Substituted heteroaryl-heteroaryl glucagon receptor agonists and their use as therapies

Abstract

Disclosed herein are compounds 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

SUBSTITUTED HETERO AR YL-HETEROARYL GLUCAGON RECEPTOR AGONISTS AND THEIR USE AS THERAPIESTECHNICAL FIELD

[0001] Disclosed herein are compounds of formula (I) 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. Moreover, compounds disclosed herein can be administered orally which provides convenience as compared to known therapies which are generally administered by injections.

[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 acid levels. 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, B ring, 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 potent activity 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 are compounds of formula (I):wherein:A ring is a 5 to 10 membered heteroaryl or heterocyclic 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, and (c) -Ci-io alkoxy,(2) halogen,(3) oxo,(4) -CN,(5) -OH,(6) -C3-10 cycloalkyl,(7) -ORa, wherein Rais selected from:(a) -Ci-10 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3- 10 cycloalkyl, and(c) a 4 to 10 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N. O, and S, and(8) -C(O)NH2;B ring is a 5 to 10 membered heteroaryl or heterocyclic 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -Ci-io alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H.(b) -Ci-10 alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-10 alkyl and (b) oxo, and(9) -SO2NH2; each of R4, R4, R5, and R5is independently selected from:(D H,(2) halogen,(3) -Ci-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) -OH and (b) halogen, and(4) -C3-6 cycloalkyl;R6is selected from:(1) an aryl, and(2) a 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S: wherein each of the aryl of (1) and heteroaryl or heterocyclyl of (2) 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 (a) halogen and (b) -OH,(c) -Ci-io alkoxy, optionally substituted with 1 to 3 halogens,(d) -C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-10 alkyl, and(e) a 5 to 10 membered heteroaryl or 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, (ii) halogen, (iii) -OH, and (iv) -Ci-10 alkoxy; andR7is selected from:(1) H, and(2) -Ci-10 alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen.

[0010] In one embodiment, disclosed herein is a compound having formula (la), or a pharmaceutically acceptable salt thereof:wherein: the A ring is a 5 to 10 membered heteroaryl or heterocyclic 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) -Ci-io alkoxy,(2) halogen,(3) oxo,(4) -CN,(5) -OH,(6) -C3-10 cycloalkyl, and(7) -0Ra, wherein Rais selected from:(a) -Ci-10 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-10 cycloalkyl, and(c) a 4 to 10 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N. O, and S; the B ring is a 5 to 10 membered heteroaryl or heterocyclic 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -Ci-10 alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -Ci-10 alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN, and(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-io alkyl and (b) oxo;R4is selected from:(1) H,(2) -Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) -OH and (b) halogen, and(3) -C3-10 cycloalkyl;R6is selected from:(1) an aryl, and(2) a 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1) and heteroaryl or heterocyclyl of (2) 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 (a) halogen and (b) -OH,(c) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(d) -C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-10 alkyl, and(e) a 5 to 10 membered heteroaryl or 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, (ii) halogen, (iii) -OH, and (iv) -Ci-10 alkoxy; andR7is selected from:(1) H, and(2) -Ci-10 alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen.

[0011] In one embodiment of the compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof: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-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen, (b) -OH, and (c) -Ci-6 alkoxy,(2) halogen,(3) oxo,(4) -CN,(5) -OH,(6) -C3-6 cycloalkyl, and(7) -0Ra, wherein Rais selected from:(a) -C1-6 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S.

[0012] In one embodiment of the compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof: the A ring is a 5- or 6-membered heteroaryl ring selected from pyridyl, pyridazinyl, pyrimidyl, pyrazolyl, imidazolyl, triazolyl, and thiazolyl, 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, and (c) -C1-6 alkoxy,(2) -CN,(3) -OH,(4) -C3-6 cycloalkyl, and(5) -ORa, wherein Rais selected from:(a) -C1-6 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N. O, and S.

[0013] In one embodiment of the compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof: the B ring is a 5 to 10 membered heteroaryl or heterocyclyl 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-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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -Ci-6 alkyl,(2) halogen,(3) -C3-6 cycloalkyl,(4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H.(b) -Ci -6 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-6alkyl,(6) oxo,(7) -CN, and(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-6 alkyl and (b) oxo.

[0014] In one embodiment of the compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof: the B ring is a 5 to 10 membered heteroaryl or heterocyclyl ring selected from pyridyl, pyridazinyl, pyrimidyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, lH-pyrrolo[2,3- b]pyridinyl, 2,3-dihydro-lH-benzo[d]imidazolyl, and benzo [d]oxazolyl, 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-6 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -Ci -6 alkyl,(2) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H.(b) -Ci-6 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-6alkyl,(3) oxo,(4) -CN, and(5) 5- or 6- membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-6 alkyl and (b) oxo.

[0015] In one embodiment of the compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof: the B ring is a 5- or 6-membered monocyclic heteroaryl or heterocyclic ring selected from pyrimidyl pyridyl, pyrimidyl, pyrazolyl, imidazolyl, thiazolyl; or the B ring is an 8 to 10 membered bicyclic heteroaryl or heterocyclic ring selected from, wherein each of RB1, RB3, RB4, RB5is 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci-io alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C MO alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-10 alkyl and (b) oxo,(9) -SO2NH2, and(10) H.

[0016] In one embodiment of the compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof:R4is selected from:(1) H, and(2) -C1-6 alkyl.

[0017] In one embodiment of the compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof, R4is -C1-6 alkyl. In one embodiment, R4is -C1-4 alkyl. In one embodiment, R4is methyl.

[0018] In one embodiment of the compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof:R6is selected from:(1) a phenyl, and(2) a 5- or 6-membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S: wherein each of the phenyl of (1) and heteroaryl or heterocyclyl of (2) 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 (a) halogen and (b) -OH,(c) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,(d) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, and(e) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-6 alkoxy.

[0019] In one embodiment of the compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof:R6is selected from:(1) a phenyl, and(2) a 5- or 6-membered heteroaryl or heterocyclic ring selected from pyridyl and pyrimidyl; wherein each of the phenyl of (1) and heteroaryl or heterocyclyl 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 (a) halogen and (b) -OH,(b) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3substituents independently selected from (i) -Ci-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -C 1-6 alkoxy.[00201 In one embodiment of the compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof, R7is selected from: (1) H and (2) -Ci-6 alkyl.

[0021] In one embodiment of the compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof, R7is H.

[0022] In one embodiment of the compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof: 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-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen, (b) -OH, and (c) -Ci-6 alkoxy,(2) halogen,(3) oxo,(4) -CN,(5) -OH,(6) -C3-6 cycloalkyl, and(7) -ORa, wherein Rais selected from:(a) -C1-6 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S; the B ring is a 5 to 10 membered heteroaryl or heterocyclyl 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-6 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -C 1-6 alkyl,(2) halogen,(3) -C3-6 cycloalkyl,(4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C1-6 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-6alkyl,(6) oxo,(7) -CN, and(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-6 alkyl and (b) oxo;R4is selected from:(1) H, and(2) -C1-6 alkyl; each of R4, R5and R5is H:R6is selected from:(1) a phenyl, and(2) a 5- or 6-membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the phenyl of (1) and heteroaryl or heterocyclyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(c) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(d) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C 1-6 alkyl, and(e) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-6 alkoxy; andR7is selected from:(1) H, and(2) -C1-6 alkyl.

[0023] In one embodiment of the compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof: the A ring is a 5- or 6-membered heteroaryl ring selected from pyridyl, pyridazinyl, pyrimidyl, pyrazolyl, imidazolyl, triazolyl. and thiazolyl, 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, and (c) -C1-6 alkoxy,(2) -CN,(3) -OH,(4) -C3-6 cycloalkyl, and(5) -ORa, wherein Rais selected from:(a) -C1-6 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S; the B ring is a 5 to 10 membered heteroaryl or heterocyclyl ring selected from pyridyl, pyridazinyl, pyrimidyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, lH-pyrrolo[2,3- b]pyridinyl, 2,3-dihydro-lH-benzo[d]imidazolyl, and benzo [d]oxazolyl, 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-6 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -Ci-6 alkyl,(2) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -Ci-6 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-6alkyl,(3) oxo,(4) -CN, and(5) 5- or 6- membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-6 alkyl and (b) oxo;R4is selected from:(1) H, and(2) -C1-6 alkyl;R6is selected from:(1) a phenyl, and(2) a 5- or 6-membered heteroaryl or heterocyclic ring selected from pyridyl and pyrimidyl; wherein each of the phenyl of (1) and heteroaryl or heterocyclyl 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 (a) halogen and (b) -OH,(b) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3substituents independently selected from (i) -Ci-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci-6 alkoxy; andR7is H.

[0024] In one embodiment of the compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof: the A ring is a 5- or 6-membered heteroaryl ring selected from pyridyl, pyridazinyl, and pyrimidyl, optionally substituted with 1 to 4 substituents independently selected from:(1) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen, (b) -OH, and (c) -Ci-4 alkoxy,(2) -CN,(3) -OH,(4) cyclopropyl, and(5) -ORa, wherein Rais selected from:(a) -Ci-4 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-4 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S; the B ring is a 5 to 10 membered heteroaryl or heterocyclyl ring selected from pyridyl, pyrimidyl. pyrazolyl, imidazolyl, thiazolyl, lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydro-lH- benzofd] imidazolyl, and benzo[d]oxazolyl, optionally substituted with 1 to 3 substituents independently selected from:(1) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -OH,(c) -O-C(O)Ci-4 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -C1-4 alkyl,(2) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C1-4 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-4alkyl,(3) oxo,(4) -CN, and(5) 5- or 6- membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-4 alkyl and (b) oxo;R4is -C1-4 alkyl; andR6is selected from:(1) a phenyl, and(2) pyridyl; wherein each of the phenyl of (1) and pyridyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(b) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-4 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-4 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci -4 alkoxy.

[0025] In one embodiment, disclosed herein is a compound of formula (lb), or a pharmaceutically acceptable salt thereof:wherein: each of 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, and (c) -Ci-6 alkoxy,(3) -C3-6 cycloalkyl,(4) -OH,(5) -CN, and(6) -ORa, wherein Rais selected from:(a) -C1-6 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N. O, and S; the B ring is a 5 to 10 membered heteroaryl or heterocyclyl 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-6 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -C1-6 alkyl,(2) halogen,(3) -C3-6 cycloalkyl,(4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C1-6 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-6alkyl,(6) oxo,(7) -CN, and(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-6 alkyl and (b) oxo;R4is selected from:(1) H, and(2) -Ci-6 alkyl;R6is selected from:(1) a phenyl, and(2) a 5- or 6-membered heteroaryl or heterocyclic ring selected from pyridyl and pyrimidyl; wherein each of the phenyl of (1) and heteroaryl or heterocyclyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(b) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci -6 alkoxy; andR7is H.

[0026] In one embodiment, disclosed herein is a compound of formula (Ic), or a pharmaceutically acceptable salt thereof: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, and (c) -Ci-6 alkoxy,(3) -C3-6 cycloalkyl,(4) -OH,(5) -CN, and(6) -ORa, wherein Rais selected from:(a) -C1-6 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S; the B ring is a 5 to 10 membered heteroaryl or heterocyclyl 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-6 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -C1-6 alkyl,(2) halogen,(3) -C3-6 cycloalkyl,(4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C1-6 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-6alkyl,(6) oxo,(7) -CN, and(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-6 alkyl and (b) oxo;R4is selected from:(1) H, and(2) -Ci-6 alkyl;R6is selected from:(1) a phenyl, and(2) a 5- or 6-membered heteroaryl or heterocyclic ring selected from pyridyl and pyrimidyl; wherein each of the phenyl of (1) and heteroaryl or heterocyclyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(b) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci -6 alkoxy; andR7is H.

[0027] In one embodiment, disclosed herein is a compound of formula (Id), or a pharmaceutically acceptable salt thereof:wherein: each of RA1and RA4is independently selected from:(1) H.(2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) halogen, (b) -OH, and (c) -Ci-6 alkoxy,(3) -C3-6 cycloalkyl,(4) -OH,(5) -CN, and(6) -ORa, wherein Rais selected from:(a) -C1-6 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S; the B ring is a 5 to 10 membered heteroaryl or heterocyclyl 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-6 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -C1-6 alkyl,(2) halogen,(3) -C3-6 cycloalkyl,(4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C1-6 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-6alkyl,(6) oxo,(7) -CN, and(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-6 alkyl and (b) oxo;R4is selected from:(1) H, and(2) -Ci-6 alkyl;R6is selected from:(1) a phenyl, and(2) a 5- or 6-membered heteroaryl or heterocyclic ring selected from pyridyl and pyrimidyl; wherein each of the phenyl of (1) and heteroaryl or heterocyclyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(b) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci -6 alkoxy; andR7is H.

[0028] In one embodiment, disclosed herein is a compound of formula (le), or a pharmaceutically acceptable salt thereof: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, and (c) -Ci-6 alkoxy,(3) -C3-6 cycloalkyl,(4) -OH,(5) -CN, and(6) -ORa, wherein Rais selected from:(a) -C1-6 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N. O, and S; the B ring is a 5 to 10 membered heteroaryl or heterocyclyl 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-6 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -C1-6 alkyl,(2) halogen,(3) -C3-6 cycloalkyl,(4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C1-6 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-6alkyl,(6) oxo,(7) -CN, and(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-6 alkyl and (b) oxo;R4is selected from:(1) H, and(2) -Ci-6 alkyl;R6is selected from:(1) a phenyl, and(2) a 5- or 6-membered heteroaryl or heterocyclic ring selected from pyridyl and pyrimidyl; wherein each of the phenyl of (1) and heteroaryl or heterocyclyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(b) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci -6 alkoxy; andR7is H.

[0029] In one embodiment, disclosed herein is a compound of formula (If), or a pharmaceutically acceptable salt thereof:wherein: each of RA1and RA3is independently selected from:(1) H,(2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) halogen, (b) -OH, and (c) -Ci-6 alkoxy,(3) -C3-6 cycloalkyl,(4) -OH,(5) -CN, and(6) -ORa, wherein Rais selected from:(a) -C1-6 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N. O, and S; the B ring is a 5 to 10 membered heteroaryl or heterocyclyl 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-6 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -C1-6 alkyl,(2) halogen,(3) -C3-6 cycloalkyl,(4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C1-6 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-6alkyl,(6) oxo,(7) -CN, and(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-6 alkyl and (b) oxo;R4is selected from:(1) H, and(2) -Ci-6 alkyl;R6is selected from:(1) a phenyl, and(2) a 5- or 6-membered heteroaryl or heterocyclic ring selected from pyridyl and pyrimidyl; wherein each of the phenyl of (1) and heteroaryl or heterocyclyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(b) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci -6 alkoxy; andR7is H.

[0030] In one embodiment of the compound of formula (lb). (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt thereof: each of RA1, RA2, and RA3, when present, is independently selected from: d) H,(2) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) halogen, (b) -OH, and (c) -C1-4 alkoxy,(3) -C3-6 cycloalkyl,(4) -OH,(5) -CN, and(6) -0Ra, wherein Rais selected from:(a) -Ci-4 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S;RA4is H; the B ring is a 5 to 10 membered heteroaryl or heterocyclyl ring selected from pyridyl, pyrimidyl, pyrazolyl, imidazolyl, thiazolyl, lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydro-lH- benzofd] imidazolyl, and benzo[d]oxazolyl, optionally substituted with 1 to 3 substituents independently selected from:(1) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -OH,(c) -O-C(O)Ci-4 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -C1-4 alkyl,(2) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C1-4 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-4alkyl,(3) oxo,(4) -CN, and(5) 5- or 6- membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-4 alkyl and (b) oxo;R4is -C1-4 alkyl;R6is selected from:(1) a phenyl, and(2) pyridyl;wherein each of the phenyl of (1) and pyridyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(b) -Ci-4 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-4 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-4 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci -4 alkoxy; andR7is H.

[0031] In one embodiment of the compound of formula (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt thereof: each of RA1, RA2, and RA3, when present, is independently selected from:(1) H,(2) -C1-3 alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) halogen, (b) -OH, (c) methoxy, and (d) ethoxy,(3) cyclopropyl,(4) cyclobutyl,(5) -OH,(6) -CN, and(7) -ORa, wherein Rais selected from:(a) methyl, optionally substituted with 1 to 3 halogens,(b) ethyl, optionally substituted with 1 to 3 halogens,(c) cyclopropyl,(d) cyclobutyl, and(e) a 4 to 6 membered heterocyclic ring containing 1 to 2 heteroatoms independently selected from N, O, and S;RA4is H;the B ring is a 5 to 10 membered heteroaryl or heterocyclyl ring selected from pyridyl, pyrimidyl, pyrazolyl, imidazolyl, thiazolyl, lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydro-lH- benzo[d]imidazolyl, and benzo[d]oxazolyl, optionally substituted with 1 to 3 substituents independently selected from:(1) -Ci-3 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -OH, and(c) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H, (ii) methyl, and (iii) ethyl,(2) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H.(b) methyl,(c) ethyl,(c) -C(O)methyl, and(e) -C(O)ethyl,(3) oxo,(4) -CN, and(5) 5- or 6- membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) methyl, (b) ethyl and (c) oxo;R4is -Ci-4 alkyl;R6is selected from:(1) a phenyl, and(2) pyridyl; wherein each of the phenyl of (1) and pyridyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(b) -Ci-4 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C 1-4 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-4 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-4 alkoxy; andR7is H.

[0032] In one embodiment, disclosed herein is a compound of formula (Ig), or a pharmaceutically acceptable salt thereof:wherein: each of RB2. RB3, RB4, RB5is 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci-10 alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H.(b) -Ci-10 alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-io alkyl and (b) oxo,(9) -SO2NH2, and(10) H.

[0033] In one embodiment, disclosed herein is a compound of formula (Ih), or a pharmaceutically acceptable salt thereof:wherein: each of RB1, RB3, RB4, RB5is 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci-10 alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C 1-10 alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-io alkyl and (b) oxo,(9) -SO2NH2, and(10) H.

[0034] In one embodiment, disclosed herein is a compound of formula (li). or a pharmaceutically acceptable salt thereof:wherein: each of RB1, RB2, RB4, RB5is 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci-10 alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C 1-10 alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-io alkyl and (b) oxo,(9) -SO2NH2, and(10) H.

[0035] In one embodiment, disclosed herein is a compound of formula (Ij). or a pharmaceutically acceptable salt thereof:wherein: each of RB1, RB3, and RB5is 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci-10 alkyl,(2) halogen,(3) -C3 10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Reand Reis independently selected from:(a) H,(b) -Ci-10 alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-io alkyl and (b) oxo,(9) -SO2NH2, and(10) H.

[0036] In one embodiment, disclosed herein is a compound of formula (Ik), or a pharmaceutically acceptable salt thereof:wherein: each of RB1, RB2, and RB5is 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci-10 alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C 1-10 alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-io alkyl and (b) oxo,(9) -SO2NH2, and(10) H.

[0037] In one embodiment, disclosed herein is a compound of formula (II), or a pharmaceutically acceptable salt thereof:wherein: each of RB1. RB3, RB4is 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci-10 alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H.(b) -Ci-10 alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-io alkyl and (b) oxo,(9) -SO2NH2, and(10) H.

[0038] In one embodiment, disclosed herein is a compound of formula (Im), or a pharmaceutically acceptable salt thereof:wherein: each of RB1. RB2, and RB4is 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci-10 alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H.(b) -Ci-10 alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-io alkyl and (b) oxo,(9) -SO2NH2, and(10) H.

[0039] In one embodiment, disclosed herein is a compound of formula (In), or a pharmaceutically acceptable salt thereof:wherein: each of RB1, RB2, and RB4is 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci-10 alkyl,(2) halogen,(3) -C3 10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens.(5) -NRCRC, wherein each of Reand Reis independently selected from:(a) H,(b) -Ci-10 alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-io alkyl and (b) oxo,(9) -SO2NH2, and(10) H.

[0040] In one embodiment, disclosed herein is a compound of formula (Io), or a pharmaceutically acceptable salt thereof:wherein: each of R6a, R6b, R6c, and R6dis independently selected from:(a) H,(b) halogen,(c) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH,(d) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens,(e) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-4 alkyl.

[0041] In one embodiment, disclosed herein is a pharmaceutical composition comprising a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im), (In), or (Io), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0042] In one embodiment, disclosed herein is a method for treating a type 2 diabetes, obesity, or overweight with at least one weight related comorbidity selected from cancer, depression, diabetes, dyslipidemia, high blood pressure, high cholesterol, obstructive sleep apnea, osteoarthritis, and heart disease comprising administering an effective amount of a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im), (In), or (Io), or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

[0043] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Hi), (li), (Ij), (Ik), (II), (Im), (In), or (Io), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0044] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ij), (Ik), (II), (Im), (In), or (Io), 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 cancer, depression, diabetes, dyslipidemia, high blood pressure, high cholesterol, obstructive sleep apnea, osteoarthritis, and heart disease.

[0045] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ij), (Ik), (II), (Im), (In), or (Io), or a pharmaceutically acceptable salt thereof, for use in the treatment of a type 2 diabetes.

[0046] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ij), (Ik), (II), (Im), (In), or (Io), or a pharmaceutically acceptable salt thereof, for use of claim 21, in the treatment of obesity.

[0047] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le). (If), (Ig), (Ih), (li), (Ij), (Ik), (II), (Im), (In), or (Io), 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.

[0048] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ij), (Ik), (II), (Im), (In), or (Io), 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 tyro sine- tyro sine (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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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, the compound herein, or a pharmaceutically acceptable salt thereof, may have one or more asymmetric centers.

[0055] 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, phosphorousatom, sulfur atom, fluorine atom, and chlorine atom, which respectively include2H,3H,13C,14C,15N,17O,18O,31P,32P,35S,18F, and36C1.[00561 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.

[0057] 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 less than 80,000 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 60.000 nM using Functional Assay I or Functional Assay II. In one embodiment, compounds of formula (I) or (la), 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) or (lb), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 10,000 nM using Functional Assay I or Functional Assay II.

[0058] In one embodiment, disclosed herein is a compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0059] In one embodiment, disclosed herein is a compound of formula (I) or (la), 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 cancer, depression, diabetes, dyslipidemia, high blood pressure, high cholesterol, obstructive sleep apnea, osteoarthritis, and heart disease.

[0060] In one embodiment, disclosed herein is a compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof, for use in the treatment of a type 2 diabetes.

[0061] In one embodiment, disclosed herein is a compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof, for use in the treatment of obesity.

[0062] In one embodiment, disclosed herein is a compound of formula (I) or (la), 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.

[0063] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ij), (Ik), (II), (Im), (In), or (Io), 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.

[0064] 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.

[0065] 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.”

[0066] 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. Such a 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.

[0067] 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. Aneffective 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.[00681 The term “treat,” “treating,” or “to treat” means attenuating, restraining, slowing, stopping or reversing the progression or severity of an existing 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.

[0069] 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 or organic 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)).

[0070] 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.

[0071] 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.

[0072] 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 alkoxy has 1 to 10 carbons with the following structure:_ Similarly, Ci-6 alkoxy has 1 to 6 carbons with the following structure:.

[0073] 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.

[0074] 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-).

[0075] The term “C3-io cycloalkyl” means a monovalent group derived by removing any single hydrogen atom from a cyclic saturated aliphatic hydrocarbon having 3 to 10 carbons. Similarly, 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 includecyclopropyl, 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- 1,1 -diyl, and cyclohexane- 1,1 -diyl.

[0076] 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-.

[0077] 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.

[0078] 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, 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, 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.[00791 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 tetrahydroindolinyl.

[0080] The compounds herein, or a pharmaceutically acceptable salt thereof, have glucagon receptor agonist effects, 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), and non-alcoholic steatohepatitis. In one embodiment, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered to asubject in the form of a pharmaceutical composition in an effective amount by an appropriate administration method.

[0081] As used herein, treatment of a subject with obesity or overweight is also known as chronic weight management.

[0082] 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.

[0083] “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).

[0084] “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.

[0085] “Impaired glucose tolerance” includes insulin-resistant impaired glucose tolerance and insulin hyposecretion.

[0086] “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, respirator}' 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.

[0087] “Coronary heart disease” includes myocardial infarction and angina pectoris.

[0088] “Dementia” includes, for example, Alzheimer's disease, vascular dementia, and diabetic dementia.

[0089] The administration method may be systemic administration including oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneousadministration, intravaginal administration, intraperitoneal administration, intravesical administration, and aspiration, as well as local administration by ointment, gels, and cream. [00901 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), (Ig), (Ih), (li), (Ij), (Ik), (II), (Im), (In), or (Io), or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] In one embodiment, a pharmaceutical composition comprises a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ij), (Ik), (II), (Im), (In), or (Io), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0095] 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.

[0096] 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.

[0097] Examples of an excipient include starch (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, and dicalcium phosphate.

[0098] Examples of a lubricant include ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, shellac, talc, carnauba wax, and paraffin.

[0099] Examples of a binding agent include polyvinyl pyrrolidone, macrogol, and compounds that are the same as the above excipient.

[0100] 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.

[0101] Examples of a stabilizer include para-oxybenzoates such as methyl paraben, and propyl paraben; benzalkonium chloride; phenols such as phenol, and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

[0102] 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.

[0103] Examples of the solvent or diluent in a liquid formulation include phenol, chlorocresol, purified water, distilled water, etc.

[0104] Examples of a surfactant or emulsifier include polysorbate 80, polyoxyl 40 stearate, lauromacrogol.

[0105] 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

[0106] The following examples are provided for illustration purposes only. The abbreviations used in the preparations and examples are as defined below.ACN - acetonitrileAcOH - acetic acid aq - aqueousBOC, Boc - te / t-butoxycarbonylCDI - l,l'-carbonyldiimidazoleDAST - diethylaminosulfur trifluorideDCE - 1,2-dichloroethaneDCM - dichloromethaneDIEA - N,N-diisopropylethylamineDIPEA - N,N-diisopropylethylamineDMA - dimethylacetamideDME - dimethoxyethaneDMF - N,N-dimethylformamideDMSO - dimethyl sulfoxide d.r. - diastereomeric ratioEDCI - l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlorideES-MS - electrospray mass spectrometryEtOAc - ethyl acetateEtOH - ethanolHATU - l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphateHPLC - high-performance liquid chromatographyIPA - isopropanol (isopropyl alcohol)KO Ac - potassium acetateKOtBu - potassium fert-butoxideLCMS - liquid chromatography-mass spectrometryLED - light-emitting diode m / z - mass-to-charge ratioMeCN - acetonitrileMeOH - methanolMeTHF - 2-methyltetrahydrofuranMS - mass spectrometryMTBE - methyl tert-butyl etherNBS - N-bromosuccinimideNMP - N-methyl-2-pyrrolidoneNMR - nuclear magnetic resonance spectroscopyPd(dppf)C12 - [l,P-bis(diphenylphosphino)ferrocene]dichloropalladium(II)RBF - round-bottom flaskRT - room temperature sat - saturatedSFC - supercritical fluid chromatographyTEA - triethylamineTFA - trifluoroacetic acidTHF - tetrahydrofuranTLC - thin-layer chromatographyTMS - trimethylsilylTris - tris(hydroxymethyl)aminomethaneUV - ultraviolet wt% - weight percent

[0107] Scheme 1 depicts the preparation of the l,3,8-triazaspiro[4.5]dec-l-en-4-one intermediate (5) beginning with a suitable protected amine (1). The PG moiety on the amine (1) is a standard amine protecting group well known to a skilled artisan, including carbamate protecting groups such as Boc. The amine (1) is reacted with NH4OAC and KCN in an appropriate solvent, such as EtOH, and stirred for at least 48 h at 80 °C. The resulting intermediate (2) is oxidized in the 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 to give amide intermediate (3). Intermediate (3) is then reacted with a suitable acyl chloride (R6-COC1) in the presence of an organic base, such as TEA, in a suitable solvent, such as THF, and then cyclized to form intermediate (4) using an alkoxide base (such as sodium ethoxide / EtOH or potassium tert- butoxide / n?rz-butanol) or hydroxide base (such as NaOH) in a solvent such as EtOH or tert- butanol at elevated temperature. Alternatively, intermediate (3) is reacted with a carboxylic acid (R6-CO2H) under amide coupling conditions such as EDCI and DIEA in a solvent such as THF, or HATU and DIEA in a solvent such as DMF, and then cyclized to intermediate (4) using an alkoxide or hydroxide base as described above.

[0108] The removal of the PG moiety on the amine of the amide (4) is achieved under conditions standard to the art. For example, where PG is Boc the intermediate amine (5) is obtained by reacting a suitable acid, such as HC1 in 1,4-dioxane, in an appropriate solvent, such as DCM.

[0109] Compounds disclosed herein may be prepared via the synthetic routes presented in Scheme 2 featuring cross-coupling reactions in various orders. The l,3,8-triazaspiro[4.5]dec-l- en-4-one intermediate (5) is reacted with intermediate (6) where X1is a halogen such as bromine or fluorine, and X2is a halide such as chlorine, bromine, or iodine, giving intermediate (9). If X1is bromine, this transformation occurs by reacting (5) and (6) in a palladium cross-coupling reaction using a palladium catalyst such as methanesulfonato(2-bis(3,5- di(trifhioromethyl)phenylphosphino)-3,6-dimethoxy-2',6'-bis(dimethylamino)-l,r-biphenyl )(2'- methylamino-l,l'-biphenyl-2-yl)palladium(II), sodium 2-methylbutan-2-olate, and a solvent such as toluene at an elevated temperature. If X1is fluorine, this transformation occurs by reacting (5) and (6) in a nucleophilic aromatic substitution (S\Ar) reaction using an inorganic base such as K3PO4. KF, K2CO3, or CS2CO3 in DMSO at an elevated temperature. Intermediate (9) then undergoes a Suzuki cross-coupling reaction with intermediate (7), wherein X3is either a boronic acid or boronic ester to give compounds of formula (I). This coupling reaction is accomplished using a palladium catalyst such as Pd(dppf)C12, methanesulfonato(2-bis(3,5- di(trifhioromethyl)phenylphosphino)-3,6-dimethoxy-2',6'-bis(dimethylamino)-l,r-biphenyl )(2'- methylamino-l,T-biphenyl-2-yl)palladium(II), or 2nd Generation SPhos Precatalyst, a base such as K2CO3, CS2CO3, or K3PO4, in an aqueous / organic solvent mixture such as MeOH, EtOH, or 1,4-dioxane in water at an elevated temperature. Alternatively, X2on intermediate (9) is converted to a boronic ester using bis(pinacolato)diboron and a palladium catalyst / basecombination such as XPhos Pd(crotyl)Cl / K2CO 2-ethyl hexanoic acid, Pd(dppf)C12 / potassium trimethylacetate or potassium terf-butoxide, or 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) / potassium acetate at an elevated temperature. Intermediate (9) is then coupled with (7) wherein X3is a halogen such as Cl, Br, or I under Suzuki cross-coupling conditions described above to give compounds of formula (I).

[0110] An alternative method can be employed wherein intermediate (6) is coupled with intermediate (7) to give intermediate (8), wherein either X2is a halogen such as Cl, Br, or I and X3is a boronic acid or boronic ester, or wherein X2is a boronic acid or ester and X3is a halogen such as Cl, Br, or I. This coupling occurs under Suzuki cross-coupling conditions described above. Intermediate (8) then undergoes a palladium coupling reaction with amine intermediate (5) using a palladium catalyst such as (SP-4-l)-[l,3-BIs[2,6-bis(l-ethylpropyl)phenyl]-4,5- dichloro-l,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium, a base such as potassium tert-butoxide, and a solvent such as 1.4-dioxane at an elevated temperature to give compounds of formula (I).

[0111] An alternative method can be employed wherein intermediate (5) is coupled with intermediate (7) and an appropriate aldehyde, wherein X3is a TMS-protected alkyne. This coupling occurs under multicomponent copper-catalyzed aldehyde-amine-alkyne conditions, using copper catalysts, such as cuprous chloride and copper(II)trifluoromethanesulfonate, and an appropriate base, such as DIPEA, in an appropriate solvent, such as acetonitrile, at an elevated temperature to give compounds of formula (I).

[0112] Within Scheme 2, chemical transformations can also be earned out on the substituents of Ring A that are not X1or X2, in order to modify Ring A. For example, these transformations can take place on intermediates (6), (8), or (9).Preparation of IntermediatesPreparation of Intermediate 1: / c / 7-Butyl (2S)-4-amino-4-cyano-2-methylpiperidine-l- carboxylate (mixture of diastereomers)

[0113] Ammonium acetate (445 g, 5.66 mol) was added in one portion to a mixture of tert-butyl (S)-2-methyl-4-oxopiperidine-l -carboxylate (490 g, 2.25 mol) in EtOH (5 L). Then KCN (225 g, 3.39 mol) was added to the reaction. The mixture was stirred at 80 °C. After 16 h, the mixture was quenched with 2 M K3PO4 (2 L), the mixture was extracted with EtOAc (3 x 2 L) and washed with H2O (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (530 g) as an oil. ES-MS m / z 140 (M-Boc).Preparation of Intermediates 2a and 2b: / ert-Butyl (2S,4S)-4-amino-4-carbamoyl-2- methylpiperidine-1 -carboxylate (Intermediate 2a) and / ert-butyl (2S,4R)-4-amino-4-carbamoyl- 2-methylpiperidine-l -carboxylate (Intermediate 2b)

[0114] To a solution of tert-butyl (2S)-4-amino-4-cyano-2-methylpiperidine-l-carboxylate (mixture of diastereomers, 530 g, 2.08 mol) in DMSO (270 mL) and MeOH (2500 mL) was added NaOH (5 M aq., 451 mL, 2.26 mol) at 10 °C and then H2O2 (276 mL, 30% wt., 2.70 mol) was added to the mixture, the mixture was stirred at 25 °C. After 1 h, the aq. phase was quenched with aq. NaiSCL (2000 mL). The mixture was filtered, the filtrate was extracted with DCM / MeOH (10 / 1, 5 x 2000 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 10% MeOH in DCM to give Intermediate 2a (10 g) as an oil and Intermediate 2b (180 g) as a solid. Both Intermediates 2a and 2b: ES-MS m / z 158 (M-Boc).Preparation of Intermediate 3: 2-Cyclopropylbenzoyl chloride

[0115] Oxalyl chloride (6.09 mL, 69.4 mmol) was added to a stirred solution of 2-cyclopropyl- benzoic acid (10.0 g, 55.5 mmol) in DCM (100 mL) under nitrogen at ambient temperature. DMF (0.217 mL, 2.77 mmol) was then added. After 3 h, the mixture was concentrated under a stream of N2 to afford the title compound (10.7 g) as an oil.Preparation of Intermediate 4: te -Butyl (2S,4R)-4-carbamoyl-4-(2-cyclopropylbenzamido)-2- methylpiperidine- 1 -carboxylate;

[0116] EtsN (22 mL, 160 mmol) was added to tert-butyl (2S,4R)-4-amino-4-carbamoyl-2- methylpiperidine- 1 -carboxylate (14.42 g, 56.04 mmol) in DCM (100 mL) and stirred at ambient temperature under N2 in 500 mL RBF. A solution of 2-cyclopropylbenzoyl chloride (10.08 g, 52.24 mmol) in DCM (100 mL) was added. After 2 h, the mixture was diluted with 5% aq. citric acid (200 mL) and heptane (300 mL) and stirred vigorously. After 30 min, the mixture was filtered, and the filter cake was washed with water (200 mL) and heptane (100 m L). The solid was dried under reduced pressure overnight to give the title compound (18.03 g). ES-MS m / z 402 (M+H).Preparation of Intermediate 5: tert-Butyl (5R,7S)-2-(2-cyclopropylphenyl)-7-methyl-4-oxo- l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate

[0117] Sodium ethoxide (21 wt% in EtOH, 49 mL, 0.13 mol) was added to a stirred suspension of t rt-butyl (2S,4R)-4-carbamoyl-4-(2-cyclopropylbenzamido)-2-methylpiperidine-l- carboxylate (18.0 g, 43.5 mmol) in EtOH (0.25 L) and the mixture was heated at 60 °C. After 4 h, the mixture was partially concentrated under reduced pressure at 50 °C to 0.1 L, then stirred at ambient temperature. 5% aq. citric acid (0.50 L) was added and the mixture was extracted withEtOAc (0.30 L). The aqueous layer was extracted with a second portion of EtOAc (50 mL). The organics were combined, washed with 50 mL of 2 M aq. K2HPO4 then sat. aq. NaCl, dried over MgSCh and filtered. The organics were concentrated at 50 °C to afford the title compound (16.37 g) as a foam. ES-MS m / z 384 (M+H).Preparation of Intermediate 6: (5R,7S)-2-(2-Cyclopropylphenyl)-7-methyl-l,3,8- triazaspiro [4.5] dec - 1 -en-4- one dihydrochloride

[0118] 4 M HC1 in 1,4-dioxane (34.47 mL, 137.9 mmol) was added to a 1 L RBF containing te -butyl (5R,7S)-2-(2-cyclopropylphenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8- carboxylate (13.22 g, 34.47 mmol) in DCM (344.7 mL) and stirred at RT overnight. 200 mL of DCM was added, and the mixture was filtered. The collected solid was dried for 2 h at 50 °C in a vacuum oven to give the title compound (10.35 g) as a solid. ES-MS m / z 284 (M+H).

[0119] The free base of the title compound was prepared by stirring the hydrochloride salt in water and adding 2 M aq. K3PO4 to bring the pH to about 11.7 and collecting the solid, washing with water, and drying the solid in a vacuum oven overnight.Preparation of Intermediate 7: rert-Butyl (5R.7S)-7-methyl-4-oxo-2-(2- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate

[0120] A solution of 2-(trifluoromethoxy)benzoyl chloride (20.93 g, 93.20 mmol) in THF (50 mL) was added to a solution of tert-butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-l- carboxylate (25.13 g, 97.66 mmol) in THF (450 mL) and TEA (26 mL, 190 mmol) with stirring, at ambient temperature under N2 in a 3-neck RBF. After 45 min, sodium ethoxide (21 wt% in EtOH, 140 mL, 380 mmol) was added; and the mixture was stirred at 60 °C. After 45 min, the mixture was poured into a 2 L flask. Water (2L) was added and adjusted pH to 4 using solidcitric acid and stirred overnight at ambient temperature under a gentle sweep of nitrogen. The volume was reduced by around 0.25 L, and a gum had formed. The supernatant was decanted and discarded, and the gum rinsed with water. The gum was taken up in EtOAc (350 mL), then washed with 2 M aq. K2HPO4 and sat. aq. NaCl (75 mL each), dried over MgSCU, filtered, and concentrated at 50 °C to afford the title compound (36.44 g). ES-MS m / z 428 (M+H).Preparation of Intermediate 8: (5R,7S)-7-Methyl-2-(2-(trifluoromethoxy)phenyl)-l,3,8- triazaspiro[4.5]dec- l-en-4-one dihydrochloride

[0121] Hydrochloric acid (4.0 M in 1,4-dioxane, 79.29 mL, 317.2 mmol) was added to tert-butyl (5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-ene-8- carboxylate (36.44 g, 93% Wt., 79.29 mmol) in 1,4-dioxane (200 mL) and the mixture was heated to 60 °C. After 1 h, additional 1,4-dioxane (200 mL) was added and stirring continued. After 2 h, the reaction mixture was cooled to RT. Solids were collected from the mixture by filtration and washed with 1,4-dioxane (100 mL). The solid was dried overnight in a vacuum oven (40 °C) to give the title compound (36.52 g) as a solid. ES-MS m / z 328 (M+H).Preparation of Intermediate 9: (5R,7S)-7-Methyl-2-(2-(trifluoromethoxy)phenyl)-l,3,8- triazaspiro [4.5] dec- 1 -en-4-one

[0122] K.3PO4 (2 M aqueous, 300 mL, 600 mmol) was added in a 1 L conical flask with (5R,7S)- 7-methyl-2- (2- (trifhioromethoxy)phenyl)- 1 ,3 , 8-triazaspiro [4.5] dec- 1 -en-4-one dihydrochloride (30.0 g. 87% Wt, 65.2 mmol) and stirred. The pH was adjusted upwards to 9 using 2 M aq.K3PO4 (50 mL). EtOAc (300 mL) was added and the pH of the aqueous phase was adjusted with aq. K3PO4 (25 mL) to approx. pH 9.5. The phases were separated, and the aqueous extractedwith further portions of EtOAc (4 x 100 mL). The organics were combined and washed with a mixture of sat. aq. NaCl (100 mL) and 2 M aq. K2HPO4 (25 mL). The wash was back extracted with EtOAc (100 mL). The combined organics were dried over Na2SO4 and filtered. The organics were concentrated at 50 °C to approx. 150 (mL). Heptane (500 mL) was then added and a precipitate formed. The mixture was concentrated to approx. 500 mL over 45 min, then stirred at ambient temperature for 1 h. The mixture was filtered and the solid washed with heptane (100 mL), then dried under reduced pressure at 50 °C to give the title compound (19.78 g) as solid. ES-MS m / z. 328 (M+H).Preparation of Intermediate 10: (5R,7S)-8-(4-Iodopyridin-2-yl)-7-methyL2-(2- (trifluoromethoxy)phenyl)-l,3.8-triazaspiro[4.5]dec-l-en-4-one

[0123] 2-Fluoro-4-iodopyridine (1.72 g, 7.72 mmol) was added to a solution of (5R.7S)-7- methyl-2-(2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (2.04 g, 5.09 mmol) and CS2CO3 (6.64 g, 20.4 mmol) in DMSO (10 mL) and the mixture was stirred at 80 °C. After 16 h, the reaction mixture was diluted with H2O and extracted three times with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure The residue was purified by silica gel chromatography using a gradient of 0-50% EtOAc in cyclohexane to give the title compound (1.04 g). ES-MS m / z 531.2 (M+H).Preparation of Intermediate 11: (5R.7S)-7-Methyl-8-(4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)pyridin-2-yl)-2-(2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0124] A vial was charged with (5R,7S)-8-(4-iodopyridin-2-yl)-7-methyl-2-(2- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.546 g. 1.031 mmol), bis(pinacolato)diboron (0.401 g, 1.58 mmol), K2CO3 (0.298 g, 2.15 mmol), and XPhos Pd(crotyl)Cl (CAS # 1798782-02-1, 0.068 g, 0.101 mmol). The vial was sealed, flushed withnitrogen, then charged with 2-methyltetrahydrofuran (5 mL) and 2-ethyl hexanoic acid (0.017 mL, 0.11 mmol). The reaction mixture was heated to 40 °C. After 16 h, the reaction was diluted with EtOAc and filtered through a pad of diatomaceous earth. The layers were separated, washed with water, sat. aq. NaCl, dried over MgSCU, filtered, and concentrated to obtain a brown solid. ES-MS m / z. 531 (M+H).Preparation of Intermediate 12: (5R,7S)-2-(2-cyclopropylphenyl)-7-methyl-l,3,8- triazaspiro [4.5] dec- 1 -en-4-one

[0125] Hydrochloric acid (5.5 M in IPA, 16 mL, 88 mmol) was added to a solution of tert-butyl (5R,7S)-2-(2-cyclopropylphenyl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (8.15 g, 21.3 mmol) in IPA (25 mL) and stirred at 60 °C for 20 min, then added additional IPA (20 mL) to aid with stirring. After 6 h, the mixture was filtered and washed with IPA (30 mL). The filter cake was diluted with 50 mL water. The mixture was stirred and 2 M aq. K3PO4 solution was added bringing pH to 11.7. After 30 min, the solid was collected by filtration and washed with water until the filtrate pH reached 8-9. The solid was dried in a vacuum oven overnight to give the title compound (7.63 g). ES-MS nt / z 284.Preparation of Intermediate 13: (5R,7S)-8-(4-Bromopyridin-2-yl)-2-(2-cyclopropylphenyl)-7- methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0126] 4-Bromo-2-fluoropyridine (6.0 g, 3.5 mL, 34 mmol) was added to a solution of (5R,7S)- 2-(2-cyclopropylphenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (5.00 g, 17.1 mmol) and KL (3.08 g, 53.0 mmol) in DMSO (25 mL). The mixture was heated to 125 °C. After 8 h, the mixture was poured slowly into stirred 5% aq. citric acid (200 mL) and extracted with EtOAc (100 mL). The phases were separated and the organics were washed with water and sat. aq. NaCl(each 25 mL), then dried over MgSCU and filtered. The organics were concentrated and the residue was purified by silica gel chromatography using a gradient of 0 to 60% EtOAc in cyclohexane to give the title compound (6.75 g) as a solid. ES-MS m z 439,441 (M+H).Preparation of Intermediate 14: (5R,7S)-2-(2-Cyclopropylphenyl)-7-methyl-8-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0127] 2-Ethyl hexanoic acid (0.076 g. 0.53 mmol) and 2-methyltetrahydrofuran (25 mL) were added to a mixture of (5R,7S)-8-(4-bromopyridin-2-yl)-2-(2-cyclopropylphenyl)-7-methyl-l,3,8- triazaspiro[4.5]dec-l-en-4-one (2.50 g, 5.29 mmol), bis(pinacolato)diboron (1.90 g, 7.48 mmol), K2CO3 (1.68 g, 12.2 mmol) and XPhos Pd(crotyl)Cl (CAS # 1798782-02-1, 0.22 g, 0.33 mmol). The mixture was purged gently with nitrogen, then stirred at 40 °C under a balloon of nitrogen. After 16 h, the mixture was diluted with isopropyl acetate (25 mL), stirred for 5 min, then filtered through a pad of diatomaceous earth. The pad was rinsed with isopropyl acetate (25 mL). The combined organics were shaken with sat. aq. NaHCCh. The phases of the filtrate were separated and the organics washed with sat. aq. NaCl (25 mL). The organics were dried over MgSCU and filtered. The organics were concentrated under reduced pressure at 50 °C. The residue was taken up in EtOAc (50 mL) and HC1 (1.0 M in EtOAc, 6.0 mL, 6.0 mmol) was added over 3 min under nitrogen. After 2.5 h, the resulting solid was collected by filtration and washed with EtOAc (20 mL) and dried overnight in a vacuum oven (30 °C, 10 mbar) to give the title compound (2.63 g) as a solid. ES-MS m / z. 405 (boronic acid M+H).Preparation of Intermediate 15: 2-(4-Bromo-3-cyano-5-methyl-lH-pyrazol-l-yl)acetamide

[0128] Sodium hydride (60 wt%, 0.0774 g, 1.94 mmol) was added to a solution of 4-bromo-5- methyl-lH-pyrazole-3-carbonitrile (0.300 g, 1.61 mmol) in THE (5.38 mL) at 0 °C. After 10 min, the reaction mixture was treated with 2-bromoacetamide (0.223 g, 1.61 mmol) followed byKI (0.295 g, 1.77 mmol). The mixture was stirred at 23 °C for 1.5 h then diluted with water and concentrated under reduced pressure. The resulting solids were filtered, washed with cold water, and dried to afford the title compound (0.330 g). ES-MS m / z 243,245 (M+H).Preparation of Intermediate 16: N-(l,4-Dimethyl-lH-pyrazol-3-yl) acetamide

[0129] Acetyl chloride (0.466 mL, 6.48 mmol) was added dropwise to a solution of 1,4- dimethyl-lH-pyrazol-3-amine (0.655 g, 5.89 mmol) and TEA (1.64 mL, 11.8 mmol) in DCM (23 mL) at 0 °C and stirred. After 5 min, the solvent was removed under reduced pressure. The residue was dissolved with EtOAc, and suspension was filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure to give the title compound (0.977 g) as a solid. ES-MS m / z 154 (M+H).Preparation of Intermediate 17: N-(5-Bromo-l,4-dimethyl-lH-pyrazol-3-yl)acetamide

[0130] N-Bromosuccinimide (1.28 g, 7.07 mmol) was added to a solution of N-(l,4-dimethyl- IH-pyrazol- 3 -yl) acetamide (0.925 g, 5.43 mmol) in DCM (27 mL) at 23 °C. After 7 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 50% to 100% EtOAc in DCM. The purified product was dissolved in EtOAc and washed with sat. aq. NaHCOs, water, sat. aq. NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was dried under reduced pressure at 30-35°C to give the title compound (0.920 g) as a solid. ES-MS m / z 232,234 (M+H).Preparation of Intermediate 18: N-(4-Methylthiazol-2-yl)acetamide

[0131] Acetyl chloride (2.353 mL, 32.76 mmol) was added dropwise to a solution of 2-amino-4- methylthiazole (3.400 g, 29.78 mmol) and TEA (9.22 mL, 65.52 mmol) in DCM (74 mL) at 0°C. After 30 min, acetyl chloride (0.3 mL) was added and the mixture was stirred for 5 min, then concentrated under reduced pressure. The mixture was partially dissolved in EtOAc, filtered through a pad of diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in DCM to give a solid. EtOAc was added and resulting solid was filtered and washed with EtOAc to give the title compound (1.3 g) as a solid. ES-MS m / z 157 (M+H).Preparation of Intermediate 19: N-(5-Bromo-4-methylthiazol-2-yl)acetamide o. Brv ^g y _T / ^NH

[0132] N-Bromosuccinimide (1.663 g, 9.155 mmol) was added to a solution of N-(4- methylthiazol-2-yl) acetamide (0.1300 g, 8.323 mmol) in DCM (42 mL) at RT. After 15 min, the solvent was removed and the residue was diluted with water and EtOAc. The aqueous layer was separated, and the organic layer was washed with water and sat. aq. NaCl, dried over anhydrous Na2SO+ filtered and the solvent was removed. While EtOAc was removed, a solid precipitated which was filtered and dried under vacuum at RT overnight afforded the title compound ( 1.44 g) as a solid. ES-MS m / z 235,237 (M+H).Preparation of Intermediate 20: N-(5-Bromo-4,6-dimethylpyrimidin-2-yl)acetamide

[0133] Acetyl chloride (0.114 mL, 1.61 mmol) was added to a solution of 5-bromo-4,6- dimethyl-pyrimidin-2-amine (0.250 g, 1.24 mmol) in DCM (2.47 mL, 1.24 mmol) and TEA (0.259 mL, 1.86 mmol) at RT. After 3 h, the reaction was diluted with EtOAc and washed with sat. aq. NaHCO?. sat. aq. NaCl. dried over Na2SO+ filtered and concentrated under reduced pressure to give the title compound (0.264 g). ES-MS m / z 243,245 (M+H).Preparation of Intermediate 21: 3-(4-Bromo-3,5-dimethyl-lH-pyrazol-l-yl)-l-methylpyrrolidin- 2-one (racemic mixture)

[0134] 3-Bromo-l-methylpyrrolidin-2-one (racemic mixture, 0.306 g, 1.72 mmol) was added to a mixture of 3,5-dimethyl-4-bromopyrazole (0.207 g, 1.180 mmol) and K2CO3 (0.493 g, 3.571 mmol) in DMF (4 mL). The reaction vessel was sealed and the mixture was heated to 60 °C with vigorous stirring. After 1 h, the reaction was cooled to ambient temp and diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, 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 (0.121 g). ES-MS m / z 2122'1^ (M+H).Preparation of Intermediate 22: (5R,7S)-8-(4-Bromo-5-methylpyridin-2-yl)-7-methyl-2-(2- (trifluoromethoxy)phenyl)-l,3.8-triazaspiro[4.5]dec-l-en-4-one

[0135] A mixture of KF (0.108 g, 1.84 mmol), (5R,7S)-7-methyl-2-(2- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.203 g, 0.595 mmol) in anhydrous DMSO (0.851 mL) was purged with nitrogen. 4-Bromo-2-fhroro-5-methylpyridine (0.240 g, 1.20 mmol) was added, the reaction vessel was sealed, and the mixture was stirred at 125 °C. After 48 h, the reaction was cooled to RT, then diluted with water and EtOAc. The aqueous layer was separated, and the organic layer was washed with sat. aq. NaHCCh. water and sat. aq. NaCl, dried over anhydrous NazSCU. filtered and the solvent was removed. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in DCM to give the title compound (0.101g) as a solid. ES-MS m / z 497,499 (M+H).Preparation of Intermediate 23: (5R,7S)-7-Methyl-8-(5-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)-2-(2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en- 4-one

[0136] A mixture of (5R,7S)-8-(4-bromo-5-methylpyridin-2-yl)-7-methyl-2-(2- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.098 g, 0.19 mmol). bis(pinacolato)diboron (0.065 g, 0.252 mmol) and K2CO3 (0.068 g, 0.484 mmol) was purged with nitrogen, then anhydrous 2-methyltetrahydrofuran (2.7 mL), 2-ethyl hexanoic acid (0.003 mb. 0.019 mmol) and XPhos Pd(crotyl)Cl (CAS # 1798782-02-1, 0.010 g, 0.014 mmol) were added. The mixture was stirred at 50 °C for 16 h. More of the palladium catalyst (0.009 g) was added, and the mixture was stirred at 50 °C. After 9 h, the reaction was cooled to RT, diluted with water and EtOAc, and filtered through a pad of diatomaceous earth. The aqueous layer was separated, and the organic layer was washed with water and sat. aq. NaCl, dried over anhydrous NazSCh, filtered and the solvent was removed with a nitrogen stream at RT. After 16 h, the residue was purified by silica gel chromatography using a gradient of 0 to 25% EtOH in EtOAc to give the title compound (0.063 g) as a solid. ES-MS m / z. 545 (M+H).Preparation of Intermediate 24: 3-Bromo-2,4-dimethyl-6-nitrophenol

[0137] A mixture of 3-bromo-2,4-dimethylphenol (9.50 g, 47.2 mmol) and ACN (160 mL) was sparged with nitrogen for 3 min, then charged with iron(III) nitrate nonahydrate (6.85 g, 17.0 mmol) and heated to 70 °C for 4.5 h. The mixture was cooled to RT, diluted with water (200 mL) and filtered. The solid was washed with 450 mL water, then air-dried for 3 min to give the title compound (11.62 g) as a solid. ’H-NMR (400 MHz, DMSO-cfe) 5 10.64 (s, 1H), 7.91(s, 1H), 2.39 (s, 6H).Preparation of Intermediate 25: 6-Amino-3-bromo-2,4-dimethylphenol

[0138] A mixture of EtOH (100 mL), water (20 mL), 3-bromo-2,4-dimethyl-6-nitrophenol (7.83 g, 31.8 mmol), NH4CI (5.46 g, 100 mmol) and iron (5.64 g, 95.9 mmol) was de-gassed and refilled with nitrogen three times, and then the reaction mixture was heated to 80 °C and allowed to stir for 12 h under nitrogen. After cooling to RT, the reaction mixture was filtered through a pad of diatomaceous earth under vacuum and the filtrate was concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 30% EtOAc in petroleum ether to give the title compound (3.6 g) as a solid. ES-MS m / z 216, 218 (M+H).Preparation of Intermediate 26: 6-Bromo-5,7-dimethylbenzo[d]oxazole;

[0139] A mixture of trimethylorthoformate (17 g. 0.16 mol). 6-amino-3-bromo-2,4- dimethylphenol (3.6 g, 16 mmol) and p-toluenesulfonic acid (0.31 g, 1.8 mmol) was stirred vigorously at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0 to 10% EtOAc in petroleum ether to give the title compound (2.1 g) as a solid. ES-MS m / z 226,228 (M+H).Preparation of Intermediate 27: 2-(l ,4-Dioxan-2-yl)-6-(trifluoromethyl)nicotinic acid (racemic mixture)

[0140] 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-(t -butyl)-l,l,3,3-tetramethylguanidine (3.82 g, 21.9 mmol), (4,4'-di-t- butyl-2,2'-bipyridine)bis[3,5-difluoro-2-(5-trifhioromethyl-2-pyridinyl-kN)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. Thereaction 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 28: 2-(l,4-Dioxan-2-yl)-6-(trifluoromethyl)nicotinoyl chloride (racemic mixture)

[0141] To a mixture of DCM (30 mL) and DMF (0.1 mL) was added 2-(l,4-dioxan-2-yl)-6- (trifhioromethyl)nicotinic acid (racemic mixture, 2.85 g, 10.1 mmol), then oxalyl chloride (2.66 mL, 30.3 mmol) was added dropwise over 10 min at 0 °C under nitrogen. The mixture was stirred at 20 °C for 2 h and the mixture was concentrated under reduced pressure to give the title compound (2.80 g) as a solid. A sample of the title compound in MeOH: ES-MS m / z 292 (methyl ester M+H).Preparation of Intermediate 29: fert-Butyl (2S,4R)-4-(2-(l,4-dioxan-2-yl)-6- (trifluoromethyl)nicotinamido)-4-carbamoyl-2-methylpiperidine- 1-carboxylate (mixture of isomers)

[0142] To a vigorously stirred solution of ze / 7-butyl (2S,4R)-4-amino-4-carbamoyl-2- methylpiperidine- 1-carboxylate (2.5 g, 9.7 mmol) in DCM (15 mL) was added 2-(l,4-dioxan-2- yl)-6-(trifluoromethyl)nicotinoyl chloride (racemic mixture, 3.0 g, 8.4 mmol) in DCM (15 mL) dropwise at 0 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture wasconcentrated under reduced pressure to give the title compound (3.9 g) as a solid. ES-MS m / z 517 (M+H).Preparation of Intermediate 30: tert-Butyl (5R,7S)-2-(2-(l,4-dioxan-2-yl)-6- (trifhioromethyl)pyridin-3-yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (mixture of isomers)

[0143] To a mixture of THF (50 mL) and tert-butyl (2S,4R)-4-(2-(l,4-dioxan-2-yl)-6- (trifhioromethyl)nicotinamido)-4-carbamoyl-2-methylpiperidine- 1 -carboxylate (mixture of isomers, 3.9 g, 5.0 mmol) was added potassium tert-butoxide in tert-butanol (1 M, 50 mL, 50 mmol) at 20 °C under nitrogen, then the reaction mixture was heated to 70 °C for 12 h with vigorous stirring. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with sat. aq. NaCl (20 mL x 2), dried over Na^SCF. filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 1 to 50% EtOAc in petroleum ether to give the title compound (2.4 g) as an oil. ES-MS m z 499 (M+H).Preparation of Intermediate 31: (5R,7S)-2-(2-(l,4-Dioxan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)- 7-methyl-l,3,8-triazaspiro[4.5Jdec-l-en-4-one (mixture of isomers)

[0144] To a mixture of / e / 7-butyl (5R,7S)-2-(2-(l,4-dioxan-2-yl)-6-(trifluoromethyl)pyridin-3- yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate (mixture of isomers, 1.0 g, 1.9 mmol) in DCM (10 mL) was added TFA (2.5 mL, 31 mmol) dropwise over 5 min at 0 °C under nitrogen. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ACN (10.0 mL) and passed through ahydroxide ion exchange resin to remove TFA (pH=7-8). The eluent was concentrated under reduced pressure to give the title compound (0.71 g) as a solid. ES-MS m / z 399 (M+H).Preparation of Intermediate 32: (5R,7S)-2-(2-(l,4-Dioxan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-8-(4-bromopyridin-2-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0145] A mixture of (5R,7S)-2-(2-(l,4-dioxan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-7-methyl- l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 510 mg, 1.23 mmol), 4-bromo-2- fluoropyridine (434 mg, 2.39 mmol) and K2CO3 (512 mg, 3.67 mmol) in DMSO (5 mb) was heated to 100 °C for 5 h with vigorous stirring. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with sat. aq. NaCl (20 mL x 2), dried over NazSCh, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAc in petroleum ether, R / - 0.4) to give the title compound (250 mg) as a solid. ES-MS m / z 554, 556 (M+H).Preparation of Intermediate 33: (2-((5R,7S)-2-(2-(l,4-Dioxan-2-yl)-6-(trifluoromethyl)pyridin-3- yl)-7-methyl-4-oxo-1.3.8-triazaspiro[4.5]dec-l-en-8-yl)pyridin-4-yl)boronic acid (mixture of isomers)

[0146] A mixture of (5R,7S)-2-(2-(l,4-dioxan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-8-(4- bromopyridin-2-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 250 mg, 419 pmol), bis(pinacolato)diboron (230 mg, 879 pmol), potassium trimethylacetate (192 mg, 1.36 mmol) and Pd(dppf)C12 (35 mg, 47 pmol) in 1,4-dioxane (4 mL) was purged with nitrogen for one minute. The reaction mixture was heated to 100 °C for 2 h under nitrogen. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse-phase HPLC (column: Phenomenex lima C18 100 x 40mm, 5 pm; mobile phase: solvent A - 0.2% aq.formic acid, solvent B - ACN; gradient: 5 to 35% solvent B in solvent A) to give the title compound (100 mg) as a solid. ES-MS m / z 520 (M+H).Preparation of Intermediate 34: 3-Bromo-5-chloro-2-cyclopropoxypyridine

[0147] A mixture of DMSO (50 mL), CS2CO3 (32 g, 97 mmol), cyclopropanol (5.4 g, 6 mL, 92 mmol) and 3-bromo-5-chloro-2-fluoropyridine (5 g, 20 mmol) was heated to 100 °C for 2 h with vigorous stirring. 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 Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 10% EtOAc in petroleum ether to give the title compound (3.2 g) as a liquid. ES-MS m / z 248, 250 (M+H).Preparation of Intermediate 35: tert-Butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2- (trifluoromethyl)nicotinamido)piperidine- 1 -carboxylate

[0148] To a mixture of 2-(trifluoromethyl)nicotinic acid (48.5 g, 249 mmol), HATU (243 g, 633 mmol) and DIEA (115 g, 155 mL, 882 mmol) in DMF (1500 mL) 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 then filtered. The filter cake was washed with water (300 mL x 3) and concentrated under reduced pressure at 45 °C to give the title compound as a solid. ES-MS m / z 331 (M-Boc+H).Preparation of Intermediate 36: tert-Butyl (5R,7S)-7-methyl-4-oxo-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate

[0149] To a solution of tert-butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2- (trifluoromethyl)nicotinamido)piperidine-l -carboxylate (107 g, 249 mmol) in DMSO (400 mL) and tert-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 tert-butanol and then diluted with water (2.5 L) and extracted with EtOAc (900 mL x 4). The combined organics were washed with sat. aq. NaCl (2 L x 2), dried over NaiSCh. filtered, and concentrated to give the title compound (78.1 g) as a solid. ES-MS m / z 357 (M-tBu+H).Preparation of Intermediate 37: (5R.7S)-7-Methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one dihydrochloride

[0150] To a solution of tert-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 38: (5R,7S)-8-(5-Chloro-2-cyclopropoxypyridin-3-yl)-7-methyl-2- (2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0151] To a solution of (5R,7S)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)- 1,3,8- triazaspiro[4.5]dec-l-en-4-one dihydrochloride (500 mg, 1.29 mmol) in toluene (5 mL) wasadded 3-bromo-5-chloro-2-cyclopropoxypyridine (720 mg, 2.81 mmol), methanesulfonato(2- bis(3,5-di(trifhioromethyl)phenylphosphino)-3,6-dimethoxy-2',6'-bis(dimethylamino)-l,l'- biphenyl )(2'-methylamino-l,l'-biphenyl-2-yl)palladium(II) (150 mg, 129 pmol) and sodium 2- methylbutan-2-olate in THF (2. 5 M, 2.29 mL, 5.721 mmol) at 25 °C. The mixture was stirred at RT while purging with nitrogen for 2 min. Then the resulting mixture was stirred at 100 °C for 4 h. The reaction mixture was poured into 10 mL water, and then extracted with EtOAc (10 mL x 2). The combined organic layers were washed with sat. aq. NaCl (10 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 20% EtOAc in petroleum ether to give the title compound (253 mg) as a solid. ES-MS m / z 480, 482 (M+H).Preparation of Intermediate 39: (5R,7S)-8-(4-Bromopyridin-2-yl)-7-methyl-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0152] A mixture of (5R,7S)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-1.3,8- triazaspiro[4.5]dec-l-en-4-one dihydrochloride (500 mg, 1.24 mmol), 4-bromo-2- fluoropyridine (250 mg, 1.39 mmol) and K3PO4 (660 mg, 3.75 mmol) in DMSO (5 mL) was purged with nitrogen for one minute, then heated at 120 °C for 12 h under nitrogen with vigorous stirring. The reaction mixture was quenched by adding 20 mL water, and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with sat. aq. NaCl (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 60% EtOAc in petroleum ether to give the title compound (110 mg) as a solid. ES-MS m / z 468, 470 (M+H).Preparation of Intermediate 40: (2-((5R,7S)-7-Methyl-4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)pyridin-4-yl)boronic acid

[0153] A mixture of (5R,7S)-8-(4-bromopyridin-2-yl)-7-methyl-2-(2-(trifluoromethyl)pyridin-3- yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (110 mg, 230 pmol), bis(pinacolato)diboron (130 mg, 502 pmol) and potassium z -butoxide (110 mg, 769 pmol) in 1,4-dioxane (2 mL) was purged with nitrogen for one minute, and then Pd(dppf)Ch (18 mg, 24 pmol) was added. The mixture was purged with nitrogen for one minute, then heated to 100 °C for 12 h under nitrogen. The mixture was filtered through a pad of diatomaceous earth under reduced pressure and rinsed with 5 mL EtOAc. The filtrate was concentrated under reduced pressure at 45 °C and the residue was purified by reverse-phase HPLC (column: WePure Biotech XP tC18 150 x 40, 7 pm; mobile phase: solvent A - 10 mM aq. NH4HCO3; solvent B - ACN; gradient 55-85% solvent B in solvent A) to give the title compound (50.0 mg) as a solid. ES-MS m / z 434 (M+H).Preparation of Intermediate 41: (5R,7S)-8-(5-Chloro-2-methoxypyridin-3-yl)-7-methyl-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0154] The title compound was prepared as described in the preparation of intermediate 38 using 3-bromo-5-chloro-2-methoxypyridine, heating the reaction at 100 °C for 16 h. The product was purified by silica gel chromatography using a gradient of 0 to 80% EtOAc in petroleum ether. ES-MS m / z 454, 456 (M+H).Preparation of Intermediate 42: 3-Bromo-5-chloro-2-(methoxymethyl)pyridine

[0155] To a solution of (3-bromo-5-chloropyridin-2-yl)methanol (5.00 g, 21.4 mmol) in THF (50 mL) was added NaH (60 wt% in mineral oil, 900 mg, 22.5 mmol) in portions over 10 min at 0 °C. lodomethane (1.70 mL. 26.9 mmol) was then added dropwise at 0°C. The mixture was stirred at 20 °C for 2 h under nitrogen, then quenched with 100 mL water at 20 °C and 200 mL EtOAc and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with sat. aq. NaCl (200 mL), dried over Na?SO4, filtered and concentrated under reduced pressure.The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in petroleum ether to give the title compound (4.00 g) as a liquid. ES-MS m / z. 236, 238 (M+H).Preparation of Intermediate 43: (5R,7S)-8-(5-Chloro-2-(methoxymethyl)pyridin-3-yl)-7-methyL2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0156] The title compound was prepared as described in the preparation of intermediate 38 using 3-bromo-5-chloro-2-(methoxymethyl)pyridine, the reaction was heated at 100 °C for 12 h and the reaction mixture concentrated to dryness instead of using a water / EtOAc workup. The product was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in petroleum ether. ES-MS m / z 468, 470 (M+H).Preparation of Intermediate 44: 5-Bromo-3-((5R,7S)-7-methyl-4-oxo-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)picolinonitrile

[0157] To a solution of (5R,7S)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one dihydrochloride (3.00 g, 7.53 mmol) and K2HPO4 (3.94 g, 22.2 mmol) in DMSO (30 mL) was added 5-bromo-3-fluoropicolinonitrile (1.82 g, 8.87 mmol) at 25 °C under nitrogen. The system was de-gassed and refilled with nitrogen three times. The resulting mixture was stirred at 120 °C for 3 h, then cooled to RT and poured into water (100 mL). The mixture was extracted with EtOAc (30 mL x 3) and the combined organics were washed with sat. aq. NaCl (150 mL), dried over Na2SO4. filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (column: Phenomenex luna C18 100 x 40mm, 5 pm; mobile phase: solvent A - 0.2% aq. formic acid, solvent B - ACN; gradient 1- 30% solvent B in solvent A) to give the title compound (700 mg) as a solid. ES-MS m / z 493, 495 (M+H).Preparation of Intermediate 45: 3,5-Dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine

[0158] A mixture of 4-bromo-3,5-dimethylpyridine (570 mg, 2.91 mmol), CS2CO3 (1.52 g, 4.62 mmol), bis(pinacolato)diboron (895 mg, 3.49 mmol), palladium(II) acetate (37.4 mg, 165 pmol) and tris(4-methoxyphenyl)phosphane (74.6 mg, 210 pmol) was purged with nitrogen and then EtOAc (29.1 mL) was added. The reaction vessel was sealed and heated to 80 °C for 6 h, then the reaction mixture was cooled to RT and filtered through a pad of diatomaceous earth. The filtrate was concentrated and the residue was purified by silica gel chromatography using a 40% EtOAc in DCM to give the title compound (432 mg) as a solid. ES-MS m / z 234 (M+H).Preparation of Intermediate 46: (5R,7S)-2-(2-(l,4-dioxan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)- 8-(5-chloro-2-methoxypyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)

[0159] A mixture of (5R,7S)-2-(2-(l,4-dioxan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-7-methyl- l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 240 mg, 602 pmol), anhydrous toluene (2.0 mL), FrankenPhos Pd G4 (CAS# 1810068-35-9, 69.3 mg, 60.8 pmol) and 3-bromo-5- chloro-2-methoxypyridine (282.8 mg, 1.271 mmol) was purged with nitrogen, then sodium 2- methylbutan-2-olate in THF (1.4 M, 1.8 mL, 2.5 mmol) was added. The mixture was stirred at RT while purging with nitrogen for 1 min, then the reaction vessel was sealed and the mixture was stirred at 100 °C overnight. The mixture was cooled to RT, then diluted with aq. citric acid and EtOAc. The aqueous layer was separated, and the organic layer was washed with water and sat. aq. NaCl, dried over anhydrous Na2SO4. filtered and the solvent was removed. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in DCM to give the title compound (26 mg) as a solid. ES-MS m / z 540 (M+H).Preparation of Intermediate 47: Methyl 4-chloro-6-((5R,7S)-7-methyl-4-oxo-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)picolinate

[0160] A mixture of (5R,7S)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one dihydrochloride (10.00 g, 25.10 mmol), KF (7.4 g, 0.12 mol) and methyl 4-chloro-6-fluoropicolinate (5.1 g, 26 mmol) in DMSO (110 mL) was heated to 120 °C for 16 h under nitrogen with vigorous stirring. The reaction mixture was quenched by adding water (200 mL), and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with sat. aq. NaCl (200 mL), dried over NazSCh. filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 80% EtOAc in petroleum ether to give the title compound (5 g) as a solid. ES-MS m / z 482 (M+H).Preparation of Intermediate 48: (5R.7S)-8-(4-Chloro-6-(hydroxymethyl)pyridin-2-yl)-7-methyl- 2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0161] A mixture of methyl 4-chloro-6-((5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethyl)pyridin- 3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)picolinate (5.00 g, 9.34 mmol) in DCM (50 mL) was de-gassed and backfilled with N2 three times. IM Diisobutylaluminum hydride (1 M in toluene, 43 mL, 43 mmol) was added dropwise over 3 min at -60 °C, then the reaction vessel was degassed and backfilled with N2 three times. The reaction mixture was stirred at 25 °C for 6 h, then poured into 100 mL sat. aq. NH4CI at 0 °C, and extracted with DCM (50 mL x 3). The combined organics were washed with sat. aq. NaCl (50 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 45 to 80% EtOAc in petroleum ether to give the title compound (2.20 g) as a solid. ES-MS m / z 454 (M+H).Preparation of Intermediate 49: 4-Chloro-6-((5R,7S)-7-methyl-4-oxo-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)picolinaldehyde

[0162] To a solution of (5R,7S)-8-(4-chloro-6-(hydroxymethyl)pyridin-2-yl)-7-methyl-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (2.20 g, 4.41 mmol) in DCM (30 mL) was added Dess-Martin periodinane (2.83 g. 6.34 mmol) in batches at 0 °C. Upon complete addition, the reaction vessel was de-gassed and backfilled with N2 three times and stirred at 25 °C for 2 h. The mixture was washed with water (50 mL), extracted with DCM (30 mL x 3), and the combined organics were washed with sat. aq. NaCl, dried over Na2SC>4, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 25 to 45% EtOAc in petroleum ether to give the title compound (1.90 g) as a solid. ES-MS m / z 452 (M+H).Preparation of Intermediate 50: (5R,7S)-8-(4-Chloro-6-((E)-hydrazineylidenemethyl)pyridin-2- yl)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0163] A mixture of 4-chloro-6-((5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)- l ,3,8-triazaspiro[4.5]dec-l-en-8-yl)picolinaldehyde (500 mg, 1.02 mmol) and hydrazine hydrate (1 g, 1 mL, 0.02 mol) in EtOH (5 mL) was purged with nitrogen for 1 min then stirred vigorously at 28 °C overnight. The reaction mixture was concentrated under reduced pressure to give the title compound (300 mg) as a solid. ES-MS m / z 466 (M+H).Preparation of Intermediate 51 : (5R,7S)-8-(5-Chloro-[l,2,3]triazolo[l,5-a]pyridin-7-yl)-7- methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0164] MnCL (332 mg, 3.74 mmol) was slowly added in batches at 25 °C to a mixture of (5R,7S)-8-(4-chloro-6-((E)-hydrazineylidenemethyl)pyridin-2-yl)-7-methyl-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (300 mg, 58 wt%, 373 pmol) in DCM (3 mL). The reaction mixture was heated to 50 °C for 16 h, then concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (column: WePure Biotech XP tC18 150 x 40mm; mobile phase: 10 mM aq. NH4HCO3, solvent B - ACN; gradient: 25 to 55% solvent B in solvent A) to give the title compound (70 mg) as a solid. ES-MS m / z 464 (M+H).Preparation of Intermediate 52: (5R.7S)-8-(5-(3,5-Dimethylpyridin-4-yl)-[l,2,3]triazolo[l,5- a]pyridin-7-yl)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4- one

[0165] A mixture of (5R,7S)-8-(5-chloro-[l,2,3]triazolo[l,5-a]pyridin-7-yl)-7-methyL2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (65 mg, 0.14 mmol), 3,5- dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (70 mg, 0.29 mmol), K3PO4 (120 mg, 554 pmol) and 2nd Generation SPhos Precatalyst (CAS# 1375325-64-6, 22 mg, 30 pmol) in EtOH (4 mL) and water (1 mL) was purged with nitrogen for 1 min, then heated to 80 °C and allowed to stir for 16 h under nitrogen. The reaction mixture was filtered through a pad of diatomaceous earth, rinsed with EtOAc (10 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (column : WePure Biotech XP tC18 150 x 40 mm; mobile phase: 10 mM aq. NH4HCO3, solvent B - ACN; gradient: 20 to 50% solvent B in solvent A), then re-purified by reverse-phase HPLC (column: Phenomenex Gemini- NX Cl 8 75 x 30 mm, 3 pm; mobile phase: 10 mM aq. NH4HCO3, solvent B - ACN; gradient:15 to 45% solvent B in solvent A) to give the title compound (10 mg) as a solid. ES-MS m / z 535 (M+H).Preparation of Intermediate 53: 4-Chloro-6-(3,5-dimethylpyridin-4-yl)-3-methylpyridazine

[0166] A mixture of 4,6-dichloro-3-methylpyridazine (700 mg, 4.08 mmol), 3.5-dimethyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.06 g, 4.32 mmol), 1,1'- bis(diphenylphosphino)ferrocene (700 mg, 1.20 mmol) and CS2CO3 (3.13 g, 9.56 mmol) in 1,4- dioxane (7 mL) and water (3.5 mL) was purged with nitrogen for 1 min before and after adding palladium(II) acetate (70 mg, 0.30 mmol). The reaction mixture was heated to 80 °C and allowed to stir for 12 h under nitrogen. The reaction mixture was filtered and concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0 to 30% EtOAc in petroleum ether to give the title compound (430 m) as a solid. ES-MS m / z 234 (M+H).Preparation of Intermediate 54: tert-Butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2- (trifluoromethyl)benzamido)piperidine- 1 -carboxylate

[0167] To a solution of 2-(trifluoromethyl)benzoic acid (5.2 g, 27 mmol), DIEA (10 g, 14 mL, 80 mmol) and HATU (12 g, 32 mmol) in DMF (120 mL) was added tert-butyl (2S,4R)-4-amino- 4-carbamoyl-2-methylpiperidine-l -carboxylate (7.0 g, 27 mmol). The mixture was stirred at 28 °C for 16 h, then diluted with water (800 mL) and extracted with EtOAc (200 mL x 3). The combined organics were washed with sat. aq. NaCl, dried over anhydrous Na2SO4. filtered and concentrated to give the title compound (18.58 g, 62% purity) as a solid. ES-MS m / z 330 (M- Boc+H).Preparation of Intermediate 55: terf-Butyl (5R,7S)-7-methyl-4-oxo-2-(2- (trifluoromethyl)phenyl)-l,3,8-triazaspiro[4.5]dec-l-ene-8-carboxylate

[0168] A mixture of tert-butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2- (trifluoromethyl)benzamido)piperidine-l -carboxylate (18.58 g, 26.82 mmol) in potassium tert- butoxide (1 M in tert-butanol, 386 g. 400 mL, 400 mmol) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 90 °C for 16 h. The reaction mixture was combined with a reaction mixture run in the same manner using 6.14 mmol of starting terf-butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2-(trifluoromethyl)benzamido)piperidine-l -carboxylate and the resulting mixture was concentrated under reduced pressure. The residue was diluted with water (800 mL) and extracted with EtOAc (100 mL x 5). The combined organics were washed with sat. aq. NaCl (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 41% EtOAc in hexanes to give the title compound (10.5 g) as an oil. ES-MS m / z 412 (M+H).Preparation of Intermediate 56: (5R,7S)-7-Methyl-2-(2-(trifluoromethyl)phenyl)-L3,8- triazaspiro [4.5] dec - 1 -en-4- one hydrochloride

[0169] A mixture of terf-butyl (5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethyl)phenyl)-l,3,8- triazaspiro[4.5]dec-l-ene-8-carboxylate (10.5 g, 23.7 mmol) in HC1 (2 M in 1,4-dioxane, 120 mL, 240 mmol) was stirred at 28 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound (9.6 g) as a solid. ES-MS m / z 312 (M+H).Preparation of Intermediate 57: (5R,7S)-8-(4-Bromopyridin-2-yl)-7-methyl-2-(2- (trifluoromethyl)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0170] To a mixture of (5R,7S)-7-methyL2-(2-(trifluoromethyl)phenyl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one hydrochloride (200 mg, 518 pmol) and 4-bromo-2-fluoropyridine (186 mg, 1.04 mmol) in DMSO (4 mL) was added K2CO3 (219 mg, 1.55 mmol). The mixture was sparged with nitrogen and stirred at 100 °C for 16 h under nitrogen atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with sat. aq. NaCl (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 5% MeOH in DCM to give the title compound (47 mg) as an oil. ES-MS m / z 467 (M+H).Preparation of Intermediate 58: 3-Bromo-5-chloro-2-cyclopropylpyridine

[0171] A mixture of 2,3-dibromo-5-chloro-pyridine (10 g, 36 mmol), CS2CO3 (30 g, 90 mmol) and potassium cyclopropyltrifluoroborate (6.3 g, 42 mmol) in 1,4-dioxane (200 mL) and water (20 mL) was de-gassed and backfilled with nitrogen three times before and after adding Pd(dppf)C12 (2.7 g, 3.6 mmol). The reaction mixture was heated to 100 °C and allowed to stir for 12 h under nitrogen. The reaction mixture was quenched by adding 200 mL water at 25 °C, and then diluted with 200 mL EtOAc and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with aq. NH4CI (100 mL x 3), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (column: Welch Xtimate C18 250 x 100mm, 10 pm; mobile phase: solvent A - 10 mM aq. NH4HCO3, solvent B - ACN: gradient: 50 to 78% solvent B in solvent A) to give the title compound (300 mg) as a solid. ES-MS m / z 232,234 (M+H).Preparation of Intermediate 59: (5R.7S)-8-(5-Chloro-2-cyclopropylpyridin-3-yl)-7-methyl-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0172] A mixture of toluene (3 mL), 3-bromo-5-chloro-2-cyclopropylpyridine (300 mg, 1.21 mmol), (5R,7S)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4- one dihydrochloride (202 mg, 520 pmol) and sodium 2-methylbutan-2-olate (271 mg, 2.45 mmol) was obtained. The mixture was purged with nitrogen for 1 min before and after adding methanesulfonato(2-bis(3,5-di(trifluoromethyl)phenylphosphino)-3.6-dimethoxy-2',6'- bis(dimethylamino)-l,l'-biphenyl )(2'-methylamino-l,T-biphenyl-2-yl)palladium(II) (61 mg, 52 pmol). The reaction mixture was heated to 100 °C and allowed to stir for 8 h under nitrogen, then filtered. The filter cake was rinsed with 2 mL MeOH and the filtrates were concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (column: Phenomenex luna C18 100 x 40mm, 5 pm; mobile phase: solvent A - 0.2% aq. formic acid, solvent B - ACN; gradient: 35 to 75% solvent B in solvent A) to give the title compound (25 mg) as a solid. ESMS m / z 464 (M+H).Preparation of Intermediate 60: Methyl 5-amino-4,6-dimethylpicolinate

[0173] To a 10.0 L autoclave with mechanical stirring was added 6-bromo-2,4-dimethylpyridin- 3-amine (75.0 g, 354 mmol), Pd(dppf)Ch (DCM adduct, 30.5 g, 36.6 mmol), palladium(II) acetate (8.21 g, 35.8 mmol), TEA (153 mL, 1.09 mol), ACN (2400 mL) and MeOH (2000 mL). The autoclave was sealed, purged, and pressurized with CO to 1000 kPa. The mixture was heated at 85 °C and stirred for 16 h. The reaction mixture from another 25 g scale was combined to this batch for work-up. The reaction was cooled to room temperature, then the reaction was filtered via suction filter and washed the filter cake with MeOH (200 mL). The filtrate was concentrated under reduced pressure at 40 °C. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in petroleum ether to give the title compound (65 g) as a solid. ESMS m / z. 181 (M+H).Preparation of Intermediate 61: Methyl 5-bromo-4,6-dimethylpicolinate

[0174] To a vigorous stirring ACN (1200 mL) solution of methyl 5-amino-4,6- dimethylpicolinate (65.0 g, 353 mmol) in a 3000 mL three-neck round bottom flask was dropwise added tert-butyl nitrite (121 mL. 993.1 mmol) at 0 °C over 20 min. Cuprous bromide (143.4 g, 994.7 mmol) was added to the reaction mixture in 40 portions at 0 °C under nitrogen. The reaction mixture was degassed and filled back with nitrogen for three times and allowed to stir vigorously at 25 °C for 16 h under nitrogen. To the reaction mixture was added DCM (1000 mL), then filtered to give the filtrate I and the filter cake I.

[0175] To filter cake I was added DCM:MeOH (1000 mL, 5:1), stirred 5 h at RT, then was filtered to give filtrate II and filter cake II.Filtrate I and filtrate II were concentrated to give product I, which was purified by silica gel chromatography using a gradient of 0 to 33% EtOAc in petroleum ether to give a first crop of the title compound (14 g).

[0176] To filter cake II was added DCM:MeOH (1000 mL, 5:1), stirred 15 h at room temperature, then was filtered to give filtrate III and filter cake HI . Filtrate HI was concentrated to give product H , which was purified by silica gel chromatography using a gradient of 0 to 33% EtOAc in petroleum ether to give a second crop of the title compound (2.5 g).

[0177] To filter cake HI was added DCM:MeOH (1000 mL, 5:1) , stirred 15 h at room temperature, then was filtered to give filtrate IV and filter cake IV. Filtrate IV was concentrated to give product IH .Product HI was purified by silica gel chromatography using a gradient of 0 to 33% EtOAc in petroleum ether to give a third crop of the title compound (4.0 g). All three crops were combined, dissolved in DCM (100 mL) and concentrated under reduced pressure to give the title compound (20.4 g) as a solid. ES-MS m / z 244, 246 (M+H).Preparation of Intermediate 62: 5-Bromo-4,6-dimethylpicolinaldehyde

[0178] To a vigorous stirring THF (400 mL) solution of methyl 5-bromo-4,6-dimethylpicolinate (20.4 g, 77.7 mmol) was added dropwise diisobutylaluminum hydride (1 M solution in toluene, 118 mL, 118 mmol) over 10 min at -65 °C. The reaction vessel was de-gassed and backfilled with nitrogen for three times, then the mixture was stirred at -65 °C for 1 h under nitrogen. The reaction mixture was quenched by addition of aq. NH4CI (500 mL), and extracted with EtOAc (200 mL x 3). The organic layers were dried over Na^SCU, filtered and concentrated under reduced pressure to give the title compound (16.0 g) as a solid. ES-MS m / z 214,216 (M+H).Preparation of Intermediate 63: 2-(5-Bromo-4,6-dimethylpyridin-2-yl)-2-hydroxyacetonitrile (racemic mixture)|0179J To a vigorous stirring water (150 mL) solution of 5-bromo-4,6-dimethylpicolinaldehyde (14.0 g, 62.8 mmol) was added a solution of sodium hydrogen sulfite (17.65 g, 168.8 mmol) in water (37 mL) dropwise over 2 min at 0 °C under nitrogen. The mixture was stirred at 0 °C for one hour, then a solution of NaCN (8.710 g, 176.8 mmol) in water (37 mL) was added dropwise over 2 min at 0 °C. The resulting mixture was stirred at 25 °C for 15 h under nitrogen. The reaction mixture was filtered, and the solid was washed with water (300 mL x 3) to give the title compound (16.4 g) as a solid. ES-MS m / z 241,243 (M+H).Preparation of Intermediate 64: 2-(5-Bromo-4,6-dimethylpyridin-2-yl)-2-hydroxyacetamide (racemic mixture)

[0180] To a vigorously stirred 1,4-dioxane (40 mL) solution of 2-(5-bromo-4,6-dimethylpyridin- 2-yl)-2-hydroxyacetonitrile (racemic mixture, 16.4 g, 31.3 mmol) was added 4M HC1 in 1,4- dioxane (100 mL, 400 mmol) dropwise over 5 min at 0 °C. The mixture was stirred at 26 °C for 1 h. The reaction mixture was adjusted with 10% aq. Na2CCh to bring pH=7, then water (400 mL) and DCM (200 mL) were added and the mixture was stirred at 25 °C for 0.5 h. The title compound as a solid was isolated by filtration from the mixture (7.02 g). ES-MS m / z 259,261 (M+H).Preparation of Intermediate 65: 2-(4,6-Dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl)-2-hydroxyacetamide (racemic mixture)

[0181] A mixture of2-(5-bromo-4,6-dimethylpyridin-2-yl)-2-hydroxyacetamide (racemic mixture, 1.00 g, 3.76 mmol), bis(pinacolato)diboron (1.44 g, 5.50 mmol), K3PO4 (1.66 g, 7.78 mmol) and methanesulfonato(tricyclohexylphosphine)(2'-amino- 1 , r-biphenyL2-yl)palladium(II) (DCM adduct, 0.25 g, 0.38 mmol) in 1,4-dioxane was purged with nitrogen for 2 min and stirred vigorously at 80 °C for 16 h. The reaction mixture was poured into 10 mL water, and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with sat. aq. NaCl (10 mL), dried over Na2SC>4, then the Na2SO4 was filtered off and further washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase HPLC (column: WePure Biotech XP tC18 150 x 40, 7 pm; mobile phase: solvent A - 10 mM aq. NH4HCO3, solvent B - ACN; gradient: 20 to 50% solvent B in solvent A) to give the title compound (200 mg) as a solid. ES-MS m / z 307 (M+H).Preparation of Intermediate 66: 2-(Tetrahydrofuran-2-yl)-6-(trifluoromethyl)nicotinic acid (racemic mixture)

[0182] 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-(tert-butyl)-l,l,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-t-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-(5- trifluoromethyl-2-pyridinyl-kN)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 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 70% EtOAc in petroleum ether to give the title compound (14.4 g) as a solid. ES-MS m / z 262 (M+H).Preparation of Intermediate 67: / c / v-Butyl (2S,4R)-4-carbamoyl-2-methyl-4-(2-(tetrahydrofuran- 2-yl)-6-(trifhioromethyl)nicotinamido)piperidine-l-carboxylate

[0183] A mixture of 2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)nicotinic acid (racemic mixture, 10.0 g, 38.2 mmol), tert-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 Na?SO4. 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 68: rert-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)

[0184] A mixture of tert-butyl (2S.4R)-4-carbamoyl-2-methyl-4-(2-(tetrahydrofuran-2-yl)-6- (trifhioromethyl)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 residue was diluted with 100 mL water and extracted with EtOAc (lOOmL x 3). The combined organic layers were washed with water (100 mL * 2), dried over NaiSCM, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 35% EtOAc in petroleum ether to give the title compound (8.1 g) as a solid. ES-MS m / z 483.2 (M+H).Preparation of Intermediate 69: (5R,7S)-7-Methyl-2-(2-(tetrahydrofuran-2-yl)-6- (trifhioromethyl)pyridin-3-yl)- 1 ,3,8-triazaspiro[4.5]dec- l-en-4-one dihydrochloride (mixture of isomers)

[0185] A mixture of tert-butyl (5R,7S)-7-methyl-4-oxo-2-(2-((RS)-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 mL) 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 70: (5R,7S)-8-(5-Chloro-2-cyclopropoxypyridin-3-yl)-7-methyL2- (2-((tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)

[0186] To a solution of (5R,7S)-7-methyL2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one dihydrochloride (mixture of isomers, 1.02 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'-bis(dimethylamino)-l,T-biphenyl )(2'- methylamino-l,T-biphenyl-2-yl)palladium(II) (0.29 g, 0.25 mmol) at 25 °C. The mixture was purged with nitrogen for 2 min, then sodium 2-methylbutan-2-olate (2.5 M solution in THF, 1.53 mL, 3.84 mmol) was added to the mixture at 100 °C. The resulting mixture was stirred at 100 °C for 16 h under nitrogen. The reaction mixture was quenched by adding 20 mL sat. aq. citric acid, and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with sat. aq. NaCl (20 mL) and dried over Na2SC>4, then the NaiSCL was filtered off and further washed with EtOAc (10 mL). The obtained filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 80% EtOAc in petroleum ether to give the title compound (400 mg) as a solid. ES-MS m / z 550 (M+H).Preparation of Intermediate 71 : (3-Bromo-5-chloro-2-(methylsulfonyl)pyridine

[0187] A mixture of 3-bromo-5-chloro-2-(methylthio)pyridine (3.5 g, 11 mmol), H2O2 (6.60 g, 5.95 mL, 30 wt% in water, 58.2 mmol) and sodium tungstate dihydrate (CAS# 10213-10-2, 95 mg, 0.29 mmol) in EtOAc (35 mL) was purged with nitrogen for 2 min, then stirred vigorously at 20 °C for 24 h. The reaction mixture was quenched by adding 50 mL water, and then extracted with EtOAc (15 mL x 3). The combined organic layers were dried over Na SO4, filtered andconcentrated under reduced pressure to give the title compound (1.98 g) as a solid. ES-MS m / z 270,272 (M+H).Preparation of Intermediate 72: 3-Bromo-5-chloro-2-(2,2,2-trifluoroethoxy)pyridine

[0188] NaH in mineral oil (0.27 g, 60 wt% 6.8 mmol) was added portion wise over 5 min to a mixture of 3-bromo-5-chloro-2-(methylsulfonyl)pyridine (1.0 g, 81 wt%, 3.0 mmol) and 2,2,2- trifluoroethan-l-ol (0.38 g, 3.7 mmol) in NMP (10 mL) and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by adding 30 mL water, and then extracted with EtOAc (10 mL x 3). Then NaiSCh was filtered off and further washed with EtOAc (30 mL). The filtrate was concentrated under reduced pressure to give the title compound (600 mg) as an oil.1H NMR (400 MHz, DMSO-tfc) 5 8.38 (d, J=2.25 Hz, 1 H) 8.29 (d, J=2.25 Hz, 1 H) 5.04 (q, J=8.96 Hz, 2 H).Preparation of Intermediate 73: (5R,7S)-8-(5-Chloro-2-(2,2,2-trifluoroethoxy)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] (5R,7S)-7-Methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)- 1,3,8- triazaspiro[4.5]dec-l-en-4-one dihydrochloride (1000 mg, 2.117 mmol) was dissolved in 60 mL sat. Na2CCL aqueous solution, then was extracted with DCM (30 mL x 8). The combined organic layers were dried over NazSCU, then the NaiSCL was filtered off and further washed with DCM (100 mL). The obtained filtrate was concentrated under reduced pressure to give the free base 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 as an oil. A mixture of this material, 3-bromo-5-chloro-2-(2,2,2- trifluoroethoxy)pyridine (600 mg, 1.80 mmol), and sodium 2-methylbutan-2-olate (800 mg, 7.23mmol) in toluene (12 mL) was purged with nitrogen for 1 min then methanesulfonato(2-bis(3,5- di(trifhioromethyl)phenylphosphino)-3,6-dimethoxy-2',6'-bis(dimethylamino)-l,l'-biphenyl )(2'- methylamino-l,l'-biphenyl-2-yl)palladium(II) (210 mg, 181 pmol) was added. The mixture was stirred at 100 °C for 2 h, then water (30 mL) was added and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over NazSCL, then the NazSCU was filtered off and further washed with EtOAc (30 mL). The obtained filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 250 x 50mm, 10 pm; Mobile phase: solvent A - lOmM aq. NH4HCO3, solvent B - ACN; gradient: 50 to 90% solvent B in solvent A) to give the title compound (60 mg) as a solid. ES-MS m / z 592 (M+H).Preparation of Intermediate 74: (5R,7S)-7-Methyl-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-8-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2- trifluoroethoxy)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0190] A mixture of (5R,7S)-8-(5-chloro-2-(2,2,2-trifluoroethoxy)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, 60 mg, 92 pmol), bis(pinacolato)diboron (58 mg, 0.22 mmol) and potassium acetate (36 mg, 0.36 mmol) in methoxycyclopentane (1.6 mL) was purged with nitrogen for 30 seconds, then methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,l'-biphenyl)(2'- methylamino-l ,T-biphenyl-2-yl)palladium(II) (8 mg, 9 pmol) was added to the mixture, and the mixture was stirred at 80 °C for 2 h under nitrogen. After cooling to RT, the reaction mixture was filtered through a pad of diatomaceous earth under reduced pressure and rinsed with 10 mL EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100 x 30mm, 10 pm; mobile phase: solvent A - 10 mM aq. NH4HCO3; solvent B - ACN; gradient: 80 to 100% solvent B in solvent A) to give the title compound (30 mg) as a solid. ES-MS m / z 684 (M+H).Preparation of Intermediate 75: 3-Bromo-5-chloro-2-(methylthio)pyridine

[0191] To a vigorous stirring isopropanol (25 mL) solution of 3-bromo-5-chloro-2- fluoropyridine (5.0 g, 23 mmol) was added sodium methanethiolate in water (9.8 g, 20 wt%, 28 mmol) dropwise over 5 min at 0 °C. The mixture was stirred at 20 °C for 2 h, then quenched by adding 40 mL water, and then extracted with EtOAc (10 mL x 3). The combined organic layers were dried over NaiSO4, filtered and concentrated under reduced pressure to give the title compound (3.5 g) as a solid. ES-MS m / z 238,240 (M+H).Preparation of Intermediate 76: 3-Bromo-5-chloro-2-(oxetan-3-yloxy)pyridine

[0192] To a mixture of 3-bromo-5-chloro-2-(methylsulfonyl)pyridine (980 mg, 2.93 mmol) and oxetan-3-ol (260 mg, 3.44 mmol) in NMP was added NaH in mineral oil (258 mg, 60 wt%, 6.45 mmol) in portions over 5min. The reaction mixture was stirred vigorously at 25 °C for 2 h, then quenched by adding 30 mL water, and then extracted with EtOAc (10 mL x 3). The organics were dried over Na2SC>4, then the NazSCU was filtered off and further washed with EtOAc (30 mL). The filtrate was concentrated under reduced pressure to give the title compound (620 mg) as an oil. ES-MS m / z 264,266 (M+H).Preparation of Intermediate 77: (5R,7S)-8-(5-Chloro-2-(oxetan-3-yloxy)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

[0193] (5R,7S)-7-Methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)- 1,3,8- triazaspiro[4.5]dec-l-en-4-one dihydrochloride (1.26 g, 2.67 mmol) was dissolved in 60 mL sat. Na2CCh aqueous solution, then was extracted with DCM (30 mL x 8). The combined organic layers were dried over NaiSCU, then the Na2SC>4 was filtered off and further washed with DCM (100 mL). The obtained filtrate was concentrated under reduced pressure to give the free base 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. A mixture of this material, 3-bromo-5-chloro-2-(oxetan-3- yloxy)pyridine (620 mg, 2.23 mmol), and sodium 2-methylbutan-2-olate (990 mg, 8.94 mmol) in toluene (12 mL) was purged with nitrogen for 2 min, then methanesulfonato(2-bis(3,5- di(trifhioromethyl)phenylphosphino)-3,6-dimethoxy-2',6'-bis(dimethylamino)-l,l'-biphenyl )(2'- methylamino-l,l'-biphenyl-2-yl)palladium(II) (270 mg, 232 pmol) was added to the mixture. The reaction mixture was stirred at 100 °C for 2 h, then quenched by adding 30 mL water, and then extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SC>4, then the Na2SO4 was filtered off and further washed with EtOAc (10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 250 x 50mm, 10 pm; mobile phase: solvent A - 10 mM aq. NH4HCO3, solvent B - ACN; gradient: 40 to 80% solvent B in solvent A) to give the title compound (30 mg) as a solid. ES-MS m / z 566, 568 (M+H).Preparation of Intermediate 78: (5R,7S)-7-Methyl-8-(2-(oxetan-3-yloxy)-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridin-3-yl)-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] A mixture of methoxycyclopentane (1.6 mL), (5R,7S)-8-(5-chloro-2-(oxetan-3- yloxy)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 (30 mg, 50 pmol), bis(pinacolato)diboron (28 mg, 0.11 mmol) and potassium acetate (16 mg, 0.16 mmol) was purged with nitrogen for 30 seconds, thenmethanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,l'-biphenyl)(2'-methylamino- l,l'-biphenyl-2-yl)palladium(II) (6 mg, 7 pmol) was added and the reaction mixture was stirred at 80 °C for 2 h under nitrogen. The reaction mixture was left at RT overnight, then filtered through a pad of diatomaceous earth under reduced pressure and rinsed with 10 mL EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 250 x 50mm, 10 pm; mobile phase: solvent A - 10 mM aq. NH4HCO3, solvent B - ACN; gradient: 40 to 85% solvent B in solvent A), to give the title compound (44 mg) as a solid. ES-MS m / z 576 (M+H).Preparation of Intermediate 79: (5R,7S)-8-(5-Chloro-2-methylpyridin-3-yl)-7-methyl-2-(2- (trifluoromethyl)pyridin-3-yl)-L3.8-triazaspiro[4.5]dec-l-en-4-one

[0195] A mixture of 1,4-dioxane (100 mL), (5R,7S)-7-methyl-2-(2-(trifluoromethyl)pyridin-3- yl)-l,3,8-triazaspiro[4.5Jdec-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 NaiSO4 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 petroleum ether to give the title compound (0.920 g) as a solid. ES-MS m / z 438 (M+H).Preparation of Intermediate 80: (5R,7S)-2,2,7-Trimethyl-l,3,8-triazaspiro[4.5]decan-4-one dihydrochloride

[0196] To a mixture of tert-butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-l- carboxylate (60.0 g, 233 mmol) in EtOH (1000 mL) was added 2,2-dimethoxypropane (74.4 g, 700 mmol) and toluenesulfonic acid (9.06 g, 46.7 mmol). The reaction mixture was stirred at 80 °C. After 16 h, the reaction mixture was cooled to RT and HC1 (4 M in 1,4-dioxane, 176 mL, 704 mmol) was added. The reaction mixture was stirred at 20 °C. After 16 h, the mixture was concentrated under reduced pressure. After —2 / 3 of the liquid was removed from the flask a white solid precipitate formed in the solution. 1000 mL of EtOAc was added and 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).

[0197] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 22. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 83: (5R,7S)-8-(5-Bromo-2-methoxypyridin-3-yl)-2,2,7-trimethyl- l,3,8-triazaspiro[4.5]decan-4-one

[0198] To a mixture of (5R,7S)-8-(5-bromo-2-(methylsulfonyl)pyridin-3-yl)-2,2,7-trimethyl- l,3,8-triazaspiro[4.5]decan-4-one (63 wt%; 84 g, 120 mmol) in MeOH (92.4 mL) and NMP (630 mL) was added sodium methoxide (34 g, 623 mmol). The reaction mixture was stirred vigorously at 45 °C for 2 h and cooled to RT. The mixture was poured into water (2.0 L) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with sat. aq. NaCl (100 mL), dried over Na SCL, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in petroleum ether, to give the title compound (80 wt%; 56 g) as a solid. ES-MS m / z 383,385 (M+H).Preparation of Intermediate 84: (5R,7S)-8-(5-Bromo-2-ethoxypyridin-3-yl)-2,2,7-trimethyl- l,3,8-triazaspiro[4.5]decan-4-one

[0199] To a mixture of (5R,7S)-8-(5-bromo-2-(methylsulfonyl)pyridin-3-yl)-2,2,7-trimethyl- l,3,8-triazaspiro[4.5]decan-4-one (86 wt%; 33 g, 66 mmol) in NMP (300 mL) was added sodium ethoxide (20 wt% in EtOH; 74 g, 220 mmol). The reaction mixture was stirred vigorously at 50 °C for 2 h and cooled to RT. The mixture was poured into water (500 mL) and extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with sat. aq. NaCl (2 x 400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-45% EtOAc in hexanes, to give the title compound (20 g) as a solid. ES-MS m / z 397,399 (M+H).Preparation of Intermediate 85: (2S,4R)-4-Amino-l-(5-bromo-3-hydroxy-2-nitrophenyl)-2- methylpiperidine-4-carboxamide hydrochloride

[0200] HC1 (IM aqueous; 4.11 mL, 4.11 mmol) was added to a mixture of (5R,7S)-8-(5-bromo- 3-hydroxy-2-nitrophenyl)-2,2,7-trimethyl-l,3,8-triazaspiro[4.5]decan-4-one (1.70 g, 4.11 mmol) in MeOH (20.6 mL) and water (20.6 mL). The reaction mixture was stirred at 80 °C. After 16 h, another 1 mL of IM aq. HC1 was added, and the reaction mixture was stirred at 100 °C. After 16 h, the reaction mixture was concentrated under reduced pressure to remove the MeOH and the resulting aqueous mixture was purified by reverse phase purification, eluting with 5-100% acetonitrile in (0.1M aqueous ammonium bicarbonate), to obtain the title compound (1.38 g) as a solid. ES-MS m / z 373 / 375 (M+H).

[0201] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 85. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 88: Methyl 2-cyclopropyl-6-(trifluoromethyl)nicotinate

[0202] 1,4-Dioxane (400 mL) and water (100 mL) were combined with methyl 2-chloro-6- (trifhioromethyl)nicotinate (25 g. 103 mmol), cyclopropaneboronic acid (12.1 g, 137 mmol) andK2CO3 (43.5 g, 313 mmol). The reaction mixture was de-gassed and backfilled with N2 for 3 times before and after adding chloro(crotyl)(tri-fert-butylphosphine)palladium(II) (CAS# 1334497-00-5. 4.4 g, 10.4 mmol). The reaction mixture was stirred at 90 °C for 3 h, cooled to RT, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography, eluting with 0-50% EtOAc in hexanes, to give the title compound (13.5 g) as oil. ES-MS m / z 246 (M+H).Preparation of Intermediate 89: 2-Cyclopropyl-6-(trifluoromethyl)nicotinic acid

[0203] MeOH (75 mL) was combined with methyl 2-cyclopropyl-6-(trifluoromethyl)nicotinate (13.5 g, 51.8 mmol) and NaOH (1.0 M in H2O, 75 mL, 75 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 12 h, concentrated under reduced pressure, and adjusted to pH = 3~4 with HC1 (1.0 M in H2O, 72 mL) while stirring. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (10.1 g) as solid. ES-MS m / z 232 (M+H).Preparation of Intermediate 90: 2-Cyclopropyl-6-(trifluoromethyl)nicotinoyl chloride

[0204] To a solution of 2-cyclopropyl-6-(trifhroromethyl)nicotinic acid (9.5 g, 40 mmol) in DCM (95 mL) and DME (0.1 mL) was added oxalyl chloride (16 g, 124 mmol) dropwise over 5 mins at 0 °C. The reaction mixture was stirred at 17 °C for 1 h, then concentrated under reduced pressure to give the title compound (10 g, 87.4 wt% purity) as oil. A sample was quenched by MeOH, and the MeOH solution was used for LCMS detection. ES-MS m / z 246 (M+H, methyl ester).Preparation of Intermediate 91: 6-Ethoxy-2-(trifluoromethyl)nicotinic acid

[0205] Sodium ethoxide (20% in EtOH; 30 mL, 77 mmol) was added to a solution of 6-chloro-2- (trifluoromethyl)nicotinic acid (6.32 g, 28.0 mmol) in EtOH (20 mL, 0.34 mol) at RT. The reaction mixture was heated under nitrogen at 80 °C overnight. The mixture was concentrated under reduced pressure. The solid was dissolved in water (100 mL) and extracted with diethyl ether (100 mL). The layers were separated. The aqueous layer was adjusted to pH ~l-2 with concentrated aqueous HC1 and extracted with EtOAc (2 x 150 mL). The combined organic layers were extracted with sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (6.43 g, 98%) as a brown solid. ES-MS m / z 235 (M+H).Preparation of Intermediate 92: Methyl 2-cyclobutyl-6-(trifluoromethyl)nicotinate

[0206] To a mixture of 4-amino-l,l,l-trifluorobut-3-en-2-one (20 g, 136 mmol) and toluene (200 mL) was added methyl 3-cyclobutyl-3-oxopropanoate (27 g, 169 mmol) and TFA (23 g. 197 mmol) at 20 °C. The reaction mixture was stirred vigorously at 110 °C for 16 h, cooled to RT, and concentrated under reduced pressure. The residue was diluted with EtOAc (200 mL) and aqueous Na^COi (15 wt%, 200 mL). The mixture was stirred at 20 °C for 1 h and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with sat. aq. NaCl (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 10-25% EtOAc in hexanes, to give the title compound (12 g) as an oil. ES-MS m / z 260 (M+H).Preparation of Intermediate 93: 2-Cyclobutyl-6-(trifluoromethyl)nicotinic acid

[0207] To a mixture of methyl 2-cyclobutyl-6-(trifluoromethyl) nicotinate (12 g, 44 mmol) in MeOH (30 mL), water (30 mL), and THF (30 mL) was added NaOH (3.9 g, 94 mmol). The reaction mixture was stirred at 20 °C for 1 h, then concentrated under reduced pressure. The residue was dissolved in water (150 mL), then aqueous HC1 (2.0 M; 100 mL) was added to adjust the pH to ~5. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with sat. aq. NaCl (100 mL), dried over NaiSC , filtered, and concentrated under reduced pressure to give the title compound (10.0 g) as oil. ES-MS m / z 246 (M+H).Preparation of Intermediate 94: 4-Bromo-2,2-difluorobenzo[d][l,3]dioxole-5-carboxylic acid

[0208] To a mixture of 2,2-difluorobenzo[d][l,3]dioxole-5-carboxylic acid (250 g, 1224 mmol) in THF (3 L) was added n-butyllithium (2.5 M in THF; 1.2 L, 3000 mmol) dropwise over 0.5 h at -70 °C. The reaction mixture was stirred at -70 °C for 10 min, warmed to 0 °C, and stirred at 0 °C for 1 h. NBS (660 g, 3671 mmol) was added at -70 °C. The reaction mixture was stirred at - 70 °C for 2 h, then warmed to RT and poured into water (800 mL). The pH was adjusted to ~2 with aqueous HC1 (2M) and the mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with sat. aq. NaCl (2 x 500 mL), dried over NaiSOzi, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 35-65% EtOAc in hexanes, to give the title compound (151 g) as a solid. ES-MS m / z 279,281 (M-H).Preparation of Intermediate 95: Methyl 4-bromo-2,2-difluorobenzo[d][L3]dioxole-5-carboxylate

[0209] To a mixture of 4-bromo-2,2-difluorobenzo[d][1.3]dioxole-5-carboxylic acid (151 g, 525 mmol) in toluene (2.27 L) and MeOH (760 mL) was added (trimethylsilyl)diazomethane (2.0 M in n-hexane, 1 L, 2000 mmol) dropwise over 1 h at 0 °C. The reaction mixture was stirred at 18 °C for 16 h, then quenched by adding AcOH (100 mL) at 5 °C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 10- 65% EtOAc in hexanes, to give the title compound (101 g) as a solid.TH NMR (400 MHz, DMSO-r / 6) 37.67 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 3.75 (s, 3H).Preparation of Intermediate 96: Methyl 2-cyclopropyl-4-(trifluoromethyl)benzoate

[0210] To a mixture of methyl 2-bromo-4-(trifluoromethyl)benzoate (25 g, 87 mmol) in toluene (200 mL) and water (20 mL), was added cyclopropaneboronic acid (13 g, 148 mmol), tricyclohexylphosphine (5 g, 17 mmol), K3PO4 (60 g, 279 mmol) and palladium(II) acetate (3.0 g, 13 mmol). The reaction mixture was cycled through vacuum / nitrogen (x3), then stirred at 90 °C for 3 h. The mixture was cooled to 25 °C, poured into water (150 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with sat. aq. NaCl (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 30-50% EtOAc in hexanes, to give the title compound (20 g) as a solid. ES-MS m / z 245 (M+H).

[0211] The compound in the below table was prepared in similar manner as described in the preparation of Intermediate 96. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 98: 2-Cyclopropyl-4-(trifluoromethyl)benzoic acid

[0212] To a mixture of methyl 2-cyclopropyl-4-(trifluoromethyl)benzoate (83 wt%; 20 g, 68 mmol) in MeOH (100 mL) and water (50 mL) was added LiOH monohydrate (6.0 g, 135 mmol). The reaction mixture was stirred at 25 °C for 3 h, then concentrated under reduced pressure. The residue was diluted with water (100 mL), then aqueous HC1 (1.0 M; 120 mL) was added to adjust the pH to ~5. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with sat. aq. NaCl (50 mL), dried over NaiSCU, filtered, and concentrated under reduced pressure to give the title compound (16 g) as a solid. ES-MS m / z 229 (M-H).

[0213] The compound in the below table was prepared in similar manner as described in the preparation of Intermediate 98. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 100: 2-(l-Fluorocyclobutyl)-6-(trifluoromethyl)nicotinic acid

[0214] To a solution of 2-chloro-6-(trifhioromethyl)nicotinic acid (12.0 g, 52.1 mmol) and 1- fluorocyclobutane- 1 -carboxylic acid (7.0 g, 57 mmol) in DMF (240 mL) was added 2-(tert- butyl)-l,l,3,3-tetramethylguanidine (19.5 g, 113 mmol) and phthalimide (12.2 g, 82.1 mmol). The reaction mixture was cycled through vacuum / nitrogen (x3), then (4,4'-di-t-butyl-2,2'- bipyridine)bis[3,5-difluoro-2-(5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (0.50 g, 0.44 mmol) and [4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine] nickel (II) dichloride (1.1 g, 2.7 mmol) were added. The reaction mixture was stirred at 55 °C for 12 h under irradiation with a 395 nm (200 W) LED module in a photoreactor, then cooled to RT and poured into water (100 mL). The mixture was extracted with EtOAc (6 x 100 mL). The combined organic layers were washed with sat. aq. NaCl (100 mL), dried over Na2SO4. filtered, and concentrated under reduced pressure. The residue was purified by reverse phase purification, eluting with 25-65% acetonitrile in (water with 0.2% formic acid), to obtain the title compound (7.0 g) as a solid. ES-MS m / z 264 (M+H).Preparation of Intermediate 101: Methyl 3-(l-fluorocyclopropyl)-3-oxopropanoate

[0215] To a mixture of MgCh (544 g, 5657 mmol) in EtOAc (2.5 L) was added potassium 3- methoxy-3-oxopropanoate (495 g, 3109 mmol) and TEA (972 g, 9413 mmol). The reaction mixture was stirred at 40 °C for 12 h. To a separate mixture of 1-fluorocyclopropane-l- carboxylic acid (200 g, 1883 mmol) in THF (1.0 L) was added oxalyl chloride (244 g, 1884 mmol) and DMF (1.3 g, 18 mmol) under nitrogen at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The first reaction mixture was cooled to 0 °C and transferred into the second reaction mixture dropwise at 20 °C over 10 min. The reaction mixture was stirred vigorously at 20 °C for 12 h, then poured into water (2.0 L). Aqueous HC1 (1.0 M) was added to adjust the pH to ~6-7.The mixture was extracted with MTBE (3 x 1 L). The combined organic layers were washed with sat. aq. NaCl (3 x 1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (280 g) as an oil. ES-MS m / z 161 (M+H).Preparation of Intermediate 102: Methyl 2-(l-fhiorocyclopropyl)-6-(trifluoromethyl)nicotinate

[0216] To a mixture of methyl 3-(l-fluorocyclopropyl)-3-oxopropanoate (280 g, 1613 mmol) and 4-ethoxy-l,l,l-trifluorobut-3-en-2-one (360 g, 2098 mmol) was added sodium ethoxide (20 wt% in EtOH, 885 mL, 2260 mmol) dropwise over 30 mins at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, then poured into aqueous HC1 (1.0 M; 1.5 L) and extracted with EtOAc (3 x 800 mL). The combined organic layers were dried over NazSCU, filtered, and concentrated under reduced pressure. The residue was diluted with AcOH (600 mL) and ammonium acetate (174 g, 2214 mmol) was added. The reaction mixture was stirred at 50 °C for 12 h, cooled to RT, and concentrated under reduced pressure. The residue was diluted with sat. aq. NaHCCh (1.0 L) at 0 °C and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with sat. aq. NaCl (2 x 500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-30% EtOAc in hexanes, to give the title compound (81 wt%; 150 g) as a solid. ES-MS m / z 264 (M+H).Preparation of Intermediate 103: 2-(l-Fluorocyclopropyl)-6-(trifluoromethyl)nicotinic acid

[0217] To a mixture of methyl 2-(Lfhiorocyclopropyl)-6-(trifluoromethyl)nicotinate (81 wt%; 48 g, 454 mmol) in MeOH (750 mL) was added aqueous NaOH (1.0 M; 750 mL, 750 mmol). The reaction mixture was stirred at 25 °C for 2 h, then concentrated under reduced pressure.Aqueous HC1 (1.0 M) was added to adjust the pH to ~2-3. The mixture was extracted with EtOAc (3 x 800 mL). The combined organic layers were washed with sat. aq. NaCl (2 x 1 L), dried over NazSOr, filtered, and concentrated under reduced pressure to give the title compound (110 g) as a solid. ES-MS m / z 250 (M+H).Preparation of Intermediate 104: 2-(3,6-Dihydro-2H-pyran-4-yl)-6-(trifluoromethyl)nicotinic acid

[0218] Pd(dppf)C12 (3.20 g. 4.29 mmol) was added under N2 to a 100 mL round bottom flask containing 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 added and the mixture was heated to 110 °C and stirred under N2 for 16 h. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with 0.1% AcOH in EtOAc, to give the title compound (5.50 g, 44%) as yellow solid. ES-MS m / z 274 (M+H).Preparation of Intermediate 105: 2-(Tetrahydro-2H-pyran-4-yl)-6-(trifIuoromethyl)nicotinic acid

[0219] 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 and then Pd / C (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 an atmosphere of hydrogen (15 psi). The reaction mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound (3.90 g) as a solid. ES-MS m / z 276 (M+H).Preparation of Intermediate 106: Methyl 2-(3,3-difluoroazetidin-l-yl)-6-(trifluoromethyl)nicotinate

[0220] Methyl 2-bromo-6-(trifluoromethyl)nicotinate (8.60 g, 30.0 mmol), 3,3-difluoroazetidine hydrochloride (7.90 g, 60.4 mmol), and potassium carbonate (21.00 g, 152.0 mmol) were added to a flask containing DMF (100 mL) at 20 °C. The reaction mixture was stirred vigorously at 80 °C for 3 hours. The reaction mixture was cooled to RT. The crude reaction mixture was filtered through a pad of diatomaceous earth under vacuum and was rinsed with 100 mL EtOAc. 100 mL water was added to the filtrate. The aqueous solution was extracted with 100 mL EtOAc twice. The combined organic layers were washed with 100 mL brine twice, dried over sodium sulfate, filtered and concentrated under reduced pressure. The material was purified by silica gel chromatography, eluting with 10% EtOAc in petroleum ether, to give the title compound (8.70 g.27.5 mmol) as white solid. ES-MS m / z 297 (M+H).Preparation of Intermediate 107: 2-(3.3-Difluoroazetidin-l-yl)-6-(trifluoromethyl)nicotinic acid

[0221] Lithium hydroxide monohydrate (4.00 g, 94.4 mmol) was used to prepare a solution in THF (50 mL) and water (30 mL). This solution was added to a flask containing methyl 2-(3,3- difluoroazetidin-l-yl)-6-(trifluoromethyl)nicotinate (8.70 g, 27.5 mmol) and MeOH (50 mL) at 20 °C. The reaction mixture was stirred at 20 °C for 16 hours. The crude reaction mixture was concentrated under reduced pressure to remove organic solvent. Added 2M HC1 aqueoussolution to adjust pH to 5. The aqueous solution was extracted with 100 mL EtOAc twice. The combined organic layers were washed with 100 mL brine twice, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (7.90 g, 26.7 mmol) as yellow solid. ES-MS m / z 283 (M+H).

[0222] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediates 4, 29, or 35, using the appropriate carboxylic acid or acid chloride. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:

[0223] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediates 30 or 36. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:

[0224] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediates 6 or 12. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:

[0225] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 22. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 174: 6-Chloro-3-ethoxy-4-iodopyridazine

[0226] n-Butyllithium (2.5 M in n-hexane, 27 mL, 67.5 mmol) was added to THF (150 mL) at - 35 °C. The mixture was cycled through vacuum / nitrogen (3x) and 2,2,6,6-tetramethylpiperidine (10 g, 70 mmol) was added dropwise at -35 °C. The mixture was warmed to 0 °C over 1 h, then cooled to -78 °C. and 3-chloro-6-ethoxy-pyridazine (5.0 g, 31 mmol) in THF (50 mL) was added dropwise at -78 °C over 30 min. Iodine (9.3 g, 36 mmol) was added in three portions. The reaction mixture was stirred at -78 °C for 2 h, then warmed to 15 °C. The mixture was poured into sat. aq. Na2S2Ch (150 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with sat. aq. NaCl (2 x 100 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase purification, eluting with 35-70% acetonitrile in (water with 0.2% formic acid), to obtain the title compound (1.1 g) as a solid. ES-MS m / z 285 (M+H).Preparation of Intermediate 175: (5R,7S)-8-(6-Chloro-3-ethoxypyridazin-4-yl)-2-(2-cyclopropyl- 6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0227] To a mixture of (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl- l,3,8-triazaspiro[4.5]dec-l-en-4-one (1.3 g, 3.5 mmol) in toluene (15 mL) was added 6-chloro-3- ethoxy-4-iodopyridazine (1.1 g, 3.5 mmol), sodium 2-methylbutan-2-olate (30 wt% in THF; 6.5 g, 18 mmol) and methanesulfonato(2-bis(3,5-di(trifluoromethyl)phenylphosphino)-3,6- dimethoxy-2',6'-bis(dimethylamino)-l,T-biphenyl )(2'-methylamino-l,l'-biphenyl-2- yl)palladium(II) (CAS# 1810068-35-9; 0.81 g, 0.70 mmol). The reaction mixture was purged with nitrogen for 2 min, stirred at 100 °C for 2 h, cooled to RT, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), then extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with sat. aq. NaCl (2 x 30 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase purification, eluting with 50-80% acetonitrile in (water with 0.2% formic acid), to obtain the title compound (0.41 g) as a solid. ES-MS m / z 509 (M+H).Preparation of Intermediate 176: (5R.7S)-8-(2-Amino-5-bromo-3-hydroxyphenyl)-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

[0228] EtOH (10 mL) was combined with (5R,7S)-8-(5-bromo-3-hydroxy-2-nitrophenyl)-7- methyl-2-(2-(tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)pyridin-3-yl)-L3,8- triazaspiro[4.5]dec-2-en-4-one (0.600 g, 0.980 mmol), iron (0.300 g, 5.37 mmol) and ammoniumchloride (0.300 g, 5.61 mmol) in water (2 mL) at 20 °C. The reaction mixture was stirred vigorously at 80 °C. After 1 h, the mixture was filtered, diluted with water (100 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with sat. aq. NaCl (2 x 30 mL), dried over anhydrous NaaSC , filtered, and concentrated under reduced pressure to give the title compound (0.571 g, 100%) ES-MS m / z 582 / 584 (M+H).

[0229] The compound in the below table was prepared in similar manner as described in the preparation of Intermediate 176. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 178: 6-Bromo-4-((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-en-8-yl)benzo[d]oxazol- 2(3H)-one

[0230] To a solution of (5R,7S)-8-(2-amino-5-bromo-3-hydroxyphenyl)-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(571 mg, 0.980 mmol) and CDI (320 mg, 1.97 mmol) in MeCN (5.00 mL) was added DIPEA(371 mg, 0.500 mL, 2.87 mmol). The reaction mixture was stirred at 100 °C overnight, then cooled to RT. The reaction mixture was diluted with 50 mL of water and 50 mL of EtOAc. The layers were separated and the aqueous layer was extracted with 2x 30 mL of EtOAc. The combined organic layers were dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-20% MeOH in DCM, to give the title compound (301 mg, 51%). ES-MS m / z 608 / 610 (M+H).Preparation of Intermediate 179: (5R,7S)-8-(5-Bromo-lH-indazol-7-yl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0231] To a mixture of fluoboric acid (40 wt% in water; 100 mL, 623 mmol) and (5R,7S)-8-(2- amino-5-bromo-3-methylphenyl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl- l,3,8-triazaspiro[4.5]dec-l-en-4-one (3.0 g, 5.29 mmol) was added a solution of NaNCL (1.50 g, 21.3 mmol) in water (10 mL) dropwise over 30 seconds at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then filtered. The filter cake was washed with n-hexane (20 mL). To a mixture of the filter cake and chloroform (80 mL) was added potassium acetate (3.18 g, 31.8 mmol) and 18- crown-6 (0.280 g, 1.04 mmol). The reaction mixture was stirred at 22 °C for 1 h, then poured into water (50 mL) at 15 °C. The mixture was extracted with DCM (2 x 200 mL). The combined organic layers were washed with sat. aq. NaCl (50 mL), dried over anhydrous NaiSCU, filtered, and concentrated under reduced pressure to give the title compound (2.8 g) as a solid. ES-MS m / z 547,549 (M+H).Preparation of Intermediate 180: (5R,7S)-8-(5-Bromo-1H-indazol-7-yl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-3-(4-methoxybenzyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4- one

[0232] To a mixture of (5R,7S)-8-(5-bromo-lH-indazoL7-yl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3.8-triazaspiro[4.5]dec-l-en-4-one (2.80 g, 87.6 wt% purity, 4.48 mmol) in DMF (30 mL) was added K2CO3 (2.10 g, 15.0 mmol) and 1- (chloromethyl)-4-methoxybenzene (0.950 g, 6.01 mmol) at 15 °C. The reaction mixture was stirred at 30 °C for 12 h, then poured into water (100 mL) at 15 °C. The mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with sat. aq. NaCl (2 x 50 mL), dried over anhydrous NazSCL, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in n-hexane, to give the title compound (0.66 g) as a solid. ES-MS m / z 667,669 (M+H).Preparation of Intermediate 181: (5R,7S)-8-(5-Bromo-l-methyl-lH-indazol-7-yl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-3-(4-methoxybenzyl)-7-methyl-l,3,8- triazaspiro[4.5]dec-l-en-4-one

[0233] To a mixture of (5R,7S)-8-(5-bromo-lH-indazol-7-yl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-3-(4-methoxybenzyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4- one (0.66 g, 0.927 mmol) in THF (3 mL) was added potassium / e / v-butoxide (0.20 g, 1.76 mmol)and iodomethane (0.219 g, 1.53 mmol) at 15 °C. The reaction mixture was stirred at 30 °C for 2 h, then poured into water (10 mL) at 15 °C. The mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with sat. aq. NaCl (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in n-hexane, to give the title compound (0.25 g) as a solid. ES-MS m / z 681,683 (M+H).Preparation of Intermediate 182: (5R,7S)-8-(5-Bromo-l-methyl-lH-indazol-7-yl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0234] A mixture of (5R,7S)-8-(5-bromo-l-methyl-lH-indazol-7-yl)-2-(2-cyclopropyl-6-(tri fluoromethyl )pyridin-3-yl)-3-(4-methoxybenzyl)-7-methyl-1 ,3,8-triazaspiro[4.5]dec-l -en-4- one (0.250 g, 0.332 mmol) and TFA (12 mL) was stirred at 80 °C for 24 h, then cooled to RT and concentrated under reduced pressure. The residue was diluted with sat. aq. NaHCO? to adjust the pH to ~7. The mixture was extracted with DCM (2 x 20 mL). The combined organic layers were washed with sat. aq. NaCl (20 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to give the title compound (0.20 g) as a solid. ES-MS m / z 561,563 (M+H).Preparation of Intermediate 183: 4,6-Dibromo-l,3-dihydroisobenzofuran-5-ol

[0235] To a mixture of AcOH (200 mL) and l,3-dihydroisobenzofuran-5-ol (20 g, 66 wt% purity, 97 mmol) was added NBS (35 g, 190 mmol) in batches at 20 °C. The reaction mixture was stirred at 80 °C for 12 h, cooled to RT, and concentrated under reduced pressure. Theresidue was diluted with petroleum ether / DCM / EtOAc (6:4:1, 100 mL) under stirring, then filtered. The solids were dried in a vacuum oven to give the title compound (20 g) as solid. ESMS m / z 293 (M-H).Preparation of Intermediate 184: 6-Bromo-4-(trimethylsilyl)-l,3-dihydroisobenzofuran-5-ol

[0236] To a mixture of THF (150 mL) and 4,6-dibromo- l ,3-dihydroisobenzofuran-5-ol (15 g, 47 mmol) was added bis(trimethylsilyl)amine (25 g, 150 mmol) dropwise at 20 °C. The reaction mixture was cycled through vacuum / nitrogen (3x), then stirred at 80 °C for 16 h. The mixture was cooled to RT and concentrated under reduced pressure. THF (150 mL) was added to the residue, then n-butyllithium (2.5 M in n-hexane, 40 mL, 100 mmol) was added dropwise at -70 °C. The reaction mixture was cycled through vacuum / nitrogen (3x), stirred at -70 °C for 2 h, and quenched by adding sat. aq. NH4CI (500 mL) at -70 °C. The mixture was diluted with EtOAc (500 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase purification, eluting with 60-90% acetonitrile in (water with 0.2% formic acid), to obtain the title compound (4.0 g, 70 wt% purity) as solid. ES-MS m / z 285 / 287 (M-H).Preparation of Intermediate 185: 6-Bromo-4-(trimethylsilyl)-L3-dihydroisobenzofuran-5-yl trifluoromethanesulfonate

[0237] To a solution of 6-bromo-4-(trimethylsilyl)-1.3-dihydroisobenzofuran-5-ol (4.0 g, 70 wt% purity, 9.7 mmol) in acetonitrile (40 mL) was added K2CO3 (5.0 g, 34 mmol) at 25 °C, followed by the addition of phenyl triflimide (5.0 g, 13 mmol) in batches over 5 mins at 25 °C. The reaction mixture was stirred at 80 °C for 12 h, cooled to RT, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography, eluting with 0-80% EtOAc in hexanes, then further purified by reverse phase purification, eluting with 60-90% acetonitrile in (water with 0.2% formic acid), to obtain the title compound (2.0 g) as solid. ESMS m / z 420 (M+H).Preparation of Intermediate 186: 5-Chloro-6-(methoxymethoxy)benzo[d][l,3]dioxole

[0238] NaH (7.02 g, 60% Wt, 176 mmol) was slowly added over 20 min at 0 °C to a solution of 6-chlorobenzo[d][l,3]dioxol-5-ol (26.5 g, 150 mmol) in THF (400 mL). The reaction mixture was stirred at 0 °C for 30 min, then bromomethyl methyl ether (21.0 g, 13.7 mL, 160 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched by adding 1000 mL aqueous ammonia chloride solution at 25 °C, and then extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with 1000 mL brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-10% EtOAc in petroleum ether, to give the title compound (19.8 g, 81%) as a colorless liquid. ES-MS m / z 217 / 219 (M+H).Preparation of Intermediate 187: (6-Chloro-5-(methoxymethoxy)benzo[d][l,3]dioxol-4- yl)trimethylsilane

[0239] THF (100 mL) and 5-chloro-6-(methoxymethoxy)benzo[d][l,3]dioxole (19.8 g, 74.0 mmol) were combined at -78 °C. n-Butyllithium (2.5M in THF; 32.5 mL, 81.3 mmol) was added slowly to the reaction mixture under N2. The reaction mixture was stirred at-78 °C for 30 min under N2. TMS-C1 (9.76 g, 11.4 mL, 88.0 mmol) was added and the reaction mixture was stirred at -78 °C for 2 hours under N2. The reaction mixture was quenched by adding 100 mL aqueous NH4CI at -78 °C, then diluted with 200 mL water and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with 100 mL brine, dried over MgSO4, filtered andconcentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-10% EtOAc in petroleum ether, to give the title compound (14.7 g, 86%) as a colorless oil. ES-MS m / z 289 / 291 (M+H).Preparation of Intermediate 188: 6-Chloro-4-(trimethylsilyl)benzo[d][l,3]dioxol-5-yl trifluoromethanesulfonate

[0240] DCM (150 mb) was combined with (6-chloro-5-(methoxymethoxy)benzo[d][l,3]dioxol- 4-yl)trimethylsilane (14.7 g, 43.8 mmol), sodium iodide (7.28 g. 99% Wt, 48.1 mmol) and TMS- C1 (5.3 g, 48 mmol) at 0 °C. The reaction mixture was cycled through vacuum / nitrogen (3x), then cooled to 0 °C and stirred for 1 hour under N2. The reaction mixture was passed through a small pad of silica gel, eluting with petroleum ether. The eluent was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-10% EtOAc in petroleum ether, to give the title compound (5.8 g, 17 mmol) as a red oil. ES-MS m / z 245 / 247 (M+H).

[0241] The compound in the below table was prepared in similar manner as described in the preparation of Intermediate 185. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 190: (5R,7S)-8-(6-Bromo-l,3-dihydroisobenzofuran-4-yl)-7-methyl- 2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0242] A solution of 6-bromo-4-(trimethylsilyl)-l,3-dihydroisobenzofuran-5-yl trifluoromethanesulfonate (550 mg, 1.14 mmol) in acetonitrile (5 m ) was added to a mixture of (5R,7S)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.500 g, 0.929 mmol) in THF (5 mL). CsF (0.800 g, 5.00 mmol) was added in one portion at 30 °C under N2 and the reaction mixture was stirred at 30 °C. After 12 h, the mixture was filtered and concentrated under reduced pressure. The residue was purified by reverse phase purification, eluting with 25-65% acetonitrile in (water with 0.2% formic acid), to obtain the title compound (0.045 g, 9%) as white solid. ES-MS m / z 509 / 511 (M+H).

[0243] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 190. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 193: 3,5-Dimethyl-4-((trimethylsilyl)ethynyl)pyridine

[0244] To a mixture of 4-bromo-3,5-dimethylpyridine (10.0 g, 52.7 mmol) and ethynyltrimethylsilane (7.91 g, 78.9 mmol) in DMF (100 mL) was added Cui (0.62 g, 3.2 mmol). TEA (22 mL, 0.15 mol) and bis-(triphenylphosphino)-palladous chloride (3.78 g, 5.28 mmol) under nitrogen. The reaction mixture was cycled through vacuum / nitrogen (3x), then stirred at 100 °C for 3 h. The mixture was filtered through diatomaceous earth and the filtrate was diluted with water (200 mL). The mixture was extracted with EtOAc (4 x 100 mL). The combined organic layers were washed with sat. aq. NaCl (150 mL), dried over NazSCU. filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 25-45% EtOAc in petroleum ether, to give the title compound (2.3 g, 20%) as a brown solid. ES-MS m / z 204 (M+H).Preparation of Intermediate 194: 4-Ethynyl-3,5-dimethylpyridine

[0245] To a mixture of 3,5-dimethyl-4-((trimethylsilyl)ethynyl)pyridine (0.300 g, 1.39 mmol) in MeOH (3 mL) was added potassium carbonate (0.310 g, 2.22 mmol). The reaction mixture was cycled through vacuum / nitrogen (3x), then stirred at 25 °C for 2 h under nitrogen. The mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to give the title compound (0.20 g) as a brown solid. ES-MS m / z 132 (M+H).Preparation of Intermediate 195: 8-(6-Bromo-3-(cyclopropyl(hydroxy)methyl)pyridin-2-yl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0246] To a -78 °C mixture of 6-bromo-2-(2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-4- oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)nicotinaldehyde (0.305 g, 0.58 mmol) in THF (7 mL) was added cyclopropylmagnesium bromide (0.5M in THF: 5.84 mL, 2.92 mmol), maintaining the temperature below -58 °C. The reaction mixture was stirred at -78 °C for 1 h, then quenched with sat. aq. ammonium chloride (20 mL). The mixture was diluted with EtOAC (50 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with sat. aq. NaCl (100 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure to give the title compound (0.34 g). ES-MS m / z 566 (M+H).

[0247] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 195. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 200: 8-(6-Bromo-3-(cyclopropyhnethyl)pyridin-2-yl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1.3.8-triazaspiro[4.5]dec-l-en-4-one

[0248] TFA (10 mL, 130 mmol) was added to a solution of 8-(6-bromo-3-(cyclopropyl(hydroxy)methyl)pyridin-2-yl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)- l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.43g, 0.57 mmol) and triethylsilane (5 mL, 0.30 mmol) and stirred at 40 °C for 18 h. The reaction mixture was cooled to RT and quenched with aqueouspotassium carbonate (2.0 M) to adjust the pH to ~8. The mixture was diluted with EtOAC (40 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with sat. aq. NaCl (20 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 20-40% EtOAc in n-heptane, to give the title compound (0.15 g). ES-MS m / z 550 (M+H).

[0249] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 200. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 205: 8-(5-Bromo-2-(hydroxymethyl)pyridin-3-yl)-2-(2-cyclopropyl- 6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0250] To a -60 °C mixture of methyl 5-bromo-3-(2-(2-cyclopropyl-6-(trifluoromethyl)pyridin- 3-yl)-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)picolinate (3.8 g, 6.3 mmol) in THF (40 mL) was added diisobutylaluminum hydride (IM in toluene; 25 mL, 25 mmol) dropwise over 10 min. The reaction mixture was stirred at 24 °C for 2 h, then quenched with aqueous HC1 (1.0 M; 10 mL) at 0 °C and diluted with water (100 mL). The mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with sat. aq. NaCl (50 mL), dried over NaiSCL, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-20% EtOAc in n-hexanes, to give the title compound (2.3 g). ES-MS m / z 524,526 (M+H).

[0251] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 205. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 214: 8-(5-Bromo-2-(chloromethyl)pyridin-3-yl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0252] To a mixture of 8-(5-bromo-2-(hydroxymethyl)pyridin-3-yl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-l ,3,8-triazaspiro[4.5]dec-l -en-4-one (2.3 g, 4.3 mmol) in DCM (30 mL) and DMF (0.5 mL) was added thionyl chloride (2.1 g, 17 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, diluted with DCM (20 mL), and quenched with sat. aq. NaHCCh (50 mL). The mixture was extracted with DCM (3 x 20 mL). The combined organiclayers were washed with sat. aq. NaCl (20 mL), dried over NaaSC , filtered, and concentrated under reduced pressure to give the title compound (2.0 g) as a solid. A sample quenched with MeOH showed ES-MS m / z 538,540 (M+H, methyl ether).

[0253] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 214. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 222: 8-(5-Bromo-2-(cyclopropoxymethyl)pyridin-3-yl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-l,3.8-triazaspiro[4.5]dec-l-en-4-one

[0254] To a mixture of 8-(5-bromo-2-(chloromethyl)pyridin-3-yl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (2.4 g, 4.2 mmol) in cyclopropanol (20 mL) was added KOH (85 wt%; 0.5 g, 8 mmol) in portions over 5 mins at 24 °C. The reaction mixture was stirred at 24 °C for 2 h, then diluted with water (100 mL). The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with sat. aq. NaCl (50 mL), dried over NaaSOzi, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-40% EtOAc in petroleum ether, to give the title compound (0.70 g) as a solid. ES-MS m / z 564,566 (M+H).

[0255] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 222. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 231: Ethyl 2-(6-bromo-2-((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)acetate

[0256] To a mixture of 6-bromo-2-((5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-4-oxo-l,3,8-triazaspiro[4.5Jdec-l-en-8-yl)nicotinaldehyde (9.5 g, 17 mmol) in THF (120mL) was added methyl((methylsulfinyl)methyl)sulfane (3.5 g, 28 mmol) and NaOH (1.5 g, 37 mmol). The reaction mixture was purged with nitrogen for 1 min before being stirred at 70 °C for 6 h. The mixture was cooled to RT and diluted with water (300 mL) and EtOAc (100 mL). The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with sat. aq. NaCl (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was diluted with EtOH (15 mL) and aqueous HC1 (4M; 10 mL). The mixture was stirred at 80 °C for 1 h. The mixture was cooled to RT and diluted with water (200 mL) and EtOAc (100 mL). The mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with sat. aq. NaCl (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0- 50% EtOAc in n-hexane, to give the title compound (2.0 g) as a solid. ES-MS m / z 594,596 (M+H).

[0257] The compound in the below table was prepared in similar manner as described in the preparation of Intermediate 231. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 233: (5R,7S)-8-(6-Bromo-3-(2-hydroxy-2-methylpropyl)pyridin-2- yl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4- one

[0258] To a mixture of ethyl 2-(6-bromo-2-((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)acetate (2.0 g, 3.18 mmol) in THF (20 mL) was added methylmagnesium bromide (3.0 M in 2-MeTHF; 11 mL, 33 mmol) dropwise over 5 mins at -70 °C. The reaction mixture was stirred at 20 °C for 3 h, then diluted with water (100 mL). The mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with sat. aq. NaCl (150 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in n-hexane, to give the title compound (1.3 g) as a solid. ES-MS m / z 580,582 (M+H).

[0259] The compound in the below table was prepared in similar manner as described in the preparation of Intermediate 233. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 235: (5R,7S)-8-(6-Bromo-3-(2-fluoro-2-methylpropyl)pyridin-2-yl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0260] To a mixture of (5R,7S)-8-(6-bromo-3-(2-hydroxy-2-methylpropyl)pyridin-2-yl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (1.3 g, 76.2 wt% purity, 1.7 mmol) in toluene (15 mL) was added DAST (0.6 g, 4 mmol) dropwise over 3 mins at 0 °C. The reaction mixture was stirred at 18 °C for 2 h under nitrogen, then poured into sat. aq. NaHCCh (50 mL) and diluted with EtOAc (30 mL). The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with sat. aq. NaCl (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in n-hexane, to give the title compound (0.50 g) as a solid. ES-MS m / z 582,584 (M+H).

[0261] The compound in the below table was prepared in similar manner as described in the preparation of Intermediate 235. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 237: (5R,7S)-2-(2-Cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-8- (3-(cyclopropylmethyl)-6-(tributylstannyl)pyridin-2-yl)-7-methyl- 1,3, 8-triazaspiro[4.5]dec-l -end-one

[0262] To a mixture of (5R,7S)-8-(6-chloro-3-(cyclopropylmethyl)pyridin-2-yl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.260 g, 0.478 mmol) in 1,4-dioxane (5 mL) was added LiCl (0.105 g, 2.45 mmol), tricyclohexylphosphine (0.027 g, 0.095 mmol), 1,1.1, 2,2, 2-hexabutyldistannane (0.840 g, 1.43 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.035 g, 0.049 mmol). The reaction mixture was purged with nitrogen for 0.5 min before being stirred at 110 °C for 5 h. The mixture was cooled to RT and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (SiCh, 5:1 n-hexane:EtOAc, R / = 0.4, UV) to give the title compound (0.36 g). ES-MS m / z 774 (M+H).Preparation of Intermediate 238: 4-Chloro-6-((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 picolinaldehyde

[0263] To a mixture of (5R,7S)-8-(4-chloro-6-(hydroxymethyl)pyridin-2-yl)-2-(2-cyclopropyl-6-(trifhioromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (1.0 g, 2.0 mmol)in DCM (20 mL) was added Dess-Martin periodinane (1.35 g, 3.02 mmol) in portions at 0 °C.The reaction mixture was cycled through vacuum / nitrogen (3x). The reaction mixture was stirred at 25 °C for 2 h, then filtered. The filtrate was poured into water (30 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with sat. aq. NaCl (15 mL), dried over NazSCL. filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 30-55% EtOAc in n-hexane, to give the title compound (0.94 g). ES-MS m / z 492,494 (M+H).Preparation of Intermediate 239: 4-Chloro-6-((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)picolinaldehyde oxime

[0264] To a mixture of 4-chloro-6-((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)picolinaldehyde (89 wt%; 0.940 g, 1.70 mmol) in MeOH (10 mL) was added hydroxylammonium chloride (0.180 g, 2.54 mmol) and NH4OAC (0.539 g, 6.85 mmol). The reaction mixture was purged with nitrogen for 2 min, then stirred at 25 °C for 2 h. The mixture was quenched with water (50 mL), and adjusted to pH -8-9 with sat. aq. NaHCCL. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with sat. aq. NaCl (20 mL), dried over NaiSO4, filtered, and concentrated under reduced pressure to give the title compound (0.86 g). ES-MS m / z 507,509 (M+H).Preparation of Intermediate 240: (5R,7S)-8-(6-(Aminomethyl)-4-chloropyridin-2-yl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0265] To a mixture of 4-chloro-6-((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)picolinaldehyde oxime (0.86 g, 1.66 mmol) in EtOH (10 mL) and AcOH (1.0 g, 17 mmol) was added zinc powder (0.551 g, 8.26 mmol) in portions over 2 min at 0 °C. The reaction mixture was stirred at 25 °C for 2 h, then filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.0 g) as a solid. ESMS m / z 493,495 (M+H).Preparation of Intermediate 241: N-((4-Chloro-6-((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-2- yl)methyl)formamide

[0266] A mixture of (5R,7S)-8-(6-(aminomethyl)-4-chloropyridin-2-yl)-2-(2-cyclopropyl-6- (trifhioromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (67 wt%; 1.0 g, 1.4 mmol) in formic acid (8 mL) was purged with nitrogen for 1 min, then stirred at 100 °C for 3 h. The mixture was cooled to RT and concentrated under reduced pressure to give the title compound (0.80 g) as a solid. ES-MS m / z 521,523 (M+H).Preparation of Intermediate 242: (5R,7S)-8-(7-Chloroimidazo[l,5-a]pyridin-5-yl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0267] To a mixture of N-((4-chloro-6-((5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3- yl)-7-methyl-4-oxo-L3.8-triazaspiro[4.5]dec-l-en-8-yl)pyridin-2-yl)methyl)fol•mamide (62 wt%: 1.0 g, 1.2 mmol) in toluene (10 mL) was added POCh (1.6 g, 10 mmol). The reaction mixture was purged with nitrogen for 2 min, then stirred at 110 °C for 16 h. The mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by reverse phase purification, eluting with 30-70% acetonitrile in (water with 0.2% formic acid), to obtain the title compound (0.12 g) as a solid. ES-MS m / z 503,505 (M+H).Preparation of Intermediate 243: (5R,7S)-8-(5-Bromo-2-vinylpyridin-3-yl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0268] To a mixture of methyl(triphenyl)phosphonium chloride (5.2 g, 16 mmol) in THF (30 mL) at 0 °C was added potassium terLbutoxide (1.9 g, 17 mmol) in portions over 1 min. The reaction mixture was stirred at 25 °C for 1 h, then cooled to 0 °C. A solution of 5-bromo-3- ((5R,7S)-2-(2-cyclopropyl-6-(trifhioromethyl)pyridin-3-yl)-7-methyl-4-oxo- 1,3,8- triazaspiro[4.5]dec-l-en-8-yl)picolinaldehyde (86 wt%; 2.0 g, 3.2 mmol) in THF (30 mL) was added dropwise over 1 min. The reaction mixture was stirred at 25 °C for 2 h, then quenched with water (50 mL). The mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with sat. aq. NaCl (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography,eluting with 0-50% EtOAc in n-hexane, to give the title compound (1.5 g) as a solid. ES-MS m / z 534,536 (M+H).Preparation of Intermediate 244: 8-(5-Bromo-2-(2,2-difluoroethoxy)pyridin-3-yl)-2-(2- cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0269] To a mixture of 8-(5-bromo-2-(methylsulfonyl)pyridin-3-yl)-2-(2-cyclobutyl-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (70 wt%; 1.0 g, 1.2 mmol) and 2,2-difluoroethan-l-ol (0.6 g, 7 mmol) in NMP (10 mL) was added potassium fert-butoxide (0.4 g, 4 mmol). The reaction mixture was stirred at 50 °C for 2 h, then cooled to RT and diluted with water (20 mL) and EtOAc (20 mL). The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with sat. aq. NaCl (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 50-60% EtOAc in n-hexane, to give the title compound (0.90 g) as a solid. ES-MS m / z 588,590 (M+H).

[0270] The compound in the below table was prepared in similar manner as described in the preparation of Intermediate 244. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:

[0271] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediates 11 or 33. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 253: 6-Chloro-2-methoxy-4-methylpyridin-3-amine

[0272] To a mixture of 2,6-dichloro-4-methyl-pyridin-3-amine (5.90 g, 33.3 mmol) in THF (40 mL) was added sodium methoxide (5M in MeOH; 20 mL, 100 mmol). The reaction mixture was heated at reflux for 48 h, then quenched with sat. aq. NH4CI (20 mL) and diluted with EtOAc.The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl, dried over NazSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 5-10% EtOAc in cyclohexane, to give the title compound (4.55 g) as an oil. ES-MS m / z 173 (M+H).

[0273] The compound in the below table was prepared in similar manner as described in the preparation of Intermediate 253. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 255: 5-Amino-6-methoxy-4-methylpicolinonitrile

[0274] To a degassed mixture of 6-chloro-2-methoxy-4-methylpyridin-3-amine (1.70 g. 9.85 mmol) and zinc cyanide (1.83 g, 15.6 mmol) in DMA (16 mL) was added tetrakis(triphenylphosphine)palladium(o) (1.00 g, 0.869 mmol). The mixture was cycled through vacuum / nitrogen, then subjected to microwave irradiation (150 °C, 30 min). The mixture was cooled, diluted with DCM, and filtered through diatomaceous earth. The filtrate was diluted with EtOAc and 15% aqueous NH4OH and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl (2 x), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified bysilica gel chromatography, eluting with 0-60% EtOAc in cyclohexane, to give the title compound (1.15 g) as a solid. ES-MS m / z 164 (M+H).Preparation of Intermediate 256: 5-Bromo-6-methoxy-4-methylpicolinonitrile

[0275] To a 65 °C mixture of cuprous bromide (6.71 g, 46.8 mmol) and tert-butyl nitrite (4.1 mL, 34 mmol) in acetonitrile (60 mL) was added a solution of 5-amino-6-methoxy-4- methylpicolinonitrile (1.88 g, 11.5 mmol) in acetonitrile (70 mL) dropwise over 30 min under nitrogen. The reaction mixture was stirred at 70 °C for 1 h, then cooled to RT over 1 h and diluted with EtOAc (150 mL). The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (200 mL) and 15% aqueous NH4OH (200 mL) and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0- 20% EtOAc in cyclohexane, to give the title compound (1.83 g) as a solid. ES-MS m / z 227,229 (M+H).Preparation of Intermediate 257: terf-Butyl ((5-bromo-4,6-dimethylpyridin-2- yl)methyl)carbamate

[0276] To a 0 °C mixture of 5-bromo-4,6-dimethylpicolinonitrile (3.35 g, 15.9 mmol) in MeOH (45 mL) was added THF (25 mL), followed by nickelous chloride hexahydrate (771 mg, 3.24 mmol) and di-tert-butyl dicarbonate (8.65 g, 39.6 mmol). Sodiumtetrahydroborate (3.10 g, 81.9 mmol) was added portionwise over 20 min. The reaction mixture was warmed to RT overnight, then concentrated under reduced pressure. The residue was diluted with water (300 mL), 15% aqueous NH4OH (20 mL), and EtOAc (200 mL). The layers were separated. The aqueous layerwas extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-50% EtOAc in cyclohexane, to give the title compound (3.56 g) as a solid. ES-MS m / z 315,317 (M+H).

[0277] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 257. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 260: (5-Bromo-4,6-dimethylpyridin-2-yl)methanamine

[0278] To a mixture of tert-butyl ((5-bromo-4,6-dimethylpyridin-2-yl)methyl)carbamate (2.56 g, 8.12 mmol) in DCM (85 mL) was added TFA (15 mL). The reaction mixture was stirred overnight, then concentrated under reduced pressure. The residue was diluted with toluene (20 mL) and concentrated under reduced pressure. The residue was diluted with DCM and sat. aq. NaHCCE (40 mL). The layers were separated. The aqueous layer was extracted with DCM (8 x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give the title compound (1.63 g). ES-MS m / z 215,217 (M+H).

[0279] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 260. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 263: N-((5-Bromo-4,6-dimethylpyridin-2-yl)methyl)acetamide

[0280] To a 0 °C mixture of (5-bromo-4,6-dimethylpyridin-2-yl)methanamine (1.63 g, 7.58 mmol) and TEA (1.60 mL, 11.5 mmol) in DCM (38 mL) was added acetyl chloride (0.70 m , 9.84 mmol) dropwise. The reaction mixture was stirred at 0 °C for 20 min, then warmed to RT over 1 h. The mixture was diluted with DCM and water (20 mL). The layers were separated. The aqueous layer was extracted with DCM (2 x). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 5-100% (10% MeOH in EtOAc) in cyclohexane, to give the title compound (1.61 g) as a solid. ES-MS m / z 257,259 (M+H).

[0281] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 263. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 266: N-(4-Methoxybenzyl)-N-methyl-3-oxobutanamide

[0282] To a mixture of 4-methyleneoxetan-2-one (5.0 g, 58 mmol) in THF (100 mL) was added l-(4-methoxyphenyl)-N-methylmethanamine (8.94 g, 57.9 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in n-hexane, to give the title compound (10 g) as an oil. ES-MS m / z 236 (M+H).Preparation of Intermediate 267: N-(4-Methoxybenzyl)-N-methyl-3 -oxobutanethioamide

[0283] To a mixture of N-(4-methoxybenzyl)-N-methyl-3-oxobutanamide (10 g, 40 mmol) in toluene (200 mL) was added 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane 2,4-disulfide (8.4 g, 20 mmol) at 30 °C. The reaction mixture was cycled through vacuum / nitrogen (3x), then stirred at 75 °C for 16 h. The mixture was concentrated under reduced pressure to give the crude title compound as an oil. ES-MS m / z 252 (M+H).Preparation of Intermediate 268: Ethyl 2-(5-((4-methoxybenzyl)(methyl)amino)-3-methyl-lH- pyrazol-l-yl)acetate

[0284] To a mixture of N-(4-methoxybenzyl)-N-methyl-3-oxobutanethioamide (26 wt%; 20 g, 20.7 mmol) in EtOH (200 mL) was added ethyl hydrazinoacetate hydrochloride (3.27 g, 20.7 mmol) and sodium acetate (3.44 g, 41.5 mmol) at 30 °C. The reaction mixture was stirred at 80 °C for 1 h, then cooled to RT. The mixture was poured into water (400 mL) at 5 °C and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with sat. aq. NaCl (2 x 500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-15% EtOAc in n-hexane. to give the title compound (6.0 g). ES-MS m / z 318 (M+H).Preparation of Intermediate 269: Diethyl 2-(5-bromo-4,6-dimethylpyrimidin-2-yl)malonate

[0285] To a mixture of 5-bromo-2-chloro-4,6-dimethylpyrimidine (40.0 g, 172 mmol) in DME (500 mL) was added diethyl malonate (60.8 g. 376 mmol) and CS2CO3 (145.0 g, 440.6 mmol). The reaction mixture was stirred at 90 °C for 16 h, then cooled to RT. The mixture was poured into sat. aq. NH4CI (500 mL) and diluted with EtOAc (200 mL). The mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with sat. aq. NaCl (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-20% EtOAc in n-hexane, to give the title compound (50.2 g) as an oil. ES-MS m / z 345,347 (M+H).Preparation of Intermediate 270: Ethyl 2-(5-bromo-4,6-dimethylpyrimidin-2-yl)acetate

[0286] To a mixture of diethyl 2-(5-bromo-4,6-dimethylpyrimidin-2-yl)malonate (50.2 g, 131 mmol) in DMSO (500 mL) was added a solution of sodium chloride (25.0 g, 424 mmol) in water (75 mL). The reaction mixture was stirred at 130 °C for 24 h, then cooled to RT. The mixture was poured into water (900 mL) and diluted with EtOAc (100 mL). The mixture was extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with sat. aq. NaCl (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-20% EtOAc in n-hexane, to give the title compound (26.1 g) as an oil. ES-MS m / z 273,275 (M+H).Preparation of Intermediate 271: Ethyl 2-(5-bromo-4,6-dimethylpyridin-2-yl)acetate

[0287] To a mixture of 3,6-dibromo-2,4-dimethylpyridine (100 g, 347 mmol) in DMSO (2 L) and EtOH (98 g, 2100 mmol) was added ethyl 3-oxobutanoate (273.6 g, 2081 mmol), ksp»4 (446.4 g, 2082 mmol), picolinic acid (34.8 g, 279.8 mmol) and cuprous iodide (40.0 g, 208 mmol) at 20 °C. The reaction mixture was cycled through vacuum / nitrogen (3x), then stirred at 80 °C for 12 h, cooled to RT, and filtered. The filtrate was diluted with water (5 L) and EtOAc (1 L), then extracted with EtOAc (2 x 1 L). The combined organic layers were washed with sat. aq. NaCl (2 x 800 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-20% EtOAc in n-hexane, to give the title compound (101 g) as an oil. ES-MS m / z 272,274 (M+H).Preparation of Intermediate 272: Ethyl 2-(5-amino-3-methyl-lH-pyrazol-l-yl)acetate

[0288] A mixture of (E)-3-aminobut-2-enenitrile (30.95 g. 369.4 mmol) and ethyl aminoglycinate hydrochloride (58.97 g, 370.0 mmol) in EtOH (1000 mL) was purged with nitrogen for 5 min, then stirred at 80 °C for 14 h. The mixture was cooled to RT and concentrated under reduced pressure. The residue was triturated with MTBE (500 mL) for 1 h. The mixture was filtered and the filter cake was washed with MTBE and dried in a vacuum oven at 45 °C to give the title compound (67 g) as a solid. ES-MS m / z 184 (M+H).Preparation of Intermediate 273: Ethyl 2-(3-methyl-5-(2,2,2-trifluoroacetamido)-lH-pyrazol-l- yl) acetate

[0289] To a mixture of ethyl 2-(5-amino-3-methyl-lH-pyrazol-l-yl)acetate (26.0 g, 142 mmol) in toluene (400 mL) was slowly added trifluoroaceticanhydride (21.84 mL, 156 mmol) over 5 min under nitrogen. The reaction mixture was stirred for 2 h, then concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 50-100% EtOAc in heptane, to give the title compound (22.8 g, 57%) as a white solid. ES-MS m / z 280 (M+H).Preparation of Intermediate 274: Ethyl 2-(4-bromo-5-cyclopropyl-3-methyl-lH-pyrazol-l- yl)acetate

[0290] To a mixture of 4-bromo-5-cyclopropyl-3-methyl-lH-pyrazole (70 wt%; 15 g, 52 mmol) in DMF (300 mL) was added ethyl bromoacetate (21 g, 123 mmol) and K2CO3 (18 g, 128mmol). The reaction mixture was stirred at 100 °C for 2 h, then cooled to RT. The mixture was poured into water (500 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with sat. aq. NaCl (2 x 300 mL), dried over Na2SOr, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase purification, eluting with 40-60% acetonitrile in (water with 0.2% formic acid), to obtain the title compound (2.2 g) as a solid. ES-MS m / z 287,289 (M+H).Preparation of Intermediate 275: Ethyl 2-(5-hydroxy-3-(trifluoromethyl)-lH-pyrazol-l-yl)acetate

[0291] A mixture of ethyl 4,4,4-trifluoro-3-oxobutyrate (5.0 mL, 34.0 mmol), ethylhydrazinoacetatehydrochloride (5.21 g, 33.7 mmol), and NaOAc (2.80 g, 34.1 mmol) in EtOH (100 mL) was stirred at reflux for 3 h. The mixture was cooled to RT and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-20% MeOH in DCM, to give the title compound as a solid. ESMS m / z 239 (M+H).

[0292] The compound in the below table was prepared in similar manner as described in the preparation of Intermediate 275. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 277: Ethyl 2-(5-methoxy-3-(trifluoromethyl)-lH-pyrazol-l- yl)acetate

[0293] To a mixture of ethyl 2-(5-hydroxy-3-(trifluoromethyl)-lH-pyrazol-l-yl)acetate (0.61 g,2.56 mmol) and K2CO3 (0.45 g, 3.29 mmol) in DMF (12 mL) was added iodomethane (0.33 mL,5.10 mmol). The reaction mixture was stirred at 65 °C for 18 h. The mixture was cooled to RT and diluted with EtOAc (40 mL). The organics were washed with water (2 x 20 mL) and sat. aq. NaCl (20 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0- 100% EtOAc in n-heptane, to give the title compound (0.38 g). ES-MS m / z 253 (M+H).

[0294] The compound in the below table was prepared in similar manner as described in the preparation of Intermediate 277. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 279: Ethyl 2-(4-bromo-5-methoxy-3-(trifluoromethyl)-lH-pyrazol-l- yl)acetate

[0295] To a mixture of ethyl 2-(5-methoxy-3-(trifluoromethyl)-lH-pyrazol-l-yl)acetate (0.38 g, 1.51 mmol) in acetonitrile (7.5 mL) was added NBS (0.29 g, 1.66 mmol). The reaction mixture was stirred at 65 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-60% EtOAc in cyclohexane, to give the title compound (0.32 g) as an oil. ES-MS m / z 331,333 (M+H).

[0296] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 279. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 285: Ethyl 2-(4-bromo-3-methyl-5-(2,2,2-trifluoro-N- methylacetamido)-lH-pyrazol-l-yl)acetateL0297J To a mixture of ethyl 2-(4-bromo-3-methyl-5-(2,2,2-trifluoroacetamido)-lH-pyrazol-l- yl)acetate (20.0 g, 55.8 mmol) in acetone (200.05 mL) was added potassium carbonate (19.35 g, 140 mmol). The mixture was stirred at RT for 10 min, then iodomethane (10.5 mL, 168 mmol) was added. The reaction mixture was stirred at 25 °C for 14 hours, then concentrated under reduced pressure. The residue was diluted with sat. aq. sodium bicarbonate (100 mL) and EtOAc (100 mL). The mixture was extracted with EtOAc (3 x). The combined organic layers were washed with sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 40% EtOAc in heptane, to give the title compound (17.2 g, 81%) as a white solid. ES-MS m / z 373 (M+H).

[0298] The compound in the below table was prepared in similar manner as described in the preparation of Intermediate 285. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 287: Methyl 2-(4-cyclopropyl-l-methyl-lH-pyrazol-3-yl)acetate

[0299] To a mixture of methyl 2-(4-bromo-l-methyl-lH-pyrazol-3-yl)acetate (5 g, 21 mmol) in toluene (280 mL) and water (40 mL) was added cyclopropaneboronic acid (3 g, 34 mmol) and K3PO4 (15 g, 69 mmol). The reaction mixture was cycled through vacuum / nitrogen (3x), then dichloro[l,T-bis(dicyclohexylphosphino)ferrocene]palladium(II) (CAS# 917511-90-1, 1.6 g, 2.1 mmol) was added. The reaction mixture was cycled through vacuum / nitrogen (3x). The reaction mixture was stirred at 110 °C for 1 h under nitrogen, then cooled to RT. The mixture was poured into water (200 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (200 mL), dried over NazSCL. filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in n-hexane, to give the title compound (3.0 g) as an oil. ES-MS m / z 195 (M+H).Preparation of Intermediate 288: Methyl 2-(5-bromo-4-cyclopropyl-l-methyl-lH-pyrazol-3- yl) acetate

[0300] To a mixture of methyl 2-(4-cyclopropyl-l-methyl-lH-pyrazol-3-yl)acetate (3 g, 15 mmol) in DCM (20 mL) was added bromine (3.7 g, 23 mmol) dropwise at 0 °C. The reaction mixture was stirred at 22 °C for 1 h, then quenched with sat. aq. NaiSOs (100 mL). The layerswere separated. The organic layer was washed with water (2 x 200 mL) and sat. aq. NaCl (200 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-60% EtOAc in n-hexane. to give the title compound (2.2 g) as an oil. ES-MS m / z 273,275 (M+H).Preparation of Intermediate 289: 2-(4-Bromo-5-methoxy-3-(trifluoromethyl)-lH-pyrazol-l- yl) acetamide

[0301] A mixture of ethyl 2-(4-bromo-5-methoxy-3-(trifluoromethyl)-lH-pyrazol-l-yl)acetate (0.32 g, 0.97 mmol) and ammonia (7M in MeOH; 3 mL, 21 mmol) was stirred in a sealed vial at 80 °C for 1 h. The mixture was concentrated under reduced pressure to afford the tittle compound (0.28 g) as a solid. ES-MS m / z 302,304 (M+H).

[0302] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 289. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:1From ethyl 2-(4-bromo-5-(N-ethyl-2,2,2-trifluoroacetamido)-3-methyl-lH-pyrazol- yl)acetatePreparation of Intermediate 296: (5-Bromo-l-cyclopropyl-4-methyl-lH-imidazol-2-yl)methanol

[0303] To a mixture of methyl 5-bromo-1 -cyclopropyl-4-methyl-lH-imidazole-2-carboxylate (82 wt%; 0.90 g, 2.84 mmol) in EtOH (10 mL) was added NaBFE (0.131 g, 3.43 mmol) and calcium chloride (0.320 g, 2.85 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The mixture was quenched with sat. aq. NH4CI (10 mL) and diluted with EtOAc (10 mL). The mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with sat. aq. NaCl (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (0.51 g) as a solid. ES-MS m / z 231,233 (M+H).Preparation of Intermediate 297: 5-Bromo-2-(methoxycarbonyl)-4-methylpyridine 1-oxide

[0304] To a mixture of methyl 5-bromo-4-methylpicolinate (200 g, 826 mmol) in DCM (2 L) was added carbamide peroxide (125 g, 1312 mmol) and trifluoroacetic anhydride (271 g, 1265 mmol) at 10 °C. The reaction mixture was cycled through vacuum / nitrogen (3x), then stirred atg at 10 °C for 4 h. The mixture was quenched with sat. aq. Na2SOs (2 L) at 10 °C and extracted with DCM (3 x 1 L). The combined organic layers were washed with sat. aq. NaCl (2 x 1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (199 g) as a solid. ES-MS m / z 246,248 (M+H).Preparation of Intermediate 298: Methyl 5-bromo-6-chloro-4-methylpicolinate

[0305] To a mixture of 5-bromo-2-(methoxycarbonyl)-4-methylpyridine 1-oxide (199 g, 747 mmol) in DCE (2 L) was added POCh (362 g, 2342 mmol) dropwise over 30 mins at 10 °C. The reaction mixture was stirred at 50 °C for 6 h, then cooled to RT. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (1 L), quenched with sat. aq. Na2COs (2 L) at 0 °C, and extracted with DCM (2 x 1 L). The combined organic layers were washed with sat. aq. NaCl (2 x 1 L), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-30% EtOAc in n- hexane, to give the title compound (120 g) as a solid. ES-MS m / z 264,266 (M+H).Preparation of Intermediate 299: 5-Bromo-6-methoxy-4-methylpicolinic acid

[0306] To a mixture of methyl 5-bromo-6-chloro-4-methylpicolinate (100 g, 371 mmol) in MeOH (500 mL) was added sodium methoxide (5M in MeOH; 1 L, 5000 mmol) at 10 °C. The reaction mixture was stirred at 80 °C for 6 h, cooled to RT, and concentrated under reduced pressure. The residue was adjusted to pH ~3-5 with aqueous HC1 (6M) under stirring at 10 °C, then extracted with EtOAc (3 x 1 L). The combined organic layers were washed with sat. aq. NaCl (1 L), dried over NazSCU, filtered, and concentrated under reduced pressure to give the title compound (90 g) as a solid. ES-MS m / z 246,248 (M+H).Preparation of Intermediate 300: (5-Bromo-6-methoxy-4-methylpyridin-2-yl)methanol

[0307] To a mixture of 5-bromo-6-methoxy-4-methylpicolinic acid (30 g, 117 mmol) in THF (300 mL) was added BH3 (10M in dimethyl sulfide; 110 mL, 1100 mmol) dropwise over 30 mins at 0 °C. The reaction mixture was stirred at 20 °C for 12 h, then quenched with MeOH (50 mL) at 50 °C for 30 min while stirring. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-20% EtOAc in n-hexane, to give the title compound (22 g) as a solid. ES-MS m / z 232,234 (M+H).Preparation of Intermediate 301: 3-Bromo-6-(chloromethyl)-2-methoxy-4-methylpyridine

[0308] To a mixture of (5-bromo-6-methoxy-4-methylpyridin-2-yl)methanol (87 wt%; 22 g, 82 mmol) in DCM (220 mL) and DMF (0.1 mL) was added thionyl chloride (29 g, 244 mmol) dropwise over 5 mins at 0 °C. The reaction mixture was stirred at 10 °C for 4 h, quenched with sat. aq. NaHCOs (250 mL) at 0 °C. and extracted with DCM (3 x 200 mL). The combined organic layers were washed with sat. aq. NaCl (300 mL), dried over NazSC , filtered, and concentrated under reduced pressure to give the title compound (21 g) as an oil. ES-MS m / z 250,252 (M+H).

[0309] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 301. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:1.27-1.14 (m, 4H)Preparation of Intermediate 304: 2-(5-Bromo-6-methoxy-4-methylpyridin-2-yl)acetonitrile

[0310] To a mixture of 3-bromo-6-(chloromethyl)-2-methoxy-4-methylpyridine (89 wt%: 20 g, 71 mmol) in DMSO (200 mL) was added NaCN (12.3 g, 239 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 12 h, poured into sat. aq. NaHCCh (600 mL) at 20 °C, and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with sat. aq. NaCl (2 x 300 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-20% EtOAc in n-hexane, to give the title compound (15.8 g) as a solid. ES-MS m / z 241,243 (M+H).

[0311] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 304. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 307: te / 7-Butyl 2-(5-bromo-4-methoxy-6-methylpyrimidin-2-yl)-2- cyanoacetate

[0312] To a 0 °C mixture of te -butyl 2-cyanoacetate (60 g, 425 mmol) in THF (350 mL) was added sodium hydride (60 wt% in mineral oil; 8 g. 450 mmol) portionwise. The reaction mixture was stirred at 0 °C for 30 min. 5-Bromo-2-chloro-4-methoxy-6-methylpyrimidine (35 g, 142 mmol) was added over 2 min at 0 °C. The reaction mixture was stirred at 60 °C for 12 h. The mixture was cooled to RT and poured into sat. aq. NH4CI (500 mL). The mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with sat. aq. NaCl (3 x 200 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was triturated with MTBE (100 mL) at 15 °C for 10 min. The mixture was filtered and the filter cake was dried under reduced pressure to give the title compound (33 g) as a solid. ES-MS m / z 342,344 (M+H).Preparation of Intermediate 308: 2-(5-Bromo-4-methoxy-6-methylpyrimidin-2-yl)acetonitrile

[0313] To a mixture of tert-butyl 2-(5-bromo-4-methoxy-6-methylpyrimidin-2-yl)-2- cyanoacetate (33 g, 90 mmol) in DCM (350 mL) was added TFA (178 g, 1537 mmol) dropwise over 5 min at 15 °C. The reaction mixture was stirred at 15 °C for 2 h. The mixture was concentrated under reduced pressure to give the title compound (31 g). ES-MS m / z 242,244 (M+H).Preparation of Intermediate 309: 2-(5-Bromo-4-methoxy-6-methylpyrimidin-2-yl)acetamide

[0314] To a mixture of 2-(5-bromo-4-methoxy-6-methylpyrimidin-2-yl)acetonitrile (63%; 31.0 g, 80.3 mmol) in water (30 mL) was added H2SO4 (98%, 276 g, 2764 mmol) dropwise over 5 min at 15 °C. The reaction mixture was stirred at 50 °C for 1 h. The mixture was cooled to RT and poured into water (1 L). The pH was adjusted to -10-11 with aqueous NaOH (2M) and the mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with sat. aq. NaCl (3 x 2500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with DCM (50 mL) for 15 min. The mixture was filtered and the filter cake was rinsed with DCM (10 mL) and dried under reduced pressure to give the title compound (13 g) as a solid. ES-MS m / z 260,262 (M+H).

[0315] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 309. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 313: 5-Bromo-4,6-dimethyl-2-vinylpyrimidine

[0316] To a mixture of 5-bromo-2-chloro-4,6-dimethylpyrimidine (80 g, 0.36 mol) in 1,4- dioxane (800 mL) and water (80 mL) was added 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (61 g, 0.39 mol), K2CO3 (97 g, 0.69 mol), and tetrakis(triphenylphosphine)palladium(0) (15 g, 13 mmol). The reaction mixture was cycled through vacuum / nitrogen (3x), then stirred at 100 °C for 2 h. The mixture was cooled to RT and poured into water. The mixture was extracted with EtOAc (3 X 400 mL). The combined organic layers were washed with sat. aq. NaCl (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 20-40% EtOAc in hexanes, to give the title compound as a yellow oil. ES-MS m / z 213,215 (M+H).

[0317] The compound in the below table was prepared in similar manner as described in the preparation of Intermediate 313. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:1From 2,5-dibromo-l,4-dimethyl-lH-imidazolePreparation of Intermediate 315: (R)-l-(5-Bromo-4.6-dimethylpyrimidn-2-yl)ethane-l,2-diol

[0318] To a 0 °C mixture of AD-mix-beta (192 g, 117 mmol) in n?rf-butanol (500 mL) and water (500 mL) was slowly added 5-bromo-4,6-dimethyl-2-vinylpyrimidine (30 g, 0.130 mmol). The reaction mixture was warmed to RT and stirred overnight. The mixture was poured into water (500 mL) and extracted with EtOAc (5 x 400 mL). The combined organic layers were washed with sat. aq. NaCl (4 x 300 mL), dried over NaiSCM, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 50-65% EtOAc in hexanes, to give crude product. The crude product was purified by reverse phase purification, eluting with 5-30% acetonitrile in 10 mM aqueous ammonium bicarbonate, to obtain the title compound as a white solid. ES-MS m / z 247,249 (M+H).

[0319] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 315. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:1'H NMR (400 MHz, CDC13) 8 7.08 (s, 2H), 4.73 (dd, J = 3.5, 8.0 Hz, 1H), 3.78-3.7 (m, 1H), 3.68-3.59 (m, 1H), 2.42 (s, 6H)Preparation of Intermediate 318: 2-(5-Bromo-4,6-dimethylpyridin-2-yl)-2-hydroxyacetonitrile

[0320] To a mixture of 5-bromo-4,6-dimethylpicolinaldehyde (1.6 g, 7.3 mmol) in water (30 mL) was added a solution of NaHSCL (2.4 g, 23 mmol) in water (3 mL) dropwise over 2 min at 0 °C under N2. The reaction mixture was stirred at 0 °C for 1 h, then a solution of NaCN (1.1 g, 22 mmol) in water (3 mL) was added drop wise over 2 min at 0 °C. The reaction mixture was stirred at 25 °C for 15 h, then filtered. The filtrate was poured into aqueous NaClO (10%, 500 mL) and adjusted to pH ~11 with aqueous NaOH (IM). The mixture was filtered, washed with water (3 x 300 mL), and dried to give the title compound (1.8 g) as a solid. ES-MS m / z 241,243 (M+H).Preparation of Intermediate 319: 2-(5-Bromo-4,6-dimethylpyridin-2-yl)-2-hydroxyacetamide

[0321] To a mixture of 2-(5-bromo-4,6-dimethylpyridin-2-yl)-2-hydroxyacetonitrile (41 wt%;1.8 g, 3.0 mmol) in 1,4-dioxane (10 mL) was added HC1 (4.0M in 1.4-dioxane, 20 mL, 80 mmol)dropwise over 5 min at 0 °C. The reaction mixture was stirred at 26 °C for 2 h, then adjusted to pH -7 with aqueous Na2CO3 (10 wt%). The mixture was diluted with water (40 mL) and DCM (5 mL). The mixture was filtered and the filter cake was dried under reduced pressure to give the title compound (0.80 g) as a solid. ES-MS m / z 259,261 (M+H).Preparation of Intermediate 320: (4,5-Dibromo-l -methyl- lH-imidazol-2-yl)methanol

[0322] To a mixture of (1 -methyl- lH-imidazol-2-yl)methanol (20 g, 174 mmol) in DMF (250 mL) was added KHCO3 (55 g, 546 mmol), then bromine (50 g, 306 mmol) at 0 °C. The reaction mixture was stirred at 100 °C for 5 h, then cooled to RT. The mixture was poured into ice water (300 mL), diluted with EtOAc (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with sat. aq. NaCl (2 x 100 mL), dried over NaiSCh, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 50-75% EtOAc in n-hexane, to give the title compound (18 g) as a solid. ES-MS m / z 271 (M+H).Preparation of Intermediate 321: 2-(3,5-Dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- y 1)- 1 H-pyrazol- 1 -yl)acetamide

[0323] To a 0 °C mixture of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (CAS 857530-80-4; 1.397 g, 6.290 mmol) in DMF (40 mL) was added sodium hydride (60 wt%; 503.2 mg, 12.58 mmol) portionwise over 10 min under nitrogen. The reaction mixture was stirred at 0 °C for 30 min. A solution of 2-bromoacetamide (1.041 g, 7.548 mmol) in DMF (10 mL) was added drop wise. The reaction mixture was allowed to warm slowly to RT over 2 h. The mixture was poured into water (lOOmL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with sat. aq. NaCl, dried over Na2SO4. filtered, andconcentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-10% MeOH in DCM, to give the title compound (1.35 g, 77%) as a white solid. ES-MS m / z 280 (M+H).Preparation of Intermediate 322: Ethyl 2-(5-cyclopropyl-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)acetate

[0324] To a mixture of ethyl 2-(4-bromo-5-cyclopropyl-3-methyl-lH-pyrazol-l-yl)acetate (2.2 g, 7.3 mmol) in THF (30 mL) was added n-butyllithium (2.5 M in n-hexane, 6 mL, 15 mmol) dropwise over 5 min at -65 °C. The reaction mixture was stirred at -65 °C for 20 min, then isopropoxyboronic acid pinacol ester (3 g, 20 mmol) in THF (5 mL) was added dropwise over 5 min at -65 °C. The reaction mixture was stirred at -65 °C for 0.5 h, then warmed to RT. The mixture was quenched with sat. aq. NH4CI (30 mL) at 0 °C, then extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with sat. aq. NaCl (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase prep-HPLC, eluting with 2-30% (2:1 DCM:acetonitrile) in heptane, to give the title compound (1.0 g) as a solid. ES-MS m / z 335 (M+H).

[0325] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 322. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:

[0326] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediates 45 or 65. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:(m, 1H), 3.66-3.57 (m, 1H). 2.41 (s, 6H), 1.39 (s, 12H)

[0327] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 52 or Examples 2 or 15, using the appropriate halide and boronic acid / boronate ester. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Preparation of Intermediate 341: 2-(4-(6-((5R,7S)-2-(2-Cyclopropyl-6-(trifluoromethyl)pyridin--yl)-7-methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-5-(cyclopropylmethyl)pyridin-2-yl)-5- ((4-methoxybenzyl)(methyl)amino)-3-methyl-lH-pyrazol-l-yl)acetamide

[0328] A mixture of ethyl 2-(4-(6-((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)-5-(cyclopropylmethyl)pyridin-2-yl)-5-((4- methoxybenzyl)(methyl)amino)-3-methyl-lH-pyrazol-l-yl)acetate (0.040 g, 0.049 mmol) and ammonia (7.0 M in MeOH; 1.0 mL, 7 mmol) was stirred at 70 °C for 12 h. The mixture was concentrated under reduced pressure to give the title compound (0.045 g) as a solid. ES-MS m / z 770 (M+H).Preparation of Intermediate 342: 2-(5'-(2-(2-Cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-4-oxo- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-6'-(2,2-difluoroethoxy)-2,4-dimethyl-[3,3'-bipyridin]-6- yl)acetic acid

[0329] To a mixture of ethyl 2-(5'-(2-(2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-4-oxo-l,3,8- triazaspiro[4.5]dec-l-en-8-yl)-6'-(2,2-difluoroethoxy)-2,4-dimethyl-[3,3'-bipyridin]-6-yl)acetate (0.250 g, 0.324 mmol) in MeOH (2 mL), THF (2 mL), and water (0.5 mL) was added LiOH monohydrate (0.13 g, 2.79 mmol). The reaction mixture was stirred at 25 °C for 12 h, then concentrated under reduced pressure. The residue was diluted with water (30 mL) and adjusted to pH ~3 with aqueous HC1 (3M; 10 mL). The mixture was extracted with EtOAc (3 x 10 mL).The combined organic layers were washed with sat. aq. NaCl (10 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure to give the title compound (0.20 g) as a solid. ES-MS m / z 673 (M+H).Preparation of Intermediate 343: (5R,7S)-8-(5-(4-Cyclopropyl-2-(hydroxymethyl)-l-methyl-lH- imidazol-5-yl)-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

[0330] A mixture of (5R,7S)-8-(5-(4-bromo-2-(hydroxymethyl)-l-methyl-lH-imidazol-5-yl)-2- ethoxypyridin-3-yl)-2-(2-cyclopropyl-6-(trifLuoromethyl)pyridin-3-yl)-7-methyl- 1,3,8- triazaspiro[4.5]dec-l-en-4-one (56 wt%; 1.3 g, 1.1 mmol), cyclopropylboronic acid (0.6 g, 7 mmol), K3PO4 (0.9 g, 4 mmol), toluene (25 mL) and water (3 mL) was cycled through vacuum / nitrogen (3x). Dichloro[l,r-bis(dicyclohexylphosphino)ferrocene]palladium(II) (CAS# 917511-90-1, 0.3 g, 0.4 mmol) was added. The reaction mixture was stirred at 100 °C for 2 h, cooled to RT, and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with sat. aq. NaCl (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 5-15% MeOH in DCM, to give crude product. The crude product was purified by reverse phase purification, eluting with 30- 70% acetonitrile in (lOmM aqueous ammonium bicarbonate), to obtain the title compound (0.15 g) as a solid. ES-MS m / z 624 (M+H).Preparation of Intermediate 344: (5R,7S)-8-(5-(2-(Chloromethyl)-4-cyclopropyl-l-methyl-lH- imidazol-5-yl)-2-ethoxypyridin-3-yl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7- methyl- 1 ,3,8-triazaspiro [4.5]dec- 1 -en-4-one

[0331] To a mixture of (5R,7S)-8-(5-(4-cyclopropyl-2-(hydroxymethyl)-l-methyl-lH-imidazoL 5-yl)-2-ethoxypyridin-3-yl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-l,3,8- triazaspiro[4.5Jdec-l-en-4-one (0.12 g, 0.188 mmol) in DCM (5 mL) was added thionyl chloride (0.20 g, 1.65 mmol) and DMF (0.1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h, then concentrated under reduced pressure to give the title compound (0.10 g). A sample quenched with EtOH showed ES-MS m / z 652 (M+H, ethyl ether).Preparation of Intermediate 345: 2-(4-Cyclopropyl-5-(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)-6- ethoxypyridin-3-yl)- 1-methyl- lH-imidazol-2-yl)acetonitrile

[0332] To a mixture of (5R,7S)-8-(5-(2-(chloromethyl)-4-cyclopropyl-l-methyl-lH-imidazol-5- yl)-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 (22 wt%; 0.10 g, 0.034 mmol) in DMSO (3 mL) was added NaCN (0.045 g, 0.90 mmol) and K2CO3 (0.030 g, 0.21 mmol). The reaction mixture was stirred at 25 °C for 2 h, then quenched with water (10 mL) at 18 °C, and diluted with EtOAc (5 mL). The mixture was extracted EtOAc (3 x 5 mL). The combined organic layers were washed with sat. aq. NaCl (5 mL), dried over NaiSO4, filtered, and concentrated under reduced pressure. Theresidue was purified by prep-TLC (SiCh, 5:1 DCM:MeOH, R / = 0.6, UV) to give the title compound (0.030 g). ES-MS m / z 633 (M+H).Preparation of Intermediate 346: 2-(4-(5-Cyano-6-((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-2-yl)-5 -cyclopropyl-3 -methyl- 1 H-pyrazol- 1 -yl)acetic acid

[0333] To a mixture of 6-chloro-2-((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)nicotinonitrile (0.20 g, 0.402 mmol) in IPA (1.5 mL) and water (0.5 mL) was added ethyl 2-(5-cyclopropyl-3-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)acetate (89 wt%; 0.151 g, 0.404 mmol), NaHCCE (0.105 g, 1.24 mmol), and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,l'- biphenyl)(2'-methylamino-l,T-biphenyl-2-yl)palladium(II) (CAS# 1599466-81-5; 0.039 g, 0.044 mmol). The reaction mixture was stirred at 90 °C for 16 h, cooled to RT, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase purification, eluting with 40-70% acetonitrile in (lOmM aqueous ammonium bicarbonate), to obtain the title compound (0.10 g) as a solid. ES-MS m / z 633 (M+H).

[0334] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 346. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:EXAMPLESExample 1: (5R,7S)-8-(4-(3,5-Dimethyl-lH-pyrazol-4-yl)pyridin-2-yl)-7-methyl-2-(2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0335] Pd(dppf)Ch (DCM adduct, 0.0090 g, 0.011 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 (0.0570 g, 0.107 mmol), CS2CO3 (0.1078 g, 0.3309 mmol) and 3,5-dimethyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.0404 g, 0.182 mmol) in 1,4-dioxane (0.75 mL) and water (0.25 mL) under nitrogen and stirred at 90 °C. After 3 h, the reaction was filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC [column: EVO 30 x 250 mm, 5 pm; mobile phase: solvent A: 10 mM aq. NH4HCO3, solvent B: ACN, gradient: 15%-25 % solvent B in solvent A] to give the title compound (0.063 g). ES-MS m / z 499 (M+H).Example 2: (5R,7S)-7-Methyl-8-(4-(5-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)pyridin-2-yl)-2-(2- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0336] Methanesulfonato[ 1 , 1 '-bis(diphenylphosphino)ferrocene)] (2'-amino- 1 , 1 '-biphenyl-2- yl)palladium(II) (0.0108 g, 0.0115 mmol) was added to a solution of (5R,7S)-7-methyl-8-(4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)-2-(2-(trifluoromethoxy)phenyl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one (0.0518 g, 0.0977 mmol), CS2CO3 (0.1015 g, 0.3115 mmol), and 4-bromo-5-methyl-lH-pyrrolo[2,3-B]pyridine (0.0320 g, 0.152 mmol) in 1,4-dioxane (0.75 mL) and water (0.25 mL) under nitrogen and stirred at 90 °C. After 16 h, the reaction was filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC [column: EVO 30 x 250 mm, 5 pm; mobile phase: solvent A: 10 mM aq. NH4HCO3 + 5% MeOH, solvent B: ACN, gradient: 30%-55% solvent B in solvent A] to give the title compound (0.018 g). ES-MS m / z 535 (M+H).

[0337] The examples in the following table were prepared as described in Example 2 using the appropriate aryl bromide.a. Purification mobile phase: solvent A - 0.1% aq. formic acid, solvent B - ACN, gradient used: 10-15% solvent B in solvent A. b. Purification mobile phase: solvent A - 10 mM aq. NH4HCO3 + 5% MeOH, solvent B - ACN, gradient used: 30%-55% solvent B in solvent A. c. Purification mobile phase: solvent A - 10 mM aq. NH4HCO3 + 5% MeOH, solvent B - ACN, gradient used: 25%-45% solvent B in solvent A.Example 6: (5R,7S)-8-(3'.5'-Dimethyl-[4,4'-bipyridin]-2-yl)-7-methyl-2-(2-(trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0338] The title compound was prepared as described in Example 1 using 3,5-dimethyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine, stirring the reaction at 80 °C for 16 h and using a reverse phase HPLC gradient of 33 to 67% ACN in 10 mM aq. NH4HCO3. ES-MS mJz 510 (M+H).Example 7: N-(4,6-Dimethyl-5-(2-((5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethoxy)phenyl)- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)pyridin-4-yl)pyrimidin-2-yl)acetamide

[0339] Pd(dppf)Cb (DCM adduct, 0.011 g, 0.013 mmol) was added to a solution of (5R,7S)-7- methyl-8-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)-2-(2- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.035 g. 0.066 mmol), CS2CO3 (0.054 g, 0.16 mmol) and N-(5-bromo-4,6-dimethylpyrimidin-2-yl)acetamide (0.032 g, 0.13 mmol) in 1,4-dioxane (0.66 mL) and water (0.22 mL) under nitrogen and stirred at 80 °C for 8 h. The reaction was cooled to RT, diluted with EtOAc, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC [column: Phenomenex Kinetex EVO C18 100 x 30 mm, 5 pm; mobile phase: A: 10 mM aq. NH4HCO3, B: ACN, gradient: 23%-58% B] to give the title compound. ESMS m / z 568.2 (M+H).

[0340] The following examples were prepared as described in Example 7 using the appropriate aryl bromide.a. Purification mobile phase: solvent A - 10 mM aq. NH4HCO3 + 5% MeOH, solvent B - ACN, gradient used: 23-58% solvent B in solvent A. b. Purification mobile phase: solvent A - 0.1% aq. formic acid, solvent B - ACN, gradient used: 5-39% solvent B in solvent A. c. Purification mobile phase: solvent A - 10 mM aq. NH4HCO3 + 5% MeOH, solvent B - ACN, gradient used: 23-58% solvent B in solvent A.Example 11 : N-(4-Methyl-5-(5-methyl-2-((5R,7S)-7-methyl-4-oxo-2-(2- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)pyridin-4-yl)thiazol-2-

[0341] A mixture of K3PO4 (0.028 g, 0.13 mmol), (5R,7S)-7-methyl-8-(5-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)-2-(2-(trifluoromethoxy)phenyl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one (0.031 g, 85 wt%, 0.048 mmol), N-(5-bromo-4-methylthiazol-2- yl)acetamide (0.021 g, 0.089 mmol) and Pd(dppf)C12 (DCM adduct, 0.006 g, 0.008 mmol) was purged with nitrogen. 1,4-Dioxane (0.18 mL) and water (0.061 mL) were then added, the reaction vessel was sealed, and the mixture was stirred at 100 °C. After 3 h, the reaction was cooled to RT, then diluted with water and EtOAc. The aqueous layer was discarded, and the organic layer was washed with water and sat. aq. NaCl, dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 10 to 100% EtOAc in DCM, then re-purified by reverse phase HPLC (solvent A: 0.1% aq. formic acid; solvent B: ACN + 0.1% formic acid, gradient 25 to 55% solvent B in solvent A) to give the title compound (0.004 g). ES-MS m / z 573 (M+H).Example 12: (5R,7S)-2-(2-cyclopropylphenyl)-8-(2,4-dimethyl-[3,4'-bipyridin]-2'-yl)-7-methyl- l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0342] Pd(dppf)Cb (DCM adduct, 0.025 g, 31 pmol) was added to a solution of (5R,7S)-2-(2- cyclopropylphenyl)-7-methyl-8-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)- l,3,8-triazaspiro[4.5]dec-l-en-4-one (0.075 g. 0.15 mmol), CS2CO3 (0.15 g, 0.46 mmol), and 3- bromo-2,4-lutidine (0.043 g, 0.23 mmol) in 1,4-dioxane (0.77 mb) and water (0.26 mb) under nitrogen and the reaction was heated to 100 °C in microwave reactor for 1 h. The reaction was filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC [column: Phenomenex Kintex Evo C18 100 x 30mm, 5pm; mobile phase: solvent A - 10 mM aq. NH4HCO3 + 5% MeOH, solvent B - ACN: gradient: 33%-67% solvent B in solvent A] to give the title compound (0.042 g). ES-MS m / z 499 (M+H).Example 13: (5R,7S)-2-(2-Cyclopropylphenyl)-8-(4-(3,5-dimethyl-l-(l-methyl-2-oxopyrrolidin- 3-yl)-lH-pyrazol-4-yl)pyridin-2-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of

[0343] The title compound was prepared as described in Example 12 using 3-(4-bromo-3,5- dimethyl-lH-pyrazol-l-yl)-l-methylpyrrolidin-2-one, heating the reaction at 80 °C and purifying by reverse phase HPLC [column: Phenomenex Kintex Evo C18 100 x 30mm, 5pm; mobile phase: solvent A - 10 mM aq. NH4HCO3 + 5% MeOH, solvent B - ACN: gradient: 23%-58% solvent B in solvent A], ES-MS m / z 552 (M+H).Example 14: (5R,7S)-2-(2-(l,4-Dioxan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-8-(4-(5,7- dimethylbenzo[d]oxazol-6-yl)pyridin-2-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)

[0344] A mixture of (2-((5R,7S)-2-(2-(l,4-dioxan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-4-oxo-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)pyridin-4-yl)boronic acid (mixture of isomers, 100 mg, 160 pmol), 6-bromo-5,7-dimethylbenzo[d]oxazole (51 mg, 0.19 mmol). K3PO4 (103 mg, 480 pmol) and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,l'- biphenyl)(2'-methylamino-l,r-biphenyl-2-yl)palladium(II) (14 mg, 16 pmol) in 1,4-dioxane (2 mb) and water (0.4 mL) was purged with nitrogen for 1 min, then heated to 100 °C for 5 h under nitrogen. The mixture was concentrated under reduced pressure and the residue was purified by reverse-phase HPLC (column: Phenomenex luna C18 100 x 40mm, 5 pm; mobile phase: solvent A - 0.2% aq. formic acid, solvent B - ACN; gradient: 5 to 35% solvent B in solvent A) to give the title compound (25.39 mg) as a solid. ES-MS m / z 621 (M+H).Example 15: (5R,7S)-8-(6-Cyclopropoxy-3',5'-dimethyl-[3,4'-bipyridin]-5-yl)-7-methyl-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0345] A mixture of (5R,7S)-8-(5-chloro-2-cyclopropoxypyridin-3-yl)-7-methyl-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (200 mg, 404 pmol), 3,5- dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (154 mg, 628 pmol), K3PO4 (175 mg, 820 pmol) and 2nd Generation SPhos Precatalyst (CAS# 1375325-64-6, 32 mg, 42 pmol) in EtOH (4 mL) and water (1 mL) was purged with nitrogen for 2 min then heated at 80 °C for 16 h with vigorous stirring. The reaction mixture was poured into 5 mL water, then the mixture was extracted with DCM (5 mL x 3). The organic layers were washed with sat. aq. NaCl (10 mL), dried over NaiSC , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (10% MeOH in DCM, R / = 0.6), then re-purified by reverse-phase HPLC (column: WePure Biotech XP tC18 150 x 40, 10 pm; mobile phase: solvent A - 10 mM aq. NH4HCO3. solvent B - ACN; gradient: 30 to 60% solvent B in solvent A) to give the title compound (26.08 mg) as a solid. ES-MS m / z 551 (M+H).Example 16: (5R,7S)-8-(4-(5,7-Dimethylbenzo[d]oxazol-6-yl)pyridin-2-yl)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0346] The title compound was prepared as described in the Example 14 using (2-((5R,7S)-7- methyl-4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)pyridin-4- yl)boronic acid and 6-bromo-5,7-dimethylbenzo[d]oxazole, heating the reaction to 100 °C for 2 h. The product was purified by preparative TLC (10% MeOH in DCM, R / = 0.35), re-purified by reverse-phase HPLC (column: Phenomenex luna C18 100 x 40mm, 5 pm; mobile phase: solvent A - 0.2% aq. formic acid, solvent B - ACN; gradient 10 to 45% solvent B in solvent A), then repurified again by reverse-phase HPLC (column: WePure Biotech XP tC18 150 x 40, 10 pm; mobile phase; solvent A - 10 mM aq. NH4HCO3), solvent B - ACN; gradient 27 to 57% solvent B in solvent A). ES-MS m / z 535 (M+H).Example 17; (5R,7S)-8-(6-Methoxy-3',5'-dimethyl-[3,4'-bipyridin]-5-yl)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0347] The title compound was prepared as described in Example 15 using (5R,7S)-8-(5-chloro- 2-methoxypyridin-3-yl)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec- l-en-4-one and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine. The product was purified by preparative TLC (50% EtOAc in petroleum ether, R / = 0.45), then repurified by reverse-phase HPLC (column: WePure Biotech XP tC18 150 x 40; mobile phase: solvent A - 10 mM aq. NH4HCO3, solvent B - ACN; gradient: 20 to 50% solvent B in solvent A). ES-MS m / z 525 (M+H).Example 18: (5R,7S)-8-(6-(Methoxymethyl)-3',5'-dimethyl-[3,4'-bipyridin]-5-yl)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0348] The title compound was prepared as described in Example 15 using (5R,7S)-8-(5-chloro- 2-(methoxymethyl)pyridin-3-yl)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine, heating the reaction at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure instead of a DCM / water workup. The product was purified by preparative TLC (10% MeOH in DCM, R / = 0.23), then re-purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100 x 30mm, 10 pm; mobile phase: solvent A - 10 mM aq. NH4HCO3, solvent B - ACN; gradient: 20 to 50% solvent B in solvent A). ES-MS m / z 539 (M+H).Example 19: 3',5'-Dimethyl-5-((5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)-1.3,8-triazaspiro[4.5]dec-l-en-8-yl)-[3,4'-bipyridine]-6-carbonitrile

[0349] To a solution of 5-bromo-3-((5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)- l,3,8-triazaspiro[4.5]dec-l-en-8-yl)picolinonitrile (500 mg, 993 pmol) and 3,5-dimethyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (343 mg, 1.19 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added K2CO3 (420 mg, 2.98 mmol) and Pd(dppf)Ch (74.2 mg, 99.4 pmol) at 25 °C. The mixture was de-gassed and refilled with nitrogen for three times. The resulting mixture was stirred at 100 °C for 16 h. The mixture was then quenched with water (10 mL) and extracted with EtOAc (5 mL x 3). The organic layers were washed with sat. aq. NaCl (10 mL), dried over NazSC , filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 250 x 50mm, 10 pm;mobile phase: solvent A - 10 mM aq. NH4HCO3, solvent B - ACN; gradient: 25 to 45% solvent B in solvent A) to give the title compound (130 mg) as a solid. ES-MS m / z 520 (M+H).Example 20: (5R,7S)-8-(6-(Hydroxymethyl)-3',5'-dimethyl-[3,4'-bipyridin]-5-yl)-7-methyl-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0350] To a solution of (5R,7S)-8-(6-(methoxymethyl)-3',5'-dimethyL[3,4'-bipyridin]-5-yl)-7- methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (10 mg, 17 pmol) in DCM (1 mL) was added BBn (2 M solution in DCM, 100 pL, 200 pmol) in one portion at 20 °C. The mixture was stirred at 20°C for 12 h. The reaction mixture was quenched by adding 1 mL MeOH and 0.2 mL H2O at 0 °C, then the reaction was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse-phase HPLC (column: Phenomenex lima C 18 100 x 40mm, 5 pm; mobile phase: solvent A - 0.2% aq. formic acid, solvent B - ACN; gradient 1 to 40% solvent B in solvent A) to give the title compound (2.28 mg) as a solid. ES-MS m / z 525 (M+H).Example 21: (5R,7S)-2-(2-(l,4-Dioxan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-8-(6-methoxy- 3',5'-dimethyl-[3,4'-bipyridin]-5-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0351] A mixture of K2CO3 (20.1 mg, 145 pmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (15.2 mg, 65.2 pmol), (5R,7S)-2-(2-(l,4-dioxan-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-8-(5-chloro-2-methoxypyridin-3-yl)-7-methyl- 1,3,8- triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 26 mg, 48 pmol) and methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl) (2'-methylamino- 1 , 1 '-biphenyl-2- yl)palladium(II) (8.3 mg, 9.6 pmol) was purged with nitrogen, then MeOH (0.22 mL) and water(22 pL) were added. The reaction vessel was sealed and the mixture was heated at 80 °C for 2 h. The reaction mixture was diluted with water and EtOAc and filtered through a pad of diatomaceous earth. The aqueous layer was separated, and the organic layer was washed with water and sat. aq. NaCl, dried over anhydrous NaaSCM, filtered and the solvent was removed. The residue was purified by silica gel chromatography using a gradient of 0 to 5% EtOH in EtOAc to give the title compound (29 mg). ES-MS (w / z) 611 (M+H).Example 22: (5R,7S)-8-(6-(Hydroxymethyl)-3',5'-dimethyl-[4,4'-bipyridin]-2-yl)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0352] A mixture of (5R,7S)-8-(5-(3,5-dimethylpyridin-4-yl)-[l,2,3]triazolo[l,5-a]pyridin-7-yl)- 7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (10 mg, 17 pmol) and formic acid (0.2 pL, 5 pmol) in ACN (1 mL) and water (0.2 mL) was purged with nitrogen for 2 min, then stirred vigorously at 26 °C for 2 h. The reaction mixture was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100 x 25mm, 10 pm; mobile phase: solvent A - 10 mM aq. NH4HCO3, solvent B - ACN; gradient: 10 to 40% solvent B in solvent A) to give the title compound (4.64 mg) as a solid. ES-MS m z 525.2 (M+H).Example 23: (5R,7S)-2-(2-(l,4-Dioxan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-8-(6-methoxy- 3',5'-dimethyl-[3,4'-bipyridin]-5-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers)

[0353] A mixture of (5R,7S)-2-(2-(l,4-dioxan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-8-(5- chloro-2-methoxypyridin-3-yl)-7-methyl-l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 15 mg, 28 pmol), K2CO3 (12 mg, 87 pmol) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (11 mg, 47 pmol) was purged with nitrogen and then methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,l'-biphenyl)(2'-methylamino- l,r-biphenyl-2-yl)palladium(II) (3.6 mg, 4.2 pmol), MeOH (1 mL), and water (0.1 mL) were added. The reaction vessel was sealed and the mixture was stirred at 80 °C for 4 h. The reaction was concentrated to dryness and the residue was purified by silica gel chromatography eluting with 0 to 100% EtOAc in hexanes, then 2% MeOH in EtOAc. The product was re-purified by reverse-phase HPLC (column: XBridge C18 19 x 150 mm, 5 pm; mobile phase: solvent A - 20 mM aq. NH4HCO3, solvent B - ACN; gradient: 35 to 70% solvent B in solvent A) to give the title compound (8.5 mg) as a solid. ES-MS m / z 609 (M-H).Example 24: (5R,7S)-8-(6-(3,5-Dimethylpyridin-4-yl)-3-methylpyridazin-4-yl)-7-methyl-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0354] A mixture of (5R,7S)-7-methyl-2-(2-(trifhioromethyl)pyridin-3-yl)-1.3,8- triazaspiro[4.5]dec-l-en-4-one dihydrochloride (500 mg, 1.29 mmol), 4-chloro-6-(3,5- dimethylpyridin-4-yl)-3-methylpyridazine (430 mg, 1.66 mmol), potassium tert-butoxide (643 mg, 5.44 mmol) and (SP-4-l)-[l,3-BIs[2,6-bis(l-ethylpropyl)phenyl]-4,5-dichloro-l,3-dihydro- 2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (CAS# 1612891-29-8, 50 mg, 57 pmol) in 1,4-dioxane (8 mL) was heated to 110 °C for 12 h under nitrogen. The reaction mixture was filtered through a pad of diatomaceous earth under reduced pressure and rinsed with 10 mL EtOAc. The filtrate was concentrated under reduced pressure at 45°C. The residue was purified by reverse-phase HPLC (column: Waters xbridge 150 x 25mm 10 pm; mobile phase: solvent A - 0.2% aq. formic acid, solvent B - ACN; gradient: 5 to 35% solvent B in solvent A) and then repurified by reverse-phase HPLC (column: WePure Biotech XP tC18 150 x 40mm, 7 pm; mobile phase: solvent A - 10 mM aq. NH4HCO3, solvent B - ACN; gradient: 16 to 46% solvent B in solvent A) to give the title compound (0.6 mg) as a solid. ES-MS m / z. 510 (M+H).Example 25: (5R,7S)-8-(3',5'-Dimethyl-[4,4'-bipyridin]-2-yl)-7-methyl-2-(2-(trifluoromethyl)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0355] To a mixture of (5R,7S)-8-(4-bromopyridin-2-yl)-7-methyl-2-(2- (trifluoromethyl)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (47 mg, 95 pmol), 3,5-dimethyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (45 mg, 0.19 mmol) and K2CO3 (40 mg, 0.28 mmol) in 1 ,4-dioxane (1 mL) and water (0.2 mL) was added Pd(dppf)C12 (14 mg, 19 pmol). The mixture was sparged with nitrogen and stirred at 100 °C for 16 h under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with sat. aq. NaCl (5 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversephase flash chromatography using 5% ACN in 0.2% aq. formic acid, then re-purified by reversephase HPLC (column: F-Welch Xtimate C18 40 x 200mm, 7 pm; mobile phase: solvent A - 0.225% aq. formic acid, solvent B - ACN: gradient - 0 to 26% solvent B in solvent A) to give the title compound (17.55 mg) as an oil. ES-MS m / z 494 (M+H).Example 26: (5R.7S)-8-(6-Hydroxy-3',5’-dimethyl-[3.4'-bipyridin]-5-yl)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0356] A mixture of (5R,7S)-8-(6-methoxy-3',5'-dimethyl-[3,4'-bipyridin]-5-yl)-7-methyl-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (210.0 mg, 364.3 pmol) in DCM (2 mL) was cooled to -78 °C and purged with nitrogen for one minute. BBr? (2 M solution in DCM, 1.5 mL, 3.0 mmol) was added dropwise to the reaction mixture at -78 °C over 1 min, then the mixture was allowed to stir at 28 °C for 12 h under nitrogen. The reaction mixture was quenched by adding 5 mL MeOH, then concentrated under reduced pressure. The residue waspurified by reverse-phase HPLC (column: Phenomenex luna C18 100 x 40mm, 5 pm; mobile phase: solvent A - 0.2% aq. formic acid, solvent B - ACN; gradient: 1 to 30% solvent B in solvent A) to give the title compound (60 mg) as an oil. ES-MS m / z 511 (M+H).Example 27: (5R,7S)-8-(6-(Difluoromethoxy)-3',5'-dimethyl-[3,4'-bipyridin]-5-yl)-7-methyl-2- (2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0357] A mixture of (5R,7S)-8-(6-hydroxy-3',5'-dimethyl-[3,4'-bipyridin]-5-yl)-7-methyl-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (60 mg, 99 pmol), K2CO3 (35 mg, 0.25 mmol) and sodium chloro (difluoro) acetate (18 mg, 0.12 mmol) in ACN (2 mL) was purged with nitrogen for one minute before vigorously stirring at 100 °C for 16 h. Additional sodium chloro(difluoro)acetate (10 mg, 64 pmol) was added to the reaction mixture at 28 °C.The mixture was purged with nitrogen for one minute before vigorously stirring at 100 °C for 16 h. The reaction mixture was allowed to cool down to RT, then filtered through a pad of diatomaceous earth under reduced pressure and rinsed with 10 mL ACN. The filtrate was concentrated under reduced pressure at 45 °C and the residue was purified by reverse-phase HPLC (column: Phenomenex luna C18 100 x 40mm, 5 pm; mobile phase: solvent A - 0.2% aq. formic acid, solvent B - ACN; gradient - 10 to 40% solvent B in solvent A) to give the title compound (22.27 mg) as a solid. ES-MS m / z 561 (M+H).Example 28: (5R,7S)-8-(6-Cyclopropyl-3',5’-dimethyl-[3.4'-bipyridin]-5-yl)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0358] A mixture of (5R,7S)-8-(5-chloro-2-cyclopropylpyridin-3-yl)-7-methyl-2-(2- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (25 mg, 54 pmol), 3,5- dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (15 mg, 64 pmol) and K2CO3 (18 mg, 0.13 mmol) in MeOH (0.5 mL) and water (0.05 mL) was purged with nitrogen for 20 seconds, then methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,r-biphenyl)(2'- methylamino- l,l'-biphenyl-2-yl)palladium(II) (5 mg, 6 pmol) was added to the mixture. The reaction mixture was stirred at 80 °C for 12 h under nitrogen. After cooling to RT, the reaction mixture was filtered through a pad of diatomaceous earth under reduced pressure and rinsed with 10 mL MeOH. The filtrate was concentrated under reduced pressure which was purified by preparative TLC (50% EtOAc in petroleum ether, R / = 0.4), then re-purified by reverse-phase HPLC (column: WePure Biotech XP tC18 150 x 40, 7 pm; mobile phase: solvent A - 10 mM aq. NH4HCO3, solvent B - ACN; gradient: 30 to 70% solvent B in solvent A) to give the title compound (13 mg) as a solid. ES-MS m / z 535 (M+H).Example 29: 2-(6'-Cyclopropoxy-2,4-dimethyl-5'-((5R,7S)-7-methyl-4-oxo-2-(2- (tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-[3,3'- bipyridin]-6-yl)-2-hydroxyacetamide (mixture of isomers)

[0359] A mixture of 2-(4,6-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- yl)-2-hydroxyacetamide (racemic mixture, 200 mg, 581 pmol), (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, 150 mg, 264 pmol), K3PO4 (195 mg, 914 pmol) and 2nd Generation SPhos Precatalyst (CAS# 1375325-64-6, 44 mg, 60 pmol) in MeOH (2.5 mL) and water (0.5 mL) was purged with nitrogen for 2 min, then heated at 100 °C for 2 h with vigorous stirring. The reaction mixture was poured into 10 mL water, and then extracted with EtOAc (5 mL x 3). The combined organic layers were washed with sat. aq. NaCl(10 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. The residue was purified by preparative TLC (50% Ethyl acetate in petroleum ether, R / = 0.4), then re-purified by reverse-phase-HPLC (column: WePure Biotech XP tC18 150 x 40, 7 pm; mobile phase: solvent A - 10 mM aq. NH4HCO3, solvent B - ACN; gradient 30 to 60% solvent B in solvent A) to give the title compound (13.91 mg) as a solid. ES-MS m / z. 694 (M+H).Example 30: 2-(2,4-Dimethyl-5'-((5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-6'-(2,2,2-trifluoroethoxy)- [3,3'-bipyridin]-6-yl)-2-hydroxyacetamide (mixture of isomers)[03601 A mixture of (5R,7S)-7-methyl-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3- yl)-8-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)- l,3,8-triazaspiro[4.5]dec-l-en-4-one (mixture of isomers, 30 mg, 43 pmol), 2-(5-bromo-4,6- dimethylpyridin-2-yl)-2-hydroxyacetamide (racemic mixture, 14 mg, 53 pmol) and K3PO4 (30 mg, 0.14 mmol) in 1,4-dioxane (0.5 mL) and water (0.1 mL) was purged with nitrogen for 30 seconds, then methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,r-biphenyl)(2'- methylamino- l,T-biphenyl-2-yl)palladium(II) (4 mg, 5 pmol) was added to the mixture. The reaction mixture was stirred at 100 °C for 2 h under nitrogen, then cooled to RT, poured into 2 mL water, extracted with EtOAc (1 mL x 3), and dried over Na2SO4. The Na2SO4 was filtered off and further washed with 4 mL EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (DCM:MeOH=5:l, R / =0.4). The product was re-purified by reverse-phase HPLC (Waters Xbridge BEH C18 100 x 30mm, 10 pm; mobile phase: solvent A - 10 mM aq. NH4HCO3, solvent B - ACN; gradient: 50 to 85% solvent B in solvent A) to give the title compound (26.8 mg) as a solid. ES-MS m / z 736 (M+H).Example 31: 2-(2,4-Dimethyl-5'-((5R,7S)-7-methyl-4-oxo-2-(2-(tetrahydrofuran-2-yl)-6- (trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)-6'-(oxetan-3-yloxy)-[3,3'- bipyridin]-6-yl)-2-hydroxyacetamide (mixture of isomers)

[0361] A mixture of (5R,7S)-7-methyl-8-(2-(oxetan-3-yloxy)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-3-yl)-2-(2-(tetrahydrofuran-2-yl)-6-(trifluoromethyl)pyridin-3-yl)- l,3,8-triazaspiro[4.5Jdec-l-en-4-one (44 mg, 72 wt%, 48 pmol), 2-(5-bromo-4,6- dimethylpyridin-2-yl)-2-hydroxyacetamide (racemic mixture, 16 mg, 60 pmol) and K3PO4 (40 mg, 0.19 mmol) in 1,4-dioxane (0.5 mL) and water (0.1 mL) was purged with nitrogen for 30 seconds, then methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,T-biphenyl)(2'- methylamino-l,r-biphenyl-2-yl)palladium(II) (6 mg, 7 pmol) was added and the reaction mixture was stirred at 100 °C for 2 h under nitrogen. After cooling to RT, the reaction mixture was poured into 2 mL water, and then extracted with EtOAc (1 mL x 3). The combined organic layers were dried over NazSCU, then the Na2SC>4 was filtered off and further washed with EtOAc (4 mL). The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (DCM:MeOH-5: 1 , R / =0.4). The product was re-purified by reverse-phase HPLC (WePure Biotech XPt C18 150 x 40mm, 7 pm; mobile phase: solvent A - 10 mM aq. NH4HCO3, solvent B - ACN; gradient: 25 to 55% solvent B in solvent A) to give the title compound (21.2 mg) as a solid. ES-MS m / z 710 (M+H).Example 32: (5R,7S)-7-Methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-8-(3',5',6-trimethyl-[3,4'- bipyridin]-5-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0362] 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 (105 mg, 210 pmol), 3,5- dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (101 mg, 425 pmol) and K2CO3 (89 mg, 0.64 mmol) in MeOH (5 mL) and water (1 mL) was purged with nitrogen for 2 min, then methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,r-biphenyl)(2'- methylamino- l,l'-biphenyl-2-yl)palladium(II) (38 mg, 43 pmol) was added and the reaction mixture was stirred vigorously at 80 °C for 3 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1, R / = 0.4), then re-purified by reverse-phase HPLC (column: WePure Biotech XPt C18 150 x 40, 7pm; mobile phase: solvent A - 10 mM aq. NH4HCO3, solvent B - ACN; gradient: 30%-60% solvent B in solvent A) to give the title compound (25.2 mg) as a solid. ES-MS m / z) 509 (M+H).

[0363] The compounds in the below table were prepared in similar manner as described in the preparation of Intermediate 52 or Examples 2 or 15, using the appropriate halide and boronic acid / boronate ester. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Example 102: (5R,7S)-8-(8-Chloro-3-(3,5-dimethylpyridin-4-yl)indolizin-l-yl)-7-methyl-2-(2-(triiluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one

[0364] To a solution of (5R,7S)-7-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8- triazaspiro[4.5]dec-l-en-4-one dihydrochloride (1.00 g, 2.09 mmol) and 3-chloropicolinaldehyde (0.52 g, 3.6 mmol) in acetonitrile (15 mL) was added 3,5-dimethyl-4- ((trimethylsilyl)ethynyl)pyridine (0.50 g, 2.4 mmol), copper(II)trifluoromethanesulfonate (0.32 g, 0.84 mmol), cuprous chloride (0.15 g, 1.4 mmol), and DIEA (0.74 mL, 4.2 mmol) at RT. The reaction mixture was stirred at 100 °C. After 16 h, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase purification, eluting with 40-60% acetonitrile in (lOmM aqueous ammonium bicarbonate), to obtain the title compound (0.131 g, 11%) after lyophilization. ES-MS m / z 567 (M+H).

[0365] The compounds in the below table were prepared in similar manner as described in Example 102. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Example 106: 3-(3,5-Dimethylpyridin-4-yl)-l-((5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-8-yl)indolizine-8-carbonitrile[03661 To a mixture of (5R,7S)-8-(8-bromo-3-(3.5-dimethylpyridin-4-yl)indolizin-l-yl)-7- methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one (78 wt%; 0.100g, 0.128 mmol) in DMF (3 mL) was added copper(I) cyanide (0.060 g, 0.67 mmol) in one portion at 20 °C under nitrogen. The reaction mixture was stirred at 140 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (SiCL, EtOAc, Rf = 0.5, UV) to give crude product. The crude product was purified by reverse phase purification, eluting with 30-60% acetonitrile in 10 mM aqueous ammonium bicarbonate, to obtain the title compound (0.007 g, 10%) as a yellow solid after lyophilization. ES-MS m / z 558 (M+H).Example 107: 2-(4-(6-((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)-5-(cyclopropylmethyl)pyridin-2-yl)-3-methyl-5- (methylamino)- IH-pyrazol- 1 -yl)acetamide

[0367] To a mixture of 2-(4-(6-((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)-5-(cyclopropylmethyl)pyridin-2-yl)-5-((4- methoxybenzyl)(methyl)amino)-3-methyl-lH-pyrazol-l-yl)acetamide (75 wt%; 0.045 g, 0.044 mmol) in DCE (1 mL) was added TFA (0.70 g, 59 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h, then concentrated under reduced pressure. The residue was purified by reverse phase purification, eluting with 45-75% acetonitrile in 10 mM aqueous ammonium bicarbonate, to obtain the title compound (0.026 g). ES-MS m / z 650 (M+H).Example 108: 2-(5'-(2-(2-Cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-4-oxo-l,3,8- triazaspiro[4.5]dec-l-en-8-yl)-6'-(2,2-difluoroethoxy)-2,4-dimethyl-[3,3'-bipyridin]-6-yl)-N-(2- hydroxy ethyl) acetamide

[0368] To a mixture of 2-(5'-(2-(2-Cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-4-oxo-l,3,8- triazaspiro[4.5]dec-l-en-8-yl)-6'-(2,2-difluoroethoxy)-2,4-dimethyl-[3,3'-bipyridin]-6-yl)acetic acid (68 wt%; 0.20 g, 0.201 mmol), 2-aminoethan-l-ol (0.030 g, 0.49 mmol), DIPEA (0.108 g, 0.819 mmol) and DMF (3 mL) was added HATU (0.120 g, 0.309 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 1 h, then quenched with water (0.5 mL). The mixture was purified by reverse phase purification, eluting with 30-70% acetonitrile in 10 mM aqueous ammonium bicarbonate, to obtain the title compound (0.051 g) as a solid. ES-MS m / z 716 (M+H).

[0369] The compounds in the below table were prepared in similar manner as described in Example 108. In some cases, ammonium chloride was used as the source of the amine. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table:Example 113: 2-(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)-6'-ethyl-2-methoxy-4-methyl-[3,3'-bipyridin]-6-yl)acetamide

[0370] EtOH (5 mL) was slowly added to wet Pd / C (10% wt; 0.035 g, 0.033 mmol) under an atmosphere of argon. 2-(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)-2-methoxy-4-methyl-6'-vinyl-[3,3'-bipyridin]-6-yl)acetamide (66 wt%; 0.30 g, 0.311 mmol) was added. The reaction mixture was cycled through vacuum / hydrogen three times, then stirred under hydrogen (15 psi) at 20 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (SiCL, 10:1 DCM:MeOH, Rf = 0.8, UV) to give crude product. The crude product was purified by reverse phase purification, eluting with 30-70% acetonitrile in 10 mM aqueous ammonium bicarbonate, to obtain the title compound (0.050 g) as a solid. ESMS m / z 636 (M+H).Example 114: 2-(4-Cyclopropyl-5-(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)-6-ethoxypyridin-3-yl)-l-methyl-lH- imidazol-2-yl)acetamide

[0371] To a mixture of 2-(4-cyclopropyl-5-(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)-6- ethoxypyridin-3-yl)- 1 -methyl- lH-imidazol-2-yl)acetonitrile (62 wt%; 0.030 g, 0.029 mmol) in MeOH (3 mL) and DMSO (0.5 mL) was added NaOH (0.013 g, 0.31 mmol) and H2O2 (30 wt% in H2O. 0.025 mL, 0.25 mmol) at 18 °C. The reaction mixture was stirred at 25 °C for 1 h, quenched with sat. aq. Na^SCh (0.5 mL) at 20 °C, and concentrated under reduced pressure. The residue was purified by reverse phase purification, eluting with 15-55% acetonitrile in 10 mM aqueous ammonium bicarbonate, to obtain the title compound (0.008 g) as a solid. ES-MS m / z 651 (M+H).Functional Activity Assay I and Data

[0372] Functional activity was determined using cAMP formation in human GCGR-expressing HEK-293 clonal cell lines. Each receptor cell line was treated with compound or peptide (20- point concentration response curves with 2-fold direct dilutions prepared with a Labcyte™ Echo Acoustic Liquid Handler) in Dulbecco’s Modified Eagle’s Medium (DMEM, Gibco® Cat# 31053) supplemented with IX GlutaMAX™ (Gibco® Cat# 35050061), 0.1% bovine casein (Sigma Cat# C4765-10ML), 250 pM isobutylmethylxanthin (IBMX, Acros Cat# 228420010) and 20 mM N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid (HEPES, Gibco® Cat# 15630080) in a 20 pl assay volume.

[0373] After a 30-min incubation at 37°C, the intracellular cAMP was quantitatively determined using the cAMP Gs dynamic Kit (Revvity / Cisbio, Cat# 62AM4PEJ). Briefly, intracellular cAMP levels were detected by adding the cAMP-d2 conjugate in cell lysis buffer followed by the antibody anti-cAMP-Eu3+-Cryptate, also in cell lysis buffer. The resulting competitive assay was incubated for at 60 min at RT and then detected using a PHERAstar Instrument (BMG Labtech) with excitation at 320 nm and emission at 665 nm and 620 nm. Raw data values (emission at 665nm / 620nm* 10,000) were inversely proportional to the amount of cAMP present and were converted to cAMP (nM) per well using a cAMP standard curve.

[0374] The amount of cAMP generated (nM) in each well was converted to a percent of the maximal response observed with human Glucagon(l-29) {hGCG(l-29)J. A relative EC50 (Rel EC50) and Emax value were derived by non-linear regression analysis using the percent maximal response vs. the concentration of the compound added, fitted to a four-parameter logistic equation. Rel EC50 represents geometric mean of the concentration producing one-half of the maximal stimulation (one-half of the Emax). Emavalue represents arithmetic mean of the fitted top of the concentration-response curve relative to the percent of maximal response to hGCG(l- 29).

[0375] Data for the exemplified compounds and hGCG(l-29) which is used as a reference are shown in the table below.256In Vitro Functional Assay II and Data

[0376] Functional activity was determined by measuring cAMP formation in HEK293 freestyle cell that was transiently transfected with human glucagon receptor (hGCGR) in which a phenylalanine residue at the position 345 was substituted with cysteine (hereafter F345C). The activity of ligands on hGCGR F345C cells can be potentiated by the positive allosteric modulator, 4-(3-(benzyloxy)phenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP, seeWillard, F.S. et al. Adv. Pharmacol. 2020, 88, 173-191). The hGCGR F345C cells were treated with a compound or peptide (20-point concentration response curves with 2-fold direct dilutions prepared with a Labcyte™ Echo Acoustic Liquid Handler) in DMEM (Gibco® Cat# 31053) supplemented with IX GlutaMAXIM(Gibco® Cat# 35050061), 0.1% bovine casein (Sigma® Cat# C4765-10ML), 250 pM IB MX (Acros Cat# 228420010) and 20 mM HEPES (Gibco® Cat# 15630080) in a 20 pL assay volume in the presence of 1 pM BETP.

[0377] After a 30 min of incubation at 37 °C, the intracellular cAMP was quantitatively determined using a cAMP Gs dynamic Kit (Revvity / Cisbio, Cat# 62AM4PEJ). Briefly, intracellular cAMP levels were detected by adding the cAMP-d2 conjugate in cell lysis buffer followed by the antibody anti-cAMP-Eu3+-Cryptate, also in cell lysis buffer. The resulting competitive assay was incubated for 60 minutes at RT and then detected using a PHERAstar Instrument (BMG Labtech) with excitation at 320 nm and emission at 665 nm and 620 nm. Raw data values (emission at 665 nm / 620 nm* 10,000) were inversely proportional to the amount of cAMP present and were converted to cAMP (nM) per well using a cAMP standard curve.

[0378] The amount of cAMP generated (nM) in each well was converted to a percent of the maximal response observed with human Glucagon(2-29) [hGCG(2-29)] in the presence of 1 pM BETP. A relative EC50 (Rel EC50) and Emaxvalue were derived by non-linear regression analysis using the percent maximal response versus the concentration of compound added, fitted to a four-parameter logistic equation. Rel EC50 represents geometric mean of the concentration producing one-half of the maximal stimulation (one-half of the Emax). Emaxvalue represents arithmetic mean of the fitted top of the concentration-response curve relative to the percent of maximal response to hGCG(2-29) in the presence of 1 pM BETP.

[0379] Data for exemplary analogs, human Glucagon(l-29) [hGCG(l-29)], and hGCG(2-29) are shown in the table below.

Claims

1. CLAIMSWhat is claimed is:

1. A compound of following formula, or a pharmaceutically acceptable salt thereof:wherein:A ring is a 5 to 10 membered heteroaryl or heterocyclic 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, and (c) -Ci-io alkoxy,(2) halogen,(3) oxo.(4) -CN,(5) -OH,(6) -C3-10 cycloalkyl,(7) -0Ra, wherein Rais selected from:(a) -Ci-10 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-10 cycloalkyl, and(c) a 4 to 10 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, and(8) -C(0)NH2;B ring is a 5 to 10 membered heteroaryl or heterocyclic 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -Ci-io alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C MO alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-10 alkyl and (b) oxo, and(9) -SO2NH2; each of R4, R4, R5, and R5is independently selected from:(1) H,(2) halogen,(3) -Ci-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) -OH and (b) halogen, and(4) -C3-6 cycloalkyl;R6is selected from:(1) an aryl, and(2) a 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S:wherein each of the aryl of (1) and heteroaryl or heterocyclyl of (2) 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 (a) halogen and (b) -OH,(c) -Ci-io alkoxy, optionally substituted with 1 to 3 halogens,(d) -C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-10 alkyl, and(e) a 5 to 10 membered heteroaryl or 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, (ii) halogen, (iii) -OH, and (iv) -Ci-10 alkoxy; andR7is selected from:(1) H, and(2) -Ci-10 alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen.

2. The compound of claim 1 having formula (la), or a pharmaceutically acceptable salt thereof:wherein: the A ring is a 5 to 10 membered heteroaryl or heterocyclic 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) -Ci-10 alkoxy,(2) halogen,(3) oxo,(4) -CN,(5) -OH,(6) -C3-10 cycloalkyl, and(7) -0Ra, wherein Rais selected from:(a) -Ci-10 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-10 cycloalkyl, and(c) a 4 to 10 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S; the B ring is a 5 to 10 membered heteroaryl or heterocyclic 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -Ci-10 alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -Ci-10 alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN, and(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-io alkyl and (b) oxo; andR4is selected from:(D H,(2) -Ci-io alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) -OH and (b) halogen, and(3) -C3-10 cycloalkyl.

3. The compound any one of claims 1-2, 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, and (c) -C1-6 alkoxy,(2) halogen,(3) oxo,(4) -CN,(5) -OH,(6) -C3-6 cycloalkyl, and(7) -ORa, wherein Rais selected from:(a) -C1-6 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N. O, and S.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein:the A ring is a 5- or 6-membered heteroaryl ring selected from pyridyl, pyridazinyl, pyrimidyl, pyrazolyl, imidazolyl, triazolyl, 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, and (c) -Ci-6 alkoxy,(2) -CN,(3) -OH,(4) -C3-6 cycloalkyl, and(5) -ORa, wherein Rais selected from:(a) -C1-6 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein: the B ring is a 5 to 10 membered heteroaryl or heterocyclyl 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-6 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -Ci -6 alkyl,(2) halogen,(3) -C3-6 cycloalkyl,(4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H.(b) -Ci-6 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-6alkyl,(6) oxo,(7) -CN, and(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-6 alkyl and (b) oxo.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein: the B ring is a 5 to 10 membered heteroaryl or heterocyclyl ring selected from pyridyl, pyridazinyl, pyrimidyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, lH-pyrrolo[2,3- b]pyridinyl. 2,3-dihydro-lH-benzo[d]imidazolyl, and benzo [d]oxazolyl. 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-6 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -C 1-6 alkyl,(2) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C 1-6 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-6alkyl,(3) oxo,(4) -CN, and(5) 5- or 6- membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-6 alkyl and (b) oxo.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein: the B ring is a 5- or 6-membered monocyclic heteroaryl or heterocyclic ring selected from pyridyl, pyrimidyl, pyrazolyl, imidazolyl, thiazolyl; or the B ring is an 8 to 10 membered bicyclic heteroaryl or heterocyclic ring 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci-io alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C 1-10 alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci.io alkyl,(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-io alkyl and (b) oxo,(9) -SO2NH2, and(10) H.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein:R4is selected from:(1) H, and(2) -C1-6 alkyl.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein:R6is selected from:(1) a phenyl, and(2) a 5- or 6-membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the phenyl of (1) and heteroaryl or heterocyclyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -C 1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(c) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(d) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, and(e) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3substituents independently selected from (i) -Ci-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -C 1-6 alkoxy.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein:R6is selected from:(1) a phenyl, and(2) a 5- or 6-membered heteroaryl or heterocyclic ring selected from pyridyl and pyrimidyl; wherein each of the phenyl of (1) and heteroaryl or heterocyclyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(b) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C 1-6 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci -6 alkoxy.

11. 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, and (c) -C1-6 alkoxy,(2) halogen,(3) oxo,(4) -CN,(5) -OH,(6) -C3-6 cycloalkyl, and(7) -ORa, wherein Rais selected from:(a) -Ci-6 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S; the B ring is a 5 to 10 membered heteroaryl or heterocyclyl 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-6 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -C1-6 alkyl,(2) halogen,(3) -C3-6 cycloalkyl,(4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C1-6 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-6alkyl,(6) oxo,(7) -CN, and(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-6 alkyl and (b) oxo;R4is selected from:(1) H, and(2) -Ci-6 alkyl; each of R4, R and R5is H;R6is selected from:(1) a phenyl, and(2) a 5- or 6-membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the phenyl of (1) and heteroaryl or heterocyclyl of (2) 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 (a) halogen and (b) -OH,(c) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,(d) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C 1-6 alkyl, and(e) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci -6 alkoxy; andR7is selected from:(1) H, and(2) -C1-6 alkyl.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein:the A ring is a 5- or 6-membered heteroaryl ring selected from pyridyl, pyridazinyl, pyrimidyl, pyrazolyl, imidazolyl, triazolyl, 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, and (c) -Ci-6 alkoxy,(2) -CN,(3) -OH,(4) -C3-6 cycloalkyl, and(5) -ORa, wherein Rais selected from:(a) -C1-6 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S; the B ring is a 5 to 10 membered heteroaryl or heterocyclyl ring selected from pyridyl, pyridazinyl, pyrimidyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, lH-pyrrolo[2,3- b]pyridinyl, 2,3-dihydro-lH-benzo[d]imidazolyl, and benzo [d]oxazolyl, 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-6 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -C1-6 alkyl,(2) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C1-6 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-6alkyl,(3) oxo,(4) -CN, and(5) 5- or 6- membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-6 alkyl and (b) oxo;R4is selected from:(1) H, and(2) -Ci-6 alkyl;R6is selected from:(1) a phenyl, and(2) a 5- or 6-membered heteroaryl or heterocyclic ring selected from pyridyl and pyrimidyl; wherein each of the phenyl of (1) and heteroaryl or heterocyclyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(b) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci -6 alkoxy; andR7is H.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein: the A ring is a 5- or 6-membered heteroaryl ring selected from pyridyl, pyridazinyl, and pyrimidyl, optionally substituted with 1 to 4 substituents independently selected from:(1) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen, (b) -OH, and (c) -Ci-4 alkoxy,(2) -CN,(3) -OH,(4) cyclopropyl, and(5) -ORa, wherein Rais selected from:(a) -Ci-4 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-4 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S; the B ring is a 5 to 10 membered heteroaryl or heterocyclyl ring selected from pyridyl, pyrimidyl, pyrazolyl, imidazolyl, thiazolyl, lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydro-lH- benzo[d] imidazolyl, and benzo [d]oxazolyl. optionally substituted with 1 to 3 substituents independently selected from:(1) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -OH,(c) -O-C(O)Ci-4 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -C 1-4 alkyl,(2) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C 1-4 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-4alkyl,(3) oxo,(4) -CN, and(5) 5- or 6- membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-4 alkyl and (b) oxo;R4is -Ci-4 alkyl; andR6is selected from:(1) a phenyl, and(2) pyridyl; wherein each of the phenyl of (1) and pyridyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(b) -Ci-4 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-4 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-4 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-4 alkoxy.

14. The compound of claim 1 having formula (lb), or a pharmaceutically acceptable salt thereof:wherein: each of RA2, RA3, and RA4is independently selected from:(D H,(2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) halogen, (b) -OH, and (c) -Ci-6 alkoxy,(3) -C3-6 cycloalkyl,(4) -OH,(5) -CN, and(6) -ORa, wherein Rais selected from:(a) -C1-6 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S; the B ring is a 5 to 10 membered heteroaryl or heterocyclyl 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-6 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -C1-6 alkyl,(2) halogen,(3) -C3-6 cycloalkyl,(4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C1-6 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-6alkyl,(6) oxo,(7) -CN, and(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -Ci-6 alkyl and (b) oxo;R4is selected from:(1) H, and(2) -Ci-6 alkyl;R6is selected from:(1) a phenyl, and(2) a 5- or 6-membered heteroaryl or heterocyclic ring selected from pyridyl and pyrimidyl; wherein each of the phenyl of (1) and heteroaryl or heterocyclyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(b) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci -6 alkoxy; andR7is H.

15. The compound of claim 1 having formula (Ic), or a pharmaceutically acceptable salt thereof: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, and (c) -Ci-6 alkoxy,(3) -C3-6 cycloalkyl,(4) -OH,(5) -CN, and(6) -ORa, wherein Rais selected from:(a) -C1-6 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S; the B ring is a 5 to 10 membered heteroaryl or heterocyclyl 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-6 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -Ci -6 alkyl,(2) halogen,(3) -C3-6 cycloalkyl,(4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -Ci-6 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-6alkyl,(6) oxo,(7) -CN, and(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-6 alkyl and (b) oxo;R4is selected from:(1) H, and(2) -C1-6 alkyl;R6is selected from:(1) a phenyl, and(2) a 5- or 6-membered heteroaryl or heterocyclic ring selected from pyridyl and pyrimidyl; wherein each of the phenyl of (1) and heteroaryl or heterocyclyl 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 (a) halogen and (b) -OH,(b) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci -6 alkoxy; andR7is H.

16. The compound of claim 1 having formula (Id), or a pharmaceutically acceptable salt thereof:wherein: each of RA1and RA4is independently selected from:(1) H,(2) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) halogen, (b) -OH, and (c) -Ci-6 alkoxy,(3) -C3-6 cycloalkyl,(4) -OH,(5) -CN, and(6) -ORa, wherein Rais selected from:(a) -C1-6 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing I to 3 heteroatoms independently selected from N, O, and S; the B ring is a 5 to 10 membered heteroaryl or heterocyclyl 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-6 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -C 1-6 alkyl,(2) halogen,(3) -C3-6 cycloalkyl,(4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C1-6 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-6alkyl,(6) oxo,(7) -CN, and(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-6 alkyl and (b) oxo;R4is selected from:(1) H, and(2) -C1-6 alkyl;R6is selected from:(1) a phenyl, and(2) a 5- or 6-membered heteroaryl or heterocyclic ring selected from pyridyl and pyrimidyl; wherein each of the phenyl of (1) and heteroaryl or heterocyclyl 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 (a) halogen and (b) -OH,(b) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, and(d) a 5- or 6- membered heteroaryl or 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, (ii) halogen, (iii) -OH, and (iv) -Ci -6 alkoxy; andR7is H.

17. The compound of claim 1 having formula (le), or a pharmaceutically acceptable salt thereof: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, and (c) -Ci-6 alkoxy,(3) -C3-6 cycloalkyl,(4) -OH,(5) -CN, and(6) -ORa, wherein Rais selected from:(a) -C1-6 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N. O, and S;the B ring is a 5 to 10 membered heteroaryl or heterocyclyl 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-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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -Ci -6 alkyl,(2) halogen,(3) -C3-6 cycloalkyl,(4) -Ci 6 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H.(b) -C1-6 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-6alkyl,(6) oxo,(7) -CN, and(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-6 alkyl and (b) oxo;R4is selected from:(1) H, and(2) -C1-6 alkyl;R6is selected from:(1) a phenyl, and(2) a 5- or 6-membered heteroaryl or heterocyclic ring selected from pyridyl and pyrimidyl;wherein each of the phenyl of (1) and heteroaryl or heterocyclyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(b) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci -6 alkoxy; andR7is H.

18. The compound of claim 1 having formula (If), or a pharmaceutically acceptable salt thereof:wherein: each of RA1and RA3is independently selected from:(1) H,(2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) halogen, (b) -OH, and (c) -C1-6 alkoxy,(3) -C3-6 cycloalkyl,(4) -OH,(5) -CN, and(6) -ORa, wherein Rais selected from:(a) -Ci-6 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S; the B ring is a 5 to 10 membered heteroaryl or heterocyclyl 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-6 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci -6 alkyl,(2) halogen,(3) -C3-6 cycloalkyl,(4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H.(b) -C1-6 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-6alkyl,(6) oxo,(7) -CN, and(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-6 alkyl and (b) oxo;R4is selected from:(1) H, and(2) -Ci-6 alkyl;R6is selected from:(1) a phenyl, and(2) a 5- or 6-membered heteroaryl or heterocyclic ring selected from pyridyl and pyrimidyl; wherein each of the phenyl of (1) and heteroaryl or heterocyclyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(b) -Ci-6 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O. and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci -6 alkoxy; andR7is H.

19. The compound of any one of claims 14-18, or a pharmaceutically acceptable salt thereof, wherein: each of RA1, RA2, and RA3, when present, is independently selected from:(1) H,(2) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) halogen, (b) -OH, and (c) -C1-4 alkoxy,(3) -C3-6 cycloalkyl,(4) -OH,(5) -CN, and(6) -ORa, wherein Rais selected from:(a) -C1-4 alkyl, optionally substituted with 1 to 3 halogens,(b) a -C3-6 cycloalkyl, and(c) a 4 to 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N. O, and S;RA4is H; the B ring is a 5 to 10 membered heteroaryl or heterocyclyl ring selected from pyridyl, pyrimidyl, pyrazolyl, imidazolyl, thiazolyl, lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydro-lH- benzofd] imidazolyl, and benzo[d]oxazolyl, optionally substituted with 1 to 3 substituents independently selected from:(1) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -OH,(c) -O-C(O)Ci-4 alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and (ii) -C1-4 alkyl,(2) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C1-4 alkyl,(c) -C3-6 cycloalkyl, and(d) -C(O)Ci-4alkyl,(3) oxo,(4) -CN, and(5) 5- or 6- membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-4 alkyl and (b) oxo;R4is -Ci -4 alkyl; andR6is selected from:(1) a phenyl, and(2) pyridyl; wherein each of the phenyl of (1) and pyridyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) -C 1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(b) -Ci-4 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-4 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-4 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci -4 alkoxy.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein: each of RA1, RA2, and RA3, when present, is independently selected from:(1) H,(2) -C1-3 alkyl, optionally substituted with 1 to 3 substituents independently selected from(a) halogen, (b) -OH, (c) methoxy, and (d) ethoxy,(3) cyclopropyl,(4) cyclobutyl.(5) -OH,(6) -CN, and(7) -ORa, wherein Rais selected from:(a) methyl, optionally substituted with 1 to 3 halogens,(b) ethyl, optionally substituted with 1 to 3 halogens,(c) cyclopropyl,(d) cyclobutyl, and(e) a 4 to 6 membered heterocyclic ring containing 1 to 2 heteroatoms independently selected from N, O, and S; the B ring is a 5 to 10 membered heteroaryl or heterocyclyl ring selected from pyridyl, pyrimidyl, pyrazolyl, imidazolyl, thiazolyl, lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydro-lH- benzo[d]imidazolyl, and benzo [d]oxazolyl, optionally substituted with 1 to 3 substituents independently selected from:(1) -Ci-3 alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen,(b) -OH, and(c) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H, (ii) methyl, and (iii) ethyl,(2) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H.(b) methyl,(c) ethyl,(c) -C(O)methyl, and(e) -C(O)ethyl,(3) oxo,(4) -CN, and(5) 5- or 6- membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) methyl, (b) ethyl and (c) oxo;R4is -Ci -4 alkyl; andR6is selected from:(1) a phenyl, and(2) pyridyl;wherein each of the phenyl of (1) and pyridyl of (2) is optionally substituted with 1 to 3 substituents independently selected from:(a) -Ci-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(b) -Ci-4 alkoxy, optionally substituted with 1 to 3 halogens,(c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-4 alkyl, and(d) a 5- or 6- membered heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-4 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci -4 alkoxy.

21. The compound of claim 1 having formula (Ig), or a pharmaceutically acceptable salt thereof:wherein: each of RB2, RB3, RB4, RB5is 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci-10 alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -Ci-io alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-10 alkyl and (b) oxo,(9) -SO2NH2, and(10) H.

22. The compound of claim 1 having formula (Ih), or a pharmaceutically acceptable salt thereof:wherein: each of RB1, RB3, RB4, RB5is 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci-10 alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-io alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H.(b) -Ci-io alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-10 alkyl and (b) oxo,(9) -SO2NH2, and(10) H.

23. The compound of claim 1 having formula (li), or a pharmaceutically acceptable salt thereof:wherein: each of RB1, RB2, RB4, RB5is 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci-10 alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-io alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -C MO alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-10 alkyl and (b) oxo,(9) -SO2NH2, and(10) H.

24. The compound of claim 1 having formula (Ij), or a pharmaceutically acceptable salt thereof:wherein: each of RB1, RB3, and RB5is 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci-10 alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -Ci-10 alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl.(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-10 alkyl and (b) oxo,(9) -SO2NH2, and(10) H.

25. The compound of claim 1 having formula (Ik), or a pharmaceutically acceptable salt thereof:wherein: each of RB1, RB2, and RB5is 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci-10 alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -Ci-10 alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl.(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-10 alkyl and (b) oxo,(9) -SO2NH2, and(10) H.

26. The compound of claim 1 having formula (II), or a pharmaceutically acceptable salt thereof:wherein: each of RB1, RB3, RB4is 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci-io alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -Ci-10 alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-10 alkyl and (b) oxo,(9) -SO2NH2, and(10) H.

27. The compound of claim 1 having formula (Im), or a pharmaceutically acceptable salt thereof:wherein: each of RB1, RB2, and RB4is 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) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci-io alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -Ci-10 alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-10 alkyl and (b) oxo,(9) -SO2NH2, and(10) H.

28. The compound of claim 1 having formula (In), or a pharmaceutically acceptable salt thereof:wherein: each of RB1, RB2, and RB4is 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)CMO alkyl, and(d) -C(O)NRbRb, wherein each of Rband Rbis independently selected from (i) H and(ii) -Ci-io alkyl,(2) halogen,(3) -C3-10 cycloalkyl,(4) -Ci-10 alkoxy, optionally substituted with 1 to 3 halogens,(5) -NRCRC, wherein each of Rcand Rcis independently selected from:(a) H,(b) -Ci-10 alkyl,(c) -C3-10 cycloalkyl, and(d) -C(0)Ci-io alkyl,(6) oxo,(7) -CN,(8) 5 to 10 membered heteroaryl or heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (a) -C1-10 alkyl and (b) oxo,(9) -SO2NH2, and(10) H.

29. The compound of claim 1 having formula (Io), or a pharmaceutically acceptable salt thereof:wherein: each of R6a, R6b, R6c, and R6dis independently selected from:(a) H,(b) halogen,(c) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from(i) halogen and (ii) -OH,(d) -Ci-4 alkoxy, optionally substituted with 1 to 3 halogens,(e) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-4 alkyl.

30. The compound of claim 1, wherein the compound is chosen from:27331. A pharmaceutical composition comprising a compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

32. A method for treating a type 2 diabetes, obesity, or overweight with at least one weight related comorbidity selected from cancer, depression, diabetes, dyslipidemia, high blood pressure, high cholesterol, obstructive sleep apnea, osteoarthritis, and heart disease comprising administering an effective amount of a compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

33. A compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, for use in therapy.

34. A compound of any one of claims 1-30, 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 cancer, depression, diabetes, dyslipidemia, high blood pressure, high cholesterol, obstructive sleep apnea, osteoarthritis, and heart disease.

35. A compound or a pharmaceutically acceptable salt thereof, for use of claim 34, in the treatment of a type 2 diabetes.

36. A compound or a pharmaceutically acceptable salt thereof, for use of claim 34, in the treatment of obesity.

37. A compound or a pharmaceutically acceptable salt thereof, for use of claim 32, 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.

38. A compound of any one of claims 1-30, 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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