
+++

1bp
++++

1bq
++++

1bv
++++

1bw
+++

1bx
++++

1by
++++

1bz
++++

1ca
++++

1cb
++++

1cc
++++

1cd
++++

1ce
++++

1cf
+++

1cg
++++

1ch
+++

1ci
++++

1cj
++++

1ck
++++

1cl
++++

1cm
++++

1cn
++++

1co
++++

1cp
++++

1cq
++++

1cr
++++

1cs
++++

10j
+++

10k
+++

10l
+++

10m
++++

10n
++++

10o
++++

10p
+++

10q
++++

10r
++++

10pa
+++

11
+++

12a
+++

12b
++++

12c
++++

13
+++

14
++++

15
+++

16
++

17
++++

18a
+++

18b
++++

18c
++++

18d
++++

18e
++++

18f
++++

19a
++++

19b
++++

19c
++++

19d
+++

19e
++++

19f
++++

19g
++++

19h
++++

19i
++++

19j
++++

19k
++++

19l
++++

19m
++++

19n
++++

19o
++++

19p
++++

19q
++++

19r
++++

20
++++

21
++++

22a
++++

22b
++++

22c
++++

23
++++

24
+++

25
++++

26
+

27
+++

28
+++

29a
++++

29b
++++

29c
+++

29d
++++

29e
+++

29f
++++

29g
++++

29h
++++

29i
++++

29j
++++

29k
+++

29l
++++

29m
+++

29n
+++

29o
++++

29p
++++

29q
++++

29r
++++

29s
++++

29t
+++

29u
+++

33
+++

34a
++++

34b
++++

34c
+++

34d
+++

34e
+++

34f
+++

34g
+++

34h
++

34i
+++

34j
+++

34k
+++

34l
+++

34m
+++

34n
+++

34o
+++

34p
+++

34q
++++

34r
+++

34s
+++

34t
+++

34u
++++

34v
++++

34w
++++

34x
++++

34y
++++

34z
++++

34aa
++++

34ab
++

34ac
++++

34ad
++

34ae
++

34af
++++

34ag
++++

34ah
++++

34ai
+++

34aj
+++

34ak
+++

34al
+

34am
+++

34an
++++

34ao
++++

34ap
+++

34aq
++++

34ar
++++

34as
++++

34at
+++

34au
++++

34av
++++

34aw
++++

34ax
+++

34ay
+++

34az
++

34ba
++++

34bb
+++

34bc
+++

34bd
++++

34be
++++

34bf
+++

34bg
+++

34bh
++

34bi
++++

34bj
++++

34bk
+++

34bl
+++

34bm
+++

34bn
+++

34bo
+++

34bp
++++

34bq
+++

34bu
+++

34bv
+++

34bw
+++

34bx
+++

34by
+++

34ca
+++

34cb
+++

34cc
+++

34cd
+++

34ce
+++

34cf
++

34cg
+++

34ch
++++

34ci
+++

34cj
+++

34ck
+++

34cl
+++

34cm
+++

34cn
+++

34co
+++

34cp
+++

34cq
++++

34cr
+++

34cs
+++

34ct
++++

34cu
++++

34cv
++++

35
+++

36
+

36b
+++

36c
++++

36d
+

36e
++

36f
+++

36g
++++

37
+

38
++

39a
++

39b
+

39c
+

39d
+

39e
++

40
++

41a
++

41b
++

41c
+

41d
+

42a
++++

42b
+++

43
+

44
++

45
+++

46
+

47
++

48
++

49
++++

50
+++

51
++++

52a
++++

52b
++++

53
++++

54a
++++

54b
+++

54c
++++

54d
+++

54e
+++

54f
++++

54g
+++

54h
+

54i
+

54j
+++

54k
+++

54l
+

54m
++

55a
+++

55b
++++

55c
+++

55d
++++

55e
+++

55f
+++

55g
++

55h
+++

55i
++++

55j
+++

55k
+++

55l
+++

55m
++++

55n
++

55o
+++

55p
+++

55q
++++

55r
+++

55s
++++

55t
+++

55u
+++

55v
++++

55w
++++

55x
+++

55y
+++

55z
+++

55aa
+++

55ab
+++

55ac
+++

55ad
+++

55ae
++

55af
++

55ag
+++

55ah
+++

55ai
++++

55aj
+++

55ak
++

55al
+++

55am
+++

55an
+++

55ao
+++

55ap
+++

55aq
+++

55ar
+++

55as
+++

55at
+++

55au
+++

55av
+++

55aw
++

55ax
+++

55ay
++

55az
++++

55ba
++++

55bb
++++

55bc
++++

55bd
++++

55be
++++

55bf
+++

55bg
++++

55bh
+++

55bi
++++

55bj
++++

55bk
+++

55bl
++

55bm
++

55bn
+

55bo
+++

55bp
+++

55bq
++

55br
++

55bs
++

55bt
++

55bu
++

55bv
++

55bw
+++

55bx
++

55by
++

55bz
+++

55ca
+++

55cb
+++

55cc
+++

55cd
++

55ce
++

55cf
+

55cg
++

55ch
+++

55ci
++

55cj
++

55ck
++

55cl
+++

55cm
++

55cn
++

55co
+++

55cp
++

55cq
+++

55cr
++

55cs
++

55ct
++

55cu
++

55cv
++

55cw
++

55cx
++

55cy
++

55cz
+++

55da
++

55db
++

55dc
++++

55dd
+++

55de
+++

55df
+++

55dg
+++

55dh
+++

55di
+++

55dj
+++

55dk
+++

55dl
+++

55dm
+++

55dn
+++

55do
++++

55dp
++++

55dq
++++

56
+++

57
+++

58
+++

59
++

59b
++

59c
+++

59d
+++

60
++

61
+++

62
+++

PheOH and TH Inhibition Counter Assays

Certain compounds of the Examples were found to inhibit tryptophan hydroxylase (TPH) selectively over phenylalanine hydroxylase (PheOH). Inhibitory 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 WO 2007/089335.

Certain compounds of the invention were found to inhibit tryptophan hydroxylase (TPH) selectively over tyrosine hydroxylase (TH). Inhibitory activity against TH can be assessed according to the methods described for example in Life Sci. 39, 2185-2189 (1986), or Mol. Pharmacol. 41, 339-344 (1992), or J. Antibiot. 35, 458-462 (1982), or WO 2007/089335.

Example B
Intestinal 5-HT Depletion Assay

The efficacy of the TPH1 inhibitors of the invention was assessed for the ability to decrease intestinal serotonin concentration in mice. Mice (C57 BL6) were administered a single 150 mg/kg dose of test article by oral gavage. Each animal was euthanized by exsanguination under isoflurane anesthesia. Jejunal intestinal mucosa was isolated and homogenized in 300 μL of a buffer containing 0.3M trichloroacetic acid, 0.1M sodium acetate, 10 mM EDTA, 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 0.1N NaOH followed by determination of protein concentrations using a BCA protein assay (Pierce, Rockford, Il. 5-HT levels were normalized to protein and data were expressed as mean percent reduction of mucosal 5-HT levels relative to vehicle control±SEM (percent 5-HT reduction). All animal studies were carried out with protocols 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 animals according to the above-described in vivo assay. P-values, indicating statistical significance of the data (ANOVA) are provided in the table: * refers to P<0.05, ** refers to P<0.01, *** refers to P<0.005, and **** refers to P<0.0005.

TABLE 26

In Vivo Efficacy of TPH1 Inhibitors In Mice (reduction of

mucosal 5-HT concentrations one day after oral admini-

stration of a single 150 mg/kg dose)

Example

No.
Efficacy

1g
***

1h
**

1l
****

1m
***

1n
**

1o
**

1p
**

1y
**

5
**

10b
***

10d
***

10g
**

10h
***

10j
****

10k
*

11
****

12b
*

12c
***

16
**

22c
*

28
*

29z
**

31
*

34r
***

34s
**

34u
*

34v
*

34w
***

55k
*

55ak
**

55al
*

55am
***

55an
***

55az
***

55bc
**

55bd
***

55bg
***

63g
***

63ay
***

63az
***

63ba
***

63bd
***

63be
***

63bf
****

63bg
****

63bh
**

63bi
**

63bn
****

63bo
****

63bp
****

63bq
****

63bx
***

63by
***

63bz
**

63ch
***

63cj
***

63cl
***

63cp
***

63da
***

63dc
***

63di
***

64c
****

64e
****

64f
****

64g
*

64h
**

65a
****

66c
****

66d
****

101
***

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 mucosal 5-HT concentrations relative to vehicle-treated animals according to the following in vivo assay.

The efficacy of the TPH1 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 h following the first dose, mice were administered a second oral dose of 50 mg/kg of the appropriate compound. A third oral dose of 50 mg/kg of the appropriate test article was administered 12 h after dose 2. Following an overnight fast, each animal was euthanized by exsanguination under isoflurane 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. 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 0.1N NaOH followed by determination of protein concentrations using a BCA protein assay (Pierce, Rockford, Ill.). 5-HT levels were normalized to protein and data were expressed as mean percent reduction of mucosal 5-HT levels relative to vehicle control±SEM (percent 5-HT reduction). All animal studies were carried out with protocols approved by the Institutional Animal Care and Use Committee. P-values, indicating statistical significance of the data (ANOVA) are provided in the table: * refers to P<0.05, ** refers to P<0.01, *** refers to P<0.005, and **** refers to P<0.0005.

TABLE 27

In Vivo Efficacy of TPH1 Inhibitors In Mice (reduction of

mucosal 5-HT concentrations two days after oral admini-

stration of a single 50 mg/kg dose)

Example

No.
Efficacy

1l
***

1m
*

1n
***

1t
***

12c
***

55bg
***

63i
***

63ae
***

63aq
***

63ar
****

63aw
****

63az
***

63bd
***

63bf
***

63bg
***

63bn
****

63bo
***

63bp
***

63ch
***

63cj
**

63cl
***

63cn
****

63dc
***

63el
***

63eo
***

63ep
***

63ev
***

63ey
**

63fo
*

63ha
**

64hb
***

69a
***

69b
***

69c
***

Example D
In Vivo Assay for Inflammatory Bowel Diseases

The utility of the compounds of the invention for the treatment of inflammatory bowel diseases can be measured, for example, using the experimental models of colitis induced by trinitrobenzene sulfonic acid (TNBS), dinitrobenzene sulfonic acid (DNBS), and dextran sodium sulfate (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 invention for the treatment of pulmonary arterial hypertension (PAH), can be measured, for example, using the hypoxia mouse model, as described by Abid, S. et al. in Am. J. Physiol., Lung Cellular and Molecular Physiology 303, L500-8 (2012), or using the rat monocrotaline-induced PAH or the rat chronic hypoxia model, as described by Kay, J. M. et al. Respiration 47, 48-56 (1985).

Example G
In Vivo Assay for Allergic Airway Inflammation

The utility of the compounds of the invention for the treatment of allergic airway inflammation, can be measured, for example, using the mouse model of allergic asthma, as described by Dürk, T. et al. in Am. J. Respir. Crit. Care Med. 187, 476-485 (2013).

Example H
In Vivo Assay for Gastrointestinal Disorders

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

Example I
In Vivo Assay for Tumor Growth

The utility of the compounds of the invention for the treatment of tumor growth, can be measured, for example, using the xenograft model of cholangiocarcinoma tumor growth, as described by Alpini, G. et al. in Cancer Res. 68, 9184-93 (2008).

Example J
In Vivo Assay for Leukemia

The utility of the compounds 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 WO 2013/074889.

Example K
In Vivo Assay for Atherosclerosis

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

Various modifications of the invention, 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, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Number	Name	Date	Kind
20100331294	Black et al.	Dec 2010	A1
20120101281	Murugesan et al.	Apr 2012	A1
20130102611	Charlton et al.	Apr 2013	A1

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Number	Date	Country
61874545	Sep 2013	US
61899943	Nov 2013	US
62004385	May 2014	US

Spirocyclic compounds as tryptophan hydroxylase inhibitors

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