Glucagon receptor agonists and their use as therapies

Abstract

Disclosed herein is a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof. Also disclosed herein is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. Further disclosed herein is a method for preventing or treating a disease or condition through the modulation of the glucagon receptor using a compound of formula (I), or a pharmaceutically acceptable salt thereof.

Description

GLUCAGON RECEPTOR AGONISTS AND THEIR USE AS THERAPIESTECHNICAL FIELD

[0001] Disclosed herein are compounds which are glucagon receptor agonists. These compounds may be useful as therapeutic agents, either as a monotherapy or in combination with another therapeutic agent, for preventing or treating a disease or condition through the modulation of the glucagon receptor.BACKGROUND OF THE INVENTION

[0002] Over the past several decades, the prevalence of diseases such as type 2 diabetes, obesity, and overweight has continued to rise. T2D mellitus (T2DM) is the most common form of diabetes accounting for approximately 90% of all diabetes. T2DM is characterized by high blood glucose levels caused by insulin resistance. The current standard of care for T2DM includes diet and exercise, and treatment with oral and injectable medications including incretinbased therapies, such as glucagon-like-peptide-1 receptor agonists (GLP-1 RA) and glucosedependent insulinotropic polypeptide receptor agonists (GIP RA). Incretin-based therapies such as GLP-1 RA and GIP RA have also been approved for treating obesity and overweight.

[0003] Despite the availability of these therapies, blood glucose levels in many patients with T2DM still remain inadequately controlled. Uncontrolled diabetes leads to several conditions that impact morbidity and mortality of patients. One of the main risk factors for T2DM is obesity or overweight. It is documented that a decrease in body adiposity leads to improvement in obesity-associated co-morbidities including hyperglycemia and cardiovascular events. Therefore, additional therapies effective in glucose control and weight reduction, for example, through the modulation of the glucagon receptor, are needed for better disease management.

[0004] Glucagon is a twenty nine amino acid peptide which is secreted from the cells of the pancreas into the hepatic portal vein thereby exposing the liver to higher levels of this hormone than non-hepatic tissues. Plasma glucagon levels decrease in response to hyperglycemia, hyperinsulinemia, elevated plasma non-esterified fatty acid levels and somatostatin whereas glucagon secretion is increased in response to hypoglycemia and elevated plasma amino acidlevels. Glucagon, through activation of its receptor, is a potent activator of hepatic glucose production by activating glycogenolysis and gluconeogenesis.

[0005] The glucagon receptor GCGR is a 62 kDa protein that is activated by glucagon and is a member of the class B G-protein coupled family of receptors. Other related G-protein coupled receptors include glucagon -like peptide- 1 receptor (GLP-1), glucagon-like peptide-2 receptor (GLP-2) and gastric inhibitory polypeptide receptor. The glucagon receptor is encoded by the GCGR gene in humans and these receptors are mainly expressed in the liver with lesser amounts found in the kidney, heart, adipose tissue, spleen, thymus, adrenal glands, pancreas, cerebral cortex and gastrointestinal tract. Stimulation of the glucagon receptor results in activation of adenylate cyclase and increased levels of intracellular cAMP. Regulation of the glucagon receptor can play an important role in the treatment of T2DM, obesity or overweight, and other conditions modulated by this receptor.SUMMARY OF THE INVENTION

[0006] Despite advancement of T2DM and obesity therapies, there remains a need for treatments for T2DM with effective glucose control, and for weight loss benefits and a favorable side effect profile. Advantageously, glucagon agonists described herein have favorable properties allowing for administration of doses that provide sufficient activity at the glucagon receptor to provide the benefits of agonism of that receptor while avoiding unwanted side effects associated with too much activity.

[0007] Disclosed herein is a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein variables A ring, R1, R2, R3, R4, R4, R5, R5, R6, and R7are as defined herein.

[0008] In one embodiment, the compound of formula (I) is a glucagon receptor agonist. In one embodiment, the compound of formula (I) is a glucagon receptor agonist which has potentactivity at the glucagon receptor. In one embodiment, the compound of formula (I) can be used for preventing or treating a disease or condition through the modulation of the glucagon receptor.DESCRIPTION OF THE INVENTION

[0009] Disclosed herein is a compound of formula (I):wherein: the A ring is a 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from:(1) Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -0-C(0)Ci-io alkyl and (d) -CN,(2) halogen,(3) Ci-io alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) C3-10 cycloalkyl, optionally substituted with -CN, and (d) Ci-10 alkoxy,(4) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) C1-10 alkyl, and (c) -C(0)Ci-io alkyl,(5) -CN,(6) -O-C3-10 cycloalkyl, optionally substituted with 1 to 3 halogens,(7) oxo,(8) -C(0)NH2,(9) C3-10 cycloalkyl, and(10) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) Ci-io alkyl and (b) halogen;R1is selected from:(1) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S,(3) -NReRf, wherein:Reis selected from:(a) H,(b) Ci-io alkyl, and(c) -C(O)Ci -io alkyl, optionally substituted with 1 to 3 halogens; andRfis selected from:(a) H,(b) Ci-io alkyl, optionally substituted with 1 to 3 halogens,(c) -C(0)Ci-io alkyl, optionally substituted with 1 to 3 halogens, and(d) -C(O)NH2, optionally substituted with 1 to 2 Ci-io alkyl;(4) Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -C(O)NRaRb, wherein each of Raand Rbis independently selected from (i) H, (ii) C i-io alkyl, and (iii) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from halogen and Ci-io alkyl optionally substituted with 1 to 3 halogens,(c) -OH,(d) C3-10 cycloalkyl, optionally substituted with 1 to 3 halogens,(e) Ci-10 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,(f) -NRlaRlb, wherein each of Rlaand Rlbis independently selected from:(i) H,(ii) Ci-10 alkyl, optionally substituted with 1 to 3 halogens, and(iii) -C(0)Ci-io alkyl, optionally substituted with 1 to 3 halogens,(g) -P(O)RlcRld, wherein each of Rlcand Rldis independently selected from:(i) Ci-io alkyl, and(ii) -NRleRlf, wherein each of Rlcand Rlfis independently selected from H and Ci-io alkyl, and(h) -SO2NlgRlh, wherein each of Rlgand Rlhis independently selected from H and Ci-io alky,(5) -SO2NH2, optionally substituted with 1 to 2 C1-10 alkyl,(6) -C(0)NH2, optionally substituted with 1 to 2 C1-10 alkyl,(7) -C(O)OH, and(8) H; wherein each of the heterocyclyl of (1) and heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:(a) Ci-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH, (iii) -0-C(0)Ci-io alkyl, and (iv) -NR11Rlj, wherein each of R11and R1' is independently selected from H and C1-10 alkyl, and(b) oxo; each of R2and R3is independently selected from:(1) H,(2) Ci-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(3) -O-Rc, wherein Rcis selected from (a) H and (b) C1-10 alkyl,(4) -C(O)-Rd, wherein Rdis selected from (a) C1-10 alkyl; (b) -OH, (c) CMO alkoxy, and(d) -NR2eR2f, wherein each of R2eand R2fis independently selected from (i) H and (ii) Ci-10 alkyl, and(5) halogen; each of R4, R4, R5, and Ryis independently selected from:(1) H,(2) Ci-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) -OH and (b) halogen,(3) C3-10 cycloalkyl, and(4) halogen;R6is selected from:(1) an aryl,(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and(3) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,(c) Ci-io alkoxy, optionally substituted with 1 to 3 halogens,(d) -O-aryl, optionally substituted with 1 to 3 halogens,(e) -O-heteroaryl, wherein the heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) Ci-io alkyl, (ii) halogen, (iii) -OH, and (iv) Ci-io alkoxy,(f) -S-C i-io alkyl, optionally substituted with 1 to 3 halogens,(g) -NR6eR6f, wherein each of R6eand R6fis independently selected from (i) H, (ii) Ci-io alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,(h) a 4-6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) Ci-io alkyl and (ii) halogen,(i) an aryl, optionally substituted with 1 to 3 substituents independently selected from (i) Ci-io alkyl, (ii) halogen, and (iii) -OH,(j) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituentsindependently selected from (i) Ci-io alkyl, (ii) halogen, (iii) -OH, and (iv) Cu 10 alkoxy,(k) C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) Ci-io alkyl, optionally substituted 1-3 halogens,(l) -O-C3-10 cycloalkyl, optionally substituted with 1 to 3 halogens, and(m) -O-C2-10 alkenyl, optionally substituted with 1 to 3 halogens; andR7is selected from:(1) H,(2) Ci-10 alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen, and(3) halogen; or a pharmaceutically acceptable salt thereof.In one embodiment of the compound of formula (I) above, wherein: the A ring is a 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from:(1) Ci-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -0-C(0)Ci-io alkyl and (d) -CN,(2) halogen,(3) Ci-10 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) C3-10 cycloalkyl, optionally substituted with -CN, and (d) Ci-10 alkoxy,(4) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) C1-10 alkyl, and (c) C(0)Cnio alkyl,(5) -CN,(6) -O-C3-10 cycloalkyl, optionally substituted with 1 to 3 halogens,(7) oxo,(8) -C(O)NH2,(9) C3-10 cycloalkyl, and(10) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) Ci-io alkyl and (b) halogen;R1is selected from:(1) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S,(3) -NReRf, wherein:Reis selected from:(a) H,(b) Ci-io alkyl, and(c) -C(O)Ci -io alkyl, optionally substituted with 1 to 3 halogens; andRfis selected from:(a) H,(b) Ci-io alkyl, optionally substituted with 1 to 3 halogens,(c) -C(O)Ci -io alkyl, optionally substituted with 1 to 3 halogens, and(d) -C(O)NH2, optionally substituted with 1 to 2 Ci-io alkyl;(4) -Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -C(O)NRaRb, wherein each of Raand Rbis independently selected from (i) H and (ii) Ci-io alkyl, and(c) -OH,(5) -SO2NH2,(6) -C(O)NH2,(7) -C(O)OH, and(8) H; wherein each of the heterocyclyl of (1) and heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:(a) Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -0-C(0)CMO alkyl, and(b) oxo; each of R2and R3is independently selected from:(1) H,(2) Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(3) -O-Re, wherein Rcis selected from (a) H and (b) Ci-io alkyl,(4) -C(O)-Rd, wherein Rdis selected from (a) Cuio alkyl; (b) -OH, (c) Cuio alkoxy, and(d) -NR2eR2f, wherein each of R2eand R2fis independently selected from (i) H and (ii)Ci-io alkyl, and(5) halogen; each of R4, R4, R5, and R5is independently selected from:(1) H,(2) Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) -OH and (b) halogen,(3) C3-10 cycloalkyl, and(4) halogen;R6is selected from:(1) an aryl,(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and(3) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) Cuio alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,(c) Cuio alkoxy, optionally substituted with 1 to 3 halogens,(d) -O-aryl, optionally substituted with 1 to 3 halogens,(e) -O-heteroaryl, wherein the heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) Ci-io alkyl, (ii) halogen, (iii) -OH, and (iv) Ci-io alkoxy,(f) -S-Ci-io alkyl, optionally substituted with 1 to 3 halogens,(g) -NR6eR6f, wherein each of R6eand R6fis independently selected from (i) H, (ii) Ci-io alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,(h) a 4-6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) Ci-io alkyl and (ii) halogen,(i) an aryl, optionally substituted with 1 to 3 substituents independently selected from (i) Ci-io alkyl, (ii) halogen, and (iii) -OH,(j) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) Ci-io alkyl, (ii) halogen, (iii) -OH, and (iv) Ci-io alkoxy,(k) C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) Ci-io alkyl, optionally substituted 1-3 halogens, and(l) -O-C3-10 cycloalkyl, optionally substituted with 1 to 3 halogens; andR7is selected from:(1) H,(2) Ci-10 alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen, and(3) halogen; or a pharmaceutically acceptable salt thereof.

[0010] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:the A ring is selected from pyridyl, pyrimidyl, and thiazolyl, optionally substituted with 1 to 3 substituents independently selected from:(1) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -O-C(O)Ci-6alkyl and (d) -CN,(2) halogen,(3) Ci-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) C3-6 cycloalkyl, optionally substituted with -CN, and (d) C1-6 alkoxy,(4) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) C1-6 alkyl, and (c) -C(O)Ci-6 alkyl,(5) -CN,(6) -O-C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens,(7) oxo,(8) -C(O)NH2,(9) C3-6 cycloalkyl, and(10) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) Ci-6 alkyl and (b) halogen; andR7is H.

[0011] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: the A ring is a 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from:(1) Ci-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH and (c) -0-C(0)Ci-io alkyl,(2) halogen,(3) Ci-10 alkoxy, and(4) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) C1-10 alkyl, and (c) -C(0)Ci-io alkyl;R1is selected from:(1) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S,(3) -NReRf, wherein:Reis selected from:(a) H,(b) Ci-io alkyl, and(c) -C(O)Ci -io alkyl, optionally substituted with 1 to 3 halogens; andRfis selected from:(a) H,(b) Ci-io alkyl, optionally substituted with 1 to 3 halogens,(c) -C(0)Ci-io alkyl, optionally substituted with 1 to 3 halogens, and(d) -C(O)NH2, optionally substituted with 1 to 2 Ci-io alkyl; and(4) Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, and (c) -C(O)NRaRb, wherein each of Raand Rbis independently selected from (i) H and (ii) Ci-io alkyl; wherein each of the heterocyclyl of (1) and the heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:(a) Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -0-C(0)Ci-io alkyl, and(b) oxo; each of R2and R3is independently selected from:(1) H,(2) Ci-io alkyl, optionally substituted with 1 to 3 substituents selected from (a) halogen and (b) -OH,(3) -O-Rc, wherein Rcis selected from (a) H and (b) Ci-io alkyl,(4) -C(O)-Rd, wherein Rdis selected from (a) CMO alkyl; (b) -OH, (c) Ci-io alkoxy, and(d) -NR2eR2f, wherein each of R2eand R2fis independently selected from (i) H and (ii) Ci-io alkyl, and(5) halogen; each of R4, R4, R5, and R5is independently selected from:(1) H,(2) halogen,(3) Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) -OH and (b) halogen, and(4) C3-6 cycloalkyl;R6is an aryl, optionally substituted with 1 to 3 substituents independently selected from:(1) halogen,(2) Ci-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(3) Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(4) -O-aryl, optionally substituted with 1 to 3 halogens,(5) -O-heteroaryl, wherein the heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) C1-10 alkyl, (b) halogen, (c) -OH, and (d) C1-10 alkoxy,(6) -S-Ci-io alkyl, optionally substituted with 1 to 3 halogens,(7) -NR6eR6f, wherein each of R6eand R6fis independently selected from (a) H, (b) Ci-io alkyl, and (c) a 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,(8) a 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) C1-10 alkyl and (ii) halogen,(9) an aryl, optionally substituted with 1 to 3 substituents independently selected from (a) Ci-10 alkyl, (b) halogen, and (c) -OH, and(10) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) Ci-io alkyl, (b) halogen, (c) -OH, and (d) Ci-io alkoxy; andR7is selected from:(1) H,(2) Ci-io alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen, and(3) halogen; or a pharmaceutically acceptable salt thereof.

[0012] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: the A ring is a 5- or 6-membered heteroaryl ring selected from pyridyl, pyrimidyl, and thiazolyl, each of which is optionally substituted with 1 to 3 substituents independently selected from:(1) Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH and (c) -0-C(0)Ci-io alkyl,(2) halogen,(3) Ci-6 alkoxy, and(4) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) Ci-6 alkyl, and (c) -C(O)Ci-6 alkyl.

[0013] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (la):

[0014] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (lb):

[0015] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Ic):

[0016] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Id):

[0017] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (le):

[0018] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (If):

[0019] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Ig):(Ig)-

[0020] In one embodiment of the compound of formula (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein, when present, each of RA1, R42, RA3, and R44is independently selected from:(1) H,(2) Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -0-C(0)Ci-io alkyl and (d) -CN,(3) halogen,(4) Ci-io alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) C3-10 cycloalkyl and (d) C1-10 alkoxy,(5) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) C1-10 alkyl, and (c) -C(0)Ci-io alkyl,(6) -CN,(7) -O-C3-10 cycloalkyl, optionally substituted with 1 to 3 halogens,(8) oxo,(9) -C(O)NH2,(10) C3-10 cycloalkyl, and(11) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) Ci-io alkyl and (b) halogen.

[0021] In one embodiment of the compound of formula (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein, when present, each of RA1, RA2, RA3, and RA4is independently selected from:(1) H,(2) Ci-6 alkyl, and(3) halogen.

[0022] In one embodiment of the compound of formula (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein, when present, each of RA1, RA2, RA3, and RA4is H.

[0023] In one embodiment of the compound of formula (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein, when present, each of RA1, RA2, RA3, and RA4is independently selected from:(1) H,(2) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -O-C(O)Ci-6alkyl and (d) -CN,(3) halogen,(4) Ci-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) C3-6 cycloalkyl and (d) Ci-6 alkoxy,(5) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) Ci-6 alkyl, and (c) -C(O)Ci-6 alkyl,(6) -CN,(7) -O-C3.6 cycloalkyl, optionally substituted with 1 to 3 halogens, and(8) oxo.

[0024] In one embodiment of the compound of formula (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein, when present, each of RA1, RA2, RA3, and RA4is independently selected from:(1) H,(2) Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) halogen, (b) -OH, (c) -O-C(O)Ci-4alkyl and (d) -CN,(3) halogen,(4) C 1-4 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) C3-4 cycloalkyl and (d) C1-4 alkoxy,(5) -CN,(6) -O-C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens, and(7) oxo.

[0025] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (le), (If), or(Ig), or a pharmaceutically acceptable salt thereof, wherein R1is selected from:(1) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S,(3) -NReRf, wherein:Reis selected from:(a) H,(b) C1-6 alkyl, and(c) -C(O)Ci-6 alkyl, optionally substituted with 1 to 3 halogens; andRfis selected from:(a) H,(b) C1-6 alkyl, optionally substituted with 1 to 3 halogens,(c) -C(O)Ci-6 alkyl, optionally substituted with 1 to 3 halogens, and(d) -C(O)NH2, optionally substituted with 1 to 2 C1-6 alkyl;(4) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -C(O)NRaRb, wherein each of Raand Rbis independently selected from (i)H and (ii) Ci-6 alkyl, and(c) -OH,(5) -SO2NH2,(6) -C(O)NH2,(7) -C(O)OH, and(8) H; wherein each of the heterocyclyl of (1) and the heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:(a) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)Ci-6 alkyl, and(b) oxo.

[0026] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein R1is selected from:(1) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from:(a) Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)C 1-4 alkyl, and(b) oxo;(2) -NReRf, wherein:Reis selected from:(a) H, and(b) C1.4 alkyl, andR1is selected from:(a) H,(b) C1-4 alkyl, optionally substituted with 1 to 3 halogens,(c) -C(O)Ci-4 alkyl, optionally substituted with 1 to 3 halogens, and(d) -C(0)NH2, optionally substituted with 1 to 2 C1-4 alkyl; and(3) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -C(0)NRaRb, wherein each of Raand Rbis independently selected from (i) H and (ii) C1-4 alkyl, and(c) -OH.

[0027] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein R1is selected from:wherein the heterocyclyl is optionally substituted 1 to 3 substituents independently selected from:(a) C1-3 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)Ci-3 alkyl, and(b) oxo,(2) -NReRf, wherein:Reis selected from (a) H and (b) C1-3 alkyl; andR* is selected from:(a) H,(b) Ci-3 alkyl, optionally substituted with 1 to 3 halogens,(c) -C(O)Ci-3 alkyl, optionally substituted with 1 to 3 halogens, and(d) -C(O)NH2, optionally substituted with 1 to 2 C1-3 alkyl; and(3) C1-3 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -C(O)NRaRb, wherein each of Raand Rbis independently selected from (i) H and (ii) C1-3 alkyl, and(c) -OH.

[0028] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein:R1is selected from:(1) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is a monocyclic or a spiro bicyclic group,(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is a monocyclic or a fused bicyclic group,(3) -NReRf, wherein:Reis selected from (a) H and (b) Ci-6 alkyl; and Rfis selected from:(a) H,(b) Ci-6 alkyl, optionally substituted with 1 to 3 halogens,(c) -C(0)Ci-6 alkyl, optionally substituted with 1 to 3 halogens, and(d) -C(0)NH2, optionally substituted with 1 to 2 Ci-6 alkyl; and(4) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, and (c) -C(O)NRaRb, wherein each of Raand Rbis independently selected from (i) H and (ii) Ci-6 alkyl; wherein each of the heterocyclyl of (1) and the heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:(a) C i-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)Ci-6 alkyl, and(b) oxo.

[0029] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein:R1is selected from:(1) a 5 to 10 membered heterocyclyl selected from: (a)(2) -NReRf, wherein:Reis selected from (a) H and (b) C1-4 alkyl; andR1is selected from:(a) H,(b) C1-4 alkyl, optionally substituted with 1 to 3 halogens,(c) -C(O)Ci-4 alkyl, optionally substituted with 1 to 3 halogens, and(d) -C(0)NH2, optionally substituted with 1 to 2 C1-4 alkyl; and(3) C 1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) halogen, (b) -OH, and (c) -C(O)NRaRb, wherein each of Raand Rbis independently selected from (i) H and (ii) C1-4 alkyl; wherein the heterocyclyl of (1) is optionally substituted 1 to 4 substituents independently selected from:(a) C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)C 1-4 alkyl, and(b) oxo.

[0030] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein:R1is selected from:(2) -NReRf, wherein:Reis selected from (a) H and (b) -CH3; andRfis selected from:(a) H,(b) -CH3, optionally substituted with 1 to 3 halogens,(c) -C(O)CH3, optionally substituted with 1 to 3 halogens, and(d) -C(O)NH2, optionally substituted with 1 to 2 substituents independently selected from (i) -CH3 and (ii) -CH2CH3; and(3) Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, and (c) -C(O)NRaRb, wherein each of Raand Rbis independently selected from (i) H, (ii) methyl, and (iii) ethyl; wherein the heterocyclyl of (1) is optionally substituted with 1 to 3 substituents independently selected from:(a) -CH3, optionally substituted with 1 to 3 halogens,(b) -CH2CH3, optionally substituted with 1 to 3 halogens,(c) -CH2OH,(d) -CH2-OC(O)CH3, and(e) oxo.

[0031] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein: each of R2and R3is independently selected from:(1) H,(2) halogen,(3) C1-4 alkyl, optionally substituted with 1 to 3 substituents selected from (a) halogen and (b) -OH,(4) -O-Rc, wherein Rcis selected from (a) H and (b) C1-4 alkyl, and(5) -C(O)-Rd, wherein Rdis selected from (a) C1.4 alkyl; (b) C1-4 alkoxy, and (c) -NR2eR2f, wherein each of R2eand R2fis independently selected from (i) H and (ii) C1.4 alkyl.In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein: each of R2and R3is independently selected from:0) H,(2) halogen,(3) -CH3,(4) -CH2OH,(5) -CF3,(6) -CHF2,(7) -OH,(8) -OCH3,(9) -C(O)CH3,(10) -C(O)OCH3, and(11) -C(O)N(CH3)2.

[0032] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein:R2is selected from (1) H, (2) halogen, (3) -CH3, (4) -CHF2, and (5) -CH2OH; andR3is selected from (1) H, (2) halogen, (3) -CH3, (4) -CHF2, and (5) -CH2OH.

[0033] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein: each of R4, R4, R5, and Ryis independently selected from:(1) H,(2) halogen,(3) C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) -OH and (b) halogen, and(4) C3-6 cycloalkyl; wherein at least one of R4, R4, R5, and Ryis not H.

[0034] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein:R2is selected from (1) H, (2) halogen, (3) -CH3, (4) -CHF2, and (5) -CH2OH;R3is selected from (1) H, (2) halogen, (3) -CH3, (4) -CHF2, and (5) -CH2OH;R4is selected from (1) H, (2) -CH3, (3) -CH2OH, (4) -CHF2, and (5) -CF3; and each of R4, R5, and R5is H.

[0035] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof:R2is selected from (1) H, (2) halogen, (3) -CH3, and (4) -CHF2;R3is selected from (1) H, (2) halogen, (3) -CH3, and (4) -CHF2;R4is selected from (1) -CH3, (2) -CHF2, and (3) -CF3; and each of R4, R5, and R5is H.

[0036] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein R6is selected from:(1) a phenyl(2) a naphthyl,(3) a pyridyl,(4) a pyrazolyl, and(5) a 1,3-benzodioxolyl, wherein each of the phenyl of (1), naphthyl of (2), pyridyl of (3), pyrazolyl of (4), and 1,3-benzodioxolyl of (5) is optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,(c) Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,(d) a 4 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) Ci-6 alkyl and (ii) halogen,(e) an aryl, optionally substituted with 1 to 3 halogens,(f) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) Ci-6 alkyl, (ii) halogen, and (iii) Ci-6 alkoxy,(g) C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) Ci-6 alkyl, optionally substituted 1-3 halogens, and(h) -O-C3.6 cycloalkyl, optionally substituted with 1 to 3 halogens.

[0037] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein R6is selected from:(1) a phenyl,(2) a pyridyl,(3) a pyrazolyl, and(4) a 1,3-benzodioxolyl, wherein each of the phenyl of (1), pyridyl of (2), pyrazolyl of (3), and 1,3-benzodioxolyl of (4) is optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) Ci-4 alkyl, optionally substituted with 1 to 3 halogens,(c) Ci-4 alkoxy, optionally substituted with 1 to 3 halogens,(d) a heterocyclyl selected from (i) morpholinyl, (ii) piperidinyl, (iii) tetrahydrofuranyl, (iv) tetrahydropyranyl and (v) 1 ,4-dioxanyl, optionally substituted with 1 to 3 substituents independently selected from (i) C1-4 alkyl and (ii) halogen,(e) a phenyl, optionally substituted with 1 to 3 halogens,(f) a heteroaryl selected from (i) pyridyl, (ii) pyrazolyl, (iii) thiazolyl, (iv) isothiazolyl, (v) thienyl, and (vi) thiophenyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) -CH3, (ii) ethyl, (iii) halogen, (iv) -OH, and (v) -OCH3,(g) C3-4 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) C1.4 alkyl, optionally substituted 1-3 halogens, and(h) -O-C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens.

[0038] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein R6is selected from:(1) a phenyl,(2) a pyridyl, and(3) a pyrazolyl, wherein each of the phenyl of (1), pyridyl of (2), and pyrazolyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) methyl, optionally substituted with 1 to 3 halogens,(c) ethyl, optionally substituted with 1 to 3 halogens,(d) methoxy, optionally substituted with 1 to 3 halogens,(e) ethoxy, optionally substituted with 1 to 3 halogens,(f) a heterocyclyl selected from (i) morpholinyl, (ii) piperidinyl, (iii) tetrahydrofuranyl, (iv) tetrahydropyranyl, and (v) 1,4-dioxanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -CH3 and (ii) halogen,(g) a phenyl,(h) a heteroaryl selected from (i) pyridyl, (ii) pyrazolyl, (iii) thiazolyl, (iv) isothiazolyl, (v) thienyl, and (vi) thiophenyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) methyl, (ii) ethyl, (iii) halogen, (iv) -OH, and (v) -OCH3,(i) C3-4 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) methyl, optionally substituted 1-3 halogens, and(j) -O-C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens.

[0039] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein:R6is selected from:(1) a phenyl and(2) a naphthyl, wherein each of the phenyl of (1) and naphthyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) C 1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,(c) C1.4 alkoxy, optionally substituted with 1 to 3 halogens,(d) -O-phenyl,(e) -S-C1.4 alkyl, optionally substituted with 1 to 3 halogens,(f) -NR6eR6f, wherein each of R6eand R6fis independently selected from (i) H, (ii) C1-4 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,(g) a 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -CH3 and (ii) halogen,(h) a phenyl, optionally substituted with 1 to 3 substituents independently selected from(i) Ci-4 alkyl, (ii) halogen, and (iii) -OH, and(i) a heteroaryl selected from (i) pyridyl, (ii) pyrimidinyl, (iii) pyrazolyl, (iv) triazolyl, (v) thiazolyl, (vi) isothiazolyl, (vii) thienyl, and (viii) oxazolyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (a) C1-4 alkyl, (b) halogen, (c) -OH, and (d) C1.4 alkoxy.

[0040] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein:R6is selected from:(1) a phenyl and(2) a naphthyl, wherein each of the phenyl of (1) and naphthyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) Ci-2 alkyl, optionally substituted with 1 to 3 substituents independently selected from(i) halogen and (ii) -OH,(c) C1-3 alkoxy, optionally substituted with 1 to 3 halogens,(d) -O-phenyl,(e) -S-C1-2 alkyl, optionally substituted with 1 to 3 halogens,(f) -NR6eR6i, wherein each of R6eand R6iis independently selected from (i) H, (ii) C1-2 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,(g) a 5 or 6 membered heterocyclyl selected from (i) morpholinyl, (ii) piperidinyl, and (iii) tetrahydropyranyl, optionally substituted with 1 to 3 substituents independently selected from (i) -CH3 and (ii) halogen,(h) a phenyl, optionally substituted with 1 to 3 substituents independently selected from (i) -CH3 and (ii) halogen, and(i) a heteroaryl selected from (i) pyridyl, (ii) pyrazolyl, (iii) thiazolyl, (iv) isothiazolyl, and (v) thienyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) -CH3, (ii) ethyl, (iii) halogen, (iv) -OH, and (v) -OCH3.

[0041] In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein:R6is a phenyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -CH3, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,(c) -OCH3, optionally substituted with 1 to 3 halogens,(d) -O-phenyl,(e) -SCH3, optionally substituted with 1 to 3 halogens,(f) -NR6eR6f, wherein each of R6eand R6fis independently selected from (i) H, (ii) -CH3, and (iii) a 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,(g) a 5 or 6 membered heterocyclyl selected from (i) morpholinyl and (ii) piperidinyl, optionally substituted with 1 to 3 substituents independently selected from (i) -CH3 and (ii) halogen,(h) a phenyl, optionally substituted with 1 to 3 substituents independently selected from (i) - CH3 and (ii) halogen, and(i) a heteroaryl selected from (i) pyridyl, (ii) thiazolyl, (iii) isothiazolyl, and (iv) thienyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) -CH3, (ii) halogen, (iii) -OH, and (iv) -OCH3.In one embodiment of the compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein:R6is a phenyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -CH3, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,(c) -OCH3, optionally substituted with 1 to 3 halogens,(d) -O-phenyl,(e) a phenyl,(f) a thienyl, and(g) a pyridyl, optionally substituted with 1 to 3 substituents independently selected from (i) - CH3, (ii) halogen, (iii) -OH, and (iv) -OCH3.

[0042] In one embodiment, the compound herein, or a pharmaceutically acceptable salt thereof, may be a solvate, or a non-solvate. The solvent contained in a solvate may be either water or an organic solvent. Alcohols (for example, MeOH, EtOH, n-propanol), dimethylformamide, acetonitrile, acetone, dimethylsulfoxide may be used as the organic solvent. The proportion of the solvent molecule (for example a water molecule) against a single molecule compound herein or a pharmaceutically acceptable salt thereof, is, for example, 0.1 to 10, or more specifically, 0.5 to 6. Further, the proportion may fluctuate by humidity, the production method, and the production season.

[0043] The solvate of a compound herein, or a pharmaceutically acceptable salt thereof, may be obtained by a common method, such as precipitating the compound herein, or a pharmaceutically acceptable salt thereof, from a solvent. Further, a hydrate may be obtained by precipitating a compound herein, or a pharmaceutically acceptable salt thereof, from a water-containing organic solvent.

[0044] The solvate of a compound herein, or a pharmaceutically acceptable salt thereof, may be transformed to the compound herein, or a pharmaceutically acceptable salt thereof, by a common method such as heating in vacuo.

[0045] A compound used as a pharmaceutical active agent is the compound per se (free form), a hydrate of the free form, a pharmaceutically acceptable salt of the free form, or a hydrate of the salt.

[0046] The compound herein, or a pharmaceutically acceptable salt thereof, or a solvate of either the compound or the salt of the compound, may be used in the form of a crystalline material or in an amorphous state.

[0047] A compound herein, or a pharmaceutically acceptable salt thereof, includes all stereoisomers of the compound, for example, an enantiomer, a diastereomer (including cis- and trans- geometric isomer), the racemic form of the isomers, and other mixtures. For example, thecompound herein, or a pharmaceutically acceptable salt thereof, may have one or more asymmetric centers.

[0048] The compound herein, or a pharmaceutically acceptable salt thereof, includes an embodiment in which an atom constituting the compound molecule is an isotope, and includes an embodiment in which at least one atom is substituted with an atom having the same atomic number (proton number) and a different mass number (sum of protons and neutrons). Examples of the isotopes include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorous atom, sulfur atom, fluorine atom, and chlorine atom, which respectively include2H,3H,13C,14C,15N,17O,18O,31P,32P,35S,18F, and36C1.

[0049] In one embodiment, radioisotopes which emit radiation as they decay, such as3H or14C, are useful in pharmaceutical preparations or in vivo topographic tests of compounds. The stable isotope neither decays nor changes in their amount, nor have radioactivity, so they can be used safely. When the atom constituting the compound herein, or a pharmaceutically acceptable salt thereof, is an isotope, it may be transformed according to the common method by replacing the reagent used in synthesis with a reagent containing the corresponding isotope.

[0050] In one embodiment, compounds of formula (I), or a pharmaceutically acceptable salt thereof, are glucagon receptor agonists. In one embodiment, compounds of formula (I), or a pharmaceutically acceptable salt thereof, have relative EC50 (Rel EC50) values of greater than 50,000 nM using Functional Assay I or Functional Assay II as described herein. In one embodiment, compounds of formula (I), or a pharmaceutically acceptable salt thereof, have relative EC50 (Rel EC50) values of less than about 50,000 nM using Functional Assay I or Functional Assay II. In one embodiment, compounds of formula (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 25,000 nM using Functional Assay I or Functional Assay II. In one preferred embodiment, compounds of formula (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 1,000 nM using Functional Assay I or Functional Assay IE

[0051] In one embodiment, disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0052] In one embodiment, disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a type 2 diabetes, obesity, or overweight with at least one weight related comorbidity selected from diabetes, high blood pressure, high cholesterol, obstructive sleep apnea and heart disease.

[0053] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, for use in the treatment of a type 2 diabetes.

[0054] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, for use in the treatment of obesity.

[0055] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, for use in the treatment of overweight with at least one weight related comorbidity selected from diabetes, high blood pressure, high cholesterol, obstructive sleep apnea and heart disease.

[0056] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with one or more of a glucagon-like peptide-1 (GLP-1) receptor agonist, an amylin receptor agonist, a glucose-dependent insulinotropic polypeptide(GIP) agonist, and a peptide tyrosine-tyrosine (PYY) agonist, or a pharmaceutically acceptable salt thereof, in the treatment of a type 2 diabetes, obesity, or overweight with at least one weight related comorbidity selected from diabetes, high blood pressure, high cholesterol, obstructive sleep apnea and heart disease.

[0057] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains.

[0058] Reference to an element by the indefinite article “a” or “an” does not exclude the possibility that more than one element is present, unless the context clearly requires that there be one and only one element. The indefinite article “a” or “an” thus usually means “at least one.”

[0059] The term “about” means within a meaningful range of a value or values such as, a stated amount, activity, concentration, length, molecular weight, pH, time frame, temperature or volume, for example, to account for a statistical or instrument measuring sensitivity range. Sucha value or range can be within an order of magnitude typically within 20%, or more specifically within 10%, or even more specifically within 5%, of a given value or range. The allowable variation encompassed by “about” will depend upon the particular system under study, and can be readily appreciated by one of ordinary skill in the art.

[0060] The term “an effective amount” means an amount, concentration or dose of a compound described herein, or a pharmaceutically acceptable salt thereof which, upon single or multiple dose administration to an individual in need thereof, provides a desired effect in such an individual under diagnosis or treatment. An effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. An effective amount can be determined by one of ordinary skill in the art through the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount for an individual, a number of factors are considered including, but are not limited to, the size, age and general health of a subject; the specific disease or disorder involved; the degree of or involvement of or the severity of the disease or disorder; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.

[0061] The term “treat,” “treating,” or “to treat” means attenuating, restraining, slowing, stopping or reversing the progression or severity of an eixsting condition, disease, disorder or symptom. Treating includes administering a compound herein or a composition comprising a compound herein to the subject to prevent the onset of symptoms or complications, alleviating the symptoms or complications, or eliminating the condition, disease, disorder or symptom. Treating includes administering a compound or a composition comprising a compound herein to the individual to result in, for example, a reduced HbAlc level or a weight loss to the subject.

[0062] The term “a pharmaceutically acceptable salt” refers to a derivative of the compound herein, where a compound herein is modified by making an acid or a base salt thereof. Pharmaceutically acceptable salts, and processes for preparing the same, are well known in the art (see, e.g., Remington: The Science and Practice of Pharmacy, L.V. Allen, Ed., 22nd Edition, Pharmaceutical Press, 2012). By way of examples, pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, or alkali ororganic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of a compound herein formed, for example, from non-toxic inorganic or organic acids. Such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic. Pharmaceutically acceptable salts are those forms of a compound herein, 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. Pharmaceutically acceptable salt forms of a compound herein can be synthesized to contain a basic or acidic moiety by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of the compound 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, nonaqueous media like ether, EtOAc, EtOH, isopropanol, or acetonitrile are preferred (see, e.g., Stahl et al., “Handbook of Pharmaceutical Salts: Properties, Selection and Use” (Wiley -VCH 2nd ed. 2011)).

[0063] The term “a pharmaceutical composition” means a composition having an effective amount of a compound herein in combination with at least one pharmaceutically acceptable excipient, such as a binder, a carrier, a diluent, a lubricant, a pharmaceutical flow agent, and / or other pharmaceutically acceptable excipients.

[0064] The term “halogen” means a fluorine, a chlorine, a bromine, or an iodine. In one embodiment, a halogen is selected from fluorine and chlorine. In one embodiment, a halogen is a fluorine.

[0065] The term "alkoxy" refers to the following chemical group:, wherein R is an alkyl group as defined herein and the point of attachment is through the oxygen. For example, Ci-io-5-0— C alkoxy has 1 to 10 carbons with the following structure: *1 10. Similarly, Ci-6 alkoxy has 1 to 6 carbons with the following structure:

[0066] The term “Ci-io alkyl” means a straight chain or a branched chain alkyl group containing 1 to 10 carbons. Similarly, “Ci-6 alkyl” means a straight chain or a branched chain alkyl group containing 1 to 6 carbons. Examples of a Ci-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, 1 -methylpropyl, n-pentyl, isopentyl, 2- methylbutyl, 1,1 -dimethylpropyl, 1 -ethylpropyl, n-hexyl, 4-methylpentyl, and 2-ethylbutyl.

[0067] The term "alkylene" refers to an alkanediyl group, i.e., a divalent saturated acyclic hydrocarbon group which may be linear or branched. For example, a "Ci-6 alkylene" means an alkylene group having 1 to 6 carbon atoms. Exemplary Ci-4 alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), propylene (e.g, -CH2- CH2-CH2-, -CH(-CH2-CH3)-, -CH2-CH(-CH3)-, or -CH(- CH3)-CH2-), or butylene (e.g, -CH2- CH2-CH2-CH2-).

[0068] The term “C3-6 cycloalkyl” means a monovalent group derived by removing any single hydrogen atom from a cyclic saturated aliphatic hydrocarbon having 3 to 6 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. When two groups together form a C3-6 cycloalkane ring, the resulting group is bivalent. Non-limiting examples include cyclopropane- 1,1 -diyl, cyclobutane- 1,1 -diyl, cyclopentane-l,l-diyl, and cyclohexane- 1,1 -diyl.

[0069] When the two groups on two carbon atoms are combined to form a C3-6 carbocyclic ring, the resulting ring forms a condensed ring. Non-limiting examples include ring structures such that the two carbon atoms are linked by -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.

[0070] The term “aryl” means an aromatic carbocyclic group, and it may contain a non-aromatic portion in addition to the aromatic portion. The ring may be monocyclic, or it may be a bicyclic aryl that is condensed with a benzene ring or a monocyclic aryl ring. Examples include, but are not limited to, phenyl, naphthyl, azulenyl, isochromanyl, 2,4-dihydro-lH-isoquinolin-3-onyl, and l,3-dihydrobenzimidazol-2-onyl. In one embodiment, an aryl is a phenyl. In one embodiment, an aryl is a naphthyl.

[0071] The term "heteroaryl" refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, forexample, one, two, three, or four) ring heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). The term “5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S” means an heteroaryl group that contains 5 to 10 ring atoms including 1 to 3 hetero atoms independently selected from N, O, and S. The ring may be a monocyclic heteroaryl, or it may be a bicyclic heteroaryl that is condensed with a benzene ring or a monocyclic heteroaryl ring. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl , triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzooxazolyl, benzooxadiazolyl, benzoimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imidazopyridyl, benzoisoxazolyl, and benzoisothiazolyl.

[0072] The term "heterocyclyl" refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring, and / or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group contains one or more (such as, for example, one, two, three, or four) ring heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i .e., to form an oxo group), and further wherein said ring group may be saturated or partially unsaturated (i.e., unsaturated but not aromatic). The term “5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S” means a heterocyclyl group that contains 5 to 10 ring atoms including 1 to 3 heteroatoms independently selected from N, O, and S. The ring may be a monocyclic ring, a bicyclic ring or a spiro ring.Examples include, but are not limited to, oxetanyl, azetidinyl, 3,7-dioxa-9- azabicyclo[3.3.1]nonanyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, 2,6- diazaspiro[3.3]heptyl, 2-thia-6-azaspiro[3.3]heptyl, l,3-diazaspiro[4.4]nonanyl, 2-oxa-5,7- diazaspiro[3.4]octanyl, 8-oxa-l,3-diazaspiro[4.5]decanyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, pyrazolidinyl, thianyl, oxanyl, thioxanyl, indolinyl, isoindolinyl, and tetrahy droindoliny 1.

[0073] The compound herein, or a pharmaceutically acceptable salt thereof, has a glucagon receptor agonist effect, and may be used for the prevention or therapy of a disease or condition through a modulation of the glucagon receptor. In one embodiment, the disease or condition is selected from Type 2 diabetes, hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus (Type 1 diabetes), diabetic complication, obesity, overweight, hypertension, dyslipidemia, metabolic syndrome, hyperinsulinemia, nighttime hypoglycemia, hyperlipidemia, arteriosclerosis, myocardial infarction, coronary heart disease, brain infarction, non-alcoholic fatty liver disease (NAFLD), dementia, and non-alcoholic steatohepatitis. In one embodiment, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered to a subject in the form of a pharmaceutical composition in an effective amount by an appropriate administration method.

[0074] As used herein, treatment of a subject with obesity or overweight is also known as chronic weight management.

[0075] The term “overweight with at least one weight related comorbidity” refers to a disease or condition of being overweight and at least one weight related comorbidity selected from cancer, depression, diabetes, dyslipidemia, high blood pressure, high cholesterol, obstructive sleep apnea, osteoarthritis, and heart disease. In one embodiment, a subject being overweight is defined as having a body mass index (BMI) of >25 to <30.

[0076] “Diabetes” herein is a state or a disease in which the metabolism for generating and using glucose becomes deficient due to a failure in maintaining an appropriate blood glucose level in the body, and encompasses insulin-dependent diabetes mellitus (Type 1 diabetes) and noninsulin-dependent diabetes mellitus (Type 2 diabetes).

[0077] “Hyperglycemia” refers to a state in which the plasma glucose level while fasting or after administration of glucose is higher than the normal value (e.g. 80 to 110 mg / dL in human while fasting), and it is a typical symptom of diabetes.

[0078] “Impaired glucose tolerance” includes insulin-resistant impaired glucose tolerance and insulin hyposecretion.

[0079] “Diabetic complication” is a complication caused by diabetes or hyperglycemia, and may be acute complex or chronic complex. The term “acute complex” includes, for example, ketoacidosis, and infectious disease (e.g. skin infection, soft tissue infection, biliary system infection, respiratory system infection, urinary tract infection), and the “chronic complex” includes, for example, microangiopathy (e.g. nephropathy, retinopathy), neuropathy (e.g. sensory nerve disorder, motor nerve disorder, autonomic nerve disorder), and gangrene. Major diabetes complexes include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

[0080] “Coronary heart disease” includes myocardial infarction and angina pectoris.

[0081] “Dementia” includes, for example, Alzheimer's disease, vascular dementia, and diabetic dementia.

[0082] The administration method may be systemic administration including oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intravaginal administration, intraperitoneal administration, intravesical administration, and aspiration, as well as local administration by ointment, gels, and cream.

[0083] In one embodiment, a method for treating a disease or condition regulated by a glucagon receptor agonist comprises administering an effective amount of a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

[0084] In one embodiment, the effective amount to be administered may be appropriately determined according to the severity of the symptom, the age, the body weight, the relative health state, whether other drugs are combined, and the method of administration.

[0085] In one embodiment, the compound herein is co-administered with a second active agent. In one embodiment, additional active agent is selected from, the second active agent is selected from the group consisting of a glucagon-like peptide-1 (GLP-1) receptor agonist, an amylin receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) agonist, a peptide tyrosine-tyrosine (PYY) agonist, and a mixture thereof.

[0086] The administration method may be systemic administration including oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intravaginal administration, intraperitoneal administration, intravesical administration, and aspiration, as well as local administration by ointment, gels, and cream.

[0087] In one embodiment, a pharmaceutical composition comprises a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0088] In one embodiment, a pharmaceutical composition comprising a compound herein, or a pharmaceutically acceptable salt thereof, is formulated into a certain pharmaceutical formulation (dosage form). Examples of such pharmaceutical formulations include a tablet, a capsule, granules, powders, subtle granules, pills, aqueous or non-aqueous solution or suspension.Further, the compound herein, or a pharmaceutically acceptable salt thereof, may also be used in the form of various controlled release preparations. Examples of such controlled release preparations include, for example, those to be imbedded in the body, those applied to the oral mucosa or nasal mucosa. The solution or suspension may be filled in containers suited for dividing into respective administration amounts to be stored.

[0089] The various pharmaceutical formulations may be produced by a well-known method by mixing a compound herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. Examples of such additives include, but are not limited to, an excipient, a lubricant, a binding agent, a disintegrator, a stabilizer, a dispersant, a diluent, a surfactant, or an emulsifier.

[0090] Examples of an excipient include starch (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, and dicalcium phosphate.

[0091] Examples of a lubricant include ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, shellac, talc, carnauba wax, and paraffin.

[0092] Examples of a binding agent include polyvinyl pyrrolidone, macrogol, and compounds that are the same as the above excipient.

[0093] Examples of a disintegrator include chemically modified starch and cellulose, such as croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone, and compounds that are the same as the above excipient.

[0094] Examples of a stabilizer include / ?ara-oxybenzoates such as methyl paraben, and propyl paraben; benzalkonium chloride; phenols such as phenol, and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

[0095] Examples of a dispersant include cellulose derivative (Arabic rubber, tragacanth, methyl cellulose, etc ), stearic acid polyesters, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbate, and sorbitan fatty acid ester.

[0096] Examples of the solvent or diluent in a liquid formulation include phenol, chlorocresol, purified water, distilled water, etc.

[0097] Examples of a surfactant or emulsifier include polysorbate 80, polyoxyl 40 stearate, lauromacrogol.

[0098] The content of the compound herein, or a pharmaceutically acceptable salt thereof, in the pharmaceutical formulation can vary by the dosage form, and is generally from 0.01 to 90 wt%.EXAMPLES

[0099] The following examples are provided for illustration purposes only. The abbreviations used in the preparations and examples are as defined below.ACN acetonitrile aq. aqueousBoc. Zc' / V-butoxycarbonylDCM dichloromethaneDIEA diisopropylethylamineDMF dimethylformamideDMSO dimethylsulfoxide d.r. diastereomeric ratioES-MS electrospray mass spectrometryEtsN or TEA triethylamineEtOAc ethyl acetateEtOH ethanolHATU hexafluorophosphate azabenzotri azole tetramethyl uraniumHMDS bis(trimethylsilyl)amineHPLC high performance liquid chromatographyIPA isopropanolKOAc potassium acetateKO / Bu potassium tert-butoxideLiHMDS lithium bis(trimethylsilyl)amideMeOH methanolMTBE methyl / c / 7-butyl ether m z mass-to-charge ratioRBF round-bottom flaskRT room temperature sat. saturatedSFC supercritical fluid chromatographyTBAF tetrabutylammonium fluorideTFA trifluoroacetic acidTHF tetrahydrofuranTLC thin layer chromatographyTris tri s(hydroxymethyl)aminom ethaneWt or wt weight

[0100] In the schemes below, all substituents unless otherwise indicated, are as previously defined. The reagents and starting materials are either commercially available or may be prepared by methods well known to one of ordinary skill in the art, some of which are presented in the preparations below. Without limiting the scope of the invention, the following schemes, preparations, and examples are provided to further illustrate the invention.

[0101] In the following schemes, unless otherwise stated, Ra, Rb, R1, R2, R3, R4, R4’, R5, R5’, R6, and R7are as defined in Formula (I), RA3and RA4are as defined in Formula (lb), X1is defined as a halogen (i.e., Cl, Br or I) or boronic ester, X2is defined as a halogen (i.e., Br), boronic ester or tritiate such that one of X1and X2is halogen and the other is a boronic ester or tritiate. Aromatic and heteroaromatic halides can be converted to boronic esters or acids using methods known to one of skill in the art. For example, aromatic and heteroaromatic halides can be converted to boronic acids using a palladium catalyst such as methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl)(2'-methylamino- 1 , 1 '-biphenyl -2- yl)palladium(II), a base such as potassium acetate, and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) in a solvent such as methoxy cyclopentane at elevated temperatures, then purification by by reverse phase prep-HPLC using an acidic buffered aqueous-organic solvent gradient. Alternatively, aromatic and heteroaromatic halides can be converted to boronic esters using a palladium catalyst such as [(l,2,3-eta)-2-buten-l-yl]chloro[dicyclohexyl[2',4',6'-tris(l- methylethyl)[l,r-biphenyl]-2-yl]phosphine]palladium, a carbonate base such as K2CO3, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane), 2-ethyl hexanoic acid and a organic solvent such as 1,4-di oxane at elevated temperatures.Scheme 1

[0102] Scheme 1 depicts the preparations of compounds of Formula I beginning with a suitable intermediate (i) and the arene (ii) under Suzuki coupling conditions well known in the art. For example, intermediate (i) and the arene (ii) may be reacted with an appropriate palladium catalyst, such as [4-(di- / er / -butylphosphino)-A,A-dimethylaniline-2-(2'- aminobiphenyl)]palladium(II) methanesulfonate (“Aphos Pd G3”, Chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino- l , 1 '- biphenyl)]palladium(II) (“Xphos Palladacycle”), tetrakis(triphenylphosphine)palladium(0) (“Pd(PPh3)4”) or Pd CI2 (dppf)-DCM, in the presence of a suitable base, such as K3PO4, K2CO3 or CS2CO3, in an appropriate solvent, such as 1,4- dioxane and H2O, at 90 °C at least.Scheme 2

[0103] Scheme 2 illustrates the preparations of compounds of Formula la beginning with a suitable l,3,8-triazaspiro[4.5]dec-l-en-4-one intermediate (iii) and an appropriate biaryl intermediate (iv) under nucleophilic aromatic substitution conditions well known in the art. Suitable nucleophilic aromatic substitution conditions include reacting a compound bearing an appropriate halogen X3on an aromatic moiety, such as a fluorine or chlorine, with a suitable nucleophilic reactant such as an amine. The reaction occurs in the presence of a suitable organic base, such as CS2CO3, in an appropriate organic solvent, such as DMSO or DMF, at 100 °C at least.Scheme 3

[0104] Scheme 3 depicts the preparation of intermediate (i) beginning with a suitable protected amine (v). The protecting group on amine (v) is a standard amine protecting group well known in the art, including carbamate protecting groups. Amine (v) is reacted with ammonium acetate (“NH40ac”) and KCN in an appropriate solvent, such as EtOH, and stirred for at least 48 h at 80 °C. The resulting intermediate (vi) is reacted with a suitable acyl chloride in the presence of an appropriate base, such as Na CO3, NaHCCE or EtjN, in a suitable solvent, such as DCM or THF for at least 2 h at RT. Alternatively, amine (vi) is reacted under amide coupling conditions well known in the art and include reacting an appropriate carboxylic acid with amine (vi) in a suitable solvent such as DMF, with an appropriate coupling agent, such as HATU, in presence of a suitable base, such as DIEA. Intermediate (vii) is cyclized to form the l,3,8-triazaspiro[4.5]dec- 1-en -4-one core in presence of an appropriate oxidizing agent, such as H2O2, and a suitable base, such as NaOH, in an appropriate solvent, such as EtOH, DMSO or MeOH, at 80 °C.

[0105] Alternatively, the nitrile group of intermediate (vi) is first converted to the carbamoyl group under the aforementioned conditions for the formation of intermediate (vii) to give intermediate (xix). Intermediate (viii) is obtained by the sequential amidation (previously described) giving (xx) and cyclization conditions in the presence of a suitable base, such as PyO / Bu or Ko / Bu, in an appropriate solvent, such as / c / 7-butanol (“z-BuOH”) or EtOH, at 60 °C at least.

[0106] The removal of the protecting group moiety on the amine of amide (viii) is achieved under acidic conditions standard in the art. Intermediate amine (iii) is obtained by reacting a suitable acid, such as HC1 in 1,4-di oxane, in an appropriate solvent, such as DCM, for at least 4 h. The deprotected amine (iii) is reacted with a suitable heteroaryl halide under nucleophilic aromatic substitution conditions, in the presence of an appropriate base, such as CS2CO3, in an appropriate organic solvent, such as DMSO or DMF, at 80 °C for 18 h.

[0107] Alternatively, intermediate (i) is generated under Buchwald-Hartwig cross coupling conditions via a reaction of a suitable heteroaryl halide and amine (iii) in the presence of an appropriate catalyst system, such as tris(dibenzylideneacetone)dipalladium(0) (“Pd2(dba)3”) and 2’-dicyclohexylphosphino-2-(A,A-dimethylamino)biphenyl, in the presence of a suitable base, such as NaO / Bu, in an appropriate solvent, such as 1,4-di oxane, at 120 °C for 12 h.Scheme 4

[0108] Scheme 4 illustrates the preparations of biaryl intermediate (iv) beginning with a suitable phenyl bromide (ix). Under Suzuki coupling conditions, phenyl bromide (ix) and an appropriate heteroaryl boronic acid are reacted with a suitable palladium catalyst, such Pd(dppf)Ch.DCM, in the presence of a suitable base, such as K2CO3 or CS2CO3, in an appropriate solvent, such as 1,4- dioxane and H2O, at 80 °C at least.

[0109] A skilled artisan will appreciate that protecting groups employed in the preparation of the compounds of Formula I may be removed as necessary or desired at any convenient point in the synthesis.Scheme 5

[0110] Scheme 5 shows the preparation of intermediate (xvi), which is useful for the preparation of compounds of Formula I. The nitrile group of intermediate (vi) is first converted in the carbamoyl group using H2O2 and aq. NaOH in MeOH and DMSO to give (x). Amide (x, wherein “PG” is a protecting group such as Boc) is cyclized to (xi) using toluenesulfonic acid and 2,2- dimethoxypropane in an alcohol solvent such as EtOH at elevated temperature. Amine (xi) is coupled with halo-heteroaromatic intermediate (xii, wherein X is Br or Cl and X’ is I or Br) using a palladium catalyst such as methanesulfonato(2-bis(3,5- di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',6'-bis(dimethylamino)-l,r-biphenyl )(2'- methylamino-l,l'-biphenyl-2-yl)palladium(II) and a base such as sodium 2-methylbutan-2-olate in a solvent such as toluene at elevated temperature to give (xiii), which is then converted to amide-amine (xiv) using aq. HC1 in MeOH and water at elevated temperature. Amine (xiv) is then reacted with an acid R6-CO2H using amide coupling conditions such as HATU and DIEA in a solvent such as ACN to give amide (xv), which is then cyclized using a base such as potassium ter -butoxide in an alcohol solvent such as EtOH at elevated temperature to give (xvi).Scheme 6

[0111] Scheme 6 shows the preparation of intermediate (xviii), which is useful for the preparation of compounds of Formula (lb). An alcohol W-OH, wherein “W” is a C1-C10 alkyl group as defined in Formula (lb), is reacted with sodium hydride in an organic solvent such as THF, and then intermediate (xvii, wherein “X” is a halogen such as bromine) is added to the reaction which gives intermediate (xviii).Scheme 7

[0112] Scheme 7 shows the preparation of intermediates useful in the preparation of compounds disclosed herein. Y is as described in the scheme, PG is a protecting group such as -Boc, when Y is -CO2H, the intermediates shown here (xxii - xxvii) are analogous to R6-CC>2H which is used in Scheme 3 to prepare compounds of the present invention. Starting intermediate (xxi) is coupled with an aryl or heteroaryl boronic acid or ester using palladium cross-coupling conditions known to one skilled in the art, for example, using l,l’-bis(di- / -butylphosphino)ferrocene palladium di chloride, a carbonate base such as K2CO3, and an aqueous-orgnic solvent such as 1,4-di oxane in water at elevated temperature to give (xxii). Compound (xxi) can be coupled with bromocyclobutane using picolinimidamide hydrochloride, tetrabutylammonium iodide, nickel chloride, and zinc at elevated temperature to give (xxiii). Compound (xxi) can be coupled with either 1,4-di oxane-2-carboxylic acid or tetrahydrofuran-2-carboxylic acid to give (xxiv) or (xxv), respectively using 2-( / ert-butyl)-l,l,3,3-tetramethylguanidine, (4,4'-di- / -butyl-2,2'- bipyridine)bis[3, 5-difluoro-2-(5-tri fluoromethyl -2 -pyridinyl-K?V)phenyl-KC]iridium(III) hexafluorophosphate, and [4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine] nickel (II) dichloride under irradiation with 395 nm light at elevated temperature in a solvent such as DMF.Compound (xxi) can be coupled with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane using a palladium catalyst such as Pd(dppf)C12, a carbonate base such as K2CO3, in an aqueous-organic solvent mixture such as 1,4-di oxane in water at elevated temperature. The product of the coupling is then reduced using hydrogen gas and a palladium on carbon catalyst in a solvent such as EtOAc at elevated temperature to give (xxvi). Compound (xxi) can be coupled with cyclopropylboronic acid, a palladium catalyst such as palladium diacetate with tri cyclohexylphosphine, a base such as K3PO4 in a solvent mixture such as toluene and water at elevated temperature to give (xxvii).Scheme 8

[0113] Scheme 8 shows the perparation of intermediates useful in the preparation of compounds disclosed herein. Aldehyde (xxviii) is reacted with methyltriphenylphosphonium bromide which is pre-treated with n-butyllithium in a THF mixture at -78 °C, giving (xxix) which is then reacted with N-methylmorpholine-N-oxide and potassium osmate(VI) in / c / 7-butanol and water to give (xxx). Alternatively, this reaction can be accomplished asymmetrically using AD-mix-alpha and AD-mix-beta. Aldehyde (xxviii) is reacted with an alkylmagnesium bromide go give (xxxi), which is then treated with NaH and reacted with iodomethane to give (xxxii). Reaction of trimethyl silyl cyanide with (xxxii) using ferric chloride gives (xxxiii), which is then converted to amide (xxxiv) using H2O2 and K2CO3. Aldehyde (xxviii) is converted to (xxxv) using NaCN in water. Amide (xxxvi) is prepared from (xxxv) using concentrated aq. HC1 and HC1 in 1,4- di oxane, and then is hydrolyzed to give (xxxvii) using water and HC1 in 1,4-di oxane at elevated temperature. Esterification of (xxxv) with HC1 in MeOH at elevated temperature gives (xl), which is then converted to mesylate (xli) using methanesulfonyl chloride and TEA in DCM. MeOH is treated with NaH and then reacted with mesylate (xli) to give (xxxviii), which is then converted to (xxxix) using HATU, DIEA, and NH4CI in DMF. In a similar manner, (xli) is converted to (xlii) and then (xliii).Scheme 9

[0114] Scheme 9 shows the preparation of intermediates useful in the preparation of compounds disclosed herein. Nitrile (xliv) is reduced with BH3 in THF, then coupling with alkyl carboxylic acids using conditions well-known to one skilled in the art, or reaction with acetic anhydride and TEA in DCM gives (xlvi).Scheme 10

[0115] Scheme 10 shows the preparation of intermediates useful in the preparation of compounds disclosed herein. Alcohol (xlvii) is converted to the chloride (xlviii) using SOC12 in DMF at 0 °C, which is then reacted with thiourea in EtOH at elevated temperature to give (xlix). Compound (xlix) is converted to sulfonyl chloride (1) using N-chlorosuccinimide and aq. HC1 in ACN, which is then reacted with aq. ammonia in acetone to give (li). Chloride (xlviii) is reacted with KCN in DMSO to give (lii). Nitrile (lii) is treated with LiHMDS in THF at -78 °C and then reacted with an alkyl halide to give (liii). Compounds (lii) and (liii) are converted to amides (liv) and (Iv) respectively using H2O2 and K2CO3 in aq. DMSO.Scheme 11

[0116] Scheme 11 shows the preparation of intermediates useful in the preparation of compounds disclosed herein. Bromide (Ivi) is reacted with ammonium phosphinate and HMDSto give (Ivii), which is then treated with HMDS at elevated temperature followed by iodopropane to give (Iviii). Compound (Iviii) is then treated with oxalyl chloride and DMF in DCM followed by aq. ammonia to give (lix).Scheme 12

[0117] Scheme 12 shows the preparation of intermediates useful in the preparation of compounds disclosed herein. Aldehyde (lx) is reacted with malonic acid and piperidine at elevated temperature in pyridine to give (Ixi), followed by debenzylation and olefin reduction using palladium on carbon and hydrogen gas at elevated temperature to give (Ixii). Acid (Ixii) is coupled with ammonia in MeOH using oxalyl chloride in DMF, then phenyl triflimide and TEA in DCM gives triflate (Ixiv).Scheme 13

[0118] Scheme 13 shows the preparation of intermediates useful in the preparation of compounds disclosed herein. Halide (Ixv) is coupled with morpholin-3-one using K2CO3, racemic (lR,2R)-Nl,N2-dimethylcyclohexane-l,2-diamine and cuprous iodide at elevated temperature to give (Ixvi). Halide (Ixv) is reacted with diethyl malonate, CS2CO3, picolinic acid, and cuprous iodide at elevated temperature to give (Ixvii), which is then reduced with diisobutylaluminum hydride in diisopropyl ether to give (Ixviii). Halide (Ixv) is reacted with ethyl 3-oxobutanoate, K3PO4, and cuprous iodide in EtOH at elevated temperature to give (Ixix), which is then coupled with amines (HNRaRb) using conditions well known to the skilled artisan such as HATU and DIEA in a solvent such as DMF to give (Ixx).Scheme 14

[0119] Scheme 14 shows the preparation of intermediates useful in the preparation of compounds disclosed herein. Compound (Ixxi) is coupled with 2-(( / c / 7-butyldimethylsilyl)oxy)- N-(2,4-dimethoxybenzyl)ethan-l -amine using conditions well known to the skilled artisan such as HATU and DIEA in a solvent such as DMF to give (Ixxii), which is converted to mesylate (Ixxiii) using methanesulfonic anhydride and TEA in a solvent such as DCM. Compound (Ixxiii) is cyclized using TBAF in THF, and then the 2,4-dimethoxybenzyl group is removed using TFA in DCM at elevated temperature to give (Ixxv).Scheme 15

[0120] Scheme 15 shows the preparation of intermediates useful in the preparation of compounds disclosed herein. Mesylate (xli) is reacted with methyl 2-cyanoacetate using sodium methoxide in MeOH at elevated temperature to give (Ixxvi), which is then reduced with NaBIE and nickel ous chloride in the presence of BOC2O in MeOH to give (Ixxvii). Boc group removal with HC1 in 1,4-di oxane and DCM gives (Ixxviii), which is then cyclized to (Ixxix) using 1,8- diazabicyclo[5.4.0]undec-7-ene in ACN at elevated temperature. Ester (Ixxix) is reduced to (Ixxx) using LiBH4 in THF, then oxidation using Dess-Martin periodinane in DCM gives the aldehyde (Ixxxi). Reductive amination with dimethylamine, acetic acid, and sodium cyanoborohydride in MeOH / THF gives (Ixxxii).PREPARATIONSPreparation of Intermediate 1Zi V-Butyl (2S)-4-amino-4-cyano-2-methylpiperidine-l -carboxylate (mixture of diastereomers)

[0121] NELOac (11.0 g, 140 mmol) was added to a stirred solution of terz-butyl (S)-2-methyl-4- oxopiperidine-l-carboxylate (20 g, 94 mmol) and KCN (9.2 g, 140 mmol) in EtOH (31 L) and stirred at 80 °C. After 48 h, the reaction mixture was diluted with NazCCh sat. aq. solution (300 mL) and was extracted with EtOAc (3 x 150 mL). The organic extracts were then washed with H2O (100 mL) and NaCl sat. aq. solution (50 mL). The organic extracts were then filtered through MgSCU and the solution was concentrated to afford a mixture of diastereomers of the title compound.Preparation of Intermediate 2 terZ-Butyl (2S)-4-cyano-2-methyl-4-(2-(trifluoromethoxy)benzamido)piperidine-l -carboxylate (mixture of diastereomers)

[0122] 2-(Trifluoromethoxy)benzoyl chloride (17.65 mL, 112.8 mmol) was added to a solution of tert-butyl (2S)-4-amino-4-cyano-2-methylpiperidine-l-carboxylate (mixture of diastereomers, 27.00 g, 112.8 mmol) Na2CO3 (23.92 g, 225.6 mmol) and NaHCCh sat aq. solution (564.1 mL, 0.2 M) in DCM (564 mL) and stirred at RT. After 4 h, the reaction mixture was diluted with H2O (1000 mL) and extracted with EtOAc (3 x 500 mL). The organic extracts were washed with water (1 L) then NaCl sat. aq. solution (500 mL). The organic layers were passed through a Na2SO4 column and concentrated to afford the title compound. ES-MS (m / z) 428 (M+H).Preparation of Intermediate 3 ter / -Butyl (7S)-7-methyl-4-oxo-2-(2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-2-ene- 8-carboxylate (mixture of diastereomers)

[0123] H2O2 (63 mb, 50% Wt, 1000 mmol) was added slowly to a vigorously stirred solution of a mixture of diastereomers of / / V-butyl (2S)-4-cyano-2-methyl-4-(4-(trifluoromethoxy) benzamido) piperidine- 1 -carboxylate (48.22 g, 112.8 mmol) and NaOH (270 mL, 5 M, 1354 mmol) in EtOH (564 mL) at 80 °C. After 16 h, the reaction mixture was diluted with 500 mL of NH4CI sat. aq. solution and 30 mL of Na2S2CL aq. solution. The mixture was extracted with 3 x 200 mL of DCM. The organic extracts were passed through a Na2SC>4 column and concentrated. The resulting residue was dissolved in EtOAc (1000 mL) and passed through a pad of silica gel (100 g), washed with EtOAc (2 x 250 mL) and DCM (3 x 250 mL). The resulting solution was concentrated to afford 4: 1 d.r. of the title compound (32.40 g). ES-MS (m / z) 428 (M+H).Preparation of Intermediates 4 and 5 tert-Butyl (2S,4S)-4-amino-4-carbamoyl-2-methylpiperidine-l -carboxylate (Intermediate 4) and tert-butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-l-carboxylate (Intermediate 5)

[0124] NaOH (20.5 mL, 5.00 M, 102.5 mmol) was added to a solution of a mixture of diastereomers of tert-butyl (2S)-4-amino-4-cyano-2-methylpiperidine-l-carboxylate (22.72 g, 94.94 mmol) in MeOH (180 mL) and DMSO (1 1 mL) at 10 °C and stirred. After 5 min, H2O2 (10.5 mL, 35.5% Wt, 123.4 mmol) was slowly added over 15 min. After 1 h, Na2S20.3 sat. aq. solution (720 mL) was added and diluted with H2O (500 mL) and was extracted with DCM (3 x 100 mL). The organic layers were separated. All organic layers were combined and washed with NaCl sat. aq. solution (100 mL). The organic layers were dried over Na2SC>4, fdtered, and concentrated. The residue was purified by silica gel chromatography (20-100% of a mixture of DCM and MeOH (9: 1) in DCM) to give the first eluting isomer (Intermediate 4) as a solid and the second eluting isomer (Intermediate 5) as a solid. Both isomers: ES-MS (m / z) 258 (M+H).Preparation of Intermediate 6 tert-Butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2-(trifluoromethoxy)benzamido)piperidine-l- carboxylate

[0125] A solution of 2-(trifluoromethoxy) benzoyl chloride (7.59 g, 33.8 mmol) in DCM (30 mL) was added to a stirred solution of Zc / 7 -butyl (2S,4R)-4-amino-4-carbamoyl-2- methylpiperidine-1 -carboxylate (9.13 g, 35.5 mmol) in DCM (300 mL) and TEA (14.1 mL, 101 mmol) and was stirred. After 6 h, the reaction mixture was diluted with 2% citric acid aq. solution (300 mL) and heptane (300 mL) and stirred vigorously. After 30 min, a precipitate was collected by filtration and the resulting cake was rinsed with a mixture of each H2O (100 mL) and 1 :2 DCM / heptane (1 :2), water (150mL), heptane (150mL). The resulting solid was dried in vacuo overnight (1 kPa, 50 °C) to give the title compound. ES-MS (>» ") 346 (M-Boc).Preparation of Intermediate 7 tert-Butyl (5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l- ene-8-carboxylate

[0126] Potassium 2-methylpropan-2-olate 1 M in Z-BuOH (77.5 mL, 77.5 mmol) was added dropwise to a suspension of tert-butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2-(trifluoromethoxy) benzamido)piperidine-l -carboxylate (11.5 g, 25.8 mmol) in EtOH (152 mL) and stirred at 60 °C. After 30 min, the solvent was removed. The residue was diluted with EtOAc and a 5% citric acid aq. solution. The aq. layer was separated, and organic layer was washed with H2O andNaCl sat. aq. solution, dried over anhydrous Na2SO4, filtered and the solvent was removed in vacuo to afford a solid. The resulting solid was dried in vacuo at 35-40 °C to give the title compound. ES-MS (m / z) 428 (M+H).Preparation of Intermediate 8 / cvz-Butyl 4-oxo-2-(2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate

[0127] 2-(Trifluoromethoxy) benzoyl chloride (2.00 g, 8.60 mmol) was added to a solution of terLbutyl 4-amino-4-carbamoylpiperidine-l -carboxylate (2.00 g, 7.80 mmol) and TEA (3.30 mL, 23.0 mmol) in THF (50 mL) at 0 °C and the mixture was stirred at 20 °C for 2 h. 2- Methylpropan-2-olate pyridine (4.50 g, 39.0 mmol) in / -BuOH (30 mL) was added and the mixture was stirred at 70 °C. After 3 h, the reaction mixture was diluted with H2O (150 mL) and extracted by EtOAc (3 x 45 mL). The combined organic layers were washed with NaCl sat. aq. solution (50 mL), dried over ISfeSCU, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-50% EtOAc in petroleum ether) to give the title compound as an oil. ES-MS (m / z) 414 (M+H).Preparation of Intermediate 9Zc / 7-Butyl (5R,7S)-7-methyl-4-oxo-2-(2-(thiophen-2-yl)phenyl)-l,3,8-triazaspiro[4.5]dec-l-ene- 8 -carb oxy late

[0128] DIEA (0.78 mL, 4.50 mmol) was added to a solution of 2-(thien-2-yl) benzoic acid (0.20 g, 0.10 mmol), ZcvZ-butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-l -carboxylate (0.26 g, 1.01 mmol) and HATU (0.47 g, 1.24 mmol) in DMF (4.0 mL). The resulting solution was stirred at RT. After 2 h, the reaction mixture was diluted with 50 mL of EtOAc, washed withH2O (20 mL), NaCl sat. aq. solution (20 mL), dried over anhydrous MgSCL, filtered, and concentrated under reduce pressure. To the residue was added EtOH (10 mL) and potassium 2- methylpropan-2-olate (0.33 g, 3.00 mmol) at RT and the mixture was heated 60 °C with stirring. After 18 h, the reaction mixture was diluted with 50 mL of EtOAc, washed with H2O (30 mL) and NaCl sat. aq. solution (30 mL), dried over anhydrous MgSCE, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-60% EtOAc in cyclohexane) to give the title compound as a foam. ES-MS (m / z) 426 (M+H).

[0129] Intermediate 10 in the following table was prepared essentially as described inPreparation of Intermediate 9 using the appropriate benzoic acid.Preparation of Intermediate 11Zc / 7-Butyl (2S)-4-(2-bromo-4-(trifluoromethoxy)benzamido)-4-cyano-2-methylpiperidine-l- carboxylate (mixture of diastereomers)

[0130] Thionyl chloride (1.79 mL, 24.6 mmol) was slowly added to a solution of 2-bromo-4- (trifluoromethoxy) benzoic acid (6.67 g, 23.4 mmol) in DCM (117 mL) and stirred at RT. After 2 h, the reaction was concentrated in vacuo and the residue was added in slowly to a solution of / c / 7-butyl (2S)-4-amino-4-cyano-2-methylpiperidine-l -carboxylate (mixture of diastereomers, 5.60 g, 23.4 mmol), Na2CCh (4.96 g, 46.8 mmol) and NaHCCh sat. aq. solution (117 mL) in DCM (117 mL) and stirred at RT. After 2.5 h, the reaction was diluted with H2O (100 mL) and extracted with DCM (3 x 50 mL). The organics were dried with anhydrous Na2SO4 and concentrated in vacuo to give the title compound. ES-MS (m / z) 504,506 (M-H).Preparation of Intermediate 12 tert-butyl (5R,7S)-2-(2-bromo-4-(trifluoromethoxy)phenyl)-7-methyl-4-oxo-l,3,8- triazaspiro[4.5]dec-l-ene-8-carboxylate

[0131] To a solution of 2-bromo-4-(trifluoromethoxy)benzoic acid (7.00 g, 23.3 mmol) in DCM (100 mL) was added DMF (192 pL, 2.35 mmol) and oxalyl chloride (6.25 g, 4.33 mL, 46.8 mmol). The reaction was stirred at 20 °C for 1 h, then concentrated. To the residue was added THF (200 mL), Et3N (6.80 g, 9.37 mL, 65.9 mmol), and tert-butyl (2S,4R)-4-amino-4- carbamoyl-2-methylpiperidine-l-carboxylate (6.21 g, 24.1 mmol). The mixture was stirred at RT for 2 h, then KotBu (1.0 M in THF, 8.32 mL, 72.2 mmol) was added at 10 °C. The mixture was stirred at 70 °C for 16 h, then extracted with EtOAc (3 x 50 mL) and water (50 mL). The organics were dried over Na2SO4, fdtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in petroleum ether to give the title compound as a solid. ‘H-NMR (400 MHz, DMSO-6) 8 11.23 (br s, 1H), 7.89 (d, J= 1.3 Hz, 1H), 7.74 (d, J= 8.6 Hz, 1H), 7.59 (br d, J= 8.4 Hz, 1H), 4.10 - 3.98 (m, 1H), 3.73 (td, J= 4.7, 13.4 Hz, 1H), 3.39 - 3.32 (m, 1H), 1.85 - 1.76 (m, 1H), 1.75 - 1.61 (m, 3H), 1.40 (s, 9H), 1.24 (d, J= 6.5 Hz, 3H).Preparation of Intermediate 13 tert-Butyl (7S)-2-(2-bromo-4-(trifluoromethoxy)phenyl)-7-methyl-4-oxo-l,3,8- triazaspiro[4.5]dec-l-ene-8-carboxylate (mixture of diastereomers)

[0132] H2O2 (13 mL, 210 mmol) was added slowly to a strongly stirring mixture of tert-butyl (2S)-4-(2-bromo-4-(trifluoromethoxy)benzamido)-4-cyano-2-methylpiperidine-l-carboxylate (mixture of diastereomers, 11.8 g, 23.3 mmol), NaOH (55.9 mL, 5 M, 280 mmol), and EtOH(117 mL) at 80 °C. The reaction was stirred at 80 °C for 48 h. The reaction mixture was diluted with NH4CI sat. aq. solution and ^28263 aq. solution (10%). The mixture was then extracted with DCM and the organic extracts were passed through a Na2SC>4 column and concentrated. The residue was Purified by silica gel chromatography (0-43% EtOAc in heptane) to give the title compound. ES-MS (m / z) 508 (M+H).Preparation of Intermediate 14Z / V-Butyl (7S)-7-methyl-4-oxo-2-(5-(trifluoromethoxy)-[ 1,1 ’-biphenyl]-2-yl)- 1,3,8- triazaspiro[4.5]dec-l-ene-8-carboxylate (mixture of diastereomers)

[0133] A mixture of phenyl boronic acid pinacol ester (0.40 g, 1.98 mmol), terz-butyl (7S)-2-(2- bromo-4-(trifluoromethoxy)phenyl)-7-m ethyl -4-oxo- 1 ,3 ,8-triazaspiro[4.5]dec- 1 -ene-8- carboxylate (mixture of diastereomers, 0.50 g, 0.98 mmol), 1, 1 ’-bis(di-Z- butylphosphino)ferrocene palladium dichloride (0.129 g, 0.19 mmol), K2CO3 (0.41 g, 2.96 mmol) in 1,4-dioxane (4.49 mL), and H2O (0.50 mL) were sparged with N2 for 5 min and then stirred and heated to 80 °C. After 16 h, the reaction was filtered over diatomaceous earth and then concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc in heptane) to afford the title compound. ES-MS (m / z) 504 (M+H).

[0134] Intermediates 15-17 in the following table were prepared essentially as described in the Preparation of Intermediate 14 by using the appropriate aryl bromide and boronic acid, and cesium carbonate as a base instead of potassium carbonate.Preparation of Intermediate 18 (7S)-7-Methyl-2-(5-(trifluoromethoxy)-[l,r-biphenyl]-2-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-

[0135] HC1 in 1,4-dioxane (4 M, 0.69 mL) was added to a solution of Z / V-butyl (7S)-7-methyl-4- oxo-2-(5-(trifluoromethoxy)-[l,l’-biphenyl]-2-yl)-l,3,8-triazaspiro [4.5]dec-l-ene-8-carboxylate (mixture of diastereomers, 0.28 g, 0.99 mmol) in DCM (5.50 mL) and stirred at 23 °C. After 18 h, the suspension was filtered and solid was washed with EtOAc. The residue was dissolved in MeOH and slowly passed through an SCX cartridge (5g, previously washed with MeOH). The cartridge was washed with MeOH, and a product was eluted with around 2N NH3 in MeOH, which was concentrated in vacuo to give the title compound. ES-MS (m / z) 404 (M+H).Preparation of Intermediate 19 (5R,7S)-7-Methyl-2-(2-(tri fluoromethoxy )phenyl)-l, 3, 8-triazaspiro[4.5]dec-l-en-4-one hydrochloride

[0136] HC1 in 1,4-dioxane (29.5 mL, 4 M, 118 mmol) was added dropwise to a solution of tertbutyl (5R,7S)-7-methyl-4-oxo-2-(2-(trifluorom ethoxy) phenyl)-!, 3, 8-triazaspiro [4.5]dec-l-ene- 8-carboxylate (11.2 g, 26.2 mmol) in DCM (87 mL) and stirred. After 4 h, the resulting solid was filtered, washed with DCM, dried in vacuo at 30-35 °C for 14 h to give the title compound as a solid. ES-MS (m / z) 328 (M+H).Preparation of Intermediate 202-(2-(Trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one hydrochloride

[0137] HC1 in 1,4-dioxane (10 mL, 4 M, 26 mmol) was added to a solution of tert-butyl 4-oxo-2- (2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (1.40 g, 2.8 mmol) in DCM (10 mL) at 20 °C and the mixture was stirred. After 2 h, the reaction mixture was concentrated under reduced pressure to give the title compound. ES-MS (m / z) 314 (M+H).

[0138] Intermediates 21-25 in the following table were prepared essentially as described in the Preparation of Intermediate 20 using the appropriate Boc-protected amine.a. Compound was isolated by an extraction from a sat. aq. NaHCCh solution with 3 : 1CHCh / isopropanol .Preparation of Intermediate 264-Acetamido-2-formyl-6-methylphenyl trifluoromethanesulfonate

[0139] Trifluoromethanesulfonic anhydride (1.54 mL, 8.65 mmol) was added to a solution ofN- (3-formyl-4-hydroxy-5-methylphenyl) acetamide (prepared essentially as described in Taily, I.M.; et al. OrgLett. 2022, 24(12), 2310-2314; 1.90 g, 8.26 mmol), and Et3N (3.48 mL, 23.8 mmol) in DCM (19 mL) and the mixture was stirred at -40 °C. After 1 h, the reaction mixture was diluted with H2O (20 mL) and extracted with DCM (3 x 10 mL). The organic layers were combined, dried over Na2SC>4 filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% EtOAc in petroleum ether @ 60 mL / min) to give the title compound. ES-MS (m z) 326 (M+H).Preparation of Intermediate 274-Acetamido-2-(difluoromethyl)-6-methylphenyl trifluoromethanesulfonate

[0140] Diethylaminosulfur trifluoride (0.141 mL, 1.04 mmol) was added to a solution of 4- acetamido-2-formyl-6-methylphenyl trifluoromethanesulfonate (0.30 g, 0.61 mmol) in DCM (3 mL) and the mixture was stirred at 25 °C. After 12 h, the mixture was quenched with Nal ICO3 (3 mL). The product was extracted with DCM (3 x 3 mL). The organic layers were combined, washed with NaCl sat. aq. solution (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (30% EtOAc in petroleum ether) to give the title compound. ES-MS (zw / z) 348 (M+H).Preparation of Intermediate 28 4-(4-Bromo-3,5-dimethylphenyl)morpholin-3-one

[0141] To a mixture of 2,6-dimethyl-4-iodobromobenzene (14.97 g, 48.14 mmol) in 1,4-dioxane (0.12 L) was added morpholin-3-one (5.14 g, 50.8 mmol), K2CO3 (20.31 g, 147.0 mmol), racemic (lR,2R)-Nl,N2-dimethylcyclohexane-l,2-diamine (5.45 g, 38.3 mmol), and cuprous iodide (1.86 g, 9.77 mmol). The mixture was purged with nitrogen and heated to 110 °C for 2 days, then diluted with EtOAc (0.3 L) and 5% aq. NH4OH (0.3 L). The layers were separated and the organics were washed successively with 0.1 L of each of 5% aq. NH4OH and water, then 1 M aq. KH2PO4 (2x50 mL) and sat. aq. NaCl (50 mL). The organics were dried over MgSO4, filtered, then concentrated to a volume of 0.1 L. Heptane (0.4 L) was then added slowly and the mixture was stirred at RT for 1 h. The solids were filtered and washed with 1 :4 EtOAc / heptane (50 mL) and heptane (50 mL). The filtrate and wash were concentrated and the residue was triturated with 1 :9 EtOAc / heptane (0.1 L). A second crop of solid was collected after 1 h, washed with 1 :9 EtOAc / heptane (25 mL), then heptane (25 mL). The first and second crops of the solid were combined to give the title compound. ES-MS m / 'z 284,286 (M+H).Preparation of Intermediate 294-(4-(2-Fluoropyridin-4-yl)-3,5-dimethylphenyl)morpholin-3-one

[0142] [Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (“PdC12(dppf)-DCM”) (0.07g, 0.08 mmol) was added to a stirred solution of 4-(4-bromo-3,5- dimethylphenyl)morpholin-3-one (0.50 g, 1.76 mmol), pyridine 2-fluoro-4-boronic acid (0.37 g, 2.64 mmol) and K2CO3 (0.48 g, 3.52 mmol) in 1,4-dioxane (16 mb) and H2O (1.6 mL) and the mixture was stirred at 100 °C. After 18 h, the reaction mixture was cooled to RT, anhydrous Na2SC>4 was added, and the mixture was filtered through diatomaceous earth. The filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-20% EtOAc in DCM) to give the title compound as a solid. ES-MS (zra / z) 301 (M+H).Preparation of Intermediate 30 4-(2-Chloropyridin-4-yl)-3,5-dimethylaniline

[0143] 1,4-Dioxane (5.3 mL) and H2O (1.1 mL) were added to a vial containing (2-chloro-4- pyridinyl)boronic acid (0.30 g, 1.89 mmol) and 4-bromo-3,5-dimethylbenzenamine (0.25 g, 1.27 mmol). CS2CO3 (1.28 g, 3.96 mmol) and PdC12(dppf -DCM adduct (0.21 g, 0.25 mmol) were added to the mixture, the vial was sealed and stirred at 80 °C. After 18 h, the reaction mixture was filtered over diatomaceous earth and concentrated. The residue was diluted with DCM (50 mL) and washed with NaHCCL aq. sat. solution (3 x 25 mL), H2O, NaCl sat. aq. solution, dried over MgSCL, filtered, and dried to give the title compound. ES-MS (m / z) 233 (M+H)Preparation of Intermediate 31A-(4-(2-Chloropyridin-4-yl)-3,5-dimethylphenyl)acetamide

[0144] Acetic anhydride (0.25 mL, 2.65 mmol) was added dropwise to a solution of 4-(2- chloropyridin-4-yl)-3,5-dimethylaniline (0.29 g, 1.27 mmol) in DCM (6.4 mL) at 0 °C and stirred. After the addition was complete, the reaction mixture was left to stir at RT. After 3 h, the reaction mixture was diluted with DCM (50 mL) and washed sequentially with NaHCCL sat. aq. solution, H2O, and NaCl sat. aq. solution, and dried over lSfeSCU, filtered, dried over diatomaceous earth pad, concentrated in vacuo and purified by flash silica gel chromatography (0-40% (3 : 1 EtOAc / EtOH) in heptane) to give the title compound. ES-MS (m z) 275 (M+H).Preparation of Intermediate 324-(3,5-Dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)morpholin-3-one

[0145] A mixture of 4-(4-bromo-3,5-dimethylphenyl)morpholin-3-one (5.03 g, 16.2 mmol) in 1,4-dioxane (100 mL) was added to bis(pinacolato)diborane (5.65 g, 21.1 mmol), CS2CO3 (8.67 g, 25.3 mmol), tris(4-methoxyphenyl)-phosphine (0.64 g, 1.74 mmol) and palladium acetate (“Pd(Oac)2”) (0.39 g, 1.68 mmol) and was stirred at 130 °C for 3 h. The reaction mixture was filtered, washed with 1,4-dioxane and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% EtOAc in petroleum ether), then by reverse-phase HPLC using a gradient of 0-30% EtOH. The residue was further purified by preparative HPLC [column: Welch Ultimate® XB-CN 250 x 50 mm, 10 pm; mobile phase: 0-30% EtOH / heptane; Flowrate: 130 mL / min] to give the title compound as a solid. ES-MS ( / w z) 332 (M+H).Preparation of Intermediate 338-(4-Iodopyridin-2-yl)-2-(2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of diastereomers)

[0146] 2-Fluoro-4-iodopyridine (0.30 g, 1.0 mmol) was added to a solution of 2-(2- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of diastereomers, 0.30 g, 0.90 mmol) and CS2CO3 (0.60 g, 2.0 mmol) in DMF (6 mb) and the mixture was stirred at 80 °C. After 12 h, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over Na2SC>4. fdtered and concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (10-50% EtOAc in petroleum ether) to give the title compound as a solid. ES-MS (m / z) 517 (M+H).

[0147] Intermediates 34-37 in the following table were prepared essentially as described in the Preparation of Intermediate 33 by using the appropriate amine and fluoride.Preparation of Intermediate 38(5R, 7S)-8-(5-Chlorothiazol-2-yl)-7-methyl-2-(2-(trifluorornethoxy)phenyl)- 1,3,8- triazaspiro[4.5]dec- 1 -en-4-one

[0148] 2’-Dicyclohexylphosphino-2-(Af,.V-dimethylamino)biphenyl (0.12 g, 0.31 mmol), sodium 2-methylpropan-2-olate (0.75 g, 7.64 mmol) and Pd2(dba)s (0.143 g, 0.153 mmol) were added to a solution of (5R,7S)-7-methyl-2-(2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4- one (0.50 g, 1.53 mmol) and 2-bromo-5-chlorothiazole (0.371 g, 1.83 mmol) in 1,4-dioxane (10 mL) and the mixture was stirred at 120 °C. After 16 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% EtOAc in petroleum ether) to give the title compound. ES-MS (m / z) 445 (M+H).Preparation of Intermediate 39 (5R,7S)-8-(4-Bromopyridin-2-yl)-7-methyl-2-(2-(tri fluoromethoxy )phenyl)-l, 3,8- triazaspiro[4.5]dec- 1 -en-4-one

[0149] 4-Bromo-2-fluoropyridine (0.29 g, 1.57 mmol) was added to a solution of (5R,7S)-7- methyl-2-(2-(trifluoromethoxy) phenyl)-!, 3, 8-triazaspiro[4.5]dec-l-en-4-one (0.40 g, 1.21 mmol) and CS2CO3 (0.80 g, 2.42 mmol) in DMSO (4 mL) and the mixture was stirred at 80 °C. After 12 h, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 - 5 mL). The organic layers were combined, dried over Na2SO4 filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% EtOAc in petroleum ether) to give the title compound as an oil. ES-MS (m / z') 483,485 (M+H).

[0150] Intermediate 40 in the following table was prepared essentially as described in Preparation of Intermediate 39 by using the appropriate 2-fluoropyridine.Preparation of Intermediate 41 (2-((5R,7S)-7-Methyl-4-oxo-2-(2-(tri fluoromethoxy )phenyl)- 1,3, 8-triazaspiro[4.5]dec-l-en-8- yl)pyridin-4-yl)boronic acid

[0151] PdCh dppf) (0.025 g, 0.032 mmol) was added to a solution of (5R,7S)-8-(4- bromopyridin-2-yl)-7-methyl-2-(2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4- one (0.18 g, 0.32 mmol) and bis(pinacolato)diborane (0.11 g, 0.42 mmol) and KO Ac (0.065 g, 0.65 mmol) in 1,4-dioxane (2 mL) and the mixture was stirred at 80 °C. After 12 h, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% MeOH in DCM) to give the title compound as an oil. ES-MS (m / z) 449 (M+H).Preparation of Intermediate 42(5R,7S)-7-Methyl-8-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)-2-(2-(trifluoromethoxy)phenyl )- 1 ,3 , 8-triazaspiro[4.5] dec- 1 -en-4-one

[0152] Dichloro(l,r-bis(diphenylphosphino)ferrocene)palladium(II) (0.032 g, 0.040 mmol) was added to a solution of (5R,7S)-8-(4-iodopyridin-2-yl)-7-methyl-2-(2-(trifluoromethoxy)phenyl)- l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.218 g, 0.41 mmol), 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi- 1,3,2-dioxaborolane (0.16 g, 0.64 mmol) and KOAc (0.14 g, 1.42 mmol) in 1,4-dioxane (4 mb) and stirred at 90 °C. After 2 h, the reaction mixture was cooled to RT, diluted with H2O and extracted with EtOAc. The organic layers were combined, washed with NaCl sat. aq. solution, dried over MgSO4, filtered, and concentrated to obtain the title compound as a solid. ES-MS (m / z) 449 (M+H).Preparation of Intermediate 43(5R,7S)-8-(4-(4-Amino-2-chlorophenyl)pyridin-2-yl)-7-methyl-2-(2-(trifluoromethoxy)phenyl)-1 ,3 , 8-tri azaspiro [4.5 ]dec- 1 -en -4-one

[0153] PdC12(dppf)-DCM (0.008 g, 0.010 mmol) was added to a solution of (5R,7S)-8-(4- iodopyridin-2-yl)-7-methyl-2-(2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.052 g, 0.098 mmol), 3-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.037 g, 0.15 mmol) and CS2CO3 (0.11 g, 0.33 mmol) in l,4-dioxane / H2O (3: 1) (1.0 mL) and stirred at 90 °C. After 1 h, the reaction mixture was diluted with water and EtOAc, and extracted with EtOAc, then the combined organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure to give the title compound. ES-MS (m / z) 530 (M+2H).Preparation of Intermediate 442-(4-Bromo-3,5-dimethylphenyl)-2-hydroxyacetonitrile (racemic mixture)

[0154] NaCN (11.4 g, 229.8 mmol) was added to a solution of 4-bromo-3,5- dimethylbenzaldehyde (20.0 g, 92.0 mmol) in water (100 mL) and stirred at 20 °C. Then, a solution of NaHSO3(22.0 g, 210.0 mol) in water (100 mL) was added to the reaction mixture at 0 °C and stirred at 20 °C. After 15 h, the mixture was filtered, washed with water (3 * 100 mL) to give the title compound (26 g, 85 wt% purity) as a solid. TLC (2: 1 petroleum ether : EtOAc) R / = 0.25.Preparation of Intermediate 45 2-(4-Bromo-3,5-dimethylphenyl)-2-hydroxyacetamide (racemic mixture)

[0155] Concentrated aq. HC1 (30 mL, 36 mmol) was added dropwise to a solution of 2-(4- bromo-3,5-dimethylphenyl)-2-hydroxyacetonitrile (racemic mixture, 85 wt% purity, 10.0 g, 35.0 mmol) in HC1 (4.0 M in 1,4-dioxane, 50 mL) with vigorous stirring at 0 °C and stirred at 20 °C. After 2 h, the reaction mixture was neutralized with aq. Na2COa to pH=7, then diluted with water (30 mL) and DCM (100 mL) and stirred. After 30 min, the mixture was filtered and the solid was triturated with ACN (50 mL) and filtered to give 4.6 g of the title compound as a solid. ES-MS (m / z) 258, 260 (M+H).Preparation of Intermediate 46: (5R,7S)-2,2,7-Trimethyl-l,3,8-triazaspiro[4.5]decan-4-one dihydrochloride

[0156] To a mixture of tert-butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-l- carboxylate (60.0 g, 233 mmol) dissolved in EtOH (1000 mL) was added 2,2-dimethoxypropane (74.4 g, 700 mmol) and toluenesulfonic acid (9.06 g, 46.7 mmol) and the mixture was heated at 80 °C. After 16 h, the reaction was cooled to RT and HCI (4 M solution in 1,4-dioxane, 176 mL, 704 mmol) was added. The mixture was stirred at 20 °C for 16 h, and the solvent was removed under reduced pressure. After 2 / 3 of the liquid was removed from the flask a solid precipitatewas formed in the solution. 1000 mL of EtOAc was added and more material precipitated. The solid was filtered off and dried for 30 min to give the title compound (65 g) as a solid. ES-MS m / z' 198 (M+H).Preparation of Intermediate 47: 4-(3,6-Dihydro-2H-pyran-4-yl)-6-(trifluoromethyl)nicotinic acid

[0157] l,T-Bis(di- / -butylphosphino)ferrocene palladium dichloride (0.24 g, 0.37 mmol) was added to a suspension of 4-bromo-6-(trifluoromethyl)nicotinic acid (0.50 g, 1.85 mmol), 2-(3,6- dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.58 g, 2.78 mmol), and K2CO3 (1.28 g, 9.26 mmol) in 1,4-dioxane (3 mb) and water (1 mb). The reaction mixture was sparged with N2 for 30 seconds and stirred at 80 °C for 16 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (20 mL) and rinsed with sat. aq. Na2CO3 (4 x 5 mL). The aqueous solution was neutralized with 1 M HC1 and 10 wt% citric acid, then extracted with EtOAc (4 x 10 mL). The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (0.51 g). ES-MS m^z 274 (M+H).Preparation of Intermediate 48: 4-(Tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)nicotinic acid

[0158] A solution of 4-(3,6-dihydro-2H-pyran-4-yl)-6-(trifluoromethyl)nicotinic acid (0.51 g, 1.85 mmol) in EtOAc (30 mL) was degassed with N2 and then palladium on carbon (0.16 g, 10 wt%, 0.15 mmol) was added. The reaction mixture was evacuated and backfilled with N2 three times and then three times with H2. The reaction mixture was stirred under H2 atmosphere at ambient temperature for 16 h, then filtered through a pad of diatomaceous earth. The resulting solution was concentrated under reduced pressure to afford the title compound (0.14 g). ES-MS m / 'z 276 (M+H).Preparation of Intermediate 49: 2-(3,6-Dihydro-2H-pyran-4-yl)-6-(trifluoromethyl)nicotinic acid

[0159] Pd(dppf)Ch (3.20 g, 4.29 mmol) was added under nitrogen to a mixture of 2-chloro-6- (trifluoromethyl)nicotinic acid (10.00 g, 43.45 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (14.00 g, 65.31 mmol) in 1,4-dioxane (100 mL) and water (10 mL). K2CO3 (18.00 g, 130.2 mmol) was then added and the reaction mixture was heated to 110 °C with stirring under nitrogen for 16 h. The mixture was fdtered and concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0-80% EtOAc in hexanes + 0.1% acetic acid to give the title compound (5.50 g) as a solid. ES-MS m / z 274 (M+H).Preparation of Intermediate 50: 2-(Tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)nicotinic acid

[0160] A mixture of 2-(3,6-dihydro-2H-pyran-4-yl)-6-(trifluoromethyl)nicotinic acid (4.50 g, 15.6 mmol) in EtOAc (50 mL) was degassed with nitrogen, then palladium on carbon (4.50 g, 10 wt%, 4.23 mmol) was added. The reaction mixture was evacuated and backfilled three times with hydrogen. The mixture was stirred at 50 °C for 2 h under hydrogen (103 kPa). The reaction mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated under reduced pressure to afford the title compound (3.90 g) as a solid. ES-MS m,'z 276 (M+H).Preparation of Intermediate 51: 2-(Tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)nicotinoyl chloride

[0161] 2-(Tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)nicotinic acid (19.60 g, 91 wt%, 64.80 mmol) was stirred in DCM (0.20 L) in a 500 mL RBF with stir bar. Oxalyl chloride (11 g, 7.4 mL, 85 mmol) was added to the mixture, followed by DMF (47 mg, 50 pL, 0.65 mmol). The mixture was stirred for 1.5 h, then concentrated under reduced pressure at 40 °C to give the title compound (21.62 g) as an oil. A sample was dissolved in MeOH - ES-MS m / z 290 (methyl ester M+H).Preparation of Intermediate 52: / e / V-Butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2-(tetrahydro-2H- pyran-4-yl)-6-(trifluoromethyl)nicotinamido)piperidine-l -carboxylate

[0162] Sodium carbonate (1.0 M aq., 0.15 L, 0.15 mol) was added to a 1 L RBF with / c / 7-biityl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-l-carboxylate (17.50 g, 68.01 mmol) in THF (150 mL) and the mixture was stirred. A solution of 2-(tetrahydro-2H-pyran-4-yl)-6- (trifluoromethyl)nicotinoyl chloride (21.62 g, 88 wt%, 64.79 mmol) in THF (50 mL) was added in 5 mL portions over 20 min. After 90 min, the mixture was diluted to 1 L with water. The mixture was extracted twice with EtOAc (0.2 L, 0.1 L). The organics were washed with a mixture of water (0.1 L) and sat. aq. NaCl (0.1 L), then sat. aq. NaCl (0.1 L). The organics were dried over MgSCh and filtered. The organics were concentrated to a volume of 0.1 L. Heptane (0.2 L) was added; and the mixture was concentrated at 60 °C to give the title compound (27.38 g) as a solid. ES-MS m / z 515 (M+H).Preparation of Intermediate 53: toT-Butyl (5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydro-2H-pyran-4- yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-2-ene-8-carboxylate

[0163] Potassium ter / -butoxide (9.43 g, 84.1 mmol) was added to mixture of tert-butyl (2S,4R)- 4-carbamoyl-2-methyl-4-(2-(tetrahydro-2H-pyran-4-yl)-6- (trifluoromethyl)nicotinamido)piperidine-l -carboxylate (7.63 g, 81 wt%, 12.0 mmol) in EtOH (120 mL), and the mixture was heated to 80 °C with stirring for 16 h. The reaction mixture was cooled to RT, then water (500 mL), EtOAc (50 mL), and sat. aq. NaCl (50 mL) were added and layers were separated. The aqueous layer was extracted with EtOAc (3 * 100 mL). The organic layers were combined, dried with Na2SO4, and concentrated to give the title compound (5.89 g) as a solid. ES-MS m / 'z 497 (M+H).Preparation of Intermediate 54: (5R,7S)-7-Methyl-2-(2-(tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-2-en-4-one dihydrochloride

[0164] HC1 (4 M solution in 1,4-dioxanes, 11.9 mL, 47.6 mmol) was added to tert-butyl (5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-2-ene-8-carboxylate (5.89 g, 11.9 mmol) dissolved in DCM (119 mL) and the mixture was stirred at RT. After 16 h, EtOAc (200 mL) was added and the mixture was filtered. The solid was dried for 2 h at 50 °C under reduced pressure to give the title compound (5.02 g) as a solid. ES-MS m'z 397 (M+H).

[0165] The free base of the title compound was prepared as follows: the dihydrochloride salt (2.00 g, 4.01 mmol) was dissolved in 10 mL of water and loaded onto a 25 g SCX cartridge. The cartridge was rinsed with MeOH and the product eluted with a 2 N NHa / MeOH solution. The basic fractions were combined and concentrated to dryness to give the free base of the title compound (1.46 g).Preparation of Intermediate 55: (5R,7S)-2-(2-Cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl- 1 ,3 ,8-triazaspiro[4.5]dec- 1 -en -4-one dihydrochloride

[0166] A 250 mL one-neck round bottom flask with a magnetic stir bar was charged with 1,4- dioxane (40 mL), followed by the addition of tert-butyl (5R,7S)-2-(2-cyclopropyl-4- (trifluoromethyl)phenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (8.40 g, 17.6 mmol). A solution of HC1 in 1,4-dioxane (4 M, 60 mL, 0.24 mol) was added in one portion at 28 °C, then the mixture was stirred vigorously at 28 °C for 2 h. The reaction mixture was concentrated, then water (80 mL) was added and the mixture was lyophilized to give the title compound (7.6 g) as a solid. ES-MS m / z 352 (M+H).

[0167] The free base of the title compound was prepared by dissolving the dihydrochloride salt in 2: 1 ELCkMeOH, adjusting the pH to 7 with 20% aq. Na2C0.3, and purifying the mixture by reverse phase prep-HPLC using a gradient of 18 to 48% ACN in 10 mM aq. NH4HCO3.Preparation of Intermediate 56: (5R,7S)-8-(5-Chloro-2-methoxypyridin-3-yl)-2,2,7-trimethyl-

[0168] To a solution of (5R,7S)-2,2,7-trimethyl-l,3,8-triazaspiro[4.5]decan-4-one dihydrochloride (3.04 g, 8.68 mmol) in toluene (30 mL) was added sodium 2-methylbutan-2- olate in THF (6.45 mL, 30 wt%, 52.8 mmol), 3-bromo-5-chloro-2-methoxypyridine (3.41 g, 15.0 mmol) and methanesulfonato(2-bis(3,5-di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy- 2',6'-bis(dimethylamino)-l , 1 '-biphenyl )(2'-methylamino-l , 1 '-biphenyl-2-yl)palladium(II) (1.1 g, 0.95 mmol) at 25 °C. The mixture was de-gassed and backfilled with N2 three times, then stirred at 100 °C for 16 h. The reaction mixture was quenched by addition of water then extracted three times with EtOAc. The combined organic layers were washed with sat. aq. NaCl, dried over sodium sulfate, filtered and concentrated. The residue was purified via silica gel chromatography (1:1 PE: EtOAc) to give the title compound (1.5 g) as a solid. ES-MS m / z 339 (M+H).Preparation of Intermediate 57: (2S,4R)-4-Amino-l-(5-chloro-2-methoxypyridin-3-yl)-2- methylpiperidine-4-carboxamide

[0169] To a mixture of (5R,7S)-8-(5-chloro-2-methoxypyridin-3-yl)-2,2,7-trimethyl-l,3,8- triazaspiro[4.5]decan-4-one (1.5 g, 3.6 mmol) in MeOH (15 mL) and water (15 mL) was added HC1 (1 M aq. solution, 4.5 mL, 4.5 mmol). The reaction was stirred at 70 °C for 72 h, then adjusted to pH>7 with 1 M NHs / MeOH then concentrated under reduced pressure. The residue was purified by reverse phase prep-HPLC using a gradient of 10 to 40% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.77 g) as a solid. ES-MS m / z 299 (M+H).Preparation of Intermediate 58: (2S,4R)-l-(5-Chloro-2-methoxypyridin-3-yl)-4-(2-cyclopropyl- 4-(trifluoromethyl)benzamido)-2-methylpiperidine-4-carboxamide

[0170] A mixture of (2S,4R)-4-amino-l-(5-chloro-2-methoxypyridin-3-yl)-2-methylpiperidine- 4-carboxamide (0.09 g, 0.30 mmol), 2-cyclopropyl-4-(trifluoromethyl)benzoic acid (0.070 g, 0.30 mmol), and HATU (0034 g, 0.89 mmol) was diluted with ACN (3.0 mL). Then DIEA (0.16 mL, 0.92 mmol) was added. The reaction was stirred for 19 h, then diluted with water and DCM. The layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were concentrated under reduced pressure to give the title compound (150 mg) as an oil. ES-MS m / z 511 (M+H).Preparation of Intermediate 59: Zc / 7-butyl (2S,4R)-4-carbamoyl-4-(2-cyclopropyl-4-(trifluoromethyl)benzamido)-2-methylpiperidine-l -carboxylate

[0171] To a solution of 2-cyclopropyl-4-(trifluoromethyl)benzoic acid (4.92 g, 20.2 mmol) in DMF (50 mL) at 15 °C was added HATU (9.51 g, 24.8 mmol) and DIEA (9.60 mL 54 mmol) and stirred for 15 mins. Then Ze / 7-butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-l- carboxylate (6.26 g, 95 wt%, 23.1 mmol) was added in portions over 2 min at 15 °C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was then poured into 200 mL ice water and stirred for 30 min, resulting in precipitation. The solid was filtered and washed with 150 mL water. The solid was collected and dried under reduced pressure at 45 °C to give the title compound (10.3 g) as a solid. ES-MS m / z 470 (M+H).Preparation of Intermediate 60: / c / 7-Butyl (5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)- 7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate

[0172] To a solution of te / 7-butyl (2S,4R)-4-carbamoyl-4-(2-cyclopropyl-4- (trifluoromethyl)benzamido)-2-methylpiperidine-l -carboxylate (10.3 g, 19.6 mmol) in THF (100 mL) was added potassium / c / V-butoxide (1 M solution in terZ-butanol, 99 mb, 99.0 mmol). The reaction mixture was allowed to stir vigorously at 70 °C for 2 h, then concentrated. The residue was dissolved with ice water (220 mL), then extracted three times with DCM. The combined organic layers were washed with sat. aq. NaCl, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in PE to give the title compound (8.4 g) as a solid. ES-MS m / z 452 (M+H).Preparation of Intermediate 61 : 2-(l,4-Dioxan-2-yl)-6-(trifluoromethyl)nicotinic acid (racemic mixture)

[0173] To a solution of l,4-dioxane-2-carboxylic acid (racemic mixture, 6.07 g, 43.6 mmol) and 2-chloro-6-(trifluoromethyl)-3-pyridinecarboxylic acid (5.00 g, 21.7 mmol) in DMF (50 mL) was added 2-(to7-butyl)-l,l,3,3-tetramethylguanidine (3.82 g, 21.9 mmol), (4,4'-di-Z- butyl-2,2'-bipyridine)bis[3,5-difluoro-2-(5-trifluoromethyl-2-pyridinyl-K? / )phenyl- KC]iridium(III) hexafluorophosphate (2.02 g, 1.75 mmol), and [4,4'-bis(l,l-dimethylethyl)-2,2'- bipyridine] nickel (II) dichloride (0.52 g, 1.3 mmol). The mixture was stirred at 50 °C for 2 h under irradiation with 395 nm LED module in an integrated photoreactor under nitrogen. The reaction mixture was left at RT overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse-phase HPLC (column: Phenomenex luna C18 250mm x 100mm, 15 pm; mobile phase: solvent A - 0.02% aq. formic acid, solvent B: ACN; gradient 20 to 50% solvent B in solvent A) to give the title compound (2.85 g) as a solid. ES-MS m / z 278 (M+H).Preparation of Intermediate 62: 2-(Tetrahydrofuran-2-yl)-6-(trifluoromethyl)nicotinic acid (racemic mixture)

[0174] A mixture of 2-chloro-6-(trifluoromethyl)-3-pyridinecarboxylic acid (50.0 g, 211 mmol), tetrahydrofuran-2-carboxylic acid (racemic mixture, 32.1 mL, 317 mmol), 2-(Zc / 7-butyl)- l , 1,3,3- tetramethylguanidine (69.2 g, 396 mmol) and phthalimide (37.6 mL, 306 mmol) in DMF (400 mL) was heated to 30 °C, and then (4,4'-di- / -butyl-2,2,-bipyridine)bis[3,5-difluoro-2-(5- trifluoromethyl-2-pyridinyl-KA)phenyl-KC]iridium(III) hexafluorophosphate (12.0 g,10.5 mmol) and [4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine]nickel (II) dichloride (1.2 g, 3.0 mmol) were added to the mixture. The reaction mixture was stirred at 55 °C for 2 h under irradiation with 395 nm (200W) LED module in an integrated photoreactor, under nitrogen. The reaction mixture was poured into 500 mL water at 25 °C, and then extracted with EtOAc (800 mL x 3).The combined organic layers were washed with water (500 mb x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 70% EtOAc in PE to give the title compound (14.4 g) as a solid. ES-MS m 'z 262 (M+H).Preparation of Intermediate 63: Zc / 7-Butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2-(tetrahydrofuran- 2-yl)-6-(trifluoromethyl)nicotinamido)piperidine-l -carboxylate (mixture of isomers)

[0175] A mixture of 2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)nicotinic acid (racemic mixture, 10.0 g, 38.2 mmol), te / 7-butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-l -carboxylate (12.1 g, 45.3 mmol), DIEA (19.9 mL, 112 mmol), EDCI (11.2 g, 56.7 mmol) and 1-hydroxy-lH- benzotriazole (7.7 g, 55 mmol) in THF (100 mL) at 25 °C was obtained. The reaction mixture was stirred vigorously at 25 °C for 16 h, then poured into 100 mL water and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with water (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (15.3 g) as a solid. ES-MS m 'z 501 (M+H).Preparation of Intermediate 64: zc / V-Butyl (5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)- 6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (mixture of isomers)

[0176] A mixture of / c77-butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)nicotinamido)piperidine-l -carboxylate (15.2 g, 20.0 mmol) and NaOH (12.0 g, 294 mmol) in MeOH (150 mL) and water (50 mL) was heated to 80 °C for 8 h with vigorous stirring. The mixture was cooled to 40 °C and concentrated under reduce pressure. The residuewas diluted with 100 mL water and extracted with EtOAc (lOOmL x 3). The combined organic layers were washed with water (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 35% EtOAc in PE to give the title compound (8.1 g) as a solid. ES-MS m / z 483.2 (M+H).Preparation of Intermediate 65: (5R,7S)-7-Methyl-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one dihydrochloride (mixture of isomers)

[0177] A mixture of / crz-butyl (5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (8.0 g, 16 mmol) and HC1 (4 M in 1,4-dioxane, 40 mL, 0.16 mol) in 1,4-dioxane (80 mb) was stirred vigorously at 27 °C for 6 h, then the mixture was concentrated under reduced pressure to give the title compound (6.5 g) as a solid. ES-MS m^z 383 (M+H).Preparation of Intermediate 66: (5R,7S)-7-Methyl-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)

[0178] A solution of HC1 (4 M in 1,4-dioxane, 16 mL, 64 mmol) was added in one portion to a vigorously stirring solution of tert-butyl (5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (mixture of isomers, 3.80 g, 6.85 mmol) in 1,4-dioxane (16 mL) at RT in a RBF (100 mL). The reaction was stirred for 2 h and concentrated. The residue was dissolved in a minimum of water and concentrated ammonium hydroxide and purified by reverse phase prep-HPLC using a gradient of 3 to 43%ACN in 10 mM aq. NH4HCO3 to give the title compound (2.49 g) as a solid. ES-MS m / z 383 (M+H).Preparation of Intermediate 67: Ethyl 3-(3,6-dihydro-2H-pyran-4-yl)-l-methyl-lH-pyrazole-4- carboxylate

[0179] [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Complex with DCM (0.31 g, 0.37 mmol) was added to a solution of ethyl 3-bromo-l-methyl-lH-pyrazole-4-carboxylate (0.56 g, 2.4 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (0.77 g, 3.6 mmol), and K2CO3 (0.70 g, 5.10 mmol) in 1,4-dioxane (14 mL) and H2O (1.4 m ) under N2 atmosphere. The reaction mixture was warmed to 100 °C and stirred for 2 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc and filtered through a pad of diatomaceous earth. The resulting solution was washed with sat. aq. NH4CI, sat. aq. NaCl, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-60% EtOAc in cyclohexane) to give the title compound (0.24 g) as an oil. ES m / z 237 (M+H).Preparation of Intermediate 68: Ethyl l-methyl-3-(tetrahydro-2H-pyran-4-yl)-lH-pyrazole-4- carb oxy late

[0180] A pressure vessel was charged with Pd(OH)2 on carbon (0.76 g, 10 wt%, 0.54 mmol) and wetted with EtOAc. A solution of ethyl 3-(3,6-dihydro-2H-pyran-4-yl)-l-methyl-lH-pyrazole-4- carboxylate (0.23 g, 1.00 mmol) in EtOAc (10 mL) was added, then the vessel was evacuated and backfilled three times with N2 and then with H2. The reaction was stirred at ambient temperature under an atmosphere of H2 (310 kPa) for 16 h. The mixture was filtered through apad of diatomaceous earth, and the filtrate concentrated under reduced pressure to afford the title compound (0.26 g) as an oil. ES-MS m / z 239 (M+H).Preparation of Intermediate 69: Ethyl l-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-lH-pyrazole-4- carboxylate;

[0181] A suspension of ethyl 5-(trifhioromethyl)-lH-pyrazole-4-carboxylate (1.00 g, 4.80 mmol), 2,2,2-trifluoroethyl trifluoromethylsulfonate (0.70 mL, 4.9 mmol), and CS2CO3 (3.20 g, 9.82 mmol) in DMF (10 mL) was stirred at 100 °C for 16 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (50 mL), washed with H2O (20 mL) and sat. aq. NaCl. The resulting solution was dried over Na2SC>4, filtered and concentrated under reduced pressure to afford the title compound (1.29 g) as an oil.Preparation of Intermediate 70: l-(2,2,2-Trifluoroethyl)-3-(trifluoromethyl)-lH-pyrazole-4- carboxylic acid

[0182] LiOH (0.58 g, 24.2 mmol) was added to a solution of ethyl l-(2,2,2-trifluoroethyl)-3- (trifluoromethyl)-lH-pyrazole-4-carboxylate (1.29 g, 4.43 mmol) in EtOH (15 mL) and H2O (5 mL) and the mixture was stirred at 60 °C for 16 h. The reaction mixture was cooled to ambient temperature and the pH of the solution adjusted to around 3. The product was extracted three times with a 3 / 1 v / v solution of CHCI3 / IPA. The combined organic layers were concentrated under reduced pressure to afford the title compound (1.07 g) as a solid.Preparation of Intermediate 71 : l-Methyl-3-(tetrahydro-2H-pyran-4-yl)-lH-pyrazole-4- carboxylic acid

[0183] The title compound was prepared as described in the Preparation of Intermediate 70 using ethyl l-methyl-3-(tetrahydro-2H-pyran-4-yl)-lH-pyrazole-4-carboxylate. ES-MS m / z 211 (M+H).Preparation of Intermediate 72: (2,6-Dimethyl-4-(3-oxomorpholino)phenyl)boronic acid

[0184] Ethyleneglycol 0.118 m , 2.11 mmol) and potassium acetate (0.134 g, 1.40 mmol) were added to a solution of 4-(4-bromo-3,5-dimethylphenyl)morpholin-3-one (0.200 g, 0.702 mmol) in MeOH (2 mb). The mixture was purged three times with N2. Hypodiboric acid (0.126 g, 1.40 mmol) and chloro[(di(l -adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (0.002 g, 0.0351 mmol) were added and the mixture was purged three times with N2. The mixture was stirred at 60 °C. After 16 h, the reaction was filtered and concentrated under reduced pressure. The residue was triturated with 1 : 1 PE:MTBE (1 mb), stirred at 25 °C for 30 min, filtered and the solid was collected to give the title compound (0.030 g) as white solid. ESMS m / z 250 (M+H).Preparation of Intermediate 73: (5R,7S)-8-(4-Bromopyridin-2-yl)-7-methyl-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)

[0185] (5R,7S)-7-Methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one dihydrochloride (mixture of isomers, 0.30 g, 0.56 mmol), 4- bromo-2-fluoropyridine (0.16 g, 0.89 mmol) and potassium fluoride (0.26 g, 4.39 mmol) weresequentially added to DMSO (6 mL) in a 40 mL vial at RT. The reaction mixture was vigorously stirred at 120 °C for 16 h, poured into cold water (10 mL, 15°C) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with sat. aq. NaCl (2 x 10 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure to give a residue that was purified by reverse phase prep-HPLC using a gradient of 30 to 60% ACN in 0.2% aq. FA to give the title compound (115 mg) as a solid. ES-MS m / z 538, 540 (M+H).Preparation of Intermediate 74: (5R,7S)-8-(5-Chloro-2-methoxypyridin-3-yl)-7-methyl-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)

[0186] (5R,7S)-7-Methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one dihydrochloride (0.50 g, 1.08 mmol), 3-bromo-5-chloro-2- methoxypyridine (0.55 g, 2.42 mmol), a solution of sodium 2-methylbutan-2-olate in THF (1.74 mL, 30 wt%, 4.36 mmol) and methanesulfonato(2-bis(3,5-di(trifluoromethyl)phenylphosphino)- 3,6-dimethoxy-2',6'-bis(dimethylamino)-l,r-biphenyl )(2'-methylamino-l,l'-biphenyl-2- yl)palladium(II) (0.13 g, 0.11 mmol) were added sequentially to toluene (10 mL) in a RBF (50 mL) at RT. The system was purged with nitrogen for one minute and then stirred vigorously at 100 °C for 16 h under nitrogen. The reaction was poured into water (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with sat. aq. NaCl (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by silica gel column chromatography using 0-50% EtOAc in PE to give the title compound (122 mg) as an oil. ES-MS m / z 524 (M+H).Preparation of Intermediate 75: (5R,7S)-8-(4-Bromo-6-fluoropyridin-2-yl)-7-methyl-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)

[0187] A solution of (5R,7S)-7-methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin- 3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 0.14 g, 0.37 mmol), 4-bromo- 2,6-difluoropyridine (0.11 g, 0.06 mL, 0.56 mmol) and DIEA (0.09 g, 0.130 mL, 0.75 mmol) in DMSO (3 mL) in a sealed vessel was heated to 120 °C for 1 h with microwave heating. The reaction was cooled and loaded onto silica gel (12 g) and then purified by silica gel chromatography using a gradient of 0-100% EtOAc in cyclohexane to give the title compound (157 mg) as an oil. ES-MS m / z 556, 558 (M+H).Preparation of Intermediate 76: (5R,7S)-8-(4-Bromo-6-fluoropyridin-2-yl)-7-methyl-2-(2- (trifhioromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0188] The title compound was prepared as described in the Preparation of Intermediate 75 using (5R,7S)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one dihydrochloride. ES-MS m z 486, 488 (M+H).Preparation of Intermediate 77: (5R,7S)-8-(5-Bromo-2-(methylsulfonyl)pyridin-3-yl)-7-methyl- 2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)

[0189] Sodium bicarbonate (1.7 g, 16 mmol) was added to a mixture of (5R,7S)-7-methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one dihydrochloride (mixture of isomers, 1.8 g, 4.0 mmol) and 5-bromo-3-fluoro-2-(methylsulfonyl)pyridine (1.0 g, 3.9 mmol) in 1,4-dioxane (20 mL). The reaction was stirred at 120 °C. After 36 h, the reaction was cooled to RT, poured into water and extracted three times with EtOAc. The organics were purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in heptane to give the title compound as a solid. ES-MS m 'z 616, 618.Preparation of Intermediate 78: 5-Bromo-3-((5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)picolinonitrile

[0190] 5-Bromo-3-fluoropicolinonitrile (0.97 g, 4.7 mmol) and DIEA (2.1 g, 16 mmol) were added as a singular portion to (5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl- l,3,8-triazaspiro[4.5]dec-l-en-4-one (1.0 g, 2.7 mmol) in a solution of DMSO (10 mL). The mixture was vigorously stirred at 100 °C for 16 h with a refluxing condenser. The reaction was cooled to RT, then added ice water (40 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with sat. aq. NaCl, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 10% EtOAc in PE to give the title compound (610 mg) as a solid. ES-MS m / z 533 (M+H).Preparation of Intermediate 79: 3-Bromo-5-chloro-2-cyclopropoxypyridine;

[0191] CS2CO3 (32 g, 97 mmol) was added to a 250 mL (1-neck) round bottom flask with a magnetic stir bar, cyclopropanol (6 mL, 92 mmol), and 3-bromo-5-chloro-2-fluoropyridine (5 g, 20 mmol) in DMSO (50 mL) at 25 °C. Then the reaction mixture was allowed to stir vigorously at 100 °C for 2 h. The reaction mixture was diluted with 100 mL water and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with sat. aq. NaCl (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography using a gradient of 0 to 10% EtOAc in PE to give the title compound (3.2 g) as an oil. ES-MS m / z 248, 250.Preparation of Intermediate 80: (5R,7S)-8-(5-Chloro-2-cyclopropoxypyridin-3-yl)-7-methyl-2- (2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)

[0192] To a solution of (5R,7S)-7-methyl-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 1.02 g, 2.65 mmol) in toluene (10 mL) was added 3-bromo-5-chloro-2-cyclopropoxypyridine (1.33 g, 5.19 mmol) and methanesulfonato(2-bis(3,5-di(trifluoromethyl)phenylphosphino)-3,6- dimethoxy-2',6'-bi s(dimethylamino)- 1 , 1 '-biphenyl )(2'-methylamino- 1 , 1 '-biphenyl -2- yl)palladium(II) (0.29 g, 0.25 mmol) at 25 °C. The mixture was purged with N2 for 2 min. Then sodium 2-methylbutan-2-olate in THF (1.53 mL, 30 wt%, 3.84 mmol) was added to the mixture at 100 °C. The resulting mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was quenched by adding 20 mL saturated citric acid aqueous solution, and then extracted with EtOAc (10 mL * 3). The combined organic layers were washed with sat. aq. NaCl (20 mL), dried over Na2SO4. Then the Na2SO4 was filtered off and further washed with EtOAc (10 mL). The obtained filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0 to 80% EtOAc in PE to give the title compound (0.400 g) as a solid. ES-MS m / z 550 (M+H).Preparation of Intermediate 81 : (5R,7S)-8-(5-Chloro-2-methoxypyridin-3-yl)-2-(2-cyclopropyl- 4-(trifluoromethyl)phenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0193] A vial containing (2S,4R)-l-(5-chloro-2-methoxypyridin-3-yl)-4-(2-cyclopropyl-4- (trifluoromethyl)benzamido)-2-methylpiperidine-4-carboxamide (0.150 g, 0.294 mmol) was diluted with EtOH (1 mL) and then potassium / c77-butoxide as a 2 M solution in EtOH (0.15 mL, 0.30 mmol) was added. The reaction was then heated to 75 °C and stirred for 20 h. Additional potassium / c / 'Z-butoxide as a 2 M solution in EtOH (0. 80 mL, 1.60 mmol) was added and the reaction stirred at 75 °C for 1.5 h, then quenched with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 100% (3 : 1 EtOAc : EtOH) in heptane to give the title compound (101.5 mg) as an oil. ES-MS m / z 492 (M+H).Preparation of Intermediate 82: (5R,7S)-8-(5-Bromo-2-isopropoxypyridin-3-yl)-7-methyl-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)

[0194] Sodium hydride in mineral oil (0.02 g, 60 wt%, 0.52 mmol) was added in two small portions to propan-2-ol (0.03 g, 0.52 mmol) in THF (0.5 mL) with stirring, under nitrogen and at RT. After 5 min, (5R,7S)-8-(5-bromo-2-(methylsulfonyl)pyridin-3-yl)-7-methyl-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 0.11 g, 0.17 mmol) in THF (0.5 mL) was slowly added. After 5 h, the reaction was quenched with water and extracted three times with EtOAc. The combined organics were washed with sat. aq. NaCl, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 in 100% EtOAc in cyclohexane to give the title compound (80.9 mg) as a solid. ES-MS m z 596, 598 (M+H).

[0195] The intermediates in the following table were prepared as described in the Preparation of Intermediate 82 using the appropriate alcohol.Preparation of Intermediate 90: tert-Butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2- (trifluoromethyl)nicotinamido)piperidine- 1 -carboxylate

[0196] To a mixture of 2-(trifluoromethyl)nicotinic acid (48.5 g, 249 mmol), HATU (243.05 g, 632.81 mmol) and DIEA (115.2 g, 155 mL, 882.4 mmol) in DMF (1500 mb) was added tert- butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-l-carboxylate (70.40 g, 273.6 mmol) portionwise. Upon complete addition, the mixture was stirred at 30 °C for 10 h under nitrogen. The reaction was quenched with water (4500 mL) and the filtered. The filter cake was washed with water (300 mL * 3) and concentrated under reduced pressure at 45 °C to give the title compound (107 g) as a solid. ES-MS m / z 331 (M-Boc+H).Preparation of Intermediate 91 : tert-Butyl (5R,7S)-7-methyl-4-oxo-2-(2- (trifluoromethyl)pyridin-3-yl)-I,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate

[0197] To a solution of ter / -butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2- (trifluoromethyl)nicotinamido)piperidine-l -carboxylate (107 g, 249 mmol) in DMSO (400 mL) and ze / 7-butanol (1500 mL) was added NaOH (5 M aq. solution, 646 mL, 3228 mmol) and the mixture was heated to 100 °C for 20 h under nitrogen. The mixture was concentrated under reduced pressure to remove / e / V-butanol and then diluted with water (2.5 L) and extracted with EtOAc (900 mL * 4). The combined organics were washed with sat. aq. NaCl (2 L x 2), dried over Na2SC>4, fdtered, and concentrated to give the title compound (78.1 g) as a solid. ES-MS m / z 357 (VL / Bu+H).Preparation of Intermediate 92: (5R,7S)-7-Methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one dihydrochloride

[0198] To a solution of terZ-butyl (5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)- l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (78.1 g, 177 mmol) in DCM (400 mL) was added HC1 (4 M in 1,4-dioxane, 400 mL) dropwise at 20 °C. The mixture was stirred for 2 h under nitrogen, then concentrated under reduced pressure to give the title compound (63.2 g) as a solid. ES-MS m / z 313 (M+H).Preparation of Intermediate 93: 2-(l,4-Dioxan-2-yl)-6-(trifluoromethyl)nicotinic acid (racemic mixture)

[0199] To a solution of l,4-dioxane-2-carboxylic acid (racemic mixture, 6.07 g, 43.6 mmol) and 2-chloro-6-(trifluoromethyl)-3-pyridinecarboxylic acid (5.00 g, 21.7 mmol) in DMF (50 mL) was added 2-(terLbutyl)-l,l,3,3-tetramethylguanidine (3.82 g, 21.9 mmol), (4,4'-di- / - butyl-2,2'-bipyridine)bis[3,5-difluoro-2-(5-trifluoromethyl-2-pyridinyl-K7V)phenyl-KC]iridium(III) hexafluorophosphate (2.02 g, 1.75 mmol), and [4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine] nickel (II) dichloride (0.52 g, 1.3 mmol). The mixture was stirred at 50 °C for 2 h under irradiation with 395 nm LED module in an integrated photoreactor under nitrogen. The reaction mixture was left at RT overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC (column: Phenomenex luna C18 250mm x 100mm, 15 pm; mobile phase: solvent A - 0.02% aq. formic acid, solvent B: ACN; gradient 20 to 50% solvent B in solvent A) to give the title compound (2.85 g) as a solid. ES-MS m'z 278 (M+H).Preparation of Intermediate 94: 5-Bromo-3-fluoro-2-(methylsulfonyl)pyridine

[0200] A mixture of 5-bromo-2,3-difluoro-pyridine (9.9 g, 5.5 mL, 51 mmol) and IPA (50 mL, 50 mmol) was cooled to 0 °C. NaSCEE (24 mL, 15 wt% solution in water, 51 mmol) was added dropwise over 10 min, then the mixture was allowed to warm to 22 °C. The reaction was left to stir at RT for 2h. Sodium dioxido(dioxo)tungsten hydrate (1.7 g, 5.2 mmol) was added and the mixture was stirred for ~15 min, then cooled to an internal temperature of 5 °C. H2O2 (16 mL, 50 wt% solution in water, 0.26 mol) was slowly added via an addition funnel over no less than 1 h while maintaining the internal temperature below 25 °C. Once the addition was finished the reaction was warmed to RT and stirred. After 16 h, water (50 mL, 51 mmol) was then added and the reaction was stirred for 1 h. The suspension was then filtered and washed with water (100 mL) two times. The solid was dried in a vacuum oven at 40 - 50 °C overnight to give the title compound (8.85 g) as a solid. ES-MS m / z 254, 256 (M+H).Preparation of Intermediate 95: (5R,7S)-8-(5-Bromo-2-(methylsulfonyl)pyridin-3-yl)-2,2,7- trimethyl-l,3,8-triazaspiro[4.5]decan-4-one

[0201] Na2C0a (8.00 g, 75.0 mmol) was added to a solution of (5R,7S)-2,2,7-trimethyl-l,3,8- triazaspiro[4.5]decan-4-one dihydrochloride (5.30 g, 20.0 mmol) and 5-bromo-3-fluoro-2- (methylsulfonyl)pyridine (5.00 g, 20.0 mmol) in 1,4-dioxane (50 mL). The reaction mixture was stirred at 120 °C for 48 h. The reaction mixture was cooled to ambient temperature and diluted with DCM and sat. aq. NaHCOi. After agitation and separation, the aqueous layer was extracted twice with DCM. The combined organic layers were dried with Mg2SC>4, filtered and concentrated under reduced pressure to afford the title compound (8.39 g) as a solid. ES-MS m,'z 431, 433 (M+H).Preparation of Intermediate 96: (5R,7S)-8-(5-Bromo-2-ethoxypyridin-3-yl)-2,2,7-trimethyl- 1 , 3 , 8-triazaspiro[4.5 ] decan-4-one;

[0202] A solution of sodium ethoxide (35 mL, 21 wt% solution in EtOH, 94 mmol) was added to a stirred solution of (5R,7S)-8-(5-bromo-2-(methylsulfonyl)pyridin-3-yl)-2,2,7-trimethyl-l,3,8- triazaspiro[4.5]decan-4-one (5.15 g, 11.9 mmol) in THF (10 mL) and stirred at ambient temperature overnight. The mixture was concentrated under reduced pressure and suspended in EtOAc (200 mL) and H2O (200 mL). After agitation and separation, the aqueous layer was extracted with EtOAc (200 mL). The combined organics were washed with H2O (2 x 200 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 20% MeOH in DCM to give the title compound (4.15 g) as a solid. ES-MS m z 397, 399 (M+H).Preparation of Intermediate 97: (2S,4R)-4-Amino-l-(5-bromo-2-ethoxypyridin-3-yl)-2- methylpiperidine-4-carboxamide naphthal ene-2-sulfonate

[0203] 2-Naphthalenesulfonic acid (3.39 g, 16.3 mmol) was added to a solution of (5R,7S)-8-(5- bromo-2-ethoxypyridin-3-yl)-2,2,7-trimethyl-l,3,8-triazaspiro[4.5]decan-4-one (3.23 g, 8.13 mmol) in ACN (50 mL) and H2O (0.3 mL). The reaction mixture was stirred at 120 °C for 2 h and cooled to ambient temperature. The precipitate was fdtered and rinsed with ACN to give the title compound (1.49 g) as a solid. ES-MS m / z 357, 359 (M+H).Preparation of Intermediate 98: (5R,7S)-8-(5-Bromo-2-methoxypyridin-3-yl)-2,2,7-trimethyl- 1,3, 8 -tri azaspiro [4.5 ]decan-4-one

[0204] (5R,7S)-8-(5-Bromo-2-(methylsulfonyl)pyridin-3-yl)-2,2,7-trimethyl-l,3,8- triazaspiro[4.5]decan-4-one (8.39 g, 19.5 mmol), sodium methoxide (3.15 g, 58.3 mmol) and MeOH (8.00 mL) in NMP (50 mL) was stirred at ambient temperature for 18 h. The reaction mixture was diluted with EtOAc (200 mL) and water (200 mL). After agitation and separation, the aqueous layer was extracted with EtOAc (200 mL). The combined organics were washed with water (2 * 200 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound (7.35 g) as a solid. ES-MS m / z 383, 385 (M+H).Preparation of Intermediate 99: (2S,4R)-4-Amino-l-(5-bromo-2-methoxypyridin-3-yl)-2- methylpiperidine-4-carboxamide

[0205] HC1 (19.2 mL, 1 M solution, 19.2 mmol) was added to a solution of (5R,7S)-8-(5-bromo- 2-methoxypyridin-3-yl)-2,2,7-trimethyl-l,3,8-triazaspiro[4.5]decan-4-one (7.35 g, 19.2 mmol) in MeOH (100 mL), H2O (100 mL) and stirred at 100 °C for 3 days. The mixture was concentrated to half of its volume, evaporating most of the MeOH. The solution was then diluted with water (200 mL) and EtOAc (200 mL). The layers were agitated and separated, and the aqueous layer was extracted with EtOAc (200 mL). The aqueous solution was neutralized with a sat. aq.NaHCOs and extracted with EtOAc (3 x 200 mL). The combined organics were dried over Mg2SO4, filtered and concentrated under reduced pressure to afford the title compound (5.26 g) as a solid. ES-MS m z 343, 345 (M+H).Preparation of Intermediate 100: (5R,7S)-8-(5-Bromo-2-cyclopropoxypyridin-3-yl)-2,2,7- trimethyl-l,3,8-triazaspiro[4.5]decan-4-one

[0206] Sodium hydride (0.35 g, 60 wt%, 8.7 mmol) was added to a solution of (5R,7S)-8-(5- bromo-2-(methylsulfonyl)pyridin-3-yl)-2,2,7-trimethyl-l,3,8-triazaspiro[4.5]decan-4-one (2.4 g, 61 wt%, 3.4 mmol) and cyclopropanol (0.51 g, 8.6 mmol) in NMP (25 mL) and stirred vigorously at ambient temperature for 4 h. The reaction mixture was poured into a sat. aq. NH4CI and extracted with EtOAc (3 x 30 mL). The combined organics were washed with sat. aq. NaCl (3 x 30 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 70% EtOAc in PE to give the title compound (1.2 g) as an oil. ES-MS m / 'z 409, 411 (M+H).Preparation of Intermediate 101 : (2S,4R)-4-Amino-l-(5-bromo-2-cyclopropoxypyridin-3-yl)-2- methylpiperidine-4-carboxamide

[0207] HC1 (10.5 mL, 1 M, 10.5 mmol) was added to a solution of (5R,7S)-8-(5-bromo-2- cyclopropoxypyridin-3-yl)-2,2,7-trimethyl-l,3,8-triazaspiro[4.5]decan-4-one (12.0 g, 2.08 mmol) in MeOH (10 mL) and H2O (10 mL). The reaction mixture was stirred vigorously at 100 °C for 18 h. The reaction mixture was cooled to ambient temperature and the pH of the solution adjusted to 8~9 with a sat. aq. NaHCCh and extracted with DCM (3 x 30 mL). The combined organics were washed with sat. aq. NaCl (2 x 20 mL), dried over Na2SC>4. filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatographyusing a gradient of 0 to 25% EtOAc in PE to give the title compound (0.46 g) as an oil. ES-MS m,'z 369, 371 (M+H).Preparation of Intermediate 102: (5R,7S)-8-(4-Bromopyridin-2-yl)-2,2,7-trimethyl-l,3,8- triazaspiro[4.5]decan-4-one

[0208] CS2CO (42.2 g, 130 mmol) was added to a suspension of (5R,7S)-2,2,7-trimethyl-l,3,8- triazaspiro[4.5]decan-4-one dihydrochloride (5.00 g, 18.5 mmol) and 4-bromo-2-fluoropyridine (3.58 g, 20.4 mmol) in DMSO (37.0 mL). The reaction mixture was stirred vigorously overnight at 100 °C, then cooled to ambient temperature and diluted with 200 mL of EtOAc and 200 mL of H2O. After agitation and separation, the aqueous layer was extracted with EtOAc (200 mL). The combined organics were washed with H2O (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 15% MeOH in DCM to give the title compound (0.43 g) as an oil. ESMS m'z 353, 355 (M+H).Preparation of Intermediate 103: (2S,4R)-4-Amino-l-(4-bromopyridin-2-yl)-2-methylpiperidine- 4-carboxamide hydrochloride

[0209] Aqueous HC1 (4.25 mL, 1 M, 4.25 mmol) and H2O (28.3 mL) were added to a solution of (5R,7S)-8-(4-bromopyridin-2-yl)-2,2,7-trimethyl-l,3,8-triazaspiro[4.5]decan-4-one (1.00 g, 2.83 mmol) in MeOH (28 mL) and stirred at 100 °C overnight. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give the title compound (0.98 g). ES-MS m'z 313, 315 (M+H).Preparation of Intermediate 104: (5R,7S)-8-(4-Bromopyridin-2-yl)-7-methyl-2-(4-(tetrahydro- 2H-pyran-4-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0210] 1 -Methyl- 1 / 7-imidazole (0.21 g, 2.54 mmol) and A-(chloro(dimethylamino)methylene)- A-methylmethanaminium hexafluorophosphate (V) (0.21 g, 0.76 mmol) were added to a solution of (2S,4R)-4-amino-l-(4-bromopyridin-2-yl)-2-methylpiperidine-4-carboxamide (0.18 g, 0.56 mmol) and 4-(tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)nicotinic acid (0.14 g, 0.51 mmol) in ACN (2.5 mL) and stirred at ambient temperature for 1 h. EtOH (3 mL) and a solution of KOzBu in THF (1.5 mL, 1 M, 1.5 mmol) were added and the reaction mixture was warmed to 80 °C and stirred for 3 days. The reaction mixture was cooled to ambient temperature, quenched with sat. aq. NH4CI and extracted with EtOAc (3 * 10 mL). The combined organics were concentrated under reduced pressure and purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in heptane to give the title compound (0.08 g). ES-MS m / z 552, 554 (M+H).Preparation of Intermediate 105: (5R,7S)-8-(5-Bromo-2-methoxypyridin-3-yl)-2-(2- cyclopropylpyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0211] 2-Cyclopropylnicotinic acid (0.30 g, 1.82 mmol), DIEA (0.508 mL, 2.91 mmol) and HATU (0.83 g, 2.19 mmol, portion wise over 1 min) were added sequentially to (2S,4R)-4- amino-l-(5-bromo-2-methoxypyridin-3-yl)-2-methylpiperidine-4-carboxamide (0.500 g, 1.46 mmol) in anhydrous DMF (6 mL) at RT. The reaction was stirred overnight, poured into cold stirring water (100 mL) and stirred 30 min to give a suspension. The solid was removed by filtration, rinsed with EtOAc and discarded. The organic layer from the filtrate was washed with sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. To the residue was added 1 M solution of potassium Zer -butoxide in ZerZ-butanol (7.28 mL, 7.28 mmol) and the mixture was heated at 80 °C under nitrogen for 2 h and then allowed to stir overnight at RT. The reaction was diluted with EtOAc with stirring and the pH of the reaction mixture was adjusted to between 4-5 using an aqueous solution of 5% citric acid. The layers were separated.The aqueous layer was extracted twice with EtOAc. The combined organic layers were extracted with sat. aq. NaCl, dried over sodium sulfate, filtered, and concentrated, then dried under reduced pressure at 45 °C to give the title compound (650 mg) as a solid. ES-MS m / z 470, 472 (M+H).Preparation of Intermediate 106: Methyl 2-cyclopropyl-6-methoxynicotinate

[0212] A solution of methyl 6-chloro-2-cyclopropylnicotinate (0.30 g, 1.42 mmol) and sodium methoxide in MeOH (5.7 mL, 0.5 M, 2.83 mmol) was stirred at 55 °C overnight. The reaction mixture was diluted with EtOAc and H2O. After agitation and separation, the aqueous layer was extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (0.29 g). ES-MS m / z 208 (M+H).Preparation of Intermediate 107: 2-Cyclopropyl-6-methoxynicotinic acid

[0213] A solution of LiOH in water (1.5 mL, 2.0 M, 3.0 mmol) was added to a solution of methyl 2-cyclopropyl-6-methoxynicotinate (0.29 g, 1.42 mmol) in 1,4-dioxane (4.7 mL) and the mixture was stirred at 50 °C for 3 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (0.274 g). ES-MS m / z 194 (M+H).Preparation of Intermediate 108: (2S,4R)-l-(5-Bromo-2-methoxypyridin-3-yl)-4-(2-cyclopropyl- 4-(trifluoromethyl)benzamido)-2-methylpiperidine-4-carboxamide

[0214] DIEA (0.33 g, 3.0 Eq, 2.5 mmol) was added to a solution of 2-cyclopropyl-4- (trifluoromethyl)benzoic acid (0.21 g, 0.84 mmol), (2S,4R)-4-amino-l-(5-bromo-2- methoxypyridin-3-yl)-2-methylpiperidine-4-carboxamide (0.50 g, 0.84 mmol) and HATU (0.65 g, 1.70 mmol) in DMF (5 mL). The reaction mixture was stirred at 40 °C for 4 h, then poured into H2O (10 mL) and extracted with EtOAc (5 mL x 2). The combined organics were washed with sat. aq. NaCl (5 mL x 2), dried over ISfeSCU, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (100% EtOAc, Ry = 0.4) to give the title compound (0.86 g) as an oil. ES-MS m^z 555, 557 (M+H).

[0215] Intermediates in the following table were prepared as described in the Preparation of Intermediate 108 using the appropriate amine and carboxylic acid.Preparation of Intermediate 116: N-((2S,4R)-l-(5-Bromo-2-ethoxypyridin-3-yl)-4-carbamoyl-2- methylpiperidin-4-yl)-2-(l-(trifluoromethyl)cyclobutyl)nicotinamide

[0216] DIEA (0.7 mL, 5.9 Eq, 4.0 mmol) was added to a solution of 2-(l- (trifluoromethyl)cyclobutyl)nicotinic acid (0.19 g, 0.79 mmol), (2S,4R)-4-amino-l-(5-bromo-2- ethoxypyridin-3-yl)-2-methylpiperidine-4-carboxamide naphthalene-2-sulfonate (0.39 g, 0.69 mmol), and HATU (0.78 g, 2.1 mmol) in ACN (15 mL). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was loaded onto 20 g SCX resin and rinsedwith MeOH. Then the resin was eluted with 3.5 M ammonia in MeOH solution to elute the product, and the basic solution was concentrated under reduced pressure to afford the title compound (0.40 g) as an oil. ES-MS m / z 584, 586 (M+H).Preparation of Intermediate 117: (5R,7S)-8-(5-Bromo-2-methoxypyridin-3-yl)-2-(2-cyclopropyl-4-(tri fluoromethyl )phenyl)-7-m ethyl- 1, 3, 8-triazaspiro[4.5]dec-l-en-4-one

[0217] Potassium 2-methylpropan-2-olate (1 M solution in Z-BuOH, 2.5 mL, 2.5 mmol) was added to a solution of (2S,4R)-l-(5-bromo-2-methoxypyridin-3-yl)-4-(2-cyclopropyl-4- (trifluoromethyl)benzamido)-2-methylpiperidine-4-carboxamide (0.86 g, 36.8 wt%, 0.57 mmol) in THF (8 mL). The reaction mixture was heated to 80 °C for 3 h, poured into water (20 mL) and extracted with EtOAc (10 mL x 4). The combined organics were washed with sat. aq. NaCl (10 mL x 2), dried over Na2SO4, and the Na2SC>4 was filtered and further washed with EtOAc (10 mL x 2). The filtrate was concentrated under reduced pressure and the residue was purified by prep-TLC (EtOAc, R / = 0.6) to give the title compound (0.20 g) as a solid. ES-MS m'z 537 (M+H).Preparation of Intermediate 118: (5R,7S)-8-(5-Bromo-2-methoxypyridin-3-yl)-2-(2-cyclopropyl-6-methoxypyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0218] KO / Bu (2 M solution in THF, 4 mL, 8.0 mmol) was added to a solution of N-((2S,4R)-1- (5-bromo-2-methoxypyridin-3-yl)-4-carbamoyl-2-methylpiperidin-4-yl)-2-cyclopropyl-6- methoxynicotinamide (0.43 g, 0.83 mmol) in EtOH (4 mL). The reaction mixture was stirred at 75 °C for 3 h. The reaction mixture was cooled to ambient temperature and diluted with H2Oand EtOAc. The layers were separated and the aqueous layer extracted with EtOAc. The combined organics were concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0 to 100% 3 : 1 EtOAc : EtOH) in heptane to give the title compound (0.16 g) as a solid. ES-MS m z 502 (M+H).Preparation of Intermediate 119: (5R,7S)-8-(5-Bromo-2-ethoxypyridin-3-yl)-7-methyl-2-(2-(l- (trifluoromethyl)cyclobutyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0219] A IM solution of KO / Bu in THF (3.0 mL, 3.0 mmol) was added to a solution of N- ((2S,4R)-l-(5-bromo-2-ethoxypyridin-3-yl)-4-carbamoyl-2-methylpiperidin-4-yl)-2-(l- (trifluoromethyl)cyclobutyl)nicotinamide (0.40 g, 0.39 mmol) in EtOH (10 mL). The reaction mixture was stirred at 80 °C for 3 h. Additional KO / Bu (0.38 g, 3.33 mmol) was added and the reaction mixture stirred at 80 °C for an additional 16 h. The reaction mixture was concentrated under reduced pressure, diluted with water (100 mL) and extracted with EtOAc (3 * 100 mL). The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0 to 70% EtOAc in cyclohexane to give the title compound (0.134 g) as a solid. ES-MS m z 566, 568 (M+H).Preparation of Intermediate 120: (5R,7S)-8-(5-Bromo-2-methoxypyridin-3-yl)-7-methyl-2-(l- methyl-3-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-4-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0220] KOZBu (0.09 g, 0.76 mmol) was added to solution of (2S,4R)-l-(5-bromo-2- methoxypyri din-3 -yl)-2-methyl -4-(l -methyl -3-(tetrahydro-2H-pyran -4-yl)-lH-pyrazole-4- carboxamido)piperidine-4-carboxamide (0.08 g, 0.16 mmol) in EtOH. The mixture was heatedto 80 °C and stirred under N2 for 2 h. The reaction was diluted with EtOAc (30 mL), washed with water (10 mL x 2), sat. aq. NaCl (10 mL), dried over MgSCU, filtered and concentrated under reduced pressure to give the title compound (0.079 g) as an oil. ES-MS m / z 517, 519 (M+H).

[0221] The intermediates in the following table were prepared as described in the Preparation of Intermediate 120 using the appropriate amide.Preparation of Intermediate 124: (5R,7S)-8-(5-Chloro-2-methoxypyridin-3-yl)-7-methyl-2-(2-(tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en -4-one

[0222] A solution of sodium / <v7-amylate in THF (0.68 mL, 1.4 M, 0.95 mmol) was added to a suspension of (5R,7S)-7-methyl-2-(2-(tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)pyri din-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.10 g, 0.24 mmol), 3-bromo-5-chloro-2- methoxypyridine (0.11 g, 0.49 mmol), methanesulfonato(2-bis(3,5- di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',6'-bis(dimethylamino)-l,r-biphenyl )(2'- methylamino-l,r-biphenyl-2-yl)palladium(II) (0.03 g, 0.02 mmol) in toluene (2 mL) under N2 atmosphere and stirred at 100 °C for 18 h. The reaction mixture was cooled to ambient temperature and combined with a reaction mixture run as described above using 30 mg (76 pmol) of the starting (5R,7S)-7-methyl-2-(2-(tetrahydro-2H-pyran-4-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one. The combined mixture was diluted with EtOAc and washed with 5% aq. citric acid, water, and sat. aq. NaCl. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was eluted through 2 g silica gel with 20% EtOAc in DCM, then repurified by silica gel chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to obtain the title compound (0.04 g) as a solid. ES-MS m / z 538 (M+H).Preparation of Intermediate 125: (5R,7S)-8-(5-Chloro-2-methylpyridin-3-yl)-7-methyl-2-(2- (trifluoromethyl)pyri din-3 -yl)- 1 ,3 , 8-triazaspiro[4.5]dec- 1 -en -4-one;

[0223] A mixture of 1,4-dioxane (100 mL), (5R,7S)-7-methyl-2-(2-(trifluoromethyl)pyridin-3- yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one dihydrochloride (5.01 g, 12.9 mmol) and 3-bromo-5- chloro-2-methylpyridine (5.5 g, 26 mmol) was de-gassed and refilled with nitrogen three times. Lithium bis(trimethylsilyl)amide (1 M solution in THF, 130 mL, 130 mmol) was added dropwise over 30 min and the reaction mixture was allowed to stir at 27 °C for 4 h under nitrogen. The reaction mixture was poured into 300 mL water and then extracted with EtOAc (150 mL x 4). The combined organic layers were washed with sat. aq. NaCl (100 mL x 2) and dried over Na2SO4, then the NazSCh was filtered off and further washed with EtOAc (20 mL x 2). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0 to 55% EtOAc in PE to give the title compound (0.920 g) as a solid. ES-MS m z 438 (M+H).Preparation of Intermediate 126: (5R,7S)-8-(2-Chloro-5-methoxypyridin-4-yl)-2-(2-cyclopropyl- 4-(trifluoromethyl)phenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0224] To a vial was added toluene (6 mL), followed by the addition of (5R,7S)-2-(2- cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.550 g, 1.52 mmol), 2-chloro-4-iodo-5-methoxypyridine (0.629 g, 2.29 mmol) and a solution of sodium 2-methylbutan-2-olate in THF (1 .7 mL, 30 wt%, 4.576 mmol). The mixture was purged with N2 for 2 min before and after adding methanesulfonato(2-bis(3,5- di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',6'-bis(dimethylamino)-l,T-biphenyl )(2'- methylamino-l,T-biphenyl-2-yl)palladium(II) (0.355 g, 0.305 mmol), then the reaction mixture was allowed to stir vigorously at 100 °C for 4 h. The reaction was then filtered and concentrated. The residue was purified by prep-TLC (DCM / MeOH = 20 / 1, Ry = 0.5) to give the title compound. ES-MS m / z 493 (M+H).Preparation of Intermediate 127: (6-Methyl-5-((5R,7S)-7-methyl-4-oxo-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)pyridin-3-yl)boronic acid

[0225] A mixture of (5R,7S)-8-(5-chloro-2-methylpyridin-3-yl)-7-methyl-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.21 g, 0.41 mmol), potassium acetate (0.13 g, 1.26 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (0.22 g, 0.83 mmol) in methoxycyclopentane (2 mL) in a vial was degassed with a stream of nitrogen for 2 min. Methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl- l,r-biphenyl)(2'-methylamino-l,r-biphenyl-2-yl)palladium(II) (0.038 g, 0.043 mmol) was added, the vial was sealed and heated at 80 °C with vigorous stirring for 12 h. The reactionmixture was cooled, filtered and concentrated under reduced pressure. The residue was purified by reverse phase prep-HPLC using a gradient of 10 to 35% ACN in 0.2% aq. FA to give the title compound (103 mg) as a solid. ES-MS m / z' 448 (M+H).Preparation of Intermediate 128: (5R,7S)-2-(2-Cyclopropyl-4-(trifluoromethyl)phenyl)-8-(2- methoxy-5-(4, 4,5, 5-tetramethyl- 1,3, 2-dioxaborolan-2-yl)pyridin-3-yl)-7-m ethyl- 1,3,8- triazaspiro[4.5]dec- 1 -en-4-one

[0226] (5R,7S)-8-(5-Bromo-2-methoxypyridin-3-yl)-2-(2-cyclopropyl-4- (trifluoromethyl)phenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (1.0 g, 1.9 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.57 g, 2.2 mmol), potassium carbonate (0.8 g, 6 mmol), and [(l,2,3-eta)-2-buten-l-yl]chloro[dicyclohexyl[2',4',6'-tris(l- methylethyl)[l,r-biphenyl]-2-yl]phosphine]palladium (0.25 g, 0.37 mmol) were combined in a vial and then diluted with 1,4-dioxane (20 mL). The reaction mixture was sparged with N2 for 5 min. 2-Ethyl hexanoic acid (0.060 mL, 0.38 mmol) was added and the reaction was allowed to stir at 50 °C for 4 h. The reaction mixture was then filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in heptane to give the title compound (0.37 g) as an oil. ES-MS m / z 585 (M+H).Preparation of Intermediate 129: (5R,7S)-2-(2-Cyclopropylpyridin-3-yl)-8-(2-methoxy-5- (4, 4, 5, 5-tetramethyl- 1,3, 2-dioxaborolan-2-yl)pyridin-3-yl)-7-methyl-l, 3, 8-triazaspiro[4.5]dec-l- en-4-one

[0227] (5R,7S)-8-(5-Bromo-2-methoxypyridin-3-yl)-2-(2-cyclopropylpyridin-3-yl)-7-methyl- l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.65 g, 1.38 mmol) in methoxycyclopentane (10 mL),potassium acetate (0.41 g, 4.15 mmol), and bis(pinacolato)diborane (0.70 g, 2.77 mmol) were combined in a vial. The reaction mixture was purged with nitrogen for 10 min, then methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,l'-biphenyl)(2'-methylamino- l,T-biphenyl-2-yl)palladium(II) (0.119 g, 138 mmol) was added and the reaction was heated at 80 °C for 4 h. The reaction was cooled, filtered through diatomaceous earth using EtOAc and the filtrate concentrated. The residue was purified by reverse phase flash chromatography using a gradient of 15-30% ACN in 10 mM aq. NH4HCO3 to give the title compound (386 mg) as an oil. ES-MS shows hydrolysis of the boronic ester, m / z 434 (M-H).Preparation of Intermediate 130: (5R,7S)-8-(2-Methoxy-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-3-yl)-7-methyl-2-(2-(tetrahydro-2H-pyran-4-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0228] [(l,2,3-eta)-2-Buten-l-yl]chloro[dicyclohexyl[2',4',6'-tris(l-methylethyl)[l,T-biphenyl]- 2-yl]phosphine]palladium (0.007 g, 0.01 mmol) was added to a suspension of (5R,7S)-8-(5- chloro-2-methoxypyridin-3-yl)-7-methyl-2-(2-(tetrahydro-2H-pyran-4-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.056 g, 0.10 mmol), bis(pinacolato)diborane (0.035 g, 0.14 mmol), K2CO3 (0.036 g, 0.26 mmol), and 2-ethyl hexanoic acid (0.001 mb, 0.007 mmol) in 2-methyltetrahydrofuran (1.5 m ) under N2 atmosphere and the mixture was stirred at 50 °C for 18 h. The reaction mixture was cooled to ambient temperature, diluted with MTBE and filtered. The filtrate was washed with aq. NaHCOs, water and sat. aq. NaCl. The organics were dried over Na2SC>4, filtered and concentrated under reduced pressure to afford the title compound (0.06 g) as a solid. ES-MS m z 630 (M+H).Preparation of Intermediate 131 : (5R,7S)-8-(5-Bromo-2-oxo-l,2-dihydropyridin-3-yl)-2-(2- cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0229] To a solution of (5R,7S)-8-(5-bromo-2-methoxypyridin-3-yl)-2-(2-cyclopropyl-4- (trifluoromethyl)phenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.150 g, 0.279 mmol) in THF (2.6 mL) was added chlorotrimethylsilane (0.070 mb, 0.55 mmol) and sodium iodide (0.083 g, 0.558 mmol) at -40 °C. The resulting mixture was then allowed to warm to RT and stirred overnight. Additional chlorotrimethylsilane was added (0.070 mL, 0.55 mmol) and the mixture was stirred at RT for 3 days. Additional chlortrimethylsilane (0.100 mL, 0.79 mmol) and sodium iodide (0.090 g, 0.60 mmol) were added and the mixture was stirred at RT for 6 h, then at 35 °C for 2 days. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in heptane to give the title compound (0.0445 g) as a solid. ES-MS m / z 524 (M+H).Preparation of Intermediate 132: (5R,7S)-8-(5-Bromo-2-cyclobutoxypyridin-3-yl)-7-methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one(mixture of isomers)

[0230] Sodium hydride in mineral oil (0.017 g, 60 wt%, 0.43 mmol) was added in two small portions to cyclobutanol (0.03 g, 0.0043 mmol) in THF (0.5 mL) with stirring, under nitrogen and at RT. After 5 min, (5R,7S)-8-(5-bromo-2-(methylsulfonyl)pyridin-3-yl)-7-methyl-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 0.09 g, 0.14 mmol) in THF (0.5 mL) was slowly added. After 3 h, the reaction was quenched with water and extracted three times with EtOAc. The combined organics were washed with sat. aq. NaCl, dried over sodium sulfate, filtered, concentrated under reduced pressure. The residue was dried under reduced pressure at 45 °C to give the title compound (0.0817 g) as a solid. ES-MS m / z 608, 610 (M+H).Preparation of Intermediate 133: (5R,7S)-2-(2-(l,4-Dioxan-2-yl)-6-(trifluoromethyl)pyridin-3- yl)-8-(5-bromo-2-cyclopropoxypyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)

[0231] An aqueous solution of NaOH (0.5 mL, 4.2 M, 2.0 mmol) was added to a solution ofN- ((2S,4R)-l-(5-bromo-2-cyclopropoxypyridin-3-yl)-4-carbamoyl-2-methylpiperidin-4-yl)-2-(l,4- dioxan-2-yl)-6-(trifluoromethyl)nicotinamide (mixture of isomers, 0.56 g, 54 wt%, 0.48 mmol) in Z-BuOH (5 mL) and the mixture was purged with N2 for 2 min. The reaction was stirred vigorously at 80 °C for 2 h, then cooled to ambient temperature and poured into 20 mL of water. The mixture was extracted with EtOAc (4 >< 10 mL), then the combined organics were washed with sat. aq. NaCl (2 x 10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by prep-TLC (50% EtOAc in PE, R / = 0.4) to give the title compound (0.21 g) as a solid. ES-MS m / z 610, 612 (M+H).Preparation of Intermediate 134: 2-Bromo-l,3-dimethyl-5-vinylbenzene

[0232] A solution of n-butyllithium in cyclohexane (2 M solution, 35 mL, 70 mmol) was added dropwise over 15 min via an addition funnel to a cooled stirring suspension of methyltriphenylphosphonium bromide (25 g, 70 mmol) in THF (150 mL) in a 3-neck 500 mL RBF cooled in a dry ice / acetone bath at a rate to maintain the internal reaction temperature at less than -70°C. The reaction mixture was stirred at -78°C for 1 h, then a solution of 4-bromo- 3,5-dimethylbenzaldehyde (10 g, 47 mmol) in THF (50 mL) was added to the reaction mixture using an addition funnel over 30 min at a rate to maintain the internal reaction temperature at less than -74 °C. The reaction mixture was warmed to RT overnight with stirring, then poured into a sat. aq. solution of ammonium chloride (250 mL). The mixture was diluted with EtOAc (250mL) and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 250 mL). The combined organic phases were washed with sat. aq. NaCl, dried over Na2SC>4, fdtered, and concentrated under reduced pressure. The solid was dissolved in DCM (40 mL) with slight heating, loaded onto silica gel and purified by silica gel chromatography using a gradient of 0 to 10% EtOAc in cyclohexane to give the title compound (6.02 g) as an oil. 'H-NMR (400 MHz, CDCh) 8 7.15 (s, 2H), 6.68-6.58 (m, 1H), 5.75 (dd, J = 0.2, 4.4 Hz, 1H), 5.27 (dd, J = 0.2, 2.7 Hz, 1H), 2.44 (s, 6H).Preparation of Inter em di ate 135: l-(4-Bromo-3,5-dimethylphenyl)ethane-l,2-diol (racemic mixture)

[0233] N-Methylmorpholine-N-oxide (65 g, 530 mmol) and potassium osmate(VI) dihydrate (53 g, 140 mmol) were added sequentially to a stirred solution of 2-bromo-l,3-dimethyl-5- vinylbenzene (35 g, 120 mmol) in tert-butanol (400 mL) and water (200 mL) in a 3 -neck RBF (3 L) at RT. The reaction mixture was stirred for 2 h, poured into a sat. aq. solution of Na2SOs (1 L) and the layers separated. The aqueous layer was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with sat. aq. NaCl (200 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 45 to 60% EtOAc in PE to give the title compound (25 g) as a solid. 'H-NMR (400 MHz, CDCI3) 8 7.08 (s, 2H), 4.73 (dd, J = 3.5, 8.0 Hz, 1H), 3.78 - 3.71 (m, 1H), 3.68 - 3.60 (m, 1H), 2.42 (s, 6H).Preparation of Intermediate 136: l-(3,5-Dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)ethane-l,2-diol (racemic mixture)

[0234] 4,4,4',4',5,5,5',5'-Octamethyl-2,2l-bi(l,3,2-dioxaborolane) (55 g, 0.21 mol) and potassium acetate (33 g, 0.33 mol) were added to a solution of l-(4-bromo-3,5-dimethylphenyl)ethane-l,2- diol (racemic mixture, 25 g, 0.10 mol) in DMF (140 mb). The mixture was de-gassed and backfilled with N2 three times before and after adding mesylate[(di(l-adamantyl)-n- butylphosphine)-2-(2'-amino-l,T-biphenyl)]palladium(II) (CAS# 1651823-59-4, 9.8 g, 13 mmol). The reaction mixture was then allowed to stir at 120 °C for 2 h, then diluted with water (1 L) and extracted with EtOAc (4 * 500 mL). The combined organic layers were washed with sat. aq. NaCl (300 mL), dried over sodium sulfate, filtered and the sodium sulfate washed with EtOAc (200 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 45 to 70% EtOAc in PE. The product was repurified by reverse phase prep-HPLC using a gradient of 20 to 60% ACN in 10 mM aq. NH4HCO3 to give the title compound (29 g) as a solid. ’H-NMR (400 MHz, CDCI3) 86.94 (s, 2 H), 4.71 (dd, J = 3.6, 8 Hz, 1 H), 3.68 (dd, J = 3.6, 11.2 Hz, 1H), 3.60 (dd, J = 8 Hz, 11.2 Hz, 1H), 2.40 (s, 6H), 1.39 (s, 12 H).Preparation of Intermediate 137: 2-(3,5-Dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-2-hydroxyacetamide (racemic mixture)

[0235] l,l'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (0.61 g, 0.82 mmol) was added to a degassed suspension of 2-(4-bromo-3,5-dimethylphenyl)-2-hydroxyacetamide (racemic mixture, 5.00 g, 18.2 mmol), bis(pinacolato)diborane (5.58 g, 21.5 mmol), and potassium acetate (5.87 g, 58.6 mmol) in 1,4-dioxane (50 mL) under N2 atmosphere. The reaction mixture was warmed to 100 °C for 15 h. The reaction mixture was cooled to ambient temperature and filtered through a pad of diatomaceous earth which was rinsed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure at 45 °C to give a residue which was purified by silica gel chromatography using a gradient of 0 to 100% MeOH in DCM to give the title compound (3.02 g) as a solid. ES-MS m / z 306 (M+H).Preparation of Intermediate 138: (R)-l-(4-Bromo-3,5-dimethylphenyl)ethane-l,2-diol

[0236] A solution of AD-mix-beta (Sigma-Aldrich catalog number 392766, 14 g) in a mixture of / -BuOH (50 mL) and water (50 mL) then cooled to 0 °C. 2-Bromo-l,3-dimethyl-5- vinylbenzene (2.5 g, 12 mmol) was added slowly under nitrogen and the reaction mixture was allowed to warm to ambient temperature and stirred overnight. Additional AD-mix-beta (10 g) was added and the reaction was heated to 50 °C and stirred for 20 h. After 20 h, additional AD- mix-beta (10 g) and the reaction continued to stir at 40 °C for 7 h. The reaction mixture was cooled to RT and sodium sulfite was added (38 g). The reaction mixture was stirred for 1 h, then was diluted with EtOAc and extracted with EtOAc (x3). The combined organic layers were washed with sat. aq. NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give the title compound (1.65 g) as a solid. 'H-NMR (400 MHz, DMSO- e) 8 7.13 (s, 2H), 5.24 (d, J = 4.2 Hz, 1H), 4.69 (t, J = 5.8 Hz, 1H), 4.54 - 4.36 (m, 1H), 3.41 (td, J = 5.8, 1.5 Hz, 2H), 2.35 (s, 6H).Preparation of Intermediate 139: (S)-l-(4-Bromo-3,5-dimethylphenyl)ethane-l,2-diol

[0237] The title compound was prepared as described in the Preparation of Intermediate 138 using AD-mix-alpha (Sigma-Aldrich catalog # 392758). 'H-NMR (400 MHz, DMSO-tL) 6 7.13 (s, 2H), 5.24 (d, 1= 4.2 Hz, 1H), 4.69 (t, 1= 5.8 Hz, 1H), 4.47-4.43 (m, 1H), 3.42-3.39 (m, 2H), 2.35 (s, 6H).Preparation of Intermediate 140: 2-Bromo-5-(chloromethyl)-l,3-dimethylbenzene;

[0238] SOCh (33 g, 20.5 mL, 278 mmol) was added dropwise to a cooled stirred solution of (4- bromo-3,5-dimethylphenyl)methanol (20 g, 92 mmol) in DCM (200 mL) and DMF (1 mL) in a 3-neck RBF (500 mL) at 0 °C. The reaction mixture was warmed to RT over 2 h and then concentrated under reduced pressure to give the title compound (20.0 g) as a solid. 'H-NMR (400 MHz, DMSO- e) 8 7.23 (s, 2H), 4.66 (s, 2H), 2.40 (s, 6H).Preparation of Intermediate 141 : 2-(4-Bromo-3,5-dimethylphenyl)acetonitrile

[0239] 2-Bromo-5-(chloromethyl)-l,3-dimethylbenzene (20 g, 80 mmol) and KCN (16.7 g, 254 mmol) were sequentially added to DMSO (200 mL) at RT in a 3-neck RBF (500 mL). The reaction mixture was stirred for 16 h, diluted with water (500 mL) and EtOAc (300 mL) and the layers separated. The aqueous layer was extracted with EtOAc (2 x 300 mL). The combined organic layers were extracted with sat. aq. NaCl (50 mL), dried Na2SO4, filtered and concentrated to give the title compound (20.0 g) as a solid. ’H-NMR (400 MHz, DMSO- e) 8 7.11 (s, 2H), 3.90 (s, 2H), 2.31 (s, 6H).Preparation of Intermediate 142: 2-(4-Bromo-3,5-dimethylphenyl)acetamide

[0240] 2-(4-Bromo-3,5-dimethylphenyl)acetonitrile (20.5 g, 61.3 mmol) and K2CO3 (8.86 g, 63.5 mmol) were sequentially added to DMSO (200 mL) in a 3-neck RBF (500 mL) at 10 °C. An aqueous solution of H2O2 (13 mL, 30 wt%, 0.13 mol) was added portion wise and then thereaction mixture was allowed to warm to RT and stir for 16 h. The reaction was diluted with water (600 mL) and the resulting solid was collected by filtration, washed with water (100 mL) and then dried under vacuum at 45 °C to give the title compound (16.5 g) as a solid. ES-MS m z 242, 244 (M+H).Preparation of Intermediate 143: 2-(3,5-Dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)acetamide

[0241] A solution of 2-(4-bromo-3,5-dimethylphenyl)acetamide (16.5 g, 50.3 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (16.8 g, 65.5 mmol), potassium acetate (15.1 g, 152 mmol) and Pd(dppf)C12 (3.76 g, 5.09 mmol) in 1,4-dioxane (200 mb) was de-gassed and refilled with N2 (x3) then stirred at 100 °C for 48 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in PE to give the title compound (12.1 g) as a solid. ES-MS m 'z 290 (M+H).Preparation of Intermediate 144: 4-amino-3-ethyl-5-methylbenzonitrile

[0242] To a 250 mL 3-neck round bottom flask with a magnetic stir bar was charged with toluene (80 mL), followed by the addition of 4-bromo-2-ethyl-6-m ethylaniline (15.0 g, 68.7 mmol), KI (3.88 g, 22.2 mmol), Cui (2.22 g, 11.1 mmol), NaCN (15.0 g, 291 mmol) and methyl[2-(methylamino)ethyl]amine (9.98 g, 111 mmol) at 24 °C. Then the reaction mixture was stirred vigorously at 120 °C for 32 h, cooled down to ambient temperature and poured into water (200 mL) at 25 °C. The mixture was extracted with EtOAc (50 mL x 3). The water phase was adjusted to pH =11 with NaOH (1.0 M in H2O), then poured into aq. NaClO (10%, 200 mL)to quench the unreacted NaCN. The combined organic layer was washed with sat. aq. NaCl (100 mL x 2), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (4.10 g) as solid. ES-MS m / z 161 (M+H).Preparation of Intermediate 145: 4-bromo-3-ethyl-5-methylbenzaldehyde

[0243] To 100 mL 3-neck round bottom flask was charged with DCM (40 mL), followed by the addition of mixture of 4-bromo-3-ethyl-5-methylbenzonitrile (2.2 g, 83.4 wt% purity, 8.2 mmol). Then diisobutylaluminum hydride (1.0 M in toluene, 18 mL, 18 mmol) was added dropwise over 1 min at -70 °C. The mixture was stirred at -70 °C for 2 h and then warmed to 20 °C and stirred at 20 °C for 2 h. The reaction mixture was poured into 50 mL HC1 (1.0 M in H2O) at 25 °C, heated to 40 °C for 30 mins and then cooled to ambient temperature, diluted with H2O (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic phase was dried over ISfeSCU, filtered and the obtained filtrate was concentrated under reduced pressure to give a residue. TLC (5:1 petroleum ether: EtOAc) R / = 0.4. The residue was purified by flash silica gel chromatography using a gradient of 0 to 10% EtOAc in petroleum to give the title compound (1.30 g, 73.5 wt% purity) as oil. 'H-N.VIR (400 MHz, DMSO-t / 6) 59.96 - 9.95 (m, 1H), 7.70 (d, J = 8.4 Hz, 2H), 2.81 (q, J = 7.5 Hz, 2H), 2.46 (s, 3H), 1.24 - 1.18 (m, 3H).Preparation of Intermediate 146: rac-2-(4-bromo-3-ethyl-5-methylphenyl)-2-hydroxyacetonitrile

[0244] To a 100 mL one-neck round bottom flask was charged with H2O (5 mL) and 4-bromo-3- ethyl-5-methylbenzaldehyde (1.30 g, 73.5 wt% purity, 4.21 mmol), followed by the addition of NaHSCh (0.75 g, 6.85 mmol) in H2O (2 mL) at 5 °C. Then NaCN (0.53 g,10.6 mmol) in H2O (3 mL) was added dropwise over 5 mins at 5 °C. The resulting mixture was stirred at 22 °C for 16 h. The reaction mixture was filtered. The filtrate was quenched with aq. NaClO (10%, 100 mL)and was adjusted to pH > 11 with NaOH (1.0 M in H2O). The filter cake was rinsed with H2O (10 mL), then collected to give the title compound (0.90 g, 70 wt% purity) as solid. ’H-NMR (400 MHz, DMSO-t#,) 6 9.96 (s, 1H), 7.30 (s, 1H), 7.27 (s, 1H), 5.69 (s, 1H), 2.75 (q, J = 7.5 Hz, 2H), 2.43 - 2.35 (m, 3H), 1.17 (t, J = 7.5 Hz, 3H).Preparation of Intermediate 147: rac-2-(4-bromo-3-ethyl-5-methylphenyl)-2-hydroxyacetamide

[0245] To a 100 mL one-neck round bottom flask was charged with 1,4-di oxane (10 mL) and rac-2-(4-bromo-3-ethyl-5-methylphenyl)-2-hydroxyacetonitrile (racemic mixture, 0.90 g, 70 wt% purity, 2.48 mmol), followed by the addition of HC1 (4.0 M in 1.4-dioxane, 10 mL, 40 mmol) dropwise over 2 mins at 0 °C. The mixture was stirred at 22 °C for 12 h, quenched by adding sat. Na2C0.3 (20 mL) at 0 °C, diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3) The combined organic layer was washed with sat. aq. NaCl (20 mL x 2), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was triturated with MTBE (5 mL) at 22 °C for 15 min. The mixture was filtered, and the filter cake was rinsed with MTBE (5 mL) to give the title compound (0.25 g, 83.2 wt% purity) was obtained as solid. ES-MS m / z 271, 273 (M+H).Preparation of Intermediate 148: methyl 2-cyclopropyl-6-(trifluoromethyl)nicotinat

[0246] To a 1 L 3-neck round bottom flask was charged with 1,4-dioxane (400 mL) and H2O (100 mL) was added methyl 2-chloro-6-(trifluoromethyl)nicotinate (25.0 g, 103 mmol), cyclopropaneboronic acid (12.0 g, 136 mmol) and K2CO3 (43.0 g, 310 mmol). The mixture was de-gassed and backfilled with N2 for three times before and after adding chloro(crotyl)(tri- / c / 7- butylphosphine)palladium(II) (CAS# 1334497-00-5, 4.4 g, 10 mmol). Then the reaction mixture was stirred at 90 °C for 3 h, cooled down to ambient temperature, and concentrated underreduced pressure to give a residue. The residue was triturated with DCM (400 mL) at 22 °C for 30 mins, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (1:5 petroleum ether : EtOAc) Ry = 0.5. The residue was purified by flash silica gel chromatography using a gradient of 0 to 10% MeOH in DCM to give the title compound (13.0 g) as an oil. ES-MS m / 'z 245 (M+H).Preparation of Intermediate 149: 2-cyclopropyl-6-(trifluoromethyl)nicotinic acid

[0247] To a 250 mL one-neck round bottom flask with a magnetic stir bar was charged with MeOH (90 mL), followed by the addition of methyl 2-cyclopropyl-6-(trifluoromethyl)nicotinate (13.0 g, 52.5 mmol) and NaOH (1.0 M in H2O, 90 mL, 90 mmol) at 0 °C. The reaction mixture was stirred at 24 °C for 12 h, concentrated under reduced pressure, and adjusted to pH = 2~3 with HC1 (1.0 M in H2O, 100 mL) under stirring. The mixture was extracted with EtOAc (50 mL x 2). The combined organic layer was washed with sat. aq. NaCl (50 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (10.0 g) as solid. ES-MS m / z 213 (M+H).

[0248] Alternative Procedure: Methyl 2-cyclopropyl-6-(trifluoromethyl)nicotinate (44.87 g, 70% Wt, 128.1 mmol) was dissolved in THF (0.15 L) and MeOH (0.15 L). A solution of lithium hydroxide (9.46 g, 395 mmol) in Water (0.20 L) was added. Stirred in a 50 °C metal heating block under N2 for 2 h. The mixture was filtered through diatomaceous earth, and the cake rinsed with water (~50 mL). The filtrate was partially concentrated until most volatile solvents removed then transferred to a separating funnel and extracted with DCM (2 x 0.10 L). To aqueous layer at RT was added 5 M aq. HC1 (80 mL) with stirring in an ice bath for 30 min. The resulting solid was collected by filtration and washed with chilled 0.5 M HC1 (100 mL) then with chilled water (2 x 0.10 L). The solid was dried in a vacuum oven to give the title compound.(28.42 g). ES-MS m z 230 (M+H).Preparation of Intermediate 150: N-((2S,4R)-l-(5-bromo-2-methoxypyridin-3-yl)-4-carbamoyl- 2-methylpiperidin-4-yl)-2-cyclopropyl-6-(trifluoromethyl)nicotinamide

[0249] To a 100 mL round bottom flask with a magnetic stir was charged with DMF (20 mL), followed by the addition of (2S,4R)-4-amino-l-(5-bromo-2-methoxypyridin-3-yl)-2- methylpiperidine-4-carboxamide (6.3 g, 18 mmol), DIEA (7.2 g, 55 mmol), 2-cyclopropyl-6- (trifluoromethyl)nicotinic acid (5.7 g, 24 mmol) and HATU (8.7 g, 22 mmol) at 25 °C, then stirred for 2 h, concentrated under reduced pressure to give a residue. The residue was poured into H2O (70 mL) at 25 °C and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with sat. aq. NaCl (50 mL), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (22 g, 37.5 wt% purity) as oil. ES-MS m / z 555, 557 (M+H).Preparation of Intermediate 151 : (5R,7S)-8-(5-bromo-2-methoxypyridin-3-yl)-2-(2-cyclopropyl-6-(trifhioromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0250] To a 250 mL 3-neck round bottom flask with a magnetic stir bar was charged with THF (40 mL), followed by the addition of N-((2S,4R)-l-(5-bromo-2-methoxypyridin-3-yl)-4- carbamoyl-2-methylpiperidin-4-yl)-2-cyclopropyl-6-(trifluoromethyl)nicotinamide (22 g, 37.5 wt% purity, 15 mmol) and KO / Bu (1.0 M in Z-BuOH. 52 mL, 52 mmol) at 25 °C. Then the reaction mixture was de-gassed and refilled with N2 for 3 times, stirred at 70 °C for 2 h, cooled down to ambient temperature and poured into H2O (50 mL). The mixture was extracted with EtOAc (50 mL x 3). The combined organic layer was washed with sat. aq. NaCl (40 mL), driedover Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (10 g, 58.5 wt% purity) as oil. ES-MS m / z 538, 540 (M+H).Preparation of Intermediate 152: (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-8-(2- methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-yl)-7-methyl-l,3,8- triazaspiro[4.5]dec- 1 -en-4-one

[0251] To a 250 mL one-neck round bottom flask with a magnetic stir bar was charged with methoxy cyclopentane (100 mL), followed by the addition of (5R,7S)-8-(5-bromo-2- methoxypyridin-3-yl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyri din-3-yl)-7-methyl- 1,3,8- triazaspiro[4.5]dec-l-en-4-one (10 g, 58.5 wt% purity, 11 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (2.9 g, 11 mmol), KO Ac (2.1 g, 20 mmol) and methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl)(2'-methylamino- 1 , 1 '-biphenyl -2- yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81-5, 1.5 g, 1.7 mmol) at 25 °C. Then the reaction mixture was de-gassed and refdled with N2 for 3 times, stirred at 80 °C for 2 h, cooled down to ambient temperature, and concentrated under reduced pressure to give a residue. TLC (2: 1 petroleum ether : EtOAc) R / = 0.4. The residue was purified by flash silica gel chromatography using a gradient of 20 to 40% EtOAc in petroleum ether to give the title compound (6.7 g, 70 wt% purity) as oil. ES-MS m / z 586 (M+H).Preparation of Intermediate 153: 2-(4-bromo-3,5-dimethylphenyl)propanenitrile (racemic mixture)

[0252] To a vigorous stirring THF (1 mL) mixture of 2-(4-bromo-3,5-dimethylphenyl)acetonitrile (0.50 g, 1.82 mmol) in a 40 mL vial was added LiHMDS in THF (2.2 mL, 1 molar, 2.2 mmol)dropwise over 1 min at -70 °C. The mixture was stirred at -70 °C for 30 min, then iodomethane (0.25 g, 1.73 mmol) in THF (0.5 mL) was added dropwise at 22 °C. The resulting mixture was stirred at 22 °C (external temperature) for 2 h. The reaction mixture was poured into 20 mL NH4CI and. extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl, dried over Na2SC>4, filtered, washed with EtOAc. The obtained filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SIO2, EtOAc / n-hexane = 1 / 10, Rf = 0.6, UV) to give the title compound (0.120 g) as an oil.Preparation of Intermediate 154: 2-(4-bromo-3,5-dimethylphenyl)propanamide (racemic mixture);

[0253] To a 40 mL vail with a magnetic stir bar was charged with DMSO (5 mL), followed by the addition of 2-(4-bromo-3,5-dimethylphenyl)propanenitrile (racemic mixture, 0.120 g, 0.30 mmol) and potassium carbonate (0.044 g, 0.31 mmol)at 15 °C (external temperature). Then H2O2 (0.052 mL, 30% Wt, 0.51 mmol) was added dropwise for 1 min at 15 °C. The reaction mixture was allowed to stir vigorously for 12 h. The reaction mixture was quenched by adding 10 mL water at 20 °C (external temperature) to get the crude reaction mixture, then the crude reaction mixture was filtered with filter paper. The filter cake was rinsed with 2 mL water, and the filter cake was dried under reduced pressure to give a crude product. The aqueous phase was quenched by adding 10 mL sat. ISfeSCL. The crude product was used directly to the next step without further purification. ES-MS m / z 256 / 258 (M+H).Preparation of Intermediate 155: 2-(4-bromo-3,5-dimethylphenyl)butanenitrile (racemic mixture)

[0254] To a vigorous stirring THF (6 mL) mixture of 2-(4-bromo-3,5- dimethylphenyl)acetonitrile (0.60 g, 2.18 mmol) in a 40 mL vial was added LiHMDS in THF (2.40 mL, 2.40 mmol) dropwise over 1 min at -70 °C. The mixture was stirred at -70 °C for 30 min, then iodoethane (0.310 g, 1.95 mmol) in THF (2 mL) was added dropwise over 1 min at -70 °C. The resulting mixture was stirred at 22 °C for 12 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl, and then dried over Na2SO4. The obtained fdtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by prep-TLC (SIO2, EtOAc / n-hexane = 1 / 10, R / = 0.6, UV), then the SiO2 powder was soaked with 10 mL MeOH, and filtered under reduced pressure, rinsed with 10 mL MeOH. The filtrate was concentrated under reduced pressure afforded the product as a liquid (0.210 g with 61% purity).Preparation of Intermediate 156: 2-(4-bromo-3,5-dimethylphenyl)butanamide (racemic mixture)

[0255] To a 40 mL vail with a magnetic stir bar was charged with DMSO (2 mL), followed by the addition of 2-(4-bromo-3,5-dimethylphenyl)butanenitrile (0.210 g, 0.513 mmol) and Potassium carbonate (0.21 g, 1.49 mmol) at 15 °C(extemal temperature). Hydrogen peroxide (0.256 mL, 30% Wt, 4.81 Eq, 2.47 mmol) was dropwise added for 5 mins at 15 °C (external temperature). The reaction mixture was allowed to stir vigorously at 15 °C (external temperature) for 12 h. The reaction mixture was diluted with 10 mL (H2O) and precipitate was observed. The reaction mixture was filtered. The filter cake was rinsed with H2O, dried under reduced pressure to give the crude product (0.090 g, 67% purity). ES-MS m / z M+H=270 / 272.Preparation of Intermediate 157: (R)-l-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl)ethane- 1 ,2-diol

[0256] 1 L round bottom flask with a magnetic stir bar was charged (R)-l-(4-bromo-3,5- dimethylphenyl)ethane-l,2-diol (5.22 g, 21.3 mmol), Bis(pinacolato)diboron (7.99 g, 31.5 mmol), 1,4-Dioxane (60 mL) and sparged with N2. Potassium acetate (6.26 g, 63.8 mmol) and l,l'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (1.53 g, 2.09 mmol) were added and the reaction mixture was warmed to 100 °C and stirred for 16 h. The reaction mixture was cooled to ambient temperature and filtered through a pad of diatomaceous earth. The resulting solution was concentrated under reduced pressure to a residue. The residue was diluted with EtOAc, washed with water (500 mL). The aqueous solution was extracted with EtOAc (5 * 100 mL). The combined organics were washed with sat. aq. NaCl, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified by flash chromatography on silica gel (40-80% EA in cyclohexane) to afford the tittle compound (3.75 g). ES-MS m / z 293 (M+H).Preparation of Intermediate 158: 2-(4-bromo-3,5-dimethylphenyl)acetic acid

[0257] A suspension of 2,6-Dimethyl-4-iodobromobenzene (150.5 g, 484 mmol), ethyl 3- oxobutanoate (189.5 g, 1456 mmol), Potassium phosphate, tribasic (308.5 g, 1453 mmol), anhydrous EtOH (85 mL), Cui (18.8 g, 98.7 mmol) in DMSO (1000 mL) was purged with N2 and stirred at 80 °C for 24 h. The reaction mixture was cooled to ambient temperature, filtered through a pad of diatomaceous earth and rinsed with THF. NaOH (486 mL, 2 M, 972 mmol) was added to the resulting filtrate and stirred at 25 °C for 2 h. A second batch of NaOH (240 mL, 2 M, 480 mmol) was added and the reaction mixture stirred at 25 °C for 16 h. The reaction was quenched with water / NH4OH (1000 mL; 10 / 1). After separation of the layers, the pH of theaqueous layer was adjusted to around 2-3, by addition of 4 M HC1. The formed precipitate was filtered and the resulting solid triturated with heptane / DCM (600 mL; 10 / 1) to afford the title compound (60.6 g) as a solid. ES-MS m / z 289 (M-H).Preparation of Intermediate 159: 2-(4-bromo-3,5-dimethylphenyl)-N-(tetrahydro-2H-pyran-4- yljacetamide

[0258] A solution of Tetrahydro-2H-pyran-4-amine (0.11 g, 1.06 mmol), 2-(4-bromo-3,5- dimethylphenyl)acetic acid (0.26 g, 1.06 mmol), HATU (0.68 g, 1.67 mmol), Diisopropylethylamine (0.82 mL, 4.80 mmol) in DMF (6 mL) was stirred at ambient temperature for 4 h. The reaction mixture was diluted with EtOAc (40 mL), washed with water (2 x 20 mL), sat. aq. NaCl (20 mL), dried over anhydrous MgSCL, filtered and concentrated to afford the title compound (0.33 g) as a solid. ES-MS m 'z 326, 328 (M+H).Preparation of Intermediate 160: 2-(4-bromo-3,5-dimethylphenyl)-N-methylacetamide

[0259] Oxalyl chloride (0.30 mL, 3.42 mmol) was added to a 0 °C cooled solution of 2-(4- bromo-3,5-dimethylphenyl)acetic acid (0.27 g, 1.11 mmol) in DCM (5.0 mL) and DMF (0.05 mL) and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to an oil. The oil was dissolved in DCM (1 mL) and cooled in a 0 °C ice bath. A solution of methylamine (0.39 mL, 33 wt%, 3.36 mmol) in EtOH was added and the reaction mixture stirred for 1 h. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel (0-10% MeOH in DCM) to afford the tittle compound (0.19 g) as a solid. ES-MS m / z 256, 258 (M+H).Preparation of Intermediate 161 : 4-amino-l,l,l-trifluorobut-3-en-2-one

[0260] A solution of 4-Ethoxy-l,l,l-trifhiorobut-3-en -2-one (80 g, 450 mmol) and ammonia in MeOH (250 mL, 7 N, 1750 mmol) was stirred vigorously at 25 °C for 16 h. The mixture was concentrated under reduced pressure to obtain the crude material as a yellow oil. The oil was taken to the next step without purification.Preparation of Intermediate 162: ethyl 2-cyclobutyl-6-(trifluoromethyl)nicotinate

[0261] A solution of 4-amino-l,l,l-trifluorobut-3-en-2-one (67 g, 80 wt%, 390 mmol), ethyl 3- cyclobutyl-3-oxopropanoate (110 g, 633 mmol), and TFA (47 mL, 600 mmol) in toluene (500 mL) was stirred vigorously at 110 °C for 16 h. The reaction mixture was cooled to ambient temperature and concentrated to a residue. The residue was suspended in EtOAc (500 mL) and a 15% Na2COs solution. After separation, the aqueous layer was extracted with EtOAc (3 * 500 mL). The combined organics were washed with sat. aq. NaCl (500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified by flash chromatography on silica gel (0-40% EtOAc in n-hexane) to afford the title compound (44 g) as a liquid.Preparation of Intermediate 163: 2-cyclobutyl-6-(trifluoromethyl)nicotinic acid

[0262] NaOH (10 g, 240 mmol), was added to a solution of ethyl 2-cyclobutyL6-(trifluoromethyl)nicotinate (44 g, 157 mmol) in THF (150 mL), MeOH (150 mL), water (150mL) and stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in water (200 mL), then the pH was adjusted to 3-4 by addition of 4 N HC1. The formed precipitate was filtered and rinsed with water (5 x 100 mL) to afford the title compound (34 g) as a solid.Preparation of Intermediate 164: 2-cyclobutyl-4-(trifluoromethyl)benzoic acid;

[0263] To a 500 mL 3-neck round bottom flask with a magnetic stir bar was charged with DMA (150 mL), followed by the addition of methyl 2-bromo-4-(trifluoromethyl)benzoate (5.0 g, 17 mmol), bromocyclobutane (3.2 g, 23 mmol), picolinimidamide hydrochloride (0.7 g, 4 mmol), tetrabutylammonium iodide (10 g, 27 mmol), nickel chloride, dimethoxyethane adduct (1.2 g, 5.4 mmol) and zinc (3.6 g, 55 mmol) at 20 °C. The system was de-gassed and refilled with N2 for three times before vigorously stirring at 50 °C for 16 h. The reaction mixture was cooled to room temperature, filtered and the filter cake was washed with EtOAc (200 mL x 3). The filtrate was concentrated under reduced pressure. The residue was diluted with H2O (500 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with sat. aq. NaCl (200 mL x 2), and dried over anhydrous Na2SO4. The Na2SO4 was filtered off and further washed with EtOAc (200 mL). The obtained filtrate was concentrated under reduced pressure and the residue was purified by prep-HPLC [column: Phenomenex luna cl 8 250mm x 100mm, 15 pm; mobile phase: [A: H2O(+ 0.2% FA); B: ACN]; gradient B%: 40-75%] to give the title compound (0.500 g) as a solid. ES-MS m / z 243 (M-H).Preparation of Intermediate 165: methyl 2-chloro-4-(4,4,4-trifluorobutoxy)benzoate;

[0264] To a cooled solution of methyl 2-chloro-4-hydroxybenzoate (5.0 g, 26.0 mmol) in toluene (100 mL) in an ice bath under nitrogen was sequentially added N-{[(E)-piperidine-l- carbonyl]imino}piperidine-l -carboxamide (10.2 g, 40.3 mmol), 4,4,4-trifluorobutan-l-ol (3.4 g, 26.9 mmol), and tributyl phosphine (8.2 g, 10.0 mL, 40.3 mmol). The reaction was warmed to room temperature and stirred 36 hr. After 1 hr, the reaction mixture forms a gel. The reaction was diluted with n-heptane (250 mL), filtered to remove solids and the filtrate was concentrated to give the crude product that was purified by silica gel chromatography using 0-20% EtOAc / cyclohexane to give the title compound (7.2 g) as an oil. ES-MS m / z 297 (M+H)Preparation of Intermediate 166: methyl 2-cyclopropyl-4-(4,4,4-trifluorobutoxy)benzoate

[0265] A mixture of methyl 2-chloro-4-(4,4,4-trifluorobutoxy)benzoate (7.1 g, 24.0 mmol), potassium phosphate (10.2 g, 48.0 mmol), and cyclopropylboronic acid (7.2 g, 84.1 mmol) in Toluene (100 mL) and Water (10 mL) was purged with nitrogen at 45 °C (external temperature) in a IL RBF fitted with a reflux condenser. Tricyclohexylphosphane (0.67 g, 2.4 mmol) and palladium(II) acetate (0.54 g, 2.41 mmol) were sequentially added and the reaction mixture was heated at 120 °C (external temperature) for 20 hr. The reaction mixture was cooled to room temperature, filtered through Diatomaceous earth using EtOAc and concentrated. The crude product was purified by silica gel chromatography using 0-25% EtOAc / cyclohexane to give the title compound as an oil (6.5 g). ES-MS m z 303 (M+H)Preparation of Intermediate 167: 2-cyclopropyl-4-(4,4,4-trifluorobutoxy)benzoic acid

[0266] An aqueous solution of sodium hydroxide (16.6 mL, 5 M, 82.9 mmol) was added to a solution of methyl 2-cyclopropyl-4-(4,4,4-trifluorobutoxy)benzoate (5.012 g, 1 Eq, 16.58 mmol) in MeOH (50 mL) and Water (33 mL) at room temperature. The reaction mixture was stirred 2hr, and then concentrated to remove volatile organics under vacuum to give a mixture. The mixture was filtered through fluted filter paper to remove solids. The filtrate was treated with a 5N aqueous solution of HC1 (17 mL), diluted with water (100 mL) and stirred 30 min to give a suspension. The suspension was filtered, and the recovered solids were washed with water (10 mL) to give the title compound after drying in a vacuum oven at 45 °C overnight as a solid (3.9 g). ES-MS m'z 289 (M+H)Preparation of Intermediate 168: tert-butyl (2S,4R)-4-carbamoyl-4-(2-cyclopropyl-6- (trifluoromethyl)nicotinamido)-2-rnethylpiperidine-l -carboxylate;

[0267] HATU (11.3 g, 29.6 mmol) was added slowly to a solution of Zc / 7-butyl (2S,4R)-4- amino-4-carbamoyl-2-methylpiperidine-l -carboxylate (7.62 g, 29.6 mmol), 2-cyclopropyl-6- (trifluoromethyl)nicotinic acid (7.53 g, 32.6 mmol), DIEA (10.3 m , 7.66 g, 59.2 mmol) in DMF (100 mL) and stirred at ambient temperature for 14 h. The reaction was quenched with 200 m of ice-cold water. The formed precipitate was filtered and rinsed with water (2 x 100 mL), airdried to obtain the tittle compound (13.1 g) as a solid. ES-MS m / z 471 (M+H).

[0268] The intermediate in the following table was prepared in a manner similar to the preparation of Intermediate 168.Preparation of Intermediate 170: tert-butyl (5R,7S)-2-(6-ethoxy-2-(trifluoromethyl)pyridin-3-yl)- 7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate

[0269] A suspension of Ze / V-butyl (2S,4R)-4-carbamoyl-4-(6-chloro-2- (trifluoromethyl)nicotinamido)-2-methylpiperidine-l -carboxylate (1.278 g, 2.749 mmol), KO / Bu (1.579 g, 14.071 mmol) in EtOH (24 mb) was stirred at 80 °C for 18 h. The reaction mixture was cooled to ambient temperature and diluted with EtOAc (50 mL). The resulting solution was washed with water (2 x 20 mL), sat. aq. NaCl (20 mL), dried over anhydrous magnesium sulfate, fdtered and concentrated under reduced pressure to afford the title compound (1.26 g) as an oil. ES-MS m / z 457 (M+H).Preparation of Intermediate 171 : N-((2S,4R)-l-(5-bromo-2-methoxypyridin-3-yl)-4-carbamoyl-2-methylpiperidin-4-yl)-2-cyclobutyl-6-(trifluoromethyl)nicotinarnide

[0270] To a 100 mL 3-neck round bottom flask with a magnetic stir bar was charged with DMF (50 mL), followed by addition of 2-cyclobutyl-6-(trifluoromethyl)nicotinic acid (3.0 g, 11 mmol), (2S,4R)-4-amino-l-(5-bromo-2-methoxypyridin-3-yl)-2-methylpiperidine-4- carboxamide (4.6 g, 13 mmol), DIEA (5 g, 40 mmol) and HATU (7.7 g, 20 mmol). The mixture was purged with N2 for 2 mins before vigorously stirring at 25 °C for 2 h, diluted with H2O (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with sat. aq. NaCl (100 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (10.6 g, 51 wt% purity) as solid. ES-MS m 'z 569, 571 (M+H).Preparation of Intermediate 172: (5R,7S)-8-(5-bromo-2-methoxypyridin-3-yl)-2-(2-cyclobutyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0271] To a 100 mL one-neck round bottom flask with a magnetic stir bar was charged with EtOH (50 mL), followed by the addition of N-((2S,4R)-l-(5-bromo-2-methoxypyridin-3-yl)-4- carbamoyl-2-methylpiperidin-4-yl)-2-cyclobutyl-6-(trifluoromethyl)nicotinamide (10.6 g, 51 wt% purity, 9.48 mmol) and KO / Bu (8.68 g, 75.8 mmol). The mixture was stirred at 80 °C for 4 h, cooled down to ambient temperature and concentrated under reduced pressure to give a residue. The residue was diluted with H2O (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with sat. aq. NaCl (100 mL x 2), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give the crude product. TLC (1 :1 n-hexane: EtOAc) R / = 0.5. The residue was purified by flash silica gel chromatography using a gradient of 0 to 60% EtOAc in petroleum ether to give the title compound (19 g) as solid. ES-MS m / z 551.9, 553.7. (M+H).Preparation of Intermediate 173: (5-((5R,7S)-2-(2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-6-methoxypyridin-3-yl)boronic acid

[0272] To a 40 mL via with a magnetic stir bar was charged with 1,4-dioxane (5 mL), (5R,7S)-8- (5-bromo-2-methoxypyridin-3-yl)-2-(2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl- l,3,8-triazaspiro[4.5]dec-l-en-4-one (1.00 g, 1.68 mmol), potassium trimethylacetate (0.68 g, 4.75 mmol) and bis(pinacolato)diborane (0.80 g, 3.09 mmol). The mixture was de-gassed and refilled with N2 for three times before and after adding Methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl)(2'-methylamino- 1 , 1 '-biphenyl -2-yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81-5, 0.27 g, 0.31 mmol). Then the reaction mixture was stirred at 100 °C for 12 h under N2. The reaction mixture was concentrated under reduced pressure directly to give the crude product, which was purified by prep-HPLC using a gradient of 30 to 60% ACN in H2O (0.2% FA) to give the title compound (0.81 g) as solid. ES-MS m z 518.1 (M+H).Preparation of Intermediate 174: (5R,7S)-8-(5-bromo-2-hydroxypyridin-3-yl)-2-(2-cyclobutyl-6- (trifhjoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0273] To a vigorous stirring DCM (50 mL) mixture of (5R,7S)-8-(5-bromo-2-methoxypyridin-3-yl)-2-(2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (4.8 g, 8.6 mmol) in a 250 mL three-neck round bottom flask was added boron tribromide (2.0 M in DCM, 65 mL, 130 mmol) dropwise over 2 mins at -68 °C. The resulting mixture was stirred at 20 °C for 12 h, quenched by adding MeOH (100 mL) at 0 °C. The reaction mixture was directly concentrated under reduced pressure to give a residue, then diluted with H2O (200 mL) and extracted with DCM (100 mL x 2). The combined organic layer was washed with sat. aq. NaCl (50 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was triturated with MTBE (20 mL) at 20 °C for 15 min. The mixture was filtered, and the filter cake was the title compound (98 g) as solid. ES-MS m / z 537, 539. (M+H).Preparation of Intermediate 175: (5R,7S)-8-(5-bromo-2-(difluoromethoxy)pyridin-3-yl)-2-(2- cyclobutyl-6-(trifhioromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0274] To a 100 mL 1-neck round bottom flask with a magnetic stir bar was charged with ACN (40 mL), followed by the addition of (5R,7S)-8-(5-bromo-2-hydroxypyridin-3-yl)-2-(2- cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.40 g, 0.71 mmol), K2CO3 (0.21 g, 1.53 mmol) and sodium chloro(difluoro)acetate (0.12 g, 0.80 mmol) at 10 °C. The mixture was de-gassed and refilled with N2 for three times before vigorously stirring at 100 °C for 1 h, cooled down to room temperature, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase prep-HPLC using a gradient of 10 to 40% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.14 g) as solid. ES-MS m / z 587, 589 (M+H).Preparation of Intermediate 176: tert-butyl (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin- 3-yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate;

[0275] A solution of KOtBu (15.6 g, 139 mL, 1 M, 139 mmol) in t-BuOH was added to tertbutyl (2S,4R)-4-carbamoyl-4-(2-cyclopropyl-6-(trifluoromethyl)nicotinamido)-2- methylpiperidine-l-carboxylate and stirred at 80 °C for 3 h. The reaction mixture was diluted with EtOAc and the pH adjusted to ~4-5 by addition of a 5% citric acid solution and extracted with EtOAc. The combined organics were washed with brie, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the tittle compound (12.6 g) as a foam. ES-MS m / z 453 (M+H).Preparation of Intermediate 177: (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one dihydrochloride

[0276] A solution of HC1 (50 mL, 9.1 g, 5 M, 250 mmol) in 1,4-Dioxane was added to a solution of Zc’ / V-butyl (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-l,3,8- triazaspiro[4.5]dec-l-ene-8-carboxylate (12.6 g, 27.8 mmol) in 1,4-Dioxane (250 mL) under N2 atmosphere and stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure to afford the tittle compound (12.5 g) as a solid. ES-MS m / z 352 (M+H).Preparation of Intermediate 178: (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7- methy 1 - 1 , 3 , 8-triazaspiro[4.5 ]dec- 1 -en-4-one

[0277] To a 250 mL 1-neck round bottom flask with a magnetic stir bar was charged with EtOAc (20 mL), followed by the addition of / c77-butyl (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl) pyridin-3-yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (6.2 g, 13 mmol) and HC1 (4.0 M in EtOAc, 60 mL) at 0 °C. Then the reaction mixture was stirred vigorously at 10 °C for 12 h, concentrated under reduced pressure directly to give a residue. The residue was adjusted to pH = 7~8 with sat. aq. NaHCCh at 10 °C and further purified by reverse phase prep- HPLC using a gradient of 10 to 40% ACN in 10 mM aq. NH4HCO3 to give the title compound (4.0 g) as solid. ES-MS m / z 353 (M+H).Preparation of Intermediate 179: (5R,7S)-2-(6-ethoxy-2-(trifluoromethyl)pyridin-3-yl)-7-methyl- l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0278] TFA (15 mL) was added to a solution of Zert-butyl (5R,7S)-2-(6-ethoxy-2-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate(1.260 g, 2.760 mmol) in DCM (30 mL) and stirred at ambient temperature for 2 h. The reaction mixture was concentrated under reduced pressure to a brown oil. The oil was re-suspended in a CHCh / IPA (3 / 1 v / v) solution and washed with a saturated solution of NaHCCh. The aqueous layer was extracted twice with a CHCh / IPA solution. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound (1.066 g) as a foam. ES-MS m / z 357 (M+H).Preparation of Intermediate 180: methyl 2-cyclopropyl-6-methoxynicotinate

[0279] To a 5000 mL 3 neck RBF (with a refluxing condenser) with a magnetic stir bar was charged with Potassium phosphate, tribasic (278 g, 1.30 mol) and H2O (200 mL), the mixture was allowed to stir for 15 min (exothermic, thick slurry) and cooled to room temperature. Toluene (2500 mL) was added followed by the addition of methyl 2-chloro-6-methoxynicotinate (100 g, 471 mmol), cyclopropylboronic acid (85 g, 0.95 mol), tricyclohexylphosphine (28 g, 95 mmol) at 18 °C. The system was bubbled with N2 for 15 min. Palladium diacetate (12 g, 51 mmol) was added. The reaction mixture was sparged with N2 for another 5 min and reaction mixture was stirred vigorously at 115 °C for 3 h under N2, then stirred at RT. After 16 h, the organic layer was carefully decanted to another 5L flask, the remaining reaction mixture (-500 mL) was transferred to a separation funnel to remove the aqueous phase. The organic layer in the separation funnel was combined into the 5L flask, and filtered through a pad of diatomaceous earth, washed with EtOAc (200 mL x 2) and the filtrate was concentrated to give a residue, which was purified by flash silica gel chromatography (Eluent of 0-50% EtOAc / n-hexane gradient). The fraction was concentrated under reduced pressure to give the title compound (88 g) as grey solid. ES-MS m / z 208 (M+H).Preparation of Intermediate 181 : 2-cyclopropyl-6-ethoxynicotinic acid

[0280] To a 2 L RBF was charged with EtOH (500 mL) and methyl 2-cyclopropyl-6- methoxynicotinate (88 g, 0.41 mol), the mixture was sonicated for 10 min. Sodium ethanolate in EtOH (1000 mL, 20% Wt, 62.55 mol) at 18 °C (external temperature) was added. The resulting mixture was stirred at 80 °C (external) for 30 min and was pumped into a column oven (220 °C, external temperature) at the speed of 2.75 mL / min with the residential time of 20 min. After 240 min the reaction mixture was adjusted to pH=2~3 with IM HC1 aq. with stirring at 0 °C (external temperature), during which white of precipitate crashed out of the solution. The product was collected through filtration via Buchner funnel under reduced pressure, and the filter cake was further washed with 200 mL H2O and dried in high vac. The title compound (67 g) was obtained as a solid. ES-MS m / z 208 (M+H).Preparation of Intermediate 182: tert-butyl (2S,4R)-4-carbamoyl-4-(2-cyclopropyl-6- ethoxynicotinamido)-2-methylpiperidine-l -carboxylate;

[0281] To a 1 L 1-neck round bottom flask with a magnetic stir bar was added DMF (300 mL), followed by addition of 2-cyclopropyl-6-ethoxynicotinic acid (50 g, 0.20 mol), DIEA (0.12 0.65 mol), HATU (95 g, 0.24 mol) and ter / -butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine- 1-carboxylate (58 g, 0.21 mol) at 16 °C (external temperature). The system was de-gassed and refilled with N2 for three times before vigorously stirring at 36 °C (external temperature) for 2 h under N2. The reaction mixture was cooled down to RT and pour into IL H2O, white solids crashed out. The mixture was stirred for another 10 mins. The white precipitate was collected via filtration through a Buchner funnel, and the filter cake was washed with 200 mL H2O. tert- butyl (2S,4R)-4-carbamoyl-4-(2-cyclopropyl-6-ethoxynicotinamido)-2-methylpiperidine-l- carboxylate (76 g) was obtained as white solid. ES-MS m / z 447 (M+H).Preparation of Intermediate 183: / c / V-butyl (5R,7S)-2-(2-cyclopropyl-6-ethoxypyridin-3-yl)-7- methyl -4-oxo- 1 ,3 ,8-triazaspiro[4.5]dec- 1 -ene-8-carboxylate

[0282] 2-Methylpropan-2-olate potassium (150 g, 0.15 L, 1.32 mol) was added to a 3000 mL single neck RBF with a magnetic stir bar, EtOH (1500 mL), Ze / 7-butyl (2S,4R)-4-carbamoyl-4- (2-cyclopropyl-6-ethoxynicotinamido)-2-methylpiperidine-l -carboxylate (76 g, 84.9% Wt, 0.14 mol) at 16 °C (external temperature). The mixture was purged with N2 for 1 min before vigorously stirring at 80 °C (external temperature) for 1 h. The reaction mixture was cooled down before concentrated to -200 mL mixture. Then the obtained mixture was diluted with 500 mL EtOAc and pour into 1000 mL H2O. The Mixture was extracted with EtOAc (500 mL x 2, the two phases were easy to separate). The combined organic phase was washed with 1000 mL sat. aq. NaCl, dried over TXfeSCU. The Na2SC>4 was filtered via Buchner funnel under reduced pressure and further washed with 500 mL EtOAc. The filtrate was concentrated under reduced pressure to give crude product (73 g) was obtained as an orangish foam-like solid. ES-MS m / z 429 (M+H).Preparation of Intermediate 184: (5R,7S)-2-(2-cyclopropyl-6-ethoxypyridin-3-yl)-7-methyl- l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0283] HC1 in 1,4-dioxane (500 mL, 4 molar, 2.00 mol) was added to the reaction vessel2L single neck round bottom flask, containing ZerZ-butyl (5R,7S)-2-(2-cyclopropyl-6- ethoxypyridin-3-yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (73 g, 0.14 mol) in MeOH (200 mL) at 16 °C (external). The reaction mixture was stirred at 30 °C (external). After 1 h, the crude reaction mixture was directly concentrated under reducedpressure to give the residue (white powder after high vac). The material was purified by prep- HPLC (column: Waters Xbridge BEH C18 250 x 70mm, 10 pm, Mobile phase: A: H20(0.05% NHaPLO+lOmM NH4HCO3);B: ACN, Gradient: B from 0% to 50%) to give the title compound (46 g) as a solid. ES-MS m z 329 (M+H).Preparation of Intermediate 185: Methyl 2-cyclopropyl-6-(trifluoromethyl)nicotinate

[0284] Methyl 2-chloro-6-(trifluoromethyl)nicotinate (35.31 g, 140.0 mmol, CAS # [1073129- 57-3]) and Potassium cyclopropyltrifluoroborate (29.8 g, 201 mmol) were mixed with Toluene (0.30 L) and potassium carbonate (0.30 L, 2.0 M in water, 600 mmol). Purged with nitrogen for 10 min then added Bis(triphenylphosphine)palladium(II) dichloride (9.75 g, 13.9 mmol). The purge was continued for 5 min more, then the reaction mixture was heated in a metal heating block (setpoint 75 °C) for 13 h. The mixture was transferred to a separating funnel, and the aqueous drained off. The organics were washed with 2 M aq. K2CO3 (2 x 50 mL) then with sat. aq. NaCl (50 mL), dried over MgSO4 and filtered. The organic layer was eluted through a pad of silica gel eluting with Toluene to give the title compound. (44.87g, 70% purity). 1H NMR (400.13 MHz, CDCI3): 8.25 (d, J= 8.1 Hz, 1H), 7.45 (d, J= 8.1 Hz, 1H), 4.00 (s, 3H), 3.09-3.03 (m, 1H), 1.30-1.26 (m, 2H), 1.13-1.09 (m, 2H).Preparation of Intermediate 186: 2-cyclopropyl-6-(trifluoromethyl)nicotinoyl chloride

[0285] Oxalyl chloride (9.2 mL, 110 mmol) was added to a stirred suspension of 2-cyclopropyl- 6-(trifluoromethyl)nicotinic acid (20.21 g, 87.42 mmol) in Dichloromethane (0.20 L) at RT.N,N-Dimethylformamide (0.14 mL, 1.8 mmol) was added and the reaction was stirred at RT for18 h. The reaction was then concentrated to give the title compound as an oil that was subsequently used in the next step. (22.81 g).Preparation of Intermediate 187: tert-butyl 4-carbamoyl-4-(2-cyclopropyl-6- (trifluoromethyl)nicotinamido)piperidine- 1 -carboxylate

[0286] tert-butyl 4-amino-4-carbamoylpiperidine-l -carboxylate (22.35 g, 91.86 mmol, CAS # [288154-18-7]) was mixed with THF (0.20 L) and Sodium carbonate (1.0 M aqueous, 250 mL, 250 mmol). A solution of 2-cyclopropyl-6-(trifluoromethyl)nicotinoyl chloride (22.81 g, 87.72 mmol) in THF (0.10 L) was added. Stirred for 30 min then diluted with water (approximately 650 mL). Stirred the resulting slurry for 1 h then collected via filtration, washing with additional water. The solid was dried in a vacuum oven to give the title compound. ES-MS (m z) 457 (M+H).Preparation of Intermediate 188: tert-butyl 2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-4- oxo- 1,3, 8-triazaspiro[4.5]dec- 1 -ene-8-carboxylate

[0287] Ethanol (0.17 L) was added to tert-butyl 4-carbamoyl-4-(2-cyclopropyl-6- (trifluoromethyl)nicotinamido)piperidine-l -carboxylate (33.90 g, 72.78 mmol) in a 500 mL RBF with stir bar, mounted in a heating block (at ambient temp). Sodium ethoxide (25 wt% in EtOH, 90 mL, 0.29 mol) was added giving a thick, but was stirrable mixture. A condenser with nitrogen inlet was fitted, and heating was started with block setpoint 80 °C. Upon heating, the reaction mixture becomes a clear brown solution which was stirred for 1.5 h. The reaction was cooled to RT then poured into a stirred mixture of water (0.50 L) and saturated aqueous NH4CI (0.25 L). Stirred for 30 min, then the precipitate was collected by filtration. The precipitate wasdissolved in EtOAc (0.40 L) then washed with sat. aq. NaCl (2 * 0.15 L), dried over MgSO4, filtered and partially concentrated to approximately 0.1 L. Heptane (approx. 0.2 L) was added, and the mixture was stirred at ambient temperature. A first crop of title compound was then obtained by filtration (washed with 50 mL each of 20% EtOAc / heptane then heptane). The filtrate was then further concentrated and to approximately 0.15 L to give a second crop of title compound that was collected by filtration and washed with heptane (50 mL). The two crops of solid were combined and dried in a vacuum oven overnight to give the title compound as a cream solid (29.71 g). ES-MS (m / z): 439 (M+H), 383.0 (M-55).Preparation of Intermediate 189: 2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5 ]dec- 1 -en-4-one dimethanesulfonate

[0288] tert-butyl 2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-4-oxo-l,3,8- triazaspiro[4.5]dec-l-ene-8-carboxylate (29.71 g, 67.76 mmol) and 1-Propanol (0.30 L) were charged to a 1 L flask with stir bar, mounted in a heating block. A nitrogen inlet was fitted, and heating & stirring started (block setpoint 90 °C). Solid dissolved fully to afford a clear orange solution. Methanesulfonic acid (4.8 mL, 72 mmol) was added. After 2 h, reaction was a clear solution. After 2 additional h, added more Methanesulfonic acid (4.1 mL, 61 mmol). Stirred 10 min then removed from heat. The mixture was concentrated to afford a thick, slightly foaming gum. Added isopropyl acetate (0.40 L), a stir bar and stirred in a 60 °C block. A gummy mass formed initially, converted steadily to fine white solid. Continued stirring in heating block for 1.5 h followed by at RT for 1 h. The fine, dense solid was collected by filtration (6 cm porosity 3 glass frit, slow), washed with isopropyl acetate (0.1 L), then transferred to a vacuum oven for drying (10 mbar, 40 °C) overnight to give the title compound. (35.78 g). ES-MS m z 339 (M+H).Preparation of Intermediate 190: 2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec- 1 -en-4-one

[0289] 2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one dimethanesulfonate (5.00 g, 9.42 mmol) was dissolved in EtOAc (500 mL) and washed with saturated, aqueous sodium bicarbonate (2 300 mL). Aqueous layer further extracted with EtOAc (1 x 300 mL) then the combined organic layers were washed with 25mL of water followed by 50mL of sat. aq. NaCl then dried over MgSO4, filtered and concentrated to give the title compound. (2.91 g). ES-MS m / z 339 (M+H).Preparation of Intermediate 191 : 5-bromo-3-((5R,7S)-2-(2-cyclopropyl-6-ethoxypyridin-3-yl)-7- methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)picolinonitrile

[0290] (5R,7S)-2-(2-cyclopropyl-6-ethoxypyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en- 4-one (2.00 g, 6.02 mmol), N-ethyl-N-isopropylpropan-2-amine (3.99 g, 30.3 mmol) and 5- bromo-3-fluoropicolinonitrile (1.53 g, 95% Wt, 1.20 Eq, 7.23 mmol) were added to a 100 mL one-neck round bottom flask (with a refluxing condenser) with a magnetic stir bar in DMSO (20 mL), at 20 °C (external temperature). The system was de-gassed and refilled with N2 for three times before vigorously stirring at 80 °C (external temperature). After 16 h, the reaction mixture was allowed to cool down to room temperature. The reaction mixture was poured into 20 mL water at 20 °C (external temperature) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with sat. aq. NaCl (15 mL), dried over Na2SO4. The Na2SO4 was filtered off and further washed with 10 mL EtOAc. The obtained filtrate was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography(Eluent of 20-60% EtOAc / n-hexane gradient @ 60 mL / min) to give the title compound (1.20 g) as a solid. ES-MS m / z 508 / 510.Preparation of Intermediate 192: (5R,7S)-8-(5-bromo-2-(methylsulfonyl)pyridin-3-yl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0291] In a 350 mL pressure vessel was added (5R,7S)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one dihydrochloride (8.90 g, 20.92 mmol) in dioxane (75 mL) with stirring and under nitrogen. Finely ground sodium carbonate (7.76 g, 73.23 mmol) was then added. The vessel was sealed and heated to 120 °C overnight. Additional ground sodium carbonate was added until the reaction was complete by TLC. The reaction was cooled to rt and quenched with water (200mL). The material was extracted with EtOAc (3 x 200mL). The combined organics and washed with sat. aq. NaCl (200mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified via normal phase flash chromatography (20-80% EtOAc in cyclohexanes) to afford the title compound (9.01g) as a pale-yellow solid. ES-MS m / z 586, 588 (M+H).The intermediate in the following table was prepared in a similar manner as described in the preparation of Intermediate 192.Preparation of Intermediate 194: 8-(5-bromo-2-(methylsulfonyl)pyridin-3-yl)-2-(2-cyclopropyl- 6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0292] Into a 250mL round bottom flask containing a slurry of 2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one dimethanesulfonate (2.51 g, 4.73 mmol) and 5-bromo-3-fluoro-2-(methylsulfonyl)pyridine (1.32 g, 5.20 mmol) in 1,4- Dioxane (60 mL) was added freshly powdered Sodium carbonate (1.65 g, 15.60 mmol). The vessel was equipped with a reflux condenser and heated to 110 °C (external heating block) under Nz for 4 h. The reaction was cooled to RT, poured into NaHCO.3(aq) and extracted with EtOAc (3x 150 mL). Washed the combined organic layers with sat. aq. NaCl, dried over MgSO4, filtered and concentrated. The sample was purified via normal phase silica gel purification eluting with a 0-100% EtOAc / Cyclohexanes gradient to give the title compound as a solid (2.53 g). ES-MS m / r. 572, 574 (M+H).Preparation of Intermediate 195: tert-butyl 2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-4-oxo- l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate

[0293] tert-butyl 4-carbamoyl-4-(2-cyclopropyl-4-(trifluoromethyl)benzamido)piperidine-l- carboxylate (10.2 g, 46.2% Wt, 10.3 mmol) was dissolved in EtOH (60 mL). 2-methylpropan-2- olate potassium (6.22 g, 54.3 mmol) was added in one portion at 20 °C (external temperature).The reaction was stirred vigorously at 80 °C (external temperature) for 1 h. The reaction mixture was allowed to cooled to RT then poured into 100 mL water and extracted with EtOAc (80 mL * 3). The combined organic layers were washed with sat. aq. NaCl (100 mL), dried over Na2SO4, filtered and concentrated. The material was purified by flash silica gel chromatography using a20-60% gradient of EtOAc / n-hexanes which gave the title compound (3.90 g). ES-MS w z: 438 (M+H).Preparation of Intermediate 196: 2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-l,3,8- triazaspiro[4.5]dec- 1 -en-4-one

[0294] tert-butyl 2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-4-oxo-l,3,8-triazaspiro[4.5]dec-l- ene-8-carboxylate (3.90 g, 6.24 mmol) was mixed with EtOAc (40 mL) followed by the addition of HC1 in 1,4-dioxane (15 mL, 4 molar, 60 mmol) at 20 °C (external temperature). Then the reaction mixture was allowed to stir vigorously at 20 °C (external temperature) for 2 h. The crude reaction mixture was concentrated under reduced pressure and the residue was dissolved with water (20 mL) and adjusted to pH=8~9 with NH3.H2O (20 mL) with stirring at 10 °C (external temperature). The mixture was purified by reverse phase prep-HPLC using a 1-60% gradient of ACN / (lOmM NH4HCO3 in water) to give the title compound (2.14 g). ES-MS m z. 338 (M+H).Preparation of Intermediate 197: (5R, 7S)-8-(5-bromo-2-methoxypyri din-3 -yl)-7-methyl-2-(6- (((E)-pent-3-en-l-yl)oxy)-2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0295] DIEA (400 uL, 2.30 mmol) was added to a solution of 6-chloro-2- (trifluoromethyl)pyridine-3-carboxylic acid (0.17 g, 0.758 mmol), (2S,4R)-4-amino-l-(5-bromo- 2-methoxypyridin-3-yl)-2-methylpiperidine-4-carboxamide (0.16 g, 0.487 mmol) and HATU (0.329 g, 0.865 mpmol) in DMF (2.5 mL) at room temperature in a vial. The reaction was stirred overnight at room temperature, diluted with EtOAc, extracted 1xSat. aq. NaHCO.i, 1xsat. aq. NaCI, then dried the organics over Na2SO4, filtered and concentrated to an amber oil. The oilwas reconcentrated down 2X from dioxane (5 mL) to give an oil. Trans-3-penten-l-ol (0.500 mL, 4.87 mmol), 1,4-dioxane (3 mL), tert-butanol (1.5 mL) and potassium 2-methylpropan-2- olate (0.349 g, 3.11 mmol) were sequentially added. The reaction was placed under nitrogen and heated at 100 °C (external temperature) for 4h, quenched with an aqueous solution of Sat. NH4CI (3 mL). and then diluted with an aqueous solution Sat. NH4CI and EtOAc. The layers were separated. The organic layer was extracted 1 x sat. aq. NaCl, dried over Na SO4, filtered and concentrated. The residue was purified by silica gel chromatography using 10-100%EtOAc / cyclohexane to give the title compound as a foam (0.132 g). ES-MS m / z 582, 584 (M+H).Preparation of Intermediate 198: (5R,7S)-8-(5-bromo-2-methoxypyridin-3-yl)-2-(6-butoxy-2- (trifhioromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0296] N-ethyldiisopropylamine (0.095 mL, 0.548 mmol) was added to a solution of 6-chloro-2- (trifluoromethyl)pyridine-3-carboxylic acid (0.161 g, 0.712 mmol), (2S,4R)-4-amino-l-(5- bromo-2-methoxypyridin-3-yl)-2-methylpiperidine-4-carboxamide (0.188 g, 0.55 mmol) and HATU (0.31 g, 0.82 mmol) in DMF (2.7 mL) at room temperature in a vial. The reaction was stirred overnight at room temperature, diluted with EtOAc and extracted 1 x Sat. NaHCOa, 1xsat. aq. NaCl, dried Na2SO4, filtered and concentrated to an amber oil. The oil was taken up in n- butanol 2 x (5 mL ea.) and concentrated. The recovered oil was dissolved in butan-l-ol (10 mL) and treated with potassium 2-methylpropan-2-olate (0.62 g, 0.548 mmol) at room temperature. The reaction was heated at 90 °C for 6 h (external temperature), quenched with an aqueous solution of Sat. NH4CI (3 mL). and then diluted with an aqueous solution Sat. NH4CI and EtOAc. The layers were separated. The organic layer was extracted 1xsat. aq. NaCl, dried Na SO4, filtered and concentrated. The crude was purified by silica gel chromatography using 10-100% EtOAc / cyclohexane to give the title compound as a foam (0.146 g). ES-MS m z 570, 572 (M+H).Preparation of Intermediate 199: 8-(5-bromo-2-(methylsulfonyl)pyridin-3-yl)-2-(2-cyclopropyl- 4-(trifluoromethyl)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0297] To a 40 mL vial with a magnetic stir bar was added ACN (5 mL), 2-(2-cyclopropyl-4- (trifluoromethyl)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.50 g, 1.5 mmol), 5-bromo-3- fluoro-2-(methylsulfonyl)pyridine (0.42 g, 1.6 mmol) and Potassium phosphate, dibasic (1.1 g, 6.2 mmol) at RT. The mixture was purged with N2 for 1 min before vigorously stirring at 80 °C (external temperature) for 16 h under N2. The reaction mixture was cooled to RT, then filtered, rinsing with ACN (10 mL). The filtrate was concentrated under reduced pressure to give the title compound (0.52g). ES-MS m / z'. 571, 573 (M+H).Preparation of Intermediate 200: (5R,7S)-8-(5-bromo-2-(3,3-difluoropropoxy)pyridin-3-yl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0298] In a reaction vial sodium hydride in mineral oil (0.285 g, 60% Wt, 7.12 mmol) was added to 3, 3 -difluoropropan- l-ol (0.684 g, 7.12 mmol) in NMP (5 mL). After gas evolution visible ceased, (5R,7S)-8-(5-bromo-2-(methylsulfonyl)pyridin-3-yl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.835 g, 1.42 mmol) dissolved in NMP (5 mL) was slowly added. The vial was capped, and the reaction was allowed to stir at room temperature overnight. The reaction was quenched with water and extracted with EtOAc. The combined organics were washed with sat. aq. NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (0.317g) as a white foam. ES-MS m / z 601, 603 (M+H).Preparation of Intermediate 201 : N-((2S,4R)-l-(5-bromo-2-ethoxypyridin-3-yl)-4-carbamoyl-2- methylpiperidin-4-yl)-6-chloro-2-(trifluoromethyl)nicotinamide

[0299] Diisopropylethylamine (0.71 g, 0.95 mL, 3.6 Eq, 5.5 mmol) was added to a 20 mL vial containing a stir bar, 6-chloro-2-(trifluoromethyl)pyridine-3-carboxylic acid (0.483 g, 2.14 mmol), (2S,4R)-4-amino-l-(5-bromo-2-ethoxypyridin-3-yl)-2-methylpiperidine-4-carboxamide (0.546 g, 1.53 mmol), and HATU (1.74 g, 4.58 mmol), in ACN (10 mL) and the mixture was stirred at room temperature. After 2 h, the reaction mixture was loaded onto 50 g SCX resin, which was flushed with 3x50mL MeOH. Desired compound was eluted with 3x50mL of 2.0M ammonia: MeOH. The tiltrate was concentrated to give the title compound (0.863 g) as foam ES-MS (w / z) 564 / 566.Preparation of Intermediate 202: (5R,7S)-8-(5-bromo-2-ethoxypyridin-3-yl)-2-(6-ethoxy-2- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0300] Sodium ethoxide in EtOH (21%) (6.84 mL, 21% Wt, 18.3 mmol) was added to 100 mL tube containing N-((2S,4R)-l-(5-bromo-2-ethoxypyridin-3-yl)-4-carbamoyl-2-methylpiperidin- 4-yl)-6-chloro-2-(trifluoromethyl)nicotinamide (0.863 g, 1.53 mmol) in EtOH (20 mL). The vial was sealed and the mixture was stirred at 85 °C overnight. The reaction mixture was cooled and concentrated under reduced pressure to give residue which was diluted with 100 mL of water. The aqueous layer was extracted with 3xl00mL of EtOAc Combined organic layers, dried over MgSO4, filtered and concentrated under reduced pressure to give solid which purified by silica gel chromatography (0-100% EtOAc in hexane), afforded the title compound (0.60 g). ES-MS (m / z) 556 / 558.Preparation of Intermediate 203: (5R,7S)-8-(5-bromo-2-methoxypyridin-3-yl)-2-(2-cyclopropyl-4-(4,4,4-trifluorobutoxy)phenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one;

[0301] Potassium / cvZ-butoxidc IM in T-BuOH (7.50 mL, 1 molar, 7.49 mmol) was added to (2S,4R)-l-(5-bromo-2-methoxypyridin-3-yl)-4-(2-cyclopropyl-4-(4,4,4- trifluorobutoxy)benzamido)-2-methylpiperidine-4-carboxamide (0.920 g, 1.50 mmol) in with a stir bar in a 40 mL vial with cap and Heated to 80 °C for 1 h in a heating block. Reaction mixture was diluted with 2xEtOAc and 5% citric acid solution to adjust the pH to ~4-5 range on pH test paper. Combined organic layers, dried over Na2SO4, filtered and concentrated under reduced pressure to give white solid which dried under reduced pressure. Crude solid was purified by silica gel chromatography (0-50% EtOAc Chloroform), affording the title compound (0.49 g) as solid ES-MS (m / z) 595 / 597.Preparation of Intermediate 204: N-((2S,4R)-l-(5-bromo-2-cyclopropoxypyridin-3-yl)-4- carbarnoyl-2-methylpiperidin-4-yl)-2-cyclopropyl-6-(trifluoromethyl)nicotinamide

[0302] DIEA (0.45 mL, 2.61 mmol) was added to a solution of 2-cyclopropyl-6- (trifluoromethyl)nicotinic acid (0.13 g, 0.593 mmol), (2S,4R)-4-amino-l-(5-bromo-2- cyclopropoxypyridin-3-yl)-2-methylpiperidine-4-carboxamide (0.21 g, 0.588 mmol), HATU (0.36 g, 0.952 mmol) in DMF (3.5 mL) and stirred at ambient temperature for 17 h. The reaction mixture was diluted with EtOAc (20 mL), washed with water (2 x 20 mL), sat. aq. NaCl (20mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford the tittle compound (0.342 g) as an oil. ES-MS m / z 582, 584 (M+H).Preparation of Intermediate 205: (5R,7S)-8-(5-bromo-2-cyclopropoxypyridin-3-yl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0303] KO / Bu (0.330 g, 2.940 mmol) was added to a solution of N-((2S,4R)-l-(5-bromo-2- cyclopropoxypyridin-3-yl)-4-carbamoyl-2-methylpiperidin-4-yl)-2-cyclopropyl-6- (trifluoromethyl)nicotinamide (0.34 g, 0.587 mmol) in EtOH (6 m ) and stirred at 80 °C for 2 h. The reaction mixture was cooled to ambient temperature and diluted with EtOAc (30 mb). The resulting solution was washed with water (2 * 10 mL), sat. aq. NaCl (10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (0.297 g) as an oil. ES-MS m'z 562, 564 (M+H).Preparation of Intermediate 206: 5-bromo-3-((5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)picolinonitrile

[0304] DIEA (7.2 mL, 41 mmol) was added to a solution of (5R,7S)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (5.00 g, 14.2 mmol) and 5-bromo-3-fluoropiconitrile (5.60 g, 27 mmol) in DMSO (100 mL) at 10 °C. The reaction mixture was warmed to 100 °C and stirred for 16 h. The reaction mixture was cooled to ambient temperature and diluted with water (250 mL), extracted with EtOAc (3 * 100 mL). The combined organic layers were washed with sat. aq. NaCl (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to a residue. The residue was purifiedby flash chromatography on silica gel (0-70% EtOAc in n-hexane) to afford the title compound (3.4 g) as a solid. ES-MS m / z 532, 534 (M+H).Preparation of Intermediate 207: (6-cyano-5-((5R,7S)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)pyridin-3- yl)boronic acid

[0305] Methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,T-biphenyl)(2'- methylamino-l,T-biphenyl-2-yl)palladium(II) (0.30 g, 0.3 mmol) was added to a degassed solution of 5-bromo-3-((5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-4- oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)picolinonitrile (1.4 g, 2.5 mmol), Potassium trimethylacetate (1.2 g, 8.4 mmol), Bis(pinacolato)diborane (1.4 g, 5.4 mmol) in 1,4-Dioxane (40 mL). The reaction mixture was warmed to 100 °C and stirred for 12 h under N2 atmosphere. The reaction mixture was cooled to ambient temperature, filtered through a pad of diatomaceous earth and rinsed with ACN (20 mL). The filtrate was concentrated under reduced pressure to a residue. The residue was purified by prep-HPLC (Column: Biotage 800 g Agela Cl 8; mobile phase: [H2O (FA)-ACN]; gradient: 30-60% 30 min; 60% 10 min; 120 mL / min) to afford the title compound (1.1 g) a solid. ES-MS m z 499 (M+H).Preparation of Intermediate 208: (5R,7S)-8-(5-bromo-2-ethoxypyridin-3-yl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0306] To a 100 mL 3-neck round bottom flask with a magnetic stir bar was charged with NMP (40 mL), followed by the addition of (5R,7S)-8-(5-bromo-2-(methylsulfonyl)pyridin-3-yl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (2.8 g, 83.1 wt% purity, 4.0 mmol) and sodium ethoxide (6.3 g, 20% Wt in EtOH, 19 mmol) at 20 °C. Then the reaction mixture was stirred vigorously at 50 °C for 2 h, poured into H2O (100 mL) and then extracted with EtOAc (50 mL x 3). The combined organic layer was washed with sat. aq. NaCl (100 mL x 2), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (2.3 g, 87.3 wt% purity) as solid. ES-MS m / z 552, 554 (M+H).Preparation of Intermediate 209: (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-8-(2- ethoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-yl)-7-methyl-l,3,8- triazaspiro[4.5]dec- 1 -en-4-one

[0307] A 100 mL flask was charged with (5R,7S)-8-(5-bromo-2-ethoxypyridin-3-yl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (2.1 g, 3.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.8 g, 6.9 mmol), Potassium acetate (1.1 g, 10 mmol) and methoxy cyclopentane (21 mL) and sparged with N2 for 3 mins. Methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,l'-biphenyl)(2'- m ethylamino- l,l'-biphenyl-2-yl)palladium(II) (0.310 g, 0.353 mmol) was added and the reaction was stirred at 80 °C for 3 hrs. The reaction was cooled to rt. The material was filtered over diatomaceous earth and the filtrated concentrated under reduced pressure. The residue was then purified via normal phase flash chromatography (0-50% EtOAc / hexanes, gradient) to afford the title compound (2.1g) as solid. ES-MS m,z 600 (M+H).Preparation of Intermediate 210: 5-bromo-3-((5R,7S)-2-(6-ethoxy-2-(trifluoromethyl)pyridin-3- yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)picolinonitrile

[0308] DIEA (1.0 mb, 5.8 mmol) was added to a solution of (5R,7S)-2-(6-ethoxy-2- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (1.00 g, 2.81 mmol) and 5-bromo-3-fluoropiconitrile (0.67 g, 3.352 mmol) in DMSO (10 mL), and stirred at 100 °C for 16 h. The reaction mixture was cooled to ambient temperature and diluted with water (30 mL), extracted with EtOAc (3 * 30 mL). The combined organics were washed with water (30 mL), sat. aq. NaCl (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to a yellow oil. The oil was purified by flash chromatography on silica gel (0-60% EtOAc in cyclohexane) to afford the title compound (0.45 g) as a foam. ES-MS m / z 537, 539 (M+H).

[0309] The intermediates in the following table were prepared in a manner similar to the Preparation of Intermediate 210 using the appropriate amine.Preparation of Intermediate 212: 3-((5R,7S)-2-(6-ethoxy-2-(trifluoromethyl)pyridin-3-yl)-7- methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)picolinonitrile

[0310] 2-ethyl hexanoic acid (0.02 mL, 0.126 mmol) was added to a suspension of 5-bromo-3- ((5R,7S)-2-(6-ethoxy-2-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec- l-en-8-yl)picolinonitrile (0.32 g, 0.60 mmol), Bis(pinacolato)diboron (0.26 g, 1.01 mmol), K2CO3 (0.25 g, 1.77 mmol), [(l,2,3-eta)-2-Buten-l-yl]chloro[dicyclohexyl[2',4',6'-tris(l- methylethyl)[l,T-biphenyl]-2-yl]phosphine]palladium (0.08 g, 0.13 mmol) in 1,4-Dioxane (10 mL), under N2 atmosphere. The reaction mixture was warmed to 50 °C and stirred for 3 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (30 mL) and filtered through a pad of diatomaceous earth. The resulting solution was concentrated under reduced pressure to a obtain the crude material. The crude compound was purified by flash chromatography on silica gel (0-10% MeOH in DCM) to obtain the tittle compound (0.35 g). ES-MS m / z 503 (M+H).Preparation of Intermediate 213: (2S,4R)-1 -(5-bromo-2-methoxypyri din-3 -yl)-4-(2-cyclobutyl-4-(trifluoromethyl)benzamido)-2-methylpiperidine-4-carboxamide

[0311] 2-cyclobutyl-4-(trifluoromethyl)benzoic acid (0.50 g, 2.03 mmol), (2S,4R)-4-amino-l-(5- bromo-2-methoxypyridin-3-yl)-2-methylpiperidine-4-carboxamide (0.84 g, 2.44 mmol), DIEA (1.06 mL, 5.97 mmol) and HATU (1.54 g, 3.97 mmol) were added to a 8 mb vial with a magnetic stir bar in DMF (4 mL) at 20 °C. The mixture was purged with N2 for 2 mins and stirred. After 2 h, the reaction mixture was poured into 10 mL water and extracted with EtOAc (4 mL x 3). The combined organic layers were dried over Na2SO4. Na2SO4 was filtered off andfurther washed with EtOAc (20 mb). The obtained filtrate was concentrated under reduced pressure to give the title compound (2.12 g) as an oil. ES-MS m'z 569 / 571

[0312] The intermediate in the following table was prepared in a manner similar to the Preparation of Intermediate 213 using the appropriate amine and carboxylic acid.Preparation of Intermediate 215: (5R, 7S)-8-(5-bromo-2-methoxypyri din-3 -yl)-2-(2-cyclobutyl-4- (tri fluoromethyl )phenyl)-7-methyl-l , 3, 8-triazaspiro[4.5]dec-l -en -4-one

[0313] 2-methylpropan-2-olate potassium in t-BuOH (11.5 g, 11.8 mmol) was added to a 100 mb 3-neck round bottom flask with a refluxing condenser, magnetic stir bar , (2S,4R)-l-(5- bromo-2-methoxypyridin-3-yl)-4-(2-cyclobutyl-4-(trifluoromethyl)benzamido)-2- methylpiperidine-4-carboxamide (2.08 g, 53% Wt, 1.94 mmol) in THF (20 mb) and stirred at 80 °C (external temperature) for 2 h. The reaction mixture was cooled to room temperature, poured into 40 mb H2O and extracted with EtOAc (20 mb x 3). The combined organic layers were washed with sat. aq. NaCl (10 mb x 2), dried over Na2SO4. Na2SC>4 was filtered off and further washed with EtOAc (20 mb x 2). The obtained filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (Eluent of 0-70% EtOAc / Petroleum ether gradient) and the collected fraction was concentrated under reduced pressure to give the product (0.700 g,) as a white solid. ES-MS m 'z 550 / 552Preparation of Intermediate 216: (5R,7S)-8-(5-bromo-2-methoxypyridin-3-yl)-2-(2-butoxy-3-(tri fluoromethyl )pyridin-4-yl)-7-methyl-l, 3, 8-triazaspiro[4.5]dec-l-en-4-one

[0314] KO / Bu (0.25 g, 2.23 mmol) was added to a solution of N-((2S,4R)-l-(5-bromo-2- methoxypyridin-3-yl)-4-carbamoyl-2-methylpiperidin-4-yl)-2-chloro-3- (trifluoromethyl)isonicotinamide (0.170 g, 0.309 mmol) and 1-butanol (1.0 mb, 10 mmol) in 1,4- dioxane (2.0 mb). The reaction mixture was heated to 70 °C and stirred for 3 days. Additional KO / Bu (0.200 g, 1.784 mmol) was added and continued stirring for 2 days. The reaction was quenched with water (0.3 mb) and concentrated under reduced pressure to obtain the crude material which was taken to the next step without further purification.Preparation of Intermediate 217: (6-cyano-5-((5R,7S)-2-(2-cyclopropyl-4- (trifluoromethyl)phenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)pyridin-3-

[0315] To a 40 mb via with a magnetic stir bar was charged with 1,4-Dioxane (5 mb), 5-bromo- 3-((5R,7S)-2-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl-4-oxo-l,3,8- triazaspiro[4.5]dec-l-en-8-yl)picolinonitrile (0.70 g, 1.27 mmol), Potassium trimethylacetate (0.430 g, 3.01 mmol) and Bis(pinacolato)diborane (0.53 g, 2.03 mmol). The system was degassed and refilled with N2 for three times before and after adding Methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl)(2'-methylamino- 1 , 1 '-biphenyl-2- yl)palladium(II) (0.089 g, 0.10 mmol). Then the reaction mixture was heated to 100 °C (externaltemperature) under N2. After 12 h, the crude reaction mixture was concentrated under reduced pressure directly to give the crude product. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 100 x 40mm, 5 pm; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 30.00%-60.00%,8.00min; flow rate:50.00mL / min) to give the title compound as solid (0.51 g). ES-MS m / z 498 (M+H).

[0316] The intermediates in the following table were prepared in a manner similar to thePreparation of Intermediate 82 using the appropriate alcohol.Preparation of Intermediate 226: (5R,7S)-8-(5-bromo-2-(2,2-difluoropropoxy)pyridin-3-yl)-2-(2- cyclopropyl-4-(trifluoromethyl)phenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0317] Sodium / c / 'Z-butoxide (0.32 g, 3.34 mmol) was added to a solution of 2,2-difluoropropan- l-ol (0.32 g, 3.34 mmol) in NMP (5 mb). The resulting suspension was stirred for 1 min then asolution of (5R,7S)-8-(5-bromo-2-(methylsulfonyl)pyridin-3-yl)-2-(2-cyclopropyl-4- (trifluoromethyl)phenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.78 g, 1.34 mmol) in NMP (5 mL) was slowly added. Capped the vessel and allowed to stir at room temperature for 16 h. The reaction was quenched with water and extracted two times with EtOAc. The combined organics were washed with sat. aq. NaCl, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0-100% EtOAc in cyclohexane to give the title compound (0.376 g, 0.61 mmol, 45%) as a solid. ES-MS m / 'z 601, 603 (M+H).The intermediates in the table below were prepared in a manner similar to the Preparation ofIntermediate 226 using the appropriate alcohol and methylsulfonylpyridine, using potassium tert- butoxide instead of sodium ter / -but oxi de.a. Potassium te / 7-butoxide was used instead of sodium / e / V-butoxide.Preparation of Intermediate 229: (2S,4R)-4-amino-l-(5-bromo-2-ethoxypyridin-3-yl)-2- methylpiperidine-4-carboxamide

[0318] A solution of (5R,7S)-8-(5-bromo-2-ethoxypyridin-3-yl)-2,2,7-trimethyl-l,3,8- triazaspiro[4.5]decan-4-one (11.5 g, 23.1 mmol) in acetic acid (115 mb) and water (30 mL) was stirred at 100 °C overnight. The reaction mixture was concentrated to about half its original volume and then diluted with water (400 mL), 1 M HC1 (50 mL) and EtOAc (400 mL). The layers were agitated, then separated. The aqueous layer was neutralized with solid NaHCO? to ~ pH 8 and extracted with EtOAc (3 * 200 mL). The combined organics were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford the tittle compound (6.74 g) as an oil. ES-MS m / z 357 (M+H).

[0319] Intermediates in the following table were prepared in a manner similar to the Preparation of Intermediate 108 using the appropriate amine and carboxylic acid.Preparation of Intermediate 233: rac-methyl 2-(4-bromo-3,5-dimethylphenyl)-2-hydroxyacetate (racemic mixture)

[0320] To a vigorous stirring MeOH (50 mL) solution of rac-2-(4-bromo-3,5-dimethylphenyl)- 2-hydroxyacetonitrile (racemic mixture, 55 g, 70 wt% purity, 160 mmol) was added HC1 (4.0 M in MeOH, 500 mL) dropwise over 20 mins at 5 °C. The resulting mixture was stirred at 70 °C for 15 h, then concentrated under reduced pressure to give a residue. TLC (2: 1 petroleum ether : EtOAc) R / = 0.4. The residue was purified by flash silica gel chromatography using a gradient of 0 to 50% EtOAc in petroleum ether to give the title compound (19 g) as solid. 'H-NMR (400 MHz, DMSO-6 / 6) 5 7.20 (s, 2H), 6.11 (d, J= 5.3 Hz, 1H), 5.06 (d, J= 5.3 Hz, 1H), 3.60 (s, 3H), 2.35 (s, 6H).Preparation of Intermediate 234: rac-methyl 2-(4-bromo-3,5-dimethylphenyl)-2- ((m ethyl sulfonyl)oxy)acetate (racemic mixture)

[0321] To a vigorous stirring DCM (80 mL) solution of / v / c-methyl 2-(4-bromo-3,5- dimethylphenyl)-2-hydroxyacetate (racemic mixture, 5.0 g, 20 mmol) and TEA (6.1 g, 57 mmol) was added methanesulfonyl chloride (6.5 g, 55 mmol) in portions over 5 mins at 5 °C. The reaction mixture was de-gassed and backfilled with N2 for three times. The mixture was stirred at 20 °C for 6 h, then quenched with H2O (200 mL) and extracted with DCM (100 mL x 4). The combined organic layer was washed with sat. aq. NaCl (50 mL) and dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (2: 1 petroleum ether : EtOAc) R = 0.6. The residue was purified by flash silica gel chromatography using a gradient of 0 to 50% EtOAc in petroleum ether to give the title compound (4.6 g) as solid. ESMS m'z 367, 369 (M+NH4+).Preparation of Intermediate 235: dimethyl 2-(4-bromo-3,5-dimethylphenyl)-3-cyanosuccinate (mixture of isomers)

[0322] To a 100 mL 1-neck round bottom flask with a magnetic stir bar was charged with MeOH (30 mL), followed by the addition of rac-methyl 2-(4-bromo-3,5-dimethylphenyl)-2-((m ethyl sulfonyl )oxy)acetate (racemic mixture, 4.6 g, 13 mmol), methyl 2-cyanoacetate (1.9 g, 19 mmol) and NaOMe (30% Wt in MeOH, 5 mL, 30 mmol) at 15 °C. The mixture was purged with N2 for 1 min before vigorously stirring at 70 °C for 6 h, then cooled to ambient temperature and concentrated under reduced pressure to give the residue. TLC (2: 1 petroleum ether : EtOAc) R / = 0.6. The residue was purified by flash silica gel chromatography using a gradient of 0 to 50% EtOAc in petroleum ether to give the title compound (1.6 g, 48.5 wt% purity) as solid. ESMS m / z 352, 354 (M-H).Preparation of Intermediate 236: dimethyl 2-(4-bromo-3,5-dimethylphenyl)-3-(((terz- butoxycarbonyl)amino)methyl)succinate (mixture of isomers)

[0323] To a vigorous stirring MeOH (20 mL) solution of dimethyl 2-(4-bromo-3,5- dimethylphenyl)-3-cyanosuccinate (mixture of isomers, 1.6 g, 48.5 wt% purity, 2.2 mmol), BOC2O (2.5 g, 11 mmol) and Nickelous chloride hexahydrate (1.6 g, 6.4 mmol) was added NaBH4 (1.7 g, 44 mmol) in portions over 20 mins at 0 °C. The mixture was stirred at 18 °C for 4 h, then quenched with citric acid (2.0 M in H2O, 50 mL) at 5 °C and extracted with EtOAc (50 mL x 4). The combined organic layer was washed with sat. aq. NaCl (30 mL), dried overNa2SC>4, and then concentrated under reduced pressure to give a residue. TLC (2: 1 n-hexane : EtOAc) Ry= 0.4. The residue was purified by flash silica gel chromatography using a gradient of 0 to 50% EtOAc in petroleum ether to give the title compound (1.3 g, 58.9 wt% purity) as solid. ES-MS m z 456, 458 (M-H).Preparation of Intermediate 237: dimethyl 2-(aminomethyl)-3-(4-bromo-3,5- dimethylphenyl)succinate hydrochloride (mixture of isomers)

[0324] To a vigorous stirring 1,4-dioxane (5 mL) and DCM (5 mL) solution of dimethyl 2-(4- bromo-3,5-dimethylphenyl)-3-((( / e / 7-butoxycarbonyl)amino)methyl)succinate (mixture of isomers, 1.3 g, 58.9 wt% purity, 1.7 mmol) was added HC1 (4.0 M in 1,4-dioxane, 10 mL) dropwise over 10 mins at 18 °C. The reaction mixture was stirred at 18 °C for 4 h, then concentrated under reduced pressure to give the title compound (1.4 g, 38.8 wt% purity) as solid. ES-MS m / z 358, 360 (M+H).Preparation of Intermediate 238: rac-methyl (trans)-4-(4-bromo-3,5-dimethylphenyl)-5- oxopyrrolidine-3-carboxylate (racemic mixture)

[0325] To a 100 mL 1-neck round bottom flask with a magnetic stir bar was charged with ACN (10 mL), followed by the addition of dimethyl 2-(aminomethyl)-3-(4-bromo-3,5- dimethylphenyl)succinate hydrochloride (mixture of isomers, 1.4 g, 38.8 wt% purity, 1.4 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (0.60 g, 4.0 mmol) at 16 °C. Then the reaction mixture was stirred vigorously at 80 °C for 4 h, cooled to ambient temperature and concentrated under reduced pressure to give a residue, which was purified by reverse phase prep-HPLC using agradient of 25 to 55% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.30 g) as solid.ES-MS / « z 326, 328 (M+H).Preparation of Intermediate 239: 7'rzc-(trans)-3-(4-bromo-3,5-dimethylphenyl)-4- (hydroxymethyl)pyrrolidin-2-one (racemic mixture)

[0326] To a vigorous stirring THF (10 mL) solution of rac-methyl (trans)-4-(4-bromo-3,5- dimethylphenyl)-5-oxopyrrolidine-3-carboxylate (racemic mixture, 0.29 g, 0.85 mmol) was added LiBH4 (2.0 M in THF, 0.9 mL) dropwise over 5 mins at 0 °C. The mixture was stirred at 15 °C for 4 h, then quenched with H2O (50 mL) at 0 °C and extracted with EtOAc (30 mL x 4). The combined organic layer was washed with sat. aq. NaCl (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCL, 2: 1 n-hexane : EtOAc, Ry= 0.4, UV), then the SiO2 powder was soaked with EtOAc (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.13 g) as solid. ES-MS m z 298, 300 (M+H).Preparation of Intermediate 240: rac-(trans)-4-(4-bromo-3,5-dimethylphenyl)-5-oxopyrrolidine- 3-carbaldehyde (racemic mixture)

[0327] To a 250 mL 3-neck round bottom flask with a magnetic stir bar was charged with DCM (60 mL), followed by addition of rac-(trans)-3-(4-bromo-3,5-dimethylphenyl)-4-(hydroxymethyl)pyrrolidin-2-one (racemic mixture, 3.1 g, 54.6 wt% purity, 5.7 mmol) and Dess- Martin periodinane (9.0 g, 21 mmol) at 0 °C. The mixture was de-gassed and refilled with N2 for three times before vigorously stirring at 15 °C for 6 h, then quenched by adding sat. aq. Na2S20s(200 mL) and aq. NaHCCh (10% Wt, 200 mL) at 0 °C. The mixture was extracted with DCM (100 mL x 3). The combined organic layer was washed with sat. aq. NaCl (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (20: 1 DCM : MeOH) R / = 0.5. The residue was purified by flash silica gel chromatography using a gradient of 12 to 24% MeOH in DCM to give the title compound (1.8 g, 76.1 wt% purity) as solid. ES-MS m / z 294, 296 (M+H).Preparation of Intermediate 241: rac-(trans)-3-(4-bromo-3,5-dimethylphenyl)-4- ((dimethylamino)methyl)pyrrolidin-2-one (racemic mixture)

[0328] To a 100 mL 3-neck round bottom flask with a magnetic stir bar was charged with MeOH (10 mL), followed by addition of / -ac-(trans)-4-(4-bromo-3,5-dimethylphenyl)-5-oxopyrrolidine- 3-carbaldehyde (racemic mixture, 0.35 g, 76.1 wt% purity, 0.89 mmol), dimethylamine (2.0 M in THF, 0.70 mL, 1.40 mmol), acetic acid (0.05 mL) and sodium cyanoborohydride (0.13 g, 1.97 mmol) at 5 °C. The mixture was de-gassed and refilled with N2 for three times before vigorously stirring at 15 °C for 12 h, then quenched by adding sat. aq. NH4CI (20 mL) at 5 °C, and then extracted with EtOAc (20 mL x 3). The combined organic layer was washed with sat. aq. NaCl (20 mL), dried over Na2SO4, then filtered and the obtained filtrate was concentrated under reduced pressure to give a crude product, which was purified by reverse phase prep-HPLC using a gradient of 25 to 60% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.10 g) as solid. ES-MS m 'z 325, 327 (M+H).Preparation of Intermediate 242: rac-2-(4-bromo-3,5-dimethylphenyl)-2-hydroxyacetic acid (racemic mixture)

[0329] To a 100 mL 1-neck round bottom flask was charged with H2O (12 mL) followed by the addition of rac-2-(4-bromo-3,5-dimethylphenyl)-2-hydroxyacetamide (racemic mixture, 3 g, 100 mmol) and HC1 (4.0 M in 1,4-di oxane, 12 mL, 48 mmol). The reaction mixture was stirred at 80 °C for 3 h, cooled down to room temperature and concentrated under reduced pressure.Precipitate formed. The precipitate was collected to give the title compound as solid (3.2 g). ES-MS m / z 257, 259 (M-H).Preparation of Intermediate 243: 2-(( / cr / -butyldimethylsilyl) oxy)-N-(2, 4-dimethoxybenzyl) ethan-1 -amine

[0330] To a vigorous stirring DCE (80 mL) solution of 2,4-dimethoxybenzaldehyde (4.9 g, 28 mmol) was added 2-((ter / -butyldimethylsilyl)oxy)ethan-l -amine (5 g, 29 mmol). The mixture was de-gassed and backfilled with N2 for three times and stirred at 22 °C for 2 h. Then sodium triacetoxyborohydride (9.2 g, 42 mmol) was added in portions at 0 °C. The resulting mixture was stirred at 22 °C for 2 h, then diluted with DCM (30 mL) and washed with sat. aq. NaHCCh (80 mL). The organic layer was dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a crude product. TLC (EtOAc) R / = 0.5. The residue was purified by flash silica gel chromatography using a gradient of 60 to 90% EtOAc in n-hexane to give the title compound (5.61 g) as oil. ES-MS m / z 326 (M+H).Preparation of Intermediate 244: rac-2-(4-bromo-3,5-dimethylphenyl)-N-(2-((terL butyldimethylsilyl)oxy)ethyl)-N-(2,4-dimethoxybenzyl)-2-hydroxyacetamide (racemic mixture)

[0331] To a 100 mL 1-neck round bottom flask with a magnetic stir bar was charged with DMF (20 mL), followed by the addition of 2-((terLbutyldimethylsilyl)oxy)-N-(2,4- dimethoxybenzyl)ethan-l -amine (1.3 g, 3.9 mmol), rac-2-(4-bromo-3,5-dimethylphenyl)-2- hydroxyacetic acid (racemic mixture, 1.12 g, 3.93 mmol), DIEA (3.0 g, 23 mmol) and HATU (4.3 g, 11 mmol) at 30 °C. The mixture was de-gassed and backfilled with N2 for three times and stirred at 30 °C for 2 h, then poured into H2O (80 mL) and extracted with EtOAc (15 mL x 3). The combined organic phase was washed with sat. aq. NaCl (60 mL), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a crude product. TLC (2:1 n- hexane : EtOAc) Ry = 0.4. The residue was purified by flash silica gel chromatography using a gradient of 30 to 80% EtOAc in n-hexane to give the title compound (1.56 g) as oil. ES-MS m 'z 566, 568 (M+H).Preparation of Intermediate 245: rac-l-(4-bromo-3,5-dimethylphenyl)-2-((2-((tert- butyldimethylsilyl)oxy)ethyl)(2,4-dimethoxybenzyl)amino)-2-oxoethyl methanesulfonate (racemic mixture)

[0332] To a 100 mL 1-neck round bottom flask with a magnetic stir bar was charged with DCM (20 mL), followed by the addition of rac-2-(4-bromo-3,5-dimethylphenyl)-N-(2-((te / 7- butyldimethylsilyl)oxy)ethyl)-N-(2,4-dimethoxybenzyl)-2-hydroxyacetamide (racemic mixture, 1.06 g, 1.71 mmol), TEA (0.37 g, 3.48 mmol) and methanesulfonic anhydride (0.38 g, 2.1 mmol). The mixture was de-gassed and backfilled with N2 for three times and stirred vigorouslyat 12 °C for 1 h under N2, then diluted with H2O (20 mL) and extracted with DCM (10 mL x 3). The combined organic layer was washed with sat. aq. NaCl (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue. TLC (2: 1 n- hexane : EtOAc) R / = 0.5. The residue was purified by flash silica gel chromatography using a gradient of 0 to 100% EtOAc in n-hexane to give the title compound (0.86 g) as oil. ES-MS m / z 548, 550 (M-OSO2CH3).Preparation of Intermediate 246: rac-2-(4-bromo-3,5-dimethylphenyl)-4-(2,4- dimethoxybenzyl)morpholin-3-one (racemic mixture)

[0333] To a 40 mL vial with a magnetic stir bar was charged with THF (15 mL), followed by the addition of rac-l-(4-bromo-3,5-dimethylphenyl)-2-((2-((ter / -butyldimethylsilyl)oxy)ethyl)(2,4- dimethoxybenzyl)amino)-2-oxoethyl methanesulfonate (racemic mixture, 0.77 g, 1.10 mmol) and TBAF (1.0 M in THF, 0.58 g, 2.2 mmol). The mixture was purged with N2 for 30s and stirred at 30 °C for 2 h, then poured into H2O (15 mL) and extracted with EtOAc (10 mL * 3). The combined organic layer was washed with sat. aq. NaCl (10 mL) and dried with Na2SO4, then filtered and the obtained filtrate was concentrated under reduced pressure to give a residue. TLC (EtOAc) R / = 0.5. The residue was purified by flash silica gel chromatography using a gradient of 20 to 60% EtOAc in n-hexane to give the title compound (0.18 g) as oil. ES-MS m z 434, 436 (M+H).Preparation of Intermediate 247: rac-2-(4-bromo-3,5-dimethylphenyl)morpholin-3-one (racemic mixture)

[0334] To a 40 mL vial with a magnetic stir bar was charged with DCM (1 mL), followed by the addition of rac-2-(4-bromo-3,5-dimethylphenyl)-4-(2,4-dimethoxybenzyl)morpholin-3-one (racemic mixture, 0.17 g, 0.37 mmol) and TFA (5 mL). The mixture was purged with N2 for 10 s and vigorously stirred at 66 °C for 5 h, cooled to 12 °C, concentrated under reduced pressure to give a residue, which was diluted with DCM (10 mL), adjusted to pH = 8 by sat. aq. NaHCCh and extracted with DCM (4 mL *3). The combined organic layer was washed with sat. aq. NaCl (10 mL), dried over Na2SO4, then filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by prep-TLC (SiCh, 20: 1 DCM : MeOH, R / = 0.5, UV), then the SiCL powder was soaked with DCM (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.085 g) as oil. ESMS m / z 284, 286 (M+H).Preparation of Intermediate 248: 4-bromo-3,5-dimethylbenzyl carbamimidothioate

[0335] To a 40 mL vial with a magnetic stir bar was charged with EtOH (3 mL), followed by the addition of 2-bromo-5-(chloromethyl)-l,3-dimethylbenzene (0.20 g, 77.4 wt% purity, 0.663 mmol) and thiourea (0.052 g, 0.67 mmol) at 10 °C. The mixture was purged with N2 for 2 mins before vigorously stirring at 100 °C for 1 h, then concentrated under reduced pressure to give the title compound (0.25 g) as solid. ES-MS m z 272, 274 (M+H).Preparation of Intermediate 249: (4-bromo-3,5-dimethylphenyl)methanesulfonyl chloride

[0336] To a 40 mL vial with a magnetic stir bar was charged with ACN (4 mL), followed by the addition of 4-bromo-3,5-dimethylbenzyl carbamimidothioate (0.25 g, 0.846 mmol), N- chlorosuccinimide (0.53 g, 3.93 mmol) and HC1 (2.0 M in H2O, 0.8 mL, 1.6 mmol) at 10 °C.The mixture was purged with N2 for 2 mins before vigorously stirring at 10 °C for 1 h, then concentrated under reduced pressure to give the crude product. The crude product was triturated with H2O (5 mL) at 10 °C for 10 mins, then filtered and the filter cake was dried under reduced pressure to give the title compound (0.21 g, 84 wt% purity) as solid. 'H-NMR (400 MHz, DMSO-t / e) 5 7.08 (s, 2H), 3.63 (s, 2H), 2.32 (s, 6H).Preparation of Intermediate 250: (4-bromo-3,5-dimethylphenyl)methanesulfonamide; ()

[0337] To a 40 mL vial with a magnetic stir bar was charged with acetone (2 mL), followed by the addition of (4-bromo-3,5-dimethylphenyl)methanesulfonyl chloride (0.21 g, 84 wt% purity, 0.593 mmol) and ammonia water (25% Wt, 0.5 mL, 3 mmol) at 0 °C. The mixture was purged with N2 for 1 min before vigorously stirring at 0 °C for 2 h, then concentrated under reduced pressure to give a residue. The residue was diluted with H2O (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic layer was washed with sat. aq. NaCl (5 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (0.075 g, 81.2 wt% purity) as solid. ES-MS m / z 277, 275 (M-H).Preparation of Intermediate 251 : 2-bromo-l-fluoro-3-methyl-5-vinylbenzene

[0338] To a 100 mL 3-neck round bottom flask with a magnetic stir bar was charged with methyltriphenylphosphonium bromide (6.9 g, 18 mmol) and THF (20 mL), then the mixture was cooled to -70 °C, de-gassed and backfilled with N2 for three times before dropwise adding n- butyllithium (2.5 M in hexane, 11 mL, 18 mmol) at -70 °C. The reaction mixture was stirred at - 70 °C for 2 h under N2. Then a solution of 4-bromo-3-fluoro-5-methylbenzaldehyde (3.0 g, 13.1 mmol) in THF (10 mL) was dropwise added to the mixture at -70 °C for 1 h. The reaction mixture was warmed to 25 °C and stirred for 12 h, quenched by adding sat. aq. NH4CI (50 mL)at 0 °C, and then diluted with H2O (50 mL) and extracted with DCM (50 mL x 3). The combined organic layer was washed with sat. aq. NaCl (50 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (10: 1 n-hexane : EtOAc) R / = 0.7. The residue was purified by flash silica gel chromatography using a gradient of 0 to 10% EtOAc in n-hexane to give the title compound (1.02 g, 87.2 wt% purity) as oil.1H- NMR (400 MHz, MEOH-tL) 5 7.17 (s, 1H), 7.12 (dd, J= 1.5, 9.7 Hz, 1H), 6.66 (dd, J= 10.9, 17.6 Hz, 1H), 5.83 (d, J= 17.7 Hz, 1H), 5.32 (d, J= 10.9 Hz, 1H), 2.41 (s, 3H).Preparation of Intermediate 252: (R)-l-(4-bromo-3-fluoro-5-methylphenyl) ethane-l,2-diol

[0339] To a 500 mL 3-neck round bottom flask with a magnetic stir bar was charged with AD- MlX-alpha (10 g, 6.1 mmol), de-gassed and backfilled with N2 for three times before and after adding z-BuOH (100 mL) and H2O (100 mL). The reaction mixture was cooled to 0 °C, then 2- bromo-l-fluoro-3-methyl-5-vinylbenzene (1.02 g, 87.2 wt% purity, 4.14 mmol) was added. The mixture was warmed to 15 °C and stirred for 12 h under N2. The reaction mixture was poured into H2O (200 mL) at 25 °C and extracted with EtOAc (150 mL x 3). The combined organic layer was washed with sat. aq. NaCl (150 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (1 : 1 n-hexane : EtOAc) Ry = 0.5. The residue was purified by flash silica gel chromatography using a gradient of 0 to 50% EtOAc in n-hexane to give the title compound (0.70 g) as solid.1H-NMR (400 MHz, D SO-tL) 8 7.18 (s, 1H), 7.12 (d, J= 9.7 Hz, 1H), 5.42 (d, J= 4.5 Hz, 1H), 4.76 (t, J= 5.8 Hz, 1H), 4.50 (q, J = 5.5 Hz, 1H), 3.43 (dt, J= 3.3, 5.8 Hz, 2H), 2.38 (s, 3H).Preparation of Intermediate 253: 4-bromo-3-formyl-5-methylbenzonitrile

[0340] To aDCM (120 mL) solution of 4-bromo-3-(hydroxymethyl)-5-methylbenzonitrile (12.0 g, 84.9 wt% purity, 45.1 mmol) was added Dess-Martin periodinane (39.8 g, 92.0 mmol) in one portion at 0 °C. The mixture was stirred at 20 °C for 2 h, then poured into Na2SOa (1.0 M in H2O, 80 mL) at 25 °C and extracted with DCM (50 mL x 3). The combined organic layer was washed with sat. aq. NaCl (60 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (5: 1 petroleum ether : EtOAc) Ry = 0.6. The residue was purified by flash silica gel chromatography using a gradient of 0 to 10% EtOAc in petroleum ether to give the title compound (8.20 g, 76.7 wt% purity) as solid. 'H- NMR (400 MHz, DMSO-t / 6) 8 10.26 (s, 1H), 8.17 (d, .7 = 1.8 Hz, 1H), 8.02 (d, .7 = 1.9 Hz, 1H), 3.33 (s, 1H), 2.48 (s, 3H).Preparation of Intermediate 254: 4-bromo-3-(difluoromethyl)-5-methylbenzonitrile

[0341] To a DCM (100 mL) solution of 4-bromo-3-formyl-5-methylbenzonitrile (8.20 g, 28.1 mmol) was added diethylaminosulfur trifluoride (12 g, 76.7 wt% purity, 71 mmol) dropwise over 5 mins at 0 °C. The mixture was stirred at 20 °C for 4 h, then poured into sat. aq. NaHCCfi (100 mL) at 20 °C and extracted with DCM (80 mL x 3). The combined organic layer was washed with sat. aq. NaCl (50 mL x 2), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (5.74 g) as solid. 'H-NMR (400 MHz, DMSO-tL) 8 8.08 (s, 1H), 7.96 (s, 1H), 7.44 - 7.01 (m, 1H), 2.45 (s, 3H).Preparation of Intermediate 255: 4-bromo-3-(difluoromethyl)-5-methylbenzaldehyde ()

[0342] To a DCM (60 mL) solution of 4-bromo-3-(difluoromethyl)-5-methylbenzonitrile (5.74 g, 22.1 mmol) was added diisobutylaluminum hydride (1.0 M in toluene, 45 mL 45 mmol)dropwise over 15 mins at -60 °C. The mixture was stirred at -60 °C for 2 h, then quenched by adding H2O (30 mL) at 20 °C. The reaction mixture was adjusted to pH = 5~6 with HC1 (1.0 M in H2O, 50 mL) and then extracted with DCM (40 mL x 3). The combined organic layer was washed with sat. aq. NaCl (50 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (3 : 1 petroleum ether : EtOAc) Ry = 0.35. The residue was purified by flash silica gel chromatography using a gradient of 0 to 27% EtOAc in petroleum ether to give the title compound (4.61 g, 84.3 wt% purity) as solid. 'H- NMR (400 MHz, CHLOROFORM-; / ) 5 10.02 (s, 1H), 8.02 - 7.84 (m, 2H), 7.15 - 6.90 (m, 1H), 2.55 (s, 3H).Preparation of Intermediate 256: rac-2-(4-bromo-3-(difluoromethyl)-5-methylphenyl)-2- hydroxyacetonitrile (racemic mixture)

[0343] To a vigorous stirring THF (50 mL) and H2O (50 mL) solution of 4-bromo-3- (difluoromethyl)-5-methylbenzaldehyde (4.61 g, 84.3 wt% purity, 15.6 mmol) in a 250 mL 3- neck round bottom flask was added NaCN (8.47 g, 164 mmol) at 20 °C, then NaHSOa (4.81 g, 45.3 mmol) in H2O (50 mL) was added dropwise over 2 mins at 5 °C. The resulting mixture was stirred at 20 °C for 16 h, then separated to collect the organic phase as the title compound (4.10 g, 33.2 wt% purity, THF solution). TLC (2: 1 petroleum ether: EtOAc, UV) Ry =0.3Preparation of Intermediate 257: rac-2-(4-bromo-3-(difluoromethyl)-5-methylphenyl)-2- hydroxyacetamide (racemic mixture)

[0344] To a vigorous stirring 1,4-dioxane (20 mL) and H2O (2 mL) solution of rac-2-(4-bromo- 3-(difluoromethyl)-5-methylphenyl)-2-hydroxyacetonitrile (racemic mixture, 4.10 g, 33.2 wt%purity, 4.93 mmol) in a 100 mL 3-neck round bottom flask was added HC1 (4.0 M in 1,4- dioxane, 40 mL, 160 mmol) dropwise over 3 mins at 5 °C. The resulting mixture was stirred at 20 °C for 6 h, then concentrated under reduced pressure at 20 °C to give the crude product, which was further purified by reverse phase prep-HPLC using a gradient of 1 to 35% ACN in 10 mM aq. NH4HCO3 to give the title compound (1.45 g, 85 wt% purity) as solid. ES-MS m 'z 292, 294 (M+H).Preparation of Intermediate 258: rac-2-(4-bromo-3,5-dimethylphenyl)-2-hydroxyacetonitrile (racemic mixture)

[0345] To a 1 L 3-neck round bottom flask with a magnetic stir bar was charged with H2O (250 mL), followed by the addition of 4-bromo-3,5-dimethylbenzaldehyde (50 g, 233 mmol) and NaCN (29.2 g, 584 mmol) at 23 °C. Then a solution of NaHSCh (55 g, 528 mmol) in H2O (250 mL) was added dropwise to the reaction mixture at 5 °C over 20 mins. The reaction mixture was stirred at 23 °C for 15 h, then filtered. The filtrate was adjusted to pH >11 with NaOH (1.0 M in H2O), and aq. NaClO (10%, 2 L) was added under stirring to quench the unreacted NaCN. The filter cake was washed with H2O (300 mL x 3) to give the title compound (55 g, 70 wt% purity) as solid, which was immediately used to next step without further purification. 'H-NMR (400 MHz, DMSO-tL) 8 7.28 (s, 2H), 7.06 (br s, 1H), 5.67 (s, 1H), 2.38 (s, 6H).Preparation of Intermediate 259: rac-2-(4-bromo-3,5-dimethylphenyl)-2-methoxyacetic acid (racemic mixture)

[0346] To a vigorous stirring MeOH (80 mL) mixture of rac-methyl 2-(4-bromo-3,5- dimethylphenyl)-2-((methylsulfonyl)oxy)acetate (racemic mixture, 2 g, 6 mmol) in a 250 mL 3- neck round bottom flask was added sodium hydride (60% Wt in mineral oil, 1.2 g, 30 mmol) inportions over 20 mins at 5 °C. The mixture was stirred at 15 °C for 6 h, then diluted with H2O (20 mL) and washed with EtOAc (20 mL x3). The aqueous phase was adjusted to pH = 3~4 with HC1 (1.0 M in H2O), and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with sat. aq. NaCl (20 mL), dried over anhydrous Na2SO4, fdtered and the fdtrate was concentrated under reduced pressure to give a residue. TLC (EtOAc) R / = 0.4. The residue was purified by flash silica gel chromatography using a gradient of 0 to 50% EtOAc in n-hexane to give the title compound (0.90 g) as solid. ES-MS m z Tl\, 273 (M-H).Preparation of Intermediate 260: rac-2-(4-bromo-3,5-dimethylphenyl)-2-methoxyacetamide (racemic mixture)

[0347] To a 100 mL 3-neck round bottom flask with a magnetic stir bar was charged with DMF (10 mL), followed by the addition of rac-2-(4-bromo-3,5-dimethylphenyl)-2-methoxyacetic acid (racemic mixture, 0.90 g, 3.22 mmol), DIEA (1.2 g, 9.1 mmol), HATU (1.5 g, 3.9 mmol) and ammonium chloride (0.40 g, 7.10 mmol) at 15 °C. The mixture was de-gassed and backfilled with N2 for three times before vigorously stirring at 15 °C for 12 h, then diluted with H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with sat. aq. NaCl (30 mL), dried overNa2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (2: 1 n-hexane : EtOAc) R / = 0.4. The residue was purified by flash silica gel chromatography using a gradient of 0 to 50% EtOAc in n-hexane to give the title compound (0.30 g) as solid. ES-MS m / z 272, 274 (M+H).Preparation of Intermediate 261 : rac-(4-bromo-3,5-dimethylphenyl)(cyclopropyl)methanol (racemic mixture)

[0348] To a 250 mL three-neck round bottom flask was charged with THF (50 mL) and 4- bromo-3,5-dimethylbenzaldehyde (2 g, 8.92 mmol), de-gassed and refilled with N2 for three times. Then cyclopropylmagnesium bromide (0.5 M in THF, 27 mL, 14 mmol) was added dropwise at 0 °C over 1 min. The reaction mixture was stirred at 20 °C for 16 h, poured into H2O (50 mL) and extracted with EtOAc (20 mL x 3) The combined organic layer was washed with sat. aq. NaCl (40 mL), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (5: 1 n-hexane : EtOAc) R / = 0.4. The residue was purified by flash silica gel chromatography using a gradient of 0 to 60% EtOAc in n-hexane to give the title compound (1.1 g, 80 wt% purity) as solid.1H-NMR (400 MHz, DMSO-c / e) 5 7.17 (s, 2 H), 5.17 (d, J = 4.28 Hz, 1 H), 3.88 (dd, J =7.27, 4.10 Hz, 1 H), 2.35 (s, 6 H), 0.99 (dt, J= 7.64, 5.23 Hz, 1 H), 0.27 - 0.46 (m, 4 H).Preparation of Intermediate 262: rac- 2-bromo-5-(cyclopropyl(methoxy)methyl)-l,3- dimethylbenzene (racemic mixture)

[0349] To a 100 mL 3-neck round bottom flask with a magnetic stir bar was charged with DMF (20 mL), followed by the addition of rac-(4-bromo-3,5-dimethylphenyl)(cyclopropyl)methanol (racemic mixture, 0.80 g, 80 wt% purity, 2.51 mmol) at 20 °C. Then was added sodium hydride (0.21 g, 60% Wt in mineral oil, 5.25 mmol) in two portions at 0 °C. The mixture was stirred at 0 °C for 30 mins, then Mel (0.75 g, 0.33 mL, 5.18 mmol) was added dropwise over 1 min at 0 °C. The reaction mixture was stirred at 20 °C for 2 h, then poured into H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with sat. aq. NaCl (10 mL), dried over Na2SO4. filtered and the filtrate was concentrated under reduced pressure to give the title compound (0.67g, 73.1 wt% purity) as oil. 'H-NMR (400 MHz, CHLOROFORM-tT) 57.03 (s, 2 H), 3.42 (d, J= 8.00 Hz, 1 H), 3.25 (s, 3 H), 2.43 (s, 6 H), 0.83 - 0.90 (m, 1 H), 0.65 (br d, J = 8.63 Hz, 1 H), 0.38 - 0.53 (m, 2 H), 0.17 - 0.29 (m, 1 H).Preparation of Intermediate 263: rac- 2-(4-bromo-3,5-dimethylphenyl)-2-cyclopropylacetonitrile(racemic mixture)

[0350] To a 100 mL 3-neck round bottom flask with a magnetic stir bar was charged with DCM (20 mL), followed by the addition of rac-2-bromo-5-(cyclopropyl(methoxy)methyl)-l,3- dimethylbenzene (racemic mixture, 0.65 g, 73.1 wt% purity, 1.77 mmol) at 20 °C. Then ferric chloride (0.030 g, 0.18 mmol) and trimethylsilyl cyanide (0.27 g, 2.67 mmol) was added at 20 °C. The reaction mixture was stirred vigorously at 20 °C for 18 h, filtered and the filtrate was poured into H2O (20 mL) and then extracted with DCM (10 mL x 2). The combined organic layer was washed with sat. aq. NaCl (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC>2, L5 EtOAc : n-hexane, R / = 0.6, UV), then the SiCL powder was soaked with MeOH (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.18 g, 86.2 wt% purity) as solid. 'H-NMR (400 MHz, CHLOROFORM-r / ) 6 7.09 (s, 2 H), 3.40 (d, J = 7.51 Hz, 1 H), 2.44 (s, 6 H), 1.19 - 1.34 (m, 1 H), 0.66 - 0.79 (m, 2 H), 0.43 - 0.62 (m, 2 H).Preparation of Intermediate 264: rac-2-(4-bromo-3,5-dimethylphenyl)-2-cyclopropylacetamide (racemic mixture)

[0351] To a 40 mL vail with a magnetic stir bar was charged with DMSO (5 mL), followed by the addition of rac-2-(4-bromo-3,5-dimethylphenyl)-2-cyclopropylacetonitrile (racemic mixture, 0.16 g, 86.2 wt% purity, 0.522 mmol) and K2CO3 (0.074 g, 0.52 mmol) at 15 °C. Then H2O2 (30% Wt in H2O, 0.089 g, 0.79 mmol) was added dropwise at 15 °C. The reaction mixture wasstirred vigorously at 15 °C for 1 h, poured into H2O (10 mL) and extracted with EtOAc (5 mL x 4). The combined organic layer was washed with sat. aq. NaCl (10 mL), dried over ISfeSCU, then the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, 1 :1 EtOAc : n-hexane = 1 / 1, R / = 0.5, UV), then the SiO2 powder was soaked with MeOH (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.070 g) as solid. ES-MS m / z 282, 284 (M-H).Preparation of Intermediate 265: (5R,7S)-8-(5-chloro-2-methylpyridin-3-yl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-oneTo a 40 mL vial with a magnetic stir bar was charged with toluene (20 mL), followed by addition of (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-1-en-4-one (2.0 g, 5.51 mmol), 3-bromo-5-chloro-2-methylpyridine (2.35 g, 11.2 mmol), sodium2-methylbutan-2-olate in THF (10.5 g, 30% Wt, 28.6 mmol) and Methanesulfonato(2-bis(3,5- di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',6'-bis(dimethylamino)-l,l '-biphenyl )(2'- methylamino-l,r-biphenyl-2-yl)palladium(II) (FrankenPhos Palladacycle Gen. 4, CAS# 1810068-35-9, 1.30 g, 1.12 mmol) at 20 °C. The mixture was purged with N2 for 2 mins before vigorously stirring at 100 °C for 1 h, then poured into H2O (50 mL) and extracted with EtOAc (15 mL x 3). The combined organic layer was washed with sat. aq. NaCl (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (1:1 n-hexane : EtOAc) Ry= 0.4. The residue was purified by flash silica gel chromatography using a gradient of 0 to 100% EtOAc in n-hexane to give the title compound (0.62 g) as solid. ES-MS m / z 478, 480 (M+H).Preparation of Intermediate 266: rac-2-(4-bromo-3,5-dimethylphenyl)-2-hydroxyacetonitrile (racemic mixture)

[0352] To a 1 L 3 -neck round bottom flask with a magnetic stir bar was charged with H2O (130 mL), followed by the addition of 4-bromo-3,5-dimethylbenzaldehyde (25 g, 115 mmol) and NaCN (14 g, 280 mmol) at 15 °C. Then a solution of NaHSOs (28 g, 260 mmol) in H2O (130 mL) was added dropwise to the reaction mixture at 5 °C over 20 mins. The reaction mixture was stirred at 15 °C for 15 h, then filtered. The filtrate was adjusted to pH >11 with NaOH (1.0 M in H2O), and aq. NaClO (10%, 2 L) was added under stirring to quench the unreacted NaCN. The filter cake was washed with H2O (300 mL x 3) to give the title compound (30 g, 75 wt% purity) as solid, which was immediately used to next step without further purification. 'H-NMR (400 MHz, DMSO-tL) 8 7.28 (s, 2H), 7.12 - 6.90 (m, 1H), 5.67 (s, 1H), 2.39 (s, 6H).Preparation of Intermediate 267: rac-methyl 2-(4-bromo-3,5-dimethylphenyl)-2-hydroxyacetate (racemic mixture)

[0353] To a vigorous stirring MeOH (150 mL) solution of rac-2-(4-bromo-3,5-dimethylphenyl)- 2-hydroxyacetonitrile (racemic mixture, 30 g, 75 wt% purity, 94 mmol) was added HC1 (4.0 M in MeOH, 300 mL, 1200 mmol) dropwise over 20 mins at 5 °C. The resulting mixture was stirred at 70 °C for 15 h, then concentrated under reduced pressure to give a residue. TLC (2: 1 n-hexane : EtOAc) R / = 0.5. The residue was purified by flash silica gel chromatography using a gradient of 0 to 50% EtOAc in n-hexane to give the title compound (9.6 g) as solid. ES-MS m / z 255, 257 (M-OH).Preparation of Intermediate 268: rac-methyl 2-(4-bromo-3,5-dimethylphenyl)-2- ((methylsulfonyl)oxy)acetate (racemic mixture)

[0354] To a vigorous stirring DCM (200 mL) solution of rac-methyl 2-(4-bromo-3,5- dimethylphenyl)-2-hydroxyacetate (racemic mixture, 9.6 g, 33 mmol) and TEA (13 g, 120 mmol) was added methanesulfonyl chloride (12 g, 100 mmol) dropwise over 20 mins at 5 °C. The reaction mixture was de-gassed and backfilled with N2 for three times. The mixture was stirred at 18 °C for 6 h, then quenched with H2O (1.0 L) at 5 °C and extracted with DCM (500 mL x 4). The combined organic layer was washed with sat. aq. NaCl (100 mL) and dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (2: 1 n-hexane : EtOAc) Ry = 0.5. The residue was purified by flash silica gel chromatography using a gradient of 0 to 50% EtOAc in n-hexane to give the title compound (8.3 g) as solid. ESMS m / z 367, 369 (M+NH4+).Preparation of Intermediate 269: rac-2-(4-bromo-3,5-dimethylphenyl)-2-(2-hydroxy-2- methylpropoxy)acetic acid (racemic mixture)

[0355] To a vigorous stirring 2-methyl-2-hydroxypropanol (5.0 g, 5.0 mL, 54 mmol) in a 100 mL 3-neck round bottom flask was added sodium hydride (0.55 g, 60% Wt in mineral oil, 13.8 mmol) in three portions at 15 °C under N2. The mixture was stirred at 30 °C for 30 mins. Then rac-methyl-2-(4-bromo-3,5-dimethylphenyl)-2-((methylsulfonyl)oxy) acetate (racemic mixture, 1.00 g, 2.7 mmol) was added at 15 °C. The resulting mixture was stirred at 50 °C for 2 h, poured into H2O (15 mL) at 15 °C and then washed with EtOAc (10 mL x 3). The aqueous phase was concentrated under reduced pressure to give a residue, which was further purified by reverse phase prep-HPLC using a gradient of 10 to 45% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.30 g, 75.7 wt% purity) as solid. ES-MS m / z 329, 331 (M+H).Preparation of Intermediate 270: rac-2-(4-bromo-3,5-dimethylphenyl)-2-(2-hydroxy-2- methylpropoxy) acetamide (racemic mixture)

[0356] To a 40 mL vial with a magnetic stir bar was charged with DMF (10 mL), followed by the addition of rac-2-(4-bromo-3,5-dimethylphenyl)-2-(2-hydroxy-2-methylpropoxy)acetic acid (racemic mixture, 0.30 g, 75.7 wt% purity, 0.686 mmol), DIEA (0.36 g, 2.73 mmol), HATU (0.39 g, 1.01 mmol) and ammonium chloride (0.077 g, 1.4 mmol) at 20 °C. The mixture was stirred at 20 °C for 6 h, poured into H2O (10 mL) at 12 °C and then extracted with EtOAc (5 mL x 3). The combined organic layer was washed with sat. aq. NaCl (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by reverse phase prep-HPLC using a gradient of 25 to 75% ACN in 0.2% aq. FA to give the title compound (0.10 g, 86.5 wt% Purity) as solid. ES-MS m / z 330, 332 (M+H).Preparation of Intermediate 271 : rac-(4-bromo-3,5-dimethylbenzyl)phosphinic acid (racemic mixture)

[0357] A mixture of ammonium phosphinate (2 g, 20 mmol) and HMDS (5 g, 30 mmol) in a 40 mL vial was purged with N2 for 1 min before vigorously stirring at 110 °C for 2 h under N2.TLC (1 : 1 DCM : MeOH, R =0.5, phosphomolybdic acid). Then the reaction mixture was cooled down to 0 °C and a solution of 2-bromo-5-(bromomethyl)-l,3-dimethylbenzene (6 g, 20 mmol) in DCM (10 mL) was added dropwise to the above reaction mixture at 0 °C over 30s. The reaction mixture was stirred at 33 °C for 16 h under N2, quenched by EtOH (20 mL). Then the mixture was concentrated under reduced pressure to give a residue, which was triturated withEtOAc (20 mL) at 16 °C for 30 mins, filtered and the filter cake was dried under reduced pressure to give the title compound (1.51 g) as solid. ES-MS m / z 261, 263 (M+H).Preparation of Intermediate 272: rac-(4-bromo-3,5-dimethylbenzyl)(propyl)phosphinic acid (racemic mixture)

[0358] A mixture of rac-(4-bromo-3,5-dimethylbenzyl)phosphinic acid (racemic mixture, 1.01 g, 3.46 mmol) and HMDS (1.69 g, 10.1 mmol) in a 40 mL vial was purged with N2 for 1 min before vigorously stirring at 110 °C for 2 h under N2, then cooled down to 16 °C and iodopropane (8.90 g, 49.7 mmol) was added. The reaction mixture was stirred at 110 °C for 1 h, cooled down to room temperature, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was diluted with EtOAc (15 mL), adjusted to pH = 2~3 with HC1 (1.0 M in H2O) at 0 °C and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with sat. aq. NaCl (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (0.78 g, 83.7 wt% purity) as oil. ES-MS m / z 305, 307 (M+H).Preparation of Intermediate 273: rac-P-(4-bromo-3,5-dimethylbenzyl)-P-propylphosphinic amide (racemic mixture)

[0359] To a 50 mL 1-neck round bottom flask with a magnetic stir bar was charged with DCM (20 mL), followed by the addition of rac-(4-bromo-3,5-dimethylbenzyl)(propyl)phosphinic acid (racemic mixture, 0.78 g, 83.7 wt% purity, 2.14 mmol), DMF (0.036 mL, 0.49 mmol) and oxalyl chloride (0.566 g, 4.23 mmol) at 0 °C. The reaction mixture was degassed and purged with N2 for 3 times before vigorously stirring at 40 °C for 12 h under N2. Then ammonia (25% Wt inH2O, 2.2 g, 32 mmol) was added to above reaction mixture at 0 °C and stirred at 16 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by reverse phase prep-HPLC using a gradient of 20 to 60% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.151 g) as solid. ES-MS m z 304, 306 (M+H).Preparation of Intermediate 274: N-((2S,4R)-l-(5-bromo-2-cyanopyridin-3-yl)-4-carbamoyl-2- methylpiperidin-4-yl)-2-cyclobutyl-6-(trifluoromethyl)nicotinamide

[0360] To a 40 mL vial with a magnetic stir bar was charged with DMF (5 mL), followed by the addition of 2-cyclobutyl-6-(trifluoromethyl) nicotinic acid (0.50 g, 1.87 mmol), (2S,4R)-4- amino-l-(5-bromo-2-cyanopyridin-3-yl)-2-methylpiperidine-4-carboxamide (0.75 g, 2.1 mmol), DIEA (0.52 g, 4.0 mmol) and HATU (1.6 g, 4.1 mmol) at 20 °C. The mixture was purged with N2 for 2 mins before vigorously stirring at 20 °C for 4 h. The reaction mixture was poured into H2O (10 mL), and then extracted with EtOAc (20 mL x 3). The combined organic layer was washed with sat. aq. NaCl (20 mL x 2), dried over ISfeSCU, filtered and the filtrate was concentrated under reduced pressure to give the title compound (1.1 g, 77.8 wt% purity) as solid. ES-MS m'z 565, 567 (M+H).Preparation of Intermediate 275: 5-bromo-3-((5R,7S)-2-(2-cyclobutyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)picolinonitrile

[0361] To a 40 mL vial with a magnetic stir bar was charged with EtOH (10 mL), followed by addition of N-((2S,4R)-l-(5-bromo-2-cyanopyridin-3-yl)-4-carbamoyl-2-methylpiperidin-4-yl)- 2-cyclobutyl-6-(trifluoromethyl) nicotinamide (1.1 g, 77.8 wt% purity 1.5 mmol) and KO / Bu(1.0 g, 8.8 mmol) at 20 °C. The mixture was purged with N2 for 2 mins before vigorously stirring at 80 °C for 1 h, cooled down to room temperature, poured into H2O (20 mL), and then extracted with EtOAc (20 mL x 3). The combined organic layer was washed with sat. aq. NaCl (20 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (2 : 1 n-hexane : EtOAc) Ry = 0.4. The residue was purified by flash silica gel chromatography using a gradient of 0 to 35% EtOAc in n-hexane gradient to give the title compound (0.55 g, 1.0 mmol) as solid. ES-MS m,z 547, 549 (M+H).Preparation of Intermediate 276: (2S,4R)-l-(5-bromo-2-cyanopyridin-3-yl)-4-(2-cyclobutyl-4-(trifluorornethyl)benzamido)-2-methylpiperidine-4-carboxamide

[0362] To a 40 mL vial with a magnetic stir bar was charged with DMF (10 mL), followed by the addition of 2-cyclobutyl-4-(trifluoromethyl)benzoic acid (0.50 g, 1.99 mmol), (2S,4R)-4- amino-l-(5-bromo-2-cyanopyridin-3-yl)-2-methylpiperidine-4-carboxamide (0.72 g, 1.99 mmol), HATU (2.26 g, 5.88 mmol) and DIEA (0.51g, 3.94 mmol) at 20 °C. The mixture was stirred at 20 °C for 1 h, diluted with H2O (50 mL) and extracted with EtOAc (20 mL x 2). The combined organic layer was washed with sat. aq. NaCl (20 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (1.4 g, 70 wt% purity) as solid. ES-MS m / z 564, 566 (M+H).Preparation of Intermediate 277: 5-bromo-3-((5R,7S)-2-(2-cyclobutyl-4-(trifluoromethyl)phenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)picolinonitrile

[0363] To a 40 mL vial with a magnetic stir bar was charged with EtOH (14 mL), followed by the addition of (2S,4R)-l-(5-bromo-2-cyanopyridin-3-yl)-4-(2-cyclobutyl-4- (trifluoromethyl)benzamido)-2-methylpiperidine-4-carboxamide (1.4 g, 70 wt% purity, 1.7 mmol) and KO / Bu (0.78 g, 6.9 mmol) at 20 °C. Then the reaction mixture was stirred vigorously at 70 °C for 1 h, cooled to 20 °C, poured into H2O (100 mL), and then extracted with EtOAc (30 mL * 3). The combined organic layer was washed with sat. aq. NaCl (40 mL x2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the crude product. TLC (2: 1 n-hexane: EtOAc) Ry = 0.4. The crude product was purified by flash silica gel chromatography using a gradient of 0 to 60% EtOAc in n-hexane gradient to give the title compound (0.24 g) as solid. ES-MS m z 546, 548 (M+H).Preparation of Intermediate 278: / crt-butyl (2S,4R)-4-carbamoyl-4-(2-cyclobutyl-6- (trifluoromethyl)nicotinamido)-2-methylpiperidine-l -carboxylate

[0364] To a 40 mL vial with a magnetic stir bar was charged with DMF (10 mL), followed by addition of 2-cyclobutyl-6-(trifluoromethyl)nicotinic acid (1.0 g, 3.7 mmol), tert-butyl (2S,4R)- 4-amino-4-carbamoyl-2-methylpiperidine-l -carboxylate (1.1 g, 4.2 mmol), DIEA (1.1 g, 8.5 mmol) and HATU (2.8 g, 7.2 mmol) at 20 °C. The mixture was purged with N2 for 2 mins before vigorously stirring at 20 °C for 4 h, poured into H2O (20 mL), and then extracted with EtOAc (30 mL x 3). The combined organic layer was washed with sat. aq. NaCl (30 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (2.0 g, 71.7 wt% purity) as solid. ES-MS m / z 485 (M+H).Preparation of Intermediate 279: tert-butyl (5R,7S)-2-(2-cyclobutyl-6-(trifluoromethyl)pyridin-3- yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate

[0365] To a 40 mL vial with a magnetic stir bar was charged with EtOH (15 mL), followed by addition of te / 7-butyl (2S,4R)-4-carbamoyl-4-(2-cyclobutyl-6-(trifluoromethyl)nicotinamido)-2- methylpiperidine-1 -carboxylate (2.0 g, 71.7 wt% purity, 3.0 mmol) and KO / Bu (2.1 g, 19 mmol) at 16 °C. The mixture was purged with N2 for 1 min before vigorously stirring at 80 °C for 1 h. The reaction mixture was cooled down to room temperature, poured into H2O (50 mL) and then extracted with EtOAc (50 mL x 3). The combined organic phase was washed with sat. aq. NaCl (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (1.7 g, 70 wt% purity) as solid. ES-MS m / z 467 (M+H).Preparation of Intermediate 280: (5R,7S)-2-(2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-7- methyl -1,3 , 8-triazaspiro[4.5 ]dec- 1 -en-4-one

[0366] To a 100 mL 1-neck round bottom flask with a magnetic stir bar was charged with tert- butyl (5R,7S)-2-(2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-l,3,8- triazaspiro[4.5]dec-l-ene-8-carboxylate (1.7 g, 70 wt% purity, 2.6 mmol) and Hydrogen chloride in 1,4-dioxane (9.2 g, 40 mmol) at 16 °C. The reaction mixture was stirred vigorously at 30 °C for 4 h, then concentrated under reduced pressure. Then LiOH (4.0 M in H2O, 50 mL) was added, and the obtained mixture was stirred for 2 h at 60 °C. The mixture was concentrated directly under reduced pressure to give the crude product, which was further purified by reverse phase prep-HPLC using a gradient of 15 to 65% ACN in 10 mM aq. NH4HCO3 (containing 0.05% NH3H2O) to give the title compound (0.51 g) as solid. ES-MS m / z 367 (M+H).Preparation of Intermediate 281 : (5R, 7S)-8-(5-bromo-2-(methylsulfonyl) pyri din-3 -yl)-2-(2- cyclobutyl-6-(trifluoromethyl) pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0367] To a 40 mL vial with a magnetic stir bar was charged with 1,4-dioxane (10 mL), followed by the addition of (5R,7S)-2-(2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8- triazaspiro[4.5]dec-l-en-4-one (0.35 g, 0.95 mmol), 5-bromo-3-fluoro-2-(methylsulfonyl)pyridine (0.25 g, 0.96 mmol) and NazCCh (0.41 g, 3.81 mmol) at 15 °C. The mixture was purged with N2 for 1 min before vigorously stirring at 100 °C for 24 h under N2, cooled down to room temperature, filtered and the filtrate was concentrated under reduced pressure to give a residue. TLC (20: 1 DCM : MeOH) R / = 0.5. The residue was purified by flash silica gel chromatography using a gradient of 20 to 50% EtOAc in petroleum ether to give the title compound (0.27g, 89 wt% purity) as solid. ES-MS m / 'z 600, 602 (M+H).Preparation of Intermediate 282: (5R, 7S)-8-(5-bromo-2-(2-fluoroethoxy)pyri din-3 -yl)-2-(2- cyclobutyl-6-(trifhioromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0368] To a 40 mL vial with a magnetic stir bar was charged with NMP (6 mL), followed by the addition of (5R,7S)-8-(5-bromo-2-(methylsulfonyl)pyridin-3-yl)-2-(2-cyclobutyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.27 g, 89 wt% purity, 0.40 mmol), 2-fluoro-ethanol (0.20 g, 3.11 mmol) and KO / Bu (0.17 g, 1.46 mmol) at 15 °C. Then the reaction mixture was stirred vigorously at 30 °C for 1 h, cooled to 15 °C and poured into H2O (40 mL), then extracted with EtOAc (10 mL x 3). The combined organic layer was washed with sat. aq. NaCl (10 mL x 3), dried over Na2SO4, filtered and the filtrate wasconcentrated under reduced pressure to give a residue. TLC (20: 1 DCM : MeOH) R / = 0.5. The residue was purified by flash silica gel chromatography using a gradient of 20 to 50% EtOAc in petroleum ether to give the title compound (0.159 g) as solid. ES-MS m / z 584, 586 (M+H).Preparation of Intermediate 283: (S)-l-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl)ethane- 1 ,2-diol

[0369] To a 250 mL 3-neck round bottom flask with a magnetic stir bar was charged with (S)-l- (4-bromo-3,5-dimethylphenyl)ethane-l,2-diol (4.5 g, 18 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (11.2 g, 43.2 mmol), KOAc (4.5 g, 42 mmol) and methoxycyclopentane (60 mL). The mixture was de-gassed and refilled with N2 for three t...

Claims

CLAIMS1. A compound of formula (I):wherein: the A ring is a 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from:(1) Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -0-C(0)CMO alkyl and (d) -CN,(2) halogen,(3) Ci-io alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) C3-10 cycloalkyl, optionally substituted with -CN, and (d) Ci-10 alkoxy,(4) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) C1-10 alkyl, and (c) -C(O)Ci.10 alkyl,(5) -CN,(6) -O-C3-10 cycloalkyl, optionally substituted with 1 to 3 halogens,(7) oxo,(8) -C(O)NH2,(9) C3-10 cycloalkyl, and(10) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) Ci-io alkyl and (b) halogen;R1is selected from:(1) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S,(3) -NReRf, wherein:Reis selected from:(a) H,(b) Ci-io alkyl, and(c) -C(O)Ci -io alkyl, optionally substituted with 1 to 3 halogens; andR1is selected from:(a) H,(b) Ci-io alkyl, optionally substituted with 1 to 3 halogens,(c) -C(O)Ci -io alkyl, optionally substituted with 1 to 3 halogens, and(d) -C(O)NH2, optionally substituted with 1 to 2 Ci-io alkyl;(4) Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -C(O)NRaRb, wherein each of Raand Rbis independently selected from (i) H, (ii) C i-io alkyl, and (iii) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from halogen and Ci-io alkyl optionally substituted with 1 to 3 halogens,(c) -OH,(d) C3-10 cycloalkyl, optionally substituted with 1 to 3 halogens,(e) Ci-10 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,(f) -NRlaRlb, wherein each of Rlaand Rlbis independently selected from:(i) H,(ii) Ci-10 alkyl, optionally substituted with 1 to 3 halogens, and(iii) -C(0)Ci-io alkyl, optionally substituted with 1 to 3 halogens,(g) -P(O)RlcRld, wherein each of Rlcand Rldis independently selected from:(i) Ci-io alkyl, and(ii) -NRleRlf, wherein each of Rleand Rlfis independently selected from H and Ci-io alkyl, and(h) -SO2NRlgRlh, wherein each of Rlgand Rlhis independently selected from H and Ci-io alky,(5) -SO2NH2, optionally substituted with 1 to 2 C1-10 alkyl,(6) -C(0)NH2, optionally substituted with 1 to 2 C1-10 alkyl,(7) -C(O)OH, and(8) H; wherein each of the heterocyclyl of (1) and heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:(a) Ci-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH, (iii) -0-C(0)Ci-io alkyl, and (iv) -NR11Rlj, wherein each of R11and Rljis independently selected from H and C1-10 alkyl, and(b) oxo; each of R2and R3is independently selected from:(1) H,(2) Ci-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(3) -O-Rc, wherein Rcis selected from (a) H and (b) C1-10 alkyl,(4) -C(O)-Rd, wherein Rdis selected from (a) C1-10 alkyl; (b) -OH, (c) C1-10 alkoxy, and(d) -NR2eR2f, wherein each of R2eand R2fis independently selected from (i) H and (ii) Ci-10 alkyl, and(5) halogen; each of R4, R4, R5, and R3is independently selected from:(1) H,(2) C i-io alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) -OH and (b) halogen,(3) C3-10 cycloalkyl, and(4) halogen;R6is selected from:(1) an aryl,(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and(3) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) Ci-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,(c) C O alkoxy, optionally substituted with 1 to 3 halogens,(d) -O-aryl, optionally substituted with 1 to 3 halogens,(e) -O-heteroaryl, wherein the heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) Ci-10 alkyl, (ii) halogen, (iii) -OH, and (iv) CMO alkoxy,(f) -S-C i-io alkyl, optionally substituted with 1 to 3 halogens,(g) -NR6eR6f, wherein each of R6eand R6fis independently selected from (i) H, (ii) Ci-10 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,(h) a 4-6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) CMO alkyl and (ii) halogen,(i) an aryl, optionally substituted with 1 to 3 substituents independently selected from (i) Ci-io alkyl, (ii) halogen, and (iii) -OH,(j) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) Ci-io alkyl, (ii) halogen, (iii) -OH, and (iv) Cn io alkoxy,(k) C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) Ci-io alkyl, optionally substituted 1-3 halogens,(l) -O-C3-10 cycloalkyl, optionally substituted with 1 to 3 halogens, and(m) -O-C2-10 alkenyl, optionally substituted with 1 to 3 halogens; andR7is selected from:(1) H,(2) Ci-10 alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen, and(3) halogen; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the A ring is a 5- or 6-membered heteroaryl ring selected from pyridyl, pyrimidyl, and thiazolyl, optionally substituted with 1 to 3 substituents independently selected from:(1) C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -O-C(O)Ci-6alkyl and (d) -CN,(2) halogen,(3) C1-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) C3-6 cycloalkyl, optionally substituted with -CN, and (d) C1-6 alkoxy,(4) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) Ci-6 alkyl, and (c) -C(O)Ci-6 alkyl,(5) -O-C3-6 cycloalkyl,(6) -CN,(7) -C(O)NH2,(8) C3-6 cycloalkyl, and(9) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) Ci-6 alkyl and (b) halogen.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (la):wherein, each of R^, RA3, and RA4is independently selected from:(1) H,(2) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) halogen, (b) -OH, (c) -O-C(O)Ci-6alkyl and (d) -CN,(3) halogen,(4) Ci-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) C3-6 cycloalkyl, optionally substituted with -CN, and (d) C 1-6 alkoxy,(5) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) Ci-6 alkyl, and (c) -C(O)Ci-6 alkyl,(6) -CN,(7) -O-C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and(8) oxo.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (lb):wherein, each of RA1, RA3, and RA4is independently selected from:(1) H,(2) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -O-C(O)Ci-6alkyl and (d) -CN,(3) halogen,(4) Ci-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) C3-6 cycloalkyl, optionally substituted with -CN, and (d) C 1-6 alkoxy,(5) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) C1-6 alkyl, and (c) -C(O)Ci-6 alkyl,(6) -CN,(7) -O-C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and(8) oxo.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (Ic):wherein, each of RA1, RA2, and RA3is independently selected from:(1) H,(2) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -O-C(O)Ci-6 alkyl, optionally substituted with -CN, and (d) - CN,(3) halogen,(4) Ci-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) C3-6 cycloalkyl and (d) Ci-6 alkoxy,(5) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) Ci-6 alkyl, and (c) -C(O)Ci-6 alkyl,(6) -CN,(7) -O-C3.6 cycloalkyl, optionally substituted with 1 to 3 halogens, and(8) oxo.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (Id):wherein, each of RA2and RA4is independently selected from:(1) H,(2) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) halogen, (b) -OH, (c) -O-C(O)Ci-6alkyl and (d) -CN,(3) halogen,(4) Ci-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) C3-6 cycloalkyl, optionally substituted with -CN, and (d) C 1-6 alkoxy,(5) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) Ci-6 alkyl, and (c) -C(O)Ci-6 alkyl,(6) -CN,(7) -O-C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and(8) oxo.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (le):wherein, RA2is selected from:(1) H,(2) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -O-C(O)Ci-6 alkyl and (d) -CN,(3) halogen,(4) Ci-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) C3-6 cycloalkyl, optionally substituted with -CN, and (d) C1-6 alkoxy,(5) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) C1-6 alkyl, and (c) -C(O)Ci-6 alkyl,(6) -CN,(7) -O-C3.6 cycloalkyl, optionally substituted with 1 to 3 halogens, and(8) oxo.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (If):wherein, each of RA1, RA2, and RA4is independently selected from:(1) H,(2) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -O-C(O)Ci-6alkyl and (d) -CN,(3) halogen,(4) Ci -6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) C3-6 cycloalkyl, optionally substituted with -CN, and (d) C1-6 alkoxy,(5) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) C1-6 alkyl, and (c) -C(O)Ci-6 alkyl,(6) -CN,(7) -O-C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and(8) oxo.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (Ig):wherein, RA3is selected from:(1) H,(2) C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) halogen, (b) -OH, (c) -O-C(O)Ci-6alkyl and (d) -CN,(3) halogen,(4) Ci-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) C3-6 cycloalkyl, optionally substituted with -CN, and (d) C1-6 alkoxy,(5) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) C1-6 alkyl, and (c) -C(O)Ci-6 alkyl,(6) -CN,(7) -O-C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and(8) oxo.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: the A ring is a 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from:(1) C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) halogen, (b) -OH, (c) -O-C(O)Ci-6alkyl and (d) -CN,(2) halogen,(3) C1-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -C3-6 cycloalkyl, optionally substituted with -CN, and (d) Ci-6 alkoxy,(4) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) C1-6 alkyl, and (c) -C(O)Ci-6 alkyl,(5) -CN,(6) -O-C3-6 cycloalkyl,(7) oxo,(8) -C(O)NH2,(9) C3-6 cycloalkyl, and(10) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) Ci-6 alkyl and (b) halogen;R1is selected from:(1) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S,(3) -NReRf, wherein:Reis selected from:(a) H,(b) Ci-6 alkyl, and(c) -C(O)Ci-6 alkyl, optionally substituted with 1 to 3 halogens; andRfis selected from:(a) H,(b) Ci-6 alkyl, optionally substituted with 1 to 3 halogens,(c) -C(O)Ci-6 alkyl, optionally substituted with 1 to 3 halogens, and(d) -C(0)NH2, optionally substituted with 1 to 2 Ci-6 alkyl;(4) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -C(O)NRaRb, wherein each of Raand Rbis independently selected from (i)H, (ii) Ci-6 alkyl, and (iii) a 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,(c) -OH,(d) C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens,(e) C1-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,(f) -NRlaRlb, wherein each of Rlaand Rlbis independently selected from:(i) H,(ii) C1-6 alkyl, optionally substituted with 1 to 3 halogens, and(iii) -C(O)Ci-6 alkyl, optionally substituted with 1 to 3 halogens,(g) -P(O)RlcRld, wherein each of Rlcand Rldis independently selected from:(i) Ci-6 alkyl, and(ii) -NRleRlf, wherein each of Rleand Rlfis independently selected from H and Ci-6 alkyl, and(h) -SO2NH2,(5) -SO2NH2,(6) -C(O)NH2,(7) -C(O)OH, and(8) H; wherein each of the heterocyclyl of (1) and the heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:(a) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH, (iii) -O-C(O)Ci-6 alkyl, and (iv) - NRJ'R1-1, wherein each of R11and Rlis independently selected from H and Ci-6 alkyl, and(b) oxo; each of R2and R3is independently selected from:(1) H,(2) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(3) -O-Re, wherein Rcis selected from (a) H and (b) Ci-6 alkyl,(4) -C(O)-Rd, wherein Rdis selected from (a) Ci-6 alkyl; (b) -OH, (c) Ci-6 alkoxy, and (d) - NR2eR2t, wherein each of R2eand R2tis independently selected from (i) H and (ii) Ci-6 alkyl, and(5) halogen; each of R4, R4, R5, and Ryis independently selected from:(1) H,(2) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) -OH and (b) halogen,(3) C3.6 cycloalkyl, and(4) halogen, wherein at least one of R4, R4, R5, and R5is not H;R6is selected from:(1) a phenyl(2) a naphthyl,(3) a pyridyl,(4) a pyrazolyl, and(5) a 1,3-benzodioxolyl, wherein each of the phenyl of (1), naphthyl of (2), pyridyl of (3), pyrazolyl of (4), and 1,3-benzodioxolyl of (5) is optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,(c) Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,(d) a 4 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) Ci-6 alkyl and (ii) halogen,(e) an aryl, optionally substituted with 1 to 3 halogens,(f) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) Ci-6 alkyl, (ii) halogen, and (iii) Ci-6 alkoxy,(g) C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) Ci-6 alkyl, optionally substituted 1-3 halogens,(h) -O-C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and(i) -O-C2-6 alkenyl, optionally substituted with 1 to 3 halogens; andR7is selected from:(1) H,(2) Ci-6 alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen, and(3) halogen.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein: the A ring is a 5- or 6-membered heteroaryl ring selected from pyridyl, pyrimidyl, and thiazolyl, optionally substituted with 1 to 4 substituents independently selected from:(1) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) halogen, (b) -OH, (c) -O-C(O)Ci-6alkyl and (d) -CN,(2) halogen,(3) Ci-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) C3-6 cycloalkyl, optionally substituted with -CN, and (d) C1-6 alkoxy,(4) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) C1-6 alkyl, and (c) -C(O)Ci-6 alkyl,(5) -CN, and(6) -O-C3-6 cycloalkyl;R1is selected from:(1) a 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,(2) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S,(3) -NReRf, wherein:Reis selected from:(a) H and(b) C1-6 alkyl, andRfis selected from:(a) H,(b) Ci-6 alkyl, optionally substituted with 1 to 3 halogens,(c) -C(0)Ci-6 alkyl, optionally substituted with 1 to 3 halogens, and(d) -C(0)NH2, optionally substituted with 1 to 2 Ci-6 alkyl; and(4) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -C(O)NRaRb, wherein each of Raand Rbis independently selected from (i) H, (ii) Ci-6 alkyl, and (iii) a 5 to 6 membered heterocyclyl selected from morpholinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl and 1,4- dioxanyl,(c) -OH,(d) C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens,(e) C1-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,(f) -NRlaRlb, wherein each of Rlaand Rlbis independently selected from:(i) H,(ii) -C(O)Ci-6 alkyl, optionally substituted with 1 to 3 halogens,(g) -P(O)RlcRld, wherein each of Rlcand Rldis independently selected from:(i) C 1-6 alkyl and(ii) -NRleRn, wherein each of Rleand R" is independently selected from H and Ci-6 alkyl, and(h) -SO2NH2, wherein each of the heterocyclyl of (1) and the heteroaryl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)Ci-6 alkyl, and(b) oxo; each of R2and R3is independently selected from:(1) H,(2) halogen, and(3) Ci-4 alkyl, optionally substituted with 1 to 3 substituents selected from (a) halogen and(b) -OH; each of R4, R4, R5, and R5is independently selected from:(1) H,(2) halogen,(3) Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) -OH and (b) halogen, and(4) C3-6 cycloalkyl, wherein at least one of R4, R4, R5, and R5is not H; andR6is selected from:(1) a phenyl,(2) a pyridyl,(3) a pyrazolyl, and(4) a 1,3-benzodioxolyl, wherein each of the phenyl of (1), pyridyl of (2), pyrazolyl of (3), and 1,3-benzodioxolyl of (4) is optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) C1-4 alkyl, optionally substituted with 1 to 3 halogens,(c) C1-4 alkoxy, optionally substituted with 1 to 3 halogens,(d) a heterocyclyl selected from (i) morpholinyl, (ii) piperidinyl, (iii) tetrahydrofuranyl, (iv) tetrahydropyranyl and (v) 1 ,4-dioxanyl, optionally substituted with 1 to 3 substituents independently selected from (i) C1-4 alkyl and (ii) halogen,(e) a phenyl, optionally substituted with 1 to 3 halogens,(f) a heteroaryl selected from (i) pyridyl, (ii) pyrazolyl, (iii) thiazolyl, (iv) isothiazolyl, (v) thienyl, and (vi) thiophenyl, each of which is optionallysubstituted with 1 to 3 substituents independently selected from (i) -CH3, (ii) ethyl, (iii) halogen, (iv) -OH, and (v) -OCH3,(g) C3-4 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) C1.4 alkyl, optionally substituted 1-3 halogens,(h) -O-C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens, and(i) -O-C2-6 alkenyl, optionally substituted with 1 to 3 halogens.

12. The compound of any one of claims 3-11, or a pharmaceutically acceptable salt thereof, wherein, when present, each of RA1, R^, RA3, and RA4is independently selected from:(1) H,(2) C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -O-C(O)Ci-4alkyl and (d) -CN,(3) halogen,(4) C 1-4 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) C3-4 cycloalkyl, optionally substituted with -CN, and (d) C 1.4 alkoxy,(5) -CN,(6) -O-C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens, and(7) oxo.

13. The compound of any one of claims 1-10 and 12, or a pharmaceutically acceptable salt thereof, wherein R1is selected from:(1) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,(2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S,(3) -NReRf, wherein:Reis selected from:(a) H,(b) Ci-6 alkyl, and(c) -C(0)Ci-6 alkyl, optionally substituted with 1 to 3 halogens; andRfis selected from:(a) H,(b) Ci-6 alkyl, optionally substituted with 1 to 3 halogens,(c) -C(O)Ci-6 alkyl, optionally substituted with 1 to 3 halogens, and(d) -C(0)NH2, optionally substituted with 1 to 2 Ci-6 alkyl;(4) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -C(O)NRaRb, wherein each of Raand Rbis independently selected from (i) H, (ii) Ci-6 alkyl, and (iii) a 5 to 6 membered heterocyclyl selected from morpholinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl and 1,4- dioxanyl,(c) -OH,(d) C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens,(e) C1-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,(f) -NRlaRlb, wherein each of Rlaand Rlbis independently selected from:(i) H,(ii) -C(O)Ci-6 alkyl, optionally substituted with 1 to 3 halogens,(g) -P(O)RlcRld, wherein each of Rlcand Rldis independently selected from:(i) C i-6 alkyl and(ii) -NRleRlf, wherein each of Rleand Rlfis independently selected from H and Ci-6 alkyl, and(h) -SO2NH2,(5) -SO2NH2,(6) -C(O)NH2,(7) -C(O)OH, and(8) H;wherein each of the heterocyclyl of (1) and the heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:(a) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)Ci-6 alkyl, and(b) oxo.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R1is selected from:(1) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from:(a) Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)C 1-4 alkyl, and(b) oxo;(2) -NReRf, wherein:Reis selected from:(a) H, and(b) C1-4 alkyl, andRfis selected from:(a) H,(b) C1-4 alkyl, optionally substituted with 1 to 3 halogens,(c) -C(O)Ci-4 alkyl, optionally substituted with 1 to 3 halogens, and(d) -C(0)NH2, optionally substituted with 1 to 2 C1-4 alkyl; and(3) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -C(0)NRaRb, wherein each of Raand Rbis independently selected from (i) H and (ii) C1-4 alkyl, and (iii) a 5 to 6 membered heterocyclyl selected from morpholinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl and 1,4- dioxanyl,(c) -OH,(d) C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens,(e) C1-6 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,(f) -NRlaRlb, wherein each of Rlaand Rlbis independently selected from:(i) H,(ii) -C(O)Ci-6 alkyl, optionally substituted with 1 to 3 halogens,(g) -P(O)RlcRld, wherein each of Rlcand Rldis independently selected from:(i) C1-6 alkyl and(ii) -NRleRn, wherein each of Rleand Rnis independently selected from H and Ci-6 alkyl, and(h) -SO2NH2.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R1is selected from:(1) a 5 to 10 membered heterocyclyl selected from: (a)(2) -NReRf, wherein:Reis selected from (a) H and (b) Ci-4 alkyl; and Rfis selected from:(a) H,(b) Ci-4 alkyl, optionally substituted with 1 to 3 halogens,(c) -C(O)Ci-4 alkyl, optionally substituted with 1 to 3 halogens, and(d) -C(O)NH2, optionally substituted with 1 to 2 Ci-4 alkyl; and(3) Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -OH,(c) -C(O)NRaRb, wherein each of Raand Rbis independently selected from (i) H,(ii) C1-4 alkyl, and (iii) a 5 to 6 membered heterocyclyl selected from morpholinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl and 1,4-dioxanyl,(d) C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens,(e) C1-4 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,(f) -NRlaRlb, wherein each of Rlaand Rlbis independently selected from:(i) H,(ii) -C(O)Ci-4 alkyl, optionally substituted with 1 to 3 halogens,(g) -P(O)RlcRld, wherein each of Rlcand Rldis independently selected from:(i) C 1.4 alkyl and(ii) -NRleRn, wherein each of Rleand Rnis independently selected from H and C 1-4 alkyl, and(h) -SO2NH2; wherein the heterocyclyl of (1) is optionally substituted 1 to 4 substituents independently selected from:(a) C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen, (ii) -OH and (iii) -O-C(O)Ci-4 alkyl, and(b) oxo.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R1is selected from:(1) a 5 to 10 membered heterocyclyl selected from: (a)(2) -NReRf, wherein:Reis selected from (a) H and (b) -CH3; and Rfis selected from:(a) H,(b) -CH3, optionally substituted with 1 to 3 halogens,(c) -C(0)CH3, optionally substituted with 1 to 3 halogens, and(d) -C(0)NH2, optionally substituted with 1 to 2 substituents independently selected from (i) -CH3 and (ii) -CH2CH3; and(3) C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, and (c) -C(O)NRaRb, wherein each of Raand Rbis independently selected from (i) H, (ii) methyl, and (iii) ethyl; wherein the heterocyclyl of (1) is optionally substituted with 1 to 3 substituents independently selected from:(a) -CH3, optionally substituted with 1 to 3 halogens,(b) -CH2CH3, optionally substituted with 1 to 3 halogens,(c) -CH2OH,(d) -CH2-OC(O)CH3, and(e) oxo.

17. The compound of any one of claims 1-10 and 12-16, or a pharmaceutically acceptable salt thereof, wherein each of R2and R3is independently selected from:(1) H,(2) halogen,(3) C1-4 alkyl, optionally substituted with 1 to 3 substituents selected from (a) halogen and (b) -OH,(4) -O-Rc, wherein Rcis selected from (a) H and (b) C1-4 alkyl, and(5) -C(O)-Rd, wherein Rdis selected from (a) C1.4 alkyl; (b) C1-4 alkoxy, and (c) -NR2eR2i, wherein each of R2eand R2fis independently selected from (i) H and (ii) C1.4 alkyl.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein: R2is selected from (1) H, (2) halogen, (3) -CH3, (4) -CHF2, and (5) -CH2OH; andR3is selected from (1) H, (2) halogen, (3) -CH3, (4) -CHF2, and (5) -CH2OH.

19. The compound of any one of claims 1-10 and 12-18, or a pharmaceutically acceptable salt thereof, wherein each of R4, R4, R5, and R5is independently selected from:(1) H,(2) halogen,(3) Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) -OH and (b) halogen, and(4) C3-6 cycloalkyl, wherein at least one of R4, R4, R5, and R3is not H.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein: R2is selected from (1) H, (2) halogen, (3) -CH3, (4) -CHF2, and (5) -CH2OH;R3is selected from (1) H, (2) halogen, (3) -CH3, (4) -CHF2, and (5) -CH2OH;R4is selected from (1) -CH3, (2) -CH2OH, (3) -CHF2, and (4) -CF3; and each of R4, R5, and R3is H.

21. The compound of any one of claims 1-10 and 12-20, or a pharmaceutically acceptable salt thereof, wherein R6is selected from:(1) a phenyl(2) a naphthyl,(3) a pyridyl,(4) a pyrazolyl, and(5) a 1,3-benzodioxolyl, wherein each of the phenyl of (1), naphthyl of (2), pyridyl of (3), pyrazolyl of (4), and 1,3-benzodioxolyl of (5) is optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,(c) Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,(d) a 4 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) Ci-6 alkyl and (ii) halogen,(e) an aryl, optionally substituted with 1 to 3 halogens,(f) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) Ci-6 alkyl, (ii) halogen, and (iii) Ci-6 alkoxy,(g) C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) Ci-6 alkyl, optionally substituted 1-3 halogens, and(h) -O-C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and(i) -O-C2-6 alkenyl, optionally substituted with 1 to 3 halogens.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R6ed from:(1) a phenyl,(2) a pyridyl,(3) a pyrazolyl, and(4) a 1,3-benzodioxolyl, wherein each of the phenyl of (1), pyridyl of (2), pyrazolyl of (3), and 1,3-benzodioxolyl of (4) is optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) C1-4 alkyl, optionally substituted with 1 to 3 halogens,(c) C1-4 alkoxy, optionally substituted with 1 to 3 halogens,(d) a heterocyclyl selected from (i) morpholinyl, (ii) piperidinyl, (iii) tetrahydrofuranyl, (iv) tetrahydropyranyl and (v) 1 ,4-dioxanyl, optionallysubstituted with 1 to 3 substituents independently selected from (i) C1-4 alkyl and (ii) halogen,(e) a phenyl, optionally substituted with 1 to 3 halogens,(f) a heteroaryl selected from (i) pyridyl, (ii) pyrazolyl, (iii) thiazolyl, (iv) isothiazolyl, (v) thienyl, and (vi) thiophenyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) -CH3, (ii) ethyl, (iii) halogen, (iv) -OH, and (v) -OCH3,(g) C3-4 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) C1.4 alkyl, optionally substituted 1-3 halogens,(h) -O-C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens, and(i) -O-C2-4 alkenyl, optionally substituted with 1 to 3 halogens.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R6ed from:(1) a phenyl,(2) a pyridyl, and(3) a pyrazolyl, wherein each of the phenyl of (1), pyridyl of (2), and pyrazolyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) methyl, optionally substituted with 1 to 3 halogens,(c) ethyl, optionally substituted with 1 to 3 halogens,(d) methoxy, optionally substituted with 1 to 3 halogens,(e) ethoxy, optionally substituted with 1 to 3 halogens,(f) a heterocyclyl selected from (i) morpholinyl, (ii) piperidinyl, (iii) tetrahydrofuranyl, (iv) tetrahydropyranyl, and (v) 1,4-dioxanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -CH3 and (ii) halogen,(g) a phenyl,(h) a heteroaryl selected from (i) pyridyl, (ii) pyrazolyl, (iii) thiazolyl, (iv) isothiazolyl, (v) thienyl, and (vi) thiophenyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) methyl, (ii) ethyl, (iii) halogen, (iv) -OH, and (v) -OCH3,(i) C3-4 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) methyl, optionally substituted 1-3 halogens,(j) -O-C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens, and(k) -O-C2-4 alkenyl, optionally substituted with 1 to 3 halogens.

24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: the A ring is a 5- or 6-membered heteroaryl ring selected from pyridyl, pyrimidyl, and thiazolyl, optionally substituted with 1 to 3 substituents independently selected from:(1) Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) -O-C(O)Ci-4alkyl and (d) -CN,(2) halogen,(3) Ci-4 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, (c) C3-4 cycloalkyl, optionally substituted with -CN, and (d) C 1-4 alkoxy,(4) -NRaRb, wherein each of Raand Rbis independently selected from (a) H, (b) C1-4 alkyl, and (c) -C(O)Ci-4 alkyl,(5) -O-C3-4 cycloalkyl, and(6) -CN;R1is selected from:(1) a 5 to 10 membered heterocyclyl selected from:(2) -NRCR', wherein:Reis selected from (a) H and (b) -CH3; andRfis selected from:(a) H,(b) -CH3, optionally substituted with 1 to 3 halogens,(c) -C(0)CH3, optionally substituted with 1 to 3 halogens, and(d) -C(0)NH2, optionally substituted with 1 to 2 substituents independently selected from (i) -CH3 and (ii) -CH2CH3; and(3) C1.4 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -OH,(c) -C(O)NRaRb, wherein each of Raand Rbis independently selected from (i) H, (ii) methyl, and (iii) ethyl, and (iv) a 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from halogen and C1-4 alkyl optionally substituted with 1 to 3 halogens,(d) C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens,(e) C1-4 alkoxy, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,(f) -NRlaRlb, wherein each of Rlaand Rlbis independently selected from:(i) H,(ii) -C(O)Ci-4 alkyl, optionally substituted with 1 to 3 halogens,(g) -P(O)RleRld, wherein each of Rlcand Rldis independently selected from:(i) C 1.4 alkyl and(ii) -NRleRlf, wherein each of Rleand Rlfis independently selected from H and Ci-4 alkyl, and(h) -SO2NH2; wherein the heterocyclyl of (1) is optionally substituted with 1 to 3 substituents independently selected from:(a) -CH3, optionally substituted with 1 to 3 halogens,(b) -CH2CH3, optionally substituted with 1 to 3 halogens,(c) -CH2OH,(d) -CH2-OC(O)CH3,(e) -CH2-NH2,(f) -CH2-NHCH3,(g) -CH2CH2-NH2,(h) -CH2CH2-NHCH3, and(i) oxo;R2is selected from (1) H, (2) halogen, (3) -CH3, (4) -CHF2, and (5) -CH2OH;R3is selected from (1) H, (2) halogen, (3) -CH3, (4) -CHF2, and (5) -CH2OH;R4is selected from (1) -CH3, (2) -CH2OH, (3) -CHF2, and (4) -CF3; each of R4, R5, and R is H;R6is selected from:(1) a phenyl,(2) a pyridyl, and(3) a pyrazolyl, wherein each of the phenyl of (1), pyridyl of (2), and pyrazolyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) methyl, optionally substituted with 1 to 3 halogens,(c) ethyl, optionally substituted with 1 to 3 halogens,(d) methoxy, optionally substituted with 1 to 3 halogens,(e) ethoxy, optionally substituted with 1 to 3 halogens,(f) a heterocyclyl selected from (i) morpholinyl, (ii) piperidinyl, (iii) tetrahydrofuranyl, (iv) tetrahydropyranyl, and (v) 1,4-dioxanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -CH3 and (ii) halogen,(g) a phenyl,(h) a heteroaryl selected from (i) pyridyl, (ii) pyrazolyl, (iii) thiazolyl, (iv) isothiazolyl, (v) thienyl, and (vi) thiophenyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) -CH3, (ii) ethyl, (iii) halogen, (iv) -OH, and (v) -OCH3,(i) C3-4 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) methyl, optionally substituted 1-3 halogens,(j) -O-C3-4 cycloalkyl, optionally substituted with 1 to 3 halogens, and(k) -O-C2-4 alkenyl, optionally substituted with 1 to 3 halogens; andR7is H.

25. The compound of claim 1 selected from Examples 1-126, or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

27. A method for treating a type 2 diabetes, obesity, or overweight with at least one weight related comorbidity comprising administering an effective amount of a compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

28. A compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, for use in therapy.

29. A compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, for use in the treatment of a type 2 diabetes, obesity, or overweight with at least one weight related comorbidity selected from diabetes, high blood pressure, high cholesterol, obstructive sleep apnea and heart disease.

30. A compound or a pharmaceutically acceptable salt thereof, for use of claim 29, in the treatment of a type 2 diabetes.

31. A compound or a pharmaceutically acceptable salt thereof, for use of claim 29, in the treatment of obesity.

32. A compound or a pharmaceutically acceptable salt thereof, for use of claim 29, in the treatment of overweight with at least one weight related comorbidity selected from diabetes, high blood pressure, high cholesterol, obstructive sleep apnea and heart disease.

33. A compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with one or more of a glucagon-like peptide- 1 (GLP-1) receptor agonist, an amylin receptor agonist, a glucosedependent insulinotropic polypeptide (GIP) agonist, and a peptide tyrosine-tyrosine (PYY) agonist, or a pharmaceutically acceptable salt thereof, in the treatment of a type 2 diabetes, obesity, or overweight with at least one weight related comorbidity selected from diabetes, high blood pressure, high cholesterol, obstructive sleep apnea and heart disease.

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