Glucagon receptor agonists with ARYL linkers and their use as therapies

Abstract

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

Description

GLUCAGON RECEPTOR AGONISTS WITH ARYL LINKERS AND THEIR USE AS THERAPIES TECHNICAL FIELD

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

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

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

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

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

[0006] 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.

[0007] Disclosed herein is a compound of formula (I): , or a pharmaceuticallyring, R4, R4’, R5, R5’, R6, R7, RA1, RA2, RA3, and RA4, are 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 is a compound of formula (I): ; wherein: each of RA1, RA2, RA3, and(1) H, (2) -C1-10 alkyl, optionally substituted with 1 to 4 substituents independently selected from: (a) halogen, (b) -OR11, wherein R11is selected from: (i) H, (ii) -C1-10 alkyl, optionally substituted with 1 to 4 substituents independently selected from halogen, -C1-10alkoxy and -C3-10cycloalkyl optionally substituted with 1 to 4 halogens, (iii) -C3-10 cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from halogen and -C1-10alkyl, and (iv) 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from halogen, -OH, and -C1-10 alkyl optionally substituted with 1 to 4 halogens, (c) -C3-10cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from (i) halogen and (ii) -C1-10 alkoxy, optionally substituted with 1 to 4 halogens, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-10 alkyl, optionally substituted with -C1-10 alkoxy, and (iii) -C3-10cycloalkyl, optionally substituted with 1 to 4 halogens, and(e) 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from: (i) halogen, (ii) -OH, and (iii) -C1-10 alkyl, optionally substituted with 1 to 4 halogens, (3) -CN, (4) -C1-10 alkoxy, optionally substituted with 1 to 4 halogens, (5) -NRa1Rb1, wherein each of Ra1and Rb1is independently selected from (a) H and (b) -C1-10 alkyl, (6) -C(O)R8, wherein R8is selected from (a) H, (b) -C1-10alkyl, and (c) -NH2, (7) -SO2R9; wherein R9is selected from (a) H and (b) -C1-10 alkyl, (8) -O-C3-10 cycloalkyl, optionally substituted with 1 to 4 halogens, (9) halogen, and (10) C2-10 alkenyl, optionally substituted with 1 to 4 halogens; B ring is a 5 to 10 membered heteroaryl or 4 to 10 membered 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) -C1-10 alkyl, optionally substituted with 1 to 4 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-10 alkyl, optionally substituted with 1 to 4 halogens, (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-10 alkyl, optionally substituted with 1 to 4 halogens, (iii) -C3-10 cycloalkyl, optionally substituted with 1 to 4 halogens, and (iv) 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, (ii) -C1-10alkyl, optionally substituted with 1 to 4 halogens, and(iii) -C(O)C1-10alkyl, optionally substituted with 1 to 4 halogens, (2) halogen, (3) -C3-10 cycloalkyl, optionally substituted with 1 to 4 halogens, (4) -C1-10alkoxy, optionally substituted with 1 to 4 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-10alkyl, optionally substituted with 1 to 4 halogens, (c) -C3-10 cycloalkyl, optionally substituted with 1 to 4 halogens, and (d) -C(O)C1-10 alkyl, optionally substituted with 1 to 4 halogens, (6) oxo, and (7) -CN; and each of R4, R4’, R5, and R5’is independently selected from: (1) H, (2) -C1-10alkyl, optionally substituted with 1 to 4 substituents independently selected from (a) -OH and (b) halogen, (3) -C3-10 cycloalkyl, and (4) halogen; R6is selected from: (1) an aryl, (2) a 5 to 10 membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O, and S, and (3) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 4 substituents independently selected from: (a) halogen, (b) -C1-10alkyl, optionally substituted with 1 to 4 substituents independently selected from (i) halogen and (ii) -OH, (c) -C1-10 alkoxy, optionally substituted with 1 to 4 halogens, (d) -C3-10cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from (i) halogen and (ii) -C1-10alkyl,(e) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (i) -C1-10 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-10 alkoxy, and (f) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (i) -C1-10 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-10 alkoxy; and R7is selected from: (1) H, (2) -C1-10 alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen, and (3) halogen. In one embodiment of the compound of formula (I): each of RA1, RA2, RA3, and RA4is independently selected from: (1) H, (2) -C1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH, (3) -CN, (4) -C1-10 alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa1Rb1, wherein each of Ra1and Rb1is independently selected from (a) H and (b) -C1-10alkyl, (6) -C(O)R8, wherein R8is selected from (a) H, (b) -C1-10alkyl, and (c) -NH2, and (7) -SO2R9; wherein R9is selected from (a) H and (b) -C1-10 alkyl; 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) -C1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-10 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from (i) H and (ii) -C1-10alkyl,(2) halogen, (3) -C3-10 cycloalkyl, (4) -C1-10 alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-10 alkyl, (c) -C3-10cycloalkyl, and (d) -C(O)C1-10 alkyl, and (6) oxo; each of R4, R4’, R5, and R5’is independently selected from: (1) H, (2) -C1-10 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) -OH and (b) halogen, and (3) -C3-10cycloalkyl; R6is selected from (1) an aryl and (2) a 5 to 10 membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1) and heteroaryl of (2) is optionally substituted with 1 to 3 substituents independently selected from: (1) halogen, (2) -C1-10alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH, (3) -C1-10 alkoxy, optionally substituted with 1 to 3 halogens, (4) -C3-10 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -C1-10alkyl, and (5) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-10alkyl, (b) halogen, (c) -OH, and (d) -C1-10alkoxy; and R7is selected from: (1) H, and (2) -C1-10alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen.In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Iaa): (Iaa); wherein:each of RA1and RA2is independently selected from: (1) H, (2) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OR11, wherein R11is selected from: (i) H, (ii) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -C1-6 alkoxy and -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (iii) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6 alkyl, and (iv) 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6 alkoxy, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-6 alkyl, optionally substituted with -C1-6 alkoxy, and (iii) -C3-6cycloalkyl, and (e) 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen,(ii) -OH, and (iii) -C1-6 alkyl, optionally substituted with 1 to 3 halogens, (3) -CN, (4) -C1-6alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa1Rb1, wherein each of Ra1and Rb1is independently selected from (a) H, and (b) -C1-6 alkyl, (6) -C(O)R8, wherein R8is selected from (a) H, (b) -C1-6alkyl, and (c) -NH2, (7) -SO2R9; wherein R9is selected from (a) H and (b) -C1-6 alkyl, (8) -O-C3-6 cycloalkyl, (9) halogen, and (10) -C2-6alkenyl; the B ring is a 5 to 10 membered heteroaryl or 5 to 10 membered 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)C1-6 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6alkyl, (2) halogen, (3) -C3-6 cycloalkyl, (4) -C1-6alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from:(a) H, (b) -C1-6 alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-6alkyl, (6) oxo, and (7) -CN; R4is selected from: (1) H, (2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) -OH and (b) halogen, and (3) -C3-6cycloalkyl; R6is selected from: (1) an aryl, (2) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (3) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C1-6alkyl, 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) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -C1-6 alkyl, (e) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-6 alkyl, (b) halogen, (c) -OH, and (d) -C1-6 alkoxy, and (f) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-6alkyl, (b) halogen, (c) -OH, and (d) -C1-6alkoxy; andR7is selected from: (1) H, and (2) -C1-6 alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen.

[0010] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Ia): ; wherein:RA1is selected from: (1) H, (2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH, (3) -CN, (4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa1Rb1, wherein each of Ra1and Rb1is independently selected from (a) H, and (b) -C1-6alkyl, (6) -C(O)R8, wherein R8is selected from (a) H, (b) -C1-6alkyl, and (c) -NH2, and (7) -SO2R9; wherein R9is selected from (a) H and (b) -C1-6 alkyl; 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)C1-6 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from (i) H and (ii) -C1-6alkyl, (2) halogen,(3) -C3-6cycloalkyl, (4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6 alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-6alkyl, and (6) oxo; R4is selected from: (1) H, (2) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) -OH and (b) halogen, and (3) -C3-6 cycloalkyl; R6is selected from (1) an aryl and (2) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1) and heteroaryl of (2) is optionally substituted with 1 to 3 substituents independently selected from: (1) halogen, (2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH, (3) -C1-6alkoxy, optionally substituted with 1 to 3 halogens, (4) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -C1-6 alkyl, and (5) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-6 alkyl, (b) halogen, (c) -OH, and (d) -C1-6 alkoxy; and R7is selected from: (1) H, and (2) -C1-6 alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen.In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Ib): , wherein:W1is -CR1or -NR1; W2is -CR2or -NR2; W3is -CR3or -NR3; W4is -CR4aor -NR4a; and W5is -CR5aor -NR5a; wherein each partial dashed bond “ ” is a single bond or a double bond, provided thatwhen it is a single bond, an extra H is present on each carbon to which it is attached to satisfy the valency of those carbons; or alternatively, when it is a double bond, R1, R2, R3, R4aor R5ais absent from -NR1, -NR2, -NR3, -NR4a, or -NR5ato satisfy the valency of that N; and each of R1, R2, R3, R4aand R5ais independently selected from: (1) H, (2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-6alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and(e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6 alkyl, (3) halogen, (4) -C3-6 cycloalkyl, (5) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6 alkyl, (c) -C3-6cycloalkyl, and (d) -C(O)C1-6alkyl, (7) oxo, and (8) -CN; or alternatively, when W2is -CR2= and W5is -CR5a=, R2and R5a, together with the carbon atoms to which they are attached form a 4 to 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -C1-6 alkyl, and (c) oxo. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Ic): , wherein:W3is -CR3or -NR3; W5is -CR5aor -NR3; wherein each partial dashed bond “ ” is a single bond or a double bond, provided that whenit is a single bond, an extra H is present on each carbon to which it is attached to satisfy thevalency of those carbons; or alternatively, when it is a double bond, R3or R5ais absent from -NR3or -NR5ato satisfy the valency of that N; and each of R2, R3, R4aand R5ais independently selected from: (1) H, (2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-6 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6alkyl, (3) halogen, (4) -C3-6 cycloalkyl, (5) -C1-6alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6 alkyl, (c) -C3-6cycloalkyl, and (d) -C(O)C1-6 alkyl, (7) oxo, and (8) -CN; or alternatively, when W5is -CR5a=, R2and R5a, together with the carbon atoms to which they are attached form a 4 to 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatomsindependently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -C1-6 alkyl, and (c) oxo. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Id): , wherein:W4is -CR4a= or -N=; W5is -CR5a= or -N=; and each of R1, R2, R3, R4aand R5ais independently selected from: (1) H, (2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-6 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6alkyl, (3) halogen, (4) -C3-6 cycloalkyl, (5) -C1-6alkoxy, optionally substituted with 1 to 3 halogens,(6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6 alkyl, (c) -C3-6cycloalkyl, and (d) -C(O)C1-6 alkyl, (7) oxo, and (8) -CN; or alternatively, when W5is -CR5a=, R2and R5a, together with the carbon atoms to which they are attached form a 4 to 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -C1-6 alkyl, and (c) oxo.

[0011] In one embodiment of the compound of formula (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt thereof, wherein: W4is -N=; W5is -N=; each of RA1and RA2is independently selected from: (1) H, (2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OR11, wherein R11is selected from: (i) H, (ii) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -C1-6alkoxy and -C3-6cycloalkyl, optionally substituted with 1 to 3 halogens, (iii) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6alkyl, and (iv) 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (c) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6alkoxy,(d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-6 alkyl, optionally substituted with -C1-6 alkoxy, and (iii) -C3-6cycloalkyl, and (e) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) -OH and (iii) -C1-6alkyl, optionally substituted with 1 to 3 halogens, (3) -CN, (4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (5) -O-C3-6 cycloalkyl, (6) halogen, and (7) -C2-6 alkenyl; when present, each of R1, R2, and R3is independently selected from: (1) H, (2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-6alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6alkyl, (3) halogen,(4) -C3-6cycloalkyl, (5) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6 alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-6alkyl, (7) oxo, and (8) -CN; when present, each of R4aand R5ais H; each of R4, R4’, R5, and R5’is independently selected from: (1) H, (2) -C1-6 alkyl, (3) -C3-6cycloalkyl, and (4) halogen; R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (3) a 5 to 10 membered monocyclic or fused bicyclic heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein each of the phenyl of (1), heteroaryl of (2), and heterocyclyl of (3) 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 (i) halogen and (ii) -OH, (c) -C1-6alkoxy, 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,(e) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-6 alkoxy, and (f) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-6 alkoxy; and R7is selected from: (1) H, and (2) -C1-6 alkyl.

[0012] In one embodiment of the compound of formula (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt thereof, wherein: each of RA1and RA2is independently selected from: (1) H, (2) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OR11, wherein R11is selected from: (i) H, (ii) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -C1-4 alkoxy and -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (iii) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-4 alkyl, and (iv) 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-4 alkoxy, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-4 alkyl, optionally substituted with -C1-4 alkoxy, and (iii) -C3-6cycloalkyl, and(e) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) -OH and (iii) -C1-4 alkyl, optionally substituted with 1 to 3 halogens, (3) -CN, and (4) halogen; R1is selected from: (1) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-4 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-4 alkyl, (iii) -C3-6cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-4 alkyl, (2) halogen, (3) -C3-6cycloalkyl, and (4) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens; each of R2and R3is independently selected from: (1) H, (2) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-4alkyl, and(d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-4 alkyl, (iii) -C3-6cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-4 alkyl, (3) -C1-4alkoxy, and (4) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, and (b) -C1-6 alkyl; each of R4, R4’, R5, and R5’is independently selected from: (1) H, and (2) -C1-4 alkyl; R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl selected from pyridyl, pyridazinyl, and pyrimidyl, and (3) a 5 to 10 membered heterocyclyl selected , wherein each of the phenyl of (1), heteroaryl ofis optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH, (c) -C1-4alkoxy, 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) -C1-4 alkyl; and R7is selected from:(1) H, and (2) -C1-4 alkyl.

[0013] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Ie), wherein: , wherein:W1is -CR1or -NR1, W2is -CR2or -NR2, W3is -CR3or -NR3, and W4is -CR4aor -NR4a, wherein each partial dash bond “ ” is a single bond or a double bond, provided that whenit is a single bond, anon each carbon to which it is attached to satisfy the valency of those carbons; or alternatively, when it is a double bond, R1, R2, R3, or R4ais absent from -NR1, -NR2, -NR3or -NR4ato satisfy the valency of that N; and wherein each of R1, R2, R3, and R4ais independently selected from: (1) H, (2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-6 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6 alkyl, (iii) -C3-6 cycloalkyl, and(iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6 alkyl, (3) halogen, (4) -C3-6cycloalkyl, (5) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-6 alkyl, (7) oxo, and (8) -CN; or alternatively, when W1is -CR1= and W2is -CR2or -NR2-, R1and R2, together with the carbon and / or nitrogen atoms to which they are attached form a 4 to 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -C1-6alkyl, and (c) -NH2, optionally substituted with 1 to 2 substituents independently selected from C1-6 alkyl and -C(O)-C1-6 alkyl.

[0014] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (If), wherein: , wherein:W2is -CR2or -NR2,W3is -CR3or -NR3, and W4is -CR4aor -NR4a, wherein each partial dash bond “ ” is a single bond or a double bond, provided that whenit is a single bond, an extra H is on each carbon to which it is attached to satisfythe valency of those carbons; or alternatively, when it is a double bond, R2, R3, or R4ais absent from -NR2, -NR3, or -NR4ato satisfy the valency of that N; and wherein, when present, each of R1, R2, R3, and R4ais independently selected from: (1) H, (2) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-6alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6 alkyl, (3) halogen, (4) -C3-6 cycloalkyl, (5) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6 alkyl, (c) -C3-6cycloalkyl, and (d) -C(O)C1-6alkyl, (7) oxo, and (8) -CN;or alternatively, when W2is -CR2or -NR2, R1and R2, together with the carbon and / or nitrogen atoms to which they are attached form a 4 to 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -C1-6 alkyl, and (c) -NH2, optionally substituted with 1 to 2 C1-6 alkyl groups.

[0015] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is of formula (Ig), wherein: , wherein:each of R1, R2, and R3is independently selected from: (1) H, (2) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-6alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6alkyl, (iii) -C3-6cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6 alkyl, (3) halogen, (4) -C3-6cycloalkyl,(5) -C1-6alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-6 alkyl, (7) oxo, and (8) -CN. In one embodiment of the compound of formula (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein: each of RA1and RA2is independently selected from: (1) H, (2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OR11, wherein R11is selected from: (i) H, (ii) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -C1-6 alkoxy and -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (iii) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6alkyl, and (iv) 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (c) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6 alkoxy, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-6 alkyl, optionally substituted with -C1-6 alkoxy, and (iii) -C3-6 cycloalkyl, and(e) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) -OH and (iii) -C1-6 alkyl, optionally substituted with 1 to 3 halogens, (3) -CN, (4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (5) -O-C3-6 cycloalkyl, (6) halogen, and (7) -C2-6alkenyl; each of R1, R2, and R3is independently selected from: (1) H, (2) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-6alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6alkyl, (iii) -C3-6cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6 alkyl, (3) halogen, (4) -C3-6 cycloalkyl, (5) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H,(b) -C1-6alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-6 alkyl, (7) oxo, and (8) -CN; when present, each of R4aand R5ais H; each of R4, R4’, R5, and R5’is independently selected from: (1) H, (2) -C1-6 alkyl, (3) -C3-6cycloalkyl, and (4) halogen; R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (3) a 5 to 10 membered monocyclic or fused bicyclic heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein each of the phenyl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH, (c) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (d) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, (e) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-6 alkoxy, and (f) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-6alkoxy; andR7is selected from: (1) H, and (2) -C1-6 alkyl. In one embodiment of the compound of formula (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein: each of RA1and RA2is independently selected from: (1) H, (2) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OR11, wherein R11is selected from: (i) H, (ii) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -C1-4 alkoxy and -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (iii) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-4 alkyl, and (iv) 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-4alkoxy, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-4 alkyl, optionally substituted with -C1-4 alkoxy, and (iii) -C3-6cycloalkyl, and (e) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) -OH and (iii) -C1-4alkyl, optionally substituted with 1 to 3 halogens, (3) -CN, and(4) halogen; R1is selected from: (1) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-4 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-4 alkyl, (iii) -C3-6cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-4 alkyl, (2) halogen, (3) -C3-6cycloalkyl, and (4) -C1-4 alkoxy; each of R2and R3is independently selected from: (1) H, (2) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-4alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-4alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from:(i) H, and (ii) -C(O)C1-4 alkyl, (3) -C1-4 alkoxy, and (4) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, and (b) -C1-6 alkyl; each of R4, R4’, R5, and R5’is independently selected from: (1) H, and (2) -C1-4 alkyl; R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl selected from pyridyl, pyridazinyl, and pyrimidyl, and (3) a 5 to 10 membered heterocyclyl selected , wherein each of the phenyl of (1), heteroaryl ofis optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH, (c) -C1-4alkoxy, optionally substituted with 1 to 3 halogens, (d) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-4 alkyl; and R7is selected from: (1) H, and (2) -C1-4 alkyl.

[0016] In one embodiment of the compound of formula (I), (Iaa), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein: each of RA1and RA2is independently selected from: (1) H, (2) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen, (b) -OR11, wherein R11is selected from: (i) H, (ii) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -C1-6 alkoxy and -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (iii) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6 alkyl, and (iv) 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (c) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6 alkoxy, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-6 alkyl, optionally substituted with -C1-6 alkoxy, and (iii) -C3-6 cycloalkyl, and (e) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) -OH and (iii) -C1-6 alkyl, optionally substituted with 1 to 3 halogens, (3) -CN, (4) -C1-6alkoxy, optionally substituted with 1 to 3 halogens, (5) -O-C3-6 cycloalkyl, (6) halogen, and (7) -C2-6alkenyl.

[0017] In one embodiment of the compound of formula (I), (Iaa), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein: RA1is selected from: (1) H,(2) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OR11, wherein R11is selected from: (i) H, (ii) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -C1-4 alkoxy and -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (iii) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-4 alkyl, and (iv) 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-4 alkoxy, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-4 alkyl, optionally substituted with -C1-4 alkoxy, and (iii) -C3-6cycloalkyl, and (e) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) -OH and (iii) -C1-4 alkyl, optionally substituted with 1 to 3 halogens, (3) -CN, (4) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (5) -O-C3-6 cycloalkyl, (6) halogen, and (7) -C2-4 alkenyl; and RA2is selected from: (1) H, (2) halogen, and(3) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, and (c) -C3-6 cycloalkyl.

[0018] In one embodiment of the compound of formula (I) or (Iaa), or a pharmaceutically acceptable salt thereof, wherein: the B ring is a 5 to 10 membered monocyclic or fused bicyclic heteroaryl or heterocyclyl 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)C1-6alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6alkyl, (2) halogen, (3) -C3-6 cycloalkyl, (4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6 alkyl, (c) -C3-6cycloalkyl, and (d) -C(O)C1-6 alkyl, (6) oxo, and (7) -CN.

[0019] In one embodiment of the compound of formula (I) or (Iaa), or a pharmaceutically acceptable salt thereof, wherein: the B ring is a 5 to 6 membered monocyclic heteroaryl or heterocyclic ring selected from azetidinyl, imidazolyl, morpholinyl, oxetanyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and triazolyl; or the B ring is an 8 to 10 membered bicyclic heteroaryl or heterocyclic ring selected from benzoimidazolyl, benzothiazolyl, benzothiophenyl, benzoxazole, cinnolinyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridyl, imidazopyrimidinyl, indazolyl, indolyl, isoindolyl, isoquinolyl, pyrazolopyrazinyl, pyrazolopyridazinyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrrolopyridyl, quinazolinyl, quinolyl, and quinoxalinyl; wherein the B ring is optionally substituted with 1 to 4 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)C1-4 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-4 alkyl, (iii) -C3-6cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-4 alkyl, (2) halogen, (3) -C3-6cycloalkyl, (4) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-4alkyl,(c) -C3-6cycloalkyl, and (d) -C(O)C1-4 alkyl, (6) oxo, and (7) -CN.

[0020] In one embodiment of the compound of formula (I), (Iaa), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein: R4is selected from: (1) H, and (2) -C1-6 alkyl; and when present, each of R4’, R5, R5’is H.

[0021] In one embodiment of the compound of formula (I), (Iaa), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein: R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (3) a 5 to 10 membered monocyclic or fused bicyclic heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein each of the phenyl of (1), heteroaryl of (2), and heterocyclyl of (3) 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 (i) halogen and (ii) -OH, (c) -C1-6alkoxy, 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, (e) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-6 alkoxy, and(f) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-6 alkoxy.

[0022] In one embodiment of the compound of formula (I), (Iaa), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein: R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and thiazolyl, and (3) a 5 to 10 membered monocyclic or fused bicyclic heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein each of the phenyl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH, (c) -C1-4alkoxy, optionally substituted with 1 to 3 halogens, (d) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -C1-4 alkyl, (e) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-4 alkyl, (b) halogen, (c) -OH, and (d) -C1-4 alkoxy, and (f) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-4 alkyl, (b) halogen, (c) -OH, and (d) -C1-4 alkoxy.

[0023] In one embodiment of the compound of formula (I), (Iaa), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein: R7is selected from: (1) H, and (2) -C1-6alkyl.

[0024] In one embodiment of the compound of formula (I), (Iaa), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein: when present, each of R1, R2, R3, R4a, and R5ais independently selected from: (1) H, (2) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-4 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-4alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-4alkyl, (3) halogen, (4) -C3-6 cycloalkyl, (5) -C1-4alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-4 alkyl, (c) -C3-6cycloalkyl, and (d) -C(O)C1-4 alkyl, (7) oxo, and (8) -CN.

[0025] In one embodiment of the compound of formula (I), (Iaa), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein: when present, R1is selected from: (1) H,(2) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-4alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-4alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-4 alkyl, (3) halogen, (4) -C3-6 cycloalkyl, (5) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-4 alkyl, (c) -C3-6cycloalkyl, and (d) -C(O)C1-4alkyl, (7) oxo, and (8) -CN; and wherein, when present, each of R2, R3, R4a, and R5ais independently selected from: (1) H, (2) -C1-4 alkyl, optionally substituted with 1 to 3 halogens, (3) -C1-4alkoxy, optionally substituted with 1 to 3 halogens, (4) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from (a) H and (b) -C1-4 alkyl, and (5) oxo.

[0026] In one embodiment of the compound of formula (I), (Iaa), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, wherein: when present, R1is selected from: (1) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-4alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-4alkyl, (iii) -C3-6cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-4 alkyl, (2) halogen, (3) -C3-6 cycloalkyl, (4) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-4 alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-4alkyl; and wherein, when present, each of R2, R3, R4a, and R5ais independently selected from: (1) H, (2) -C1-4alkyl, optionally substituted with 1 to 3 halogens, (3) -C1-4 alkoxy, and (4) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from (a) H and (b) -C1-4 alkyl.

[0027] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: each of RA1and RA2is independently selected from: (1) H, (2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OR11, wherein R11is selected from: (i) H, (ii) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -C1-6alkoxy and -C3-6cycloalkyl, optionally substituted with 1 to 3 halogens, (iii) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6 alkyl, and (iv) 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6alkoxy, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-6alkyl, optionally substituted with -C1-6alkoxy, and (iii) -C3-6cycloalkyl, and (e) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) -OH and (iii) -C1-6alkyl, optionally substituted with 1 to 3 halogens, (3) -CN, (4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (5) -O-C3-6cycloalkyl, (6) halogen, and(7) -C2-6alkenyl; the B ring is a 5 to 10 membered monocyclic or fused bicyclic heteroaryl or heterocyclyl 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)C1-6 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6 alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6 alkyl, (2) halogen, (3) -C3-6cycloalkyl, (4) -C1-6alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-6 alkyl, (6) oxo, and (7) -CN; when present, each of RA3and RA4is H; R4is selected from: (1) H, and(2) -C1-6alkyl; when present, each of R4’, R5, and R5’is H; R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (3) a 5 to 10 membered monocyclic or fused bicyclic heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein each of the phenyl of (1), heteroaryl of (2), and heterocyclyl of (3) 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 (i) halogen and (ii) -OH, (c) -C1-6alkoxy, 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, (e) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-6 alkoxy, and (f) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-6 alkoxy; and R7is selected from: (1) H, and (2) -C1-6 alkyl.

[0028] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: RA1is selected from: (1) H, (2) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen,(b) -OR11, wherein R11is selected from: (i) H, (ii) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -C1-4alkoxy and -C3-6cycloalkyl, optionally substituted with 1 to 3 halogens, (iii) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-4alkyl, and (iv) 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (c) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-4alkoxy, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-4alkyl, optionally substituted with -C1-4alkoxy, and (iii) -C3-6 cycloalkyl, and (e) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) -OH and (iii) -C1-4alkyl, optionally substituted with 1 to 3 halogens, (3) -CN, (4) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (5) -O-C3-6cycloalkyl, (6) halogen, and (7) -C2-4 alkenyl; RA2is selected from: (1) H, (2) halogen, and (3) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, and (c) -C3-6cycloalkyl;the B ring is a 5 to 6 membered monocyclic heteroaryl or heterocyclyl selected from azetidinyl, imidazolyl, morpholinyl, oxetanyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and triazolyl; or the B ring is an 8 to 10 membered bicyclic heteroaryl or heterocyclic ring selected from benzoimidazolyl, benzothiazolyl, benzothiophenyl, benzoxazole, cinnolinyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridyl, imidazopyrimidinyl, indazolyl, indolyl, isoindolyl, isoquinolyl, pyrazolopyrazinyl, pyrazolopyridazinyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrrolopyridyl, quinazolinyl, quinolyl, and quinoxalinyl, wherein the B ring is optionally substituted with 1 to 3 substituents independently selected from: (1) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-4alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-4alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-4 alkyl, (2) halogen, (3) -C3-6 cycloalkyl, (4) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-4 alkyl, (c) -C3-6cycloalkyl, and (d) -C(O)C1-4alkyl,(6) oxo, and (7) -CN; R4is selected from: (1) H, and (2) -C1-4 alkyl; R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and thiazolyl, and (3) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein each of the phenyl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH, (c) -C1-4alkoxy, optionally substituted with 1 to 3 halogens, (d) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -C1-4 alkyl, (e) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-4 alkyl, (b) halogen, (c) -OH, and (d) -C1-4 alkoxy and (f) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-4 alkyl, (b) halogen, (c) -OH, and (d) -C1-4 alkoxy; and R7is selected from: (1) H, and (2) -C1-4 alkyl.

[0029] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: RA1is selected from:(1) H, (2) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -OCH3, optionally substituted with -C3-4 cycloalkyl, wherein the -C3-4 cycloalkyl is optionally substituted with 1 to 3 halogens, (d) -OCH2CH3, (e) -OCH(CH3)2, (f) -O-C3-5 cycloalkyl, (g) -C3-5cycloalkyl, optionally substituted with 1 to 3 halogens, (h) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: H, -CH3, -CH2CH3, cyclopropyl, and cyclobutyl, (i) -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, and (j) 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from -CH3, CHF2, CF3, -OH, and halogen, (3) -CN, (4) - halogen, and (5) -C2-4 alkenyl; RA2is selected from: (1) H, (2) halogen, and (3) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH; the B ring is optionally substituted with 1 to 3 substituents independently selected from: (1) -C1-2 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)CH3, and(d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from (i) H, (ii) methyl, (iii) ethyl, (iv) -C3-6 cycloalkyl, and (v) 4 to 6 membered heterocyclyl selected from oxetanyl, tetrahydro-2H-pyranyl, piperidinyl, and piperidinyl, (2) halogen, (3) -C3-6 cycloalkyl, (4) -C1-2 alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) methyl, (c) ethyl, (d) -C3-6cycloalkyl, and (e) -C(O)CH3, (6) oxo, and (7) -CN; R4is selected from: (1) H, (2) methyl, and (3) ethyl; R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and thiazolyl, and (3) a 5 to 10 membered heterocyclyl selected , wherein each of the phenyl of (1), heteroaryl ofis optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C1-4 alkyl, optionally substituted with 1 to 3 halogens, (c) -C1-4alkoxy, optionally substituted with 1 to 3 halogens, (d) -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (e) a 5 to 6 membered heteroaryl selected from furanyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, and thiophenyl, optionally substituted with 1 to 3 halogens, and(f) a 5 to 10 membered heterocyclyl selected ,,optionally substituted with 1 to 3 substituents(a) methyl, (ii) ethyl, and (iii) halogen; andR7is selected from: (1) H, (2) methyl, and (3) ethyl.

[0030] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: the B ring is a 5 to 6 membered monocyclic heteroaryl or heterocyclic ring selected from imidazolyl, morpholinyl, pyrazolyl, pyridyl, pyridazinyl, and pyrimidyl; or the B ring is an 8 to 10 membered bicyclic heteroaryl or heterocyclic ring selected from ,hetero portion of the B ring that is suitable for attachment, and wherein the B ring is optionally substituted with 1 to 3 substituents independently selected from: (1) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH,(c) -O-C(O)CH3, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from (i) H and (ii) methyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl selected from oxetanyl, tetrahydro-2H-pyranyl, piperidinyl, and piperidinyl, (2) halogen, (3) -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (4) -C1-4alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) methyl, (c) -C3-6cycloalkyl, and (d) -C(O)CH3, and (6) oxo; R4is selected from: (1) H and (2) methyl; R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and thiazolyl, and (3) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein each of the phenyl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C1-3 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH, (c) -C1-3alkoxy, optionally substituted with 1 to 3 halogens, (d) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) methyl,(e) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-2 alkyl, (b) halogen, (c) -OH, and (d) -C1-2 alkoxy, and (f) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-2 alkyl, (b) halogen, (c) -OH, and (d) -C1-2 alkoxy; and R7is selected from: (1) H and (2) methyl.

[0031] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: the B ring is a 5 to 6 membered monocyclic heteroaryl or heterocyclic ring selected from imidazolyl, morpholinyl, pyrazolyl, pyridyl, pyridazinyl, and pyrimidinyl; or the B ring is an 8 to 10 membered bicyclic heteroaryl or heterocyclic ring selected from , ,acceptable salt thereof: RA1is selected from: (1) H and (2) -C1-4alkyl, (3) -CN, (4) -OC1-4alkyl, and (5) -NH2.

[0033] In one embodiment of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof: the B ring is a 5 to 6 membered monocyclic heteroaryl or heterocyclic ring selected from azetidinyl, imidazolyl, morpholinyl, oxetanyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and triazolyl; orthe B ring is an 8 to 10 membered bicyclic heteroaryl or heterocyclic ring selected from benzoimidazolyl, benzothiazolyl, benzothiophenyl, benzoxazole, cinnolinyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridyl, imidazopyrimidinyl, indazolyl, indolyl, isoindolyl, isoquinolyl, pyrazolopyrazinyl, pyrazolopyridazinyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrrolopyridyl, quinazolinyl, quinolyl, and quinoxalinyl, wherein the B ring is 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)C1-6alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is 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) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6 alkyl, (c) -C3-6cycloalkyl, and (d) -C(O)C1-6alkyl, and (6) oxo.

[0034] In one embodiment of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, R4is selected from (1) H and (2) -C1-6alkyl;

[0035] In one embodiment of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, R6is selected from (1) a phenyl and (2) a 5 to 6 membered heteroaryl selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and thiazolyl, wherein each of the phenyl of (1) and heteroaryl of (2) is optionally substituted with 1 to 3 substituents independently selected from: (1) halogen,(2) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH, (3) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (4) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -C1-6 alkyl, and (5) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-6 alkyl, (b) halogen, (c) -OH, and (d) -C1-6 alkoxy.

[0036] In one embodiment of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof: R7is selected from (1) H and (2) -C1-6alkyl.

[0037] In one embodiment of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof: RA1is selected from: (1) H and (2) -C1-4alkyl, (3) -CN, (4) -OC1-4alkyl, and (5) -NH2; the B ring is a 5 to 6 membered monocyclic heteroaryl or heterocyclic ring selected from azetidinyl, imidazolyl, morpholinyl, oxetanyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and triazolyl; or the B ring is an 8 to 10 membered bicyclic heteroaryl or heterocyclic ring selected from benzoimidazolyl, benzothiazolyl, benzothiophenyl, benzoxazole, cinnolinyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridyl, imidazopyrimidinyl, indazolyl, indolyl, isoindolyl, isoquinolyl, pyrazolopyrazinyl, pyrazolopyridazinyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrrolopyridyl, quinazolinyl, quinolyl, and quinoxalinyl, wherein the B ring is 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)C1-6 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from (i) H and (ii) -C1-6alkyl, (2) halogen,(3) -C3-6cycloalkyl, (4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6 alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-6alkyl, and (6) oxo; R4is selected from (1) H and (2) -C1-6 alkyl; R6is selected from (1) a phenyl and (2) a 5 to 6 membered heteroaryl selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and thiazolyl, wherein each of the phenyl of (1) and heteroaryl of (2) is optionally substituted with 1 to 3 substituents independently selected from: (1) halogen, (2) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH, (3) -C1-4alkoxy, optionally substituted with 1 to 3 halogens, (4) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -C1-6 alkyl, and (5) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-4 alkyl, (b) halogen, (c) -OH, and (d) -C1-4 alkoxy; and R7is selected from (1) H and (2) -C1-6 alkyl.

[0038] In one embodiment of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof: RA1is selected from: (1) H, (2) methyl, (3) ethyl, (4) -CN, (5) methoxy, (6) ethoxy and (7) -NH2; the B ring is 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)C1-4alkyl, and(d) -C(O)NRa1Rb1, wherein each of Ra1and Rb1is independently selected from (i) H and (ii) -C1-4 alkyl, (2) halogen, (3) -C3-6cycloalkyl, (4) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-4 alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-4alkyl, and (6) oxo; R4is selected from (1) H and (2) -C1-4 alkyl; R6is selected from (1) a phenyl and (2) a 5 to 6 membered heteroaryl selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and thiazolyl, wherein each of the phenyl of (1) and heteroaryl of (2) is optionally substituted with 1 to 3 substituents independently selected from: (1) halogen, (2) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH, (3) -C1-4alkoxy, optionally substituted with 1 to 3 halogens, (4) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -C1-4 alkyl, and (5) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-4 alkyl, (b) halogen, (c) -OH, and (d) -C1-4 alkoxy; and R7is selected from (1) H and (2) -C1-4 alkyl.

[0039] In one embodiment of the compound described above, or a pharmaceutically acceptable salt thereof: RA1is selected from: (1) H, (2) methyl, (3) -CN, and (4) -O-methyl; the B ring is optionally substituted with 1 to 3 substituents independently selected from: (1) -C1-2alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen, (b) -OH, (c) -O-C(O)CH3, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from (i) H, (ii) methyl, and (iii) ethyl, (2) halogen, (3) -C3-6cycloalkyl, (4) -C1-2 alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) methyl, (c) ethyl, (d) -C3-6 cycloalkyl, and (e) -C(O)CH3, and (6) oxo; R4is selected from (1) H, (2) methyl, and (3) ethyl; R6is selected from (1) a phenyl and (2) a 5 to 6 membered heteroaryl selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and thiazolyl, wherein each of the phenyl of (1) and heteroaryl of (2) is optionally substituted with 1 to 3 substituents independently selected from: (1) halogen, (2) -C1-2 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH, (3) -C1-2alkoxy, optionally substituted with 1 to 3 halogens, (4) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) methyl, and (5) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-2 alkyl, (b) halogen, (c) -OH, and (d) -C1-2 alkoxy; and R7is selected from (1) H, (2) methyl, and (3) ethyl.

[0040] In one embodiment of the compound described above, or a pharmaceutically acceptable salt thereof: the B ring is a 5 to 6 membered monocyclic heteroaryl or heterocyclic ring selected from imidazolyl, morpholinyl, pyrazolyl, pyridyl, pyridazinyl, and pyrimidyl; or the B ring is an 8 to 10 membered bicyclic heteroaryl or heterocyclic ring selected from ,,from: (1) methyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)CH3, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from (i) H and (ii) methyl, (2) halogen, (3) -C3-6 cycloalkyl, (4) methoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from:(a) H, (b) methyl, (c) -C3-6 cycloalkyl, and (d) -C(O)CH3, and (6) oxo; R4is selected from (1) H and (2) methyl; R6is selected from (1) a phenyl and (2) a 5 to 6 membered heteroaryl selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and thiazolyl, wherein each of the phenyl of (1) and heteroaryl of (2) is optionally substituted with 1 to 3 substituents independently selected from: (1) halogen, (2) -C1-2 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH, (3) -C1-2alkoxy, optionally substituted with 1 to 3 halogens, (4) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) methyl, and (5) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-2 alkyl, (b) halogen, (c) -OH, and (d) -C1-2 alkoxy; and R7is selected from (1) H and (2) methyl.

[0041] In one embodiment of the compound described above, or a pharmaceutically acceptable salt thereof: the B ring is a 5 to 6 membered monocyclic heteroaryl or heterocyclic ring selected from imidazolyl, morpholinyl, pyrazolyl, pyridyl, pyridazinyl, and pyrimidyl; or the B ring is an 8 to 10 membered bicyclic heteroaryl or heterocyclic ring selected from , ,,[00 ereof, may be a solvate, or a non-solvate. The solvent contained in a solvate may be either water or an organic solvent. Alcohols (for example, MeOH, EtOH, n-propanol), dimethylformamide, acetonitrile, acetone, dimethylsulfoxide may be used as the organic solvent. The proportion of the solvent molecule (for example a water molecule) against a single molecule compound herein or a pharmaceutically acceptable salt thereof, is, for example, 0.1 to 10, or more specifically, 0.5 to 6. Further, the proportion may fluctuate by humidity, the production method, and the production season.

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

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

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

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

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

[0048] The compound herein, or a pharmaceutically acceptable salt thereof, includes an embodiment in which an atom constituting the compound molecule is an isotope, and includes an embodiment in which at least one atom is substituted with an atom having the same atomic number (proton number) and a different mass number (sum of protons and neutrons). Examples of the isotopes include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorous atom, sulfur atom, fluorine atom, and chlorine atom, which respectively include2H,3H,13C,14C,15N,17O,18O,31P,32P,35S,18F, and36Cl.

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

[0050] In one embodiment, compounds of formula (I), or a pharmaceutically acceptable salt thereof, are glucagon receptor agonists. In one embodiment, compounds of formula (I), or a pharmaceutically acceptable salt thereof, have relative EC50 (Rel EC50) values of less than 80,000 nM using Functional Assay as described herein. In one embodiment, compounds of formula (Ia) - (Ig), or a pharmaceutically acceptable salt thereof, have Rel EC50values of less than about 50,000 nM. In one preferred embodiment, compounds of formula (Ia) - (Ig), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 10,000 nM.

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

[0052] In one embodiment, disclosed herein is a compound of formula (I) or (Ia), 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.

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

[0054] In one embodiment, disclosed herein is a compound of formula (I) or (Ia) – (Ig), or a pharmaceutically acceptable salt thereof, for use in the treatment of obesity.

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

[0056] In one embodiment, disclosed herein is a compound of formula (I) or (Ia) – (Ig), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with one or more of a glucagon-like peptide-1 (GLP-1) receptor agonist, an amylin receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, and a peptide tyrosine-tyrosine (PYY) receptor 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. In one embodiment, a compound of formula (I) or (Ia) – (Ig), or a pharmaceutically acceptable salt thereof, is for use in simultaneous, separate, or sequential combination with one of a GLP-1 receptor agonist, an amylin receptor agonist, a GIP receptor agonist, and a PYY receptor agonist, or a pharmaceutically acceptable salt thereof. In one embodiment, a compound of formula (I) or (Ia) – (Ig), or a pharmaceutically acceptable salt thereof, is for use in simultaneous, separate, or sequential combination with two of a GLP-1 receptor agonist, an amylin receptor agonist, a GIP receptor agonist, and a PYY receptor agonist, or a pharmaceutically acceptable salt thereof. In one embodiment, the GLP-1 receptor agonist is selected from albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, tirzepatide, orforglipron, ECC5004, and GSBR-1290.

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

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

[0059] The term “about” means within a meaningful range of a value or values such as, a stated amount, activity, concentration, length, molecular weight, pH, time frame, temperature orvolume, 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.

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

[0061] The term “treat,” “treating,” or “to treat” means attenuating, restraining, slowing, stopping or reversing the progression or severity of an 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 HbA1c level or a weight loss to the subject.

[0062] The term “a pharmaceutically acceptable salt” refers to a derivative of the compound herein, where a compound herein is modified by making an acid or a base salt thereof. Pharmaceutically acceptable salts, and processes for preparing the same, are well known in the art (see, e.g., Remington: The Science and Practice of Pharmacy, L.V. Allen, Ed., 22nd Edition, Pharmaceutical Press, 2012). By way of examples, pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, or alkali ororganic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of a compound herein formed, for example, from non-toxic inorganic or organic acids. Such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic. Pharmaceutically acceptable salts are those forms of a compound herein, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salt forms of a compound herein can be synthesized to contain a basic or acidic moiety by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of the compound with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, EtOAc, EtOH, isopropanol, or acetonitrile are preferred (see, e.g., Stahl et al., “Handbook of Pharmaceutical Salts: Properties, Selection and Use” (Wiley-VCH 2nd ed. 2011)).

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

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

[0065] The term "alkoxy" refers to the following chemical , wherein R is an alkyl group as defined herein and the point of attachment is throughFor example, C1-10alkoxy has 1 to 10 carbons with the following . Similarly, C1-6alkoxyhas 1 to 6 carbons with the following .

[0066] The term “C1-10alkyl” means a straight chain or a branched chain alkyl group containing 1 to 10 carbons. Similarly, “C1-6 alkyl” means a straight chain or a branched chain alkyl group containing 1 to 6 carbons. Examples of a C1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2- methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, and 2-ethylbutyl.

[0067] The term "alkylene" refers to an alkanediyl group, i.e., a divalent saturated acyclic hydrocarbon group which may be linear or branched. For example, a "C1-6alkylene" means an alkylene group having 1 to 6 carbon atoms. Exemplary C1-4 alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), propylene (e.g., -CH2- CH2-CH2-, -CH(-CH2-CH3)-, -CH2-CH(-CH3)-, or -CH(- CH3)-CH2-), or butylene (e.g., -CH2- CH2-CH2-CH2-).

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

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

[0070] The term “aryl” means an aromatic carbocyclic group, and it may contain a non-aromatic portion in addition to the aromatic portion. The ring may be monocyclic, or it may be a bicyclic aryl that is condensed with a benzene ring or a monocyclic aryl ring. Examples include, but are not limited to, phenyl, naphthyl, azulenyl, isochromanyl, 2,4-dihydro-1H-isoquinolin-3-onyl, and 1,3-dihydrobenzimidazol-2-onyl. In one embodiment, an aryl is a phenyl. In one embodiment, an aryl is a naphthyl. In one embodiment, aryl is a C6-10 aryl.

[0071] The term "heteroaryl" refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, for example, one, two, three, or four) ring heteroatoms independently selected from N, O, and S, andthe 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, pyrazolopyrazinyl, pyrazolopyridazinyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrrolopyridyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzooxazolyl, benzooxadiazolyl, benzoimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridyl, imidazopyrimidinyl, benzoisoxazolyl, and benzoisothiazolyl.

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

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

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

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

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

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

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

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

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

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

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

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

[0084] In one embodiment, the effective amount to be administered may be appropriately determined according to the severity of the symptom, the age, the body weight, the relative health state, whether other drugs are combined, and the method of administration. In one embodiment, the above effective amount is administered once daily or twice daily for a few days, a few weeks, a few months, or several years. In one embodiment, the above dosage is administered once daily for a few days, a few weeks, a few months, or several years.

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

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

[0087] In one embodiment, a pharmaceutical composition comprises a compound of formula (I), formula (Ia), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

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

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

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

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

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

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

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

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

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

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

[0098] The following examples are provided for illustration purposed only. The abbreviations used in the preparations and examples are as defined below. ACN acetonitrile AcOH acetic acid aq. aqueous BINAP 2,2-bis(diphenylphosphino)-1,1-binaphthalene Boc tert-butoxycarbonyl Boc2O di-tert-butyl dicarbonate CDI carbonyldiimidazole CPME cyclopentylmethyl ether CSH charge surface hybrid CV column volumes DCM dichloromethane DIEA diisopropylethylamine DMA dimethylacetamide DMAP 4-dimethylaminopyridine DME dimethoxyethane DMF N,N-dimethylformamideDMSO dimethylsulfoxide d.r. diastereomeric ratio ES-MS electrospray mass spectrometry TEA triethylamine EtOAc ethyl acetate EtOH ethanol FA formic acid HATU hexafluorophosphate azabenzotriazole tetramethyl uranium HMDS 1,1,1,3,3,3-hexamethyldisilazane HPLC high performance liquid chromatography IPA isopropanol KOAc potassium acetate KOtBu potassium tert-butoxide LED light emitting diode LiHMDS lithium bis(trimethylsilyl)amide MeI methyl iodide MeOH methanol min minute(s) MeTHF 2-methyltetrahydrofuran MTBE metyl tert-butyl ether m / z mass-to-charge ratio NaOMe sodium methoxide NBS N-bromosuccinimide NH4OAc ammonium acetate NMP N-methylpyrrolidone Pd(dba)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dtbpf)Cl21,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride Pd(OAc)2 palladium acetate Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) PG protecting groupprep-HPLC preparative high performance liquid chromatography prep-TLC preparative thin-layer chromatography PyOtBu pyridine tert-butoxide RBF RBF RT or rt room temperature sat. saturated SCX strong cation exchange SFC supercritical fluid chromatography t-BuOH tert-butyl alcohol TFA trifluoroacetic acid THF tetrahydrofuran TLC thin-layer chromatography UV ultraviolet Wt or wt Weight

[0099] In the schemes below, unless otherwise indicated, RA1, RA2, RA3, RA4, R4, R4’, R5, R5’, R6, R7, and B are as defined in Formula I. The reagents and starting materials are either commercially available or may be prepared by methods well known to one of ordinary skill in the art, some of which are presented in the preparations below. Without limiting the scope of the invention, the following schemes, preparations, and examples are provided to further illustrate the invention. Scheme 1

[0100] Schem -1-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- COCl) in the presence of an organic base, such as TEA, in a suitable solvent, such as THF, or a suitable acid (R6-CO2H) using amide coupling conditions know to the skilled artisan, e.g. HATU and an organic base such as DIEA in a solvent such as DMF, and then cyclized to form intermediate (4) using an alkoxide base such as sodium ethoxide / EtOH or KOtBu / EtOH at elevated temperature.

[0101] 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 HCl in 1,4-dioxane, in an appropriate solvent, such as DCM. Scheme 2[ Scheme 2 by reacting the 1,3,8-triazaspiro[4.5]dec-1-en-4-one intermediate (5) with intermediate (6) where X1is a halide such as bromine, or silane such as -Si(CH3)3, and X2is a halide such as chlorine, bromine, or iodine. If X1is bromine, this transformation occurs by reacting (6) with lithium bis(trimethylsilyl)amide, followed by amine intermediate (5) in a solvent such as 1,4- dioxane at an elevated temperature to give intermediate (7) wherein X2is Br, or I. If X1is a silane, (6) can be reacted with amine (5) using CsF in a solvent such as ACN to give (7). The halogen in the resulting intermediate (7) may be reacted with (8) where X3is a boronic acid or boronic ester, under standard Suzuki coupling conditions to give (9). Alternatively, the halogen X2in intermediate (7) can be converted to a boronic ester using bis(pinacolato)diborane, a palladium catalyst, a carbonate base such as K2CO3, 2-ethyl hexanoic acid, and a solvent such as 2-methyltetrahydrofuran. Suzuki coupling conditions with (8) where X3is a halogen gives compound (9). Scheme 3whose use is described in Scheme 1, and in which “Z” represents various substituent groups on R6as described in Formula (I), in particular alkyl and cycloalkyl groups. Acid 10 is reacted with CDI and TEA, and then with intermediate 11 (wherein “PG” is an ester protecting group such asmethyl or ethyl) using an amine base such as TEA to give intermediate 12. Intermediate 12 is then reacted with intermediate 13 using ammonium trifluoroacetate and TFA in a solvent such as toluene at elevated temperature to give pyridine intermediate 14. Hydrolysis of the ester under aqueous basic conditions (e.g. using NaOH and water and organic solvents e.g. THF and / or MeOH) gives acid 15. Preparation of Intermediate 1: tert-Butyl (2S)-4-amino-4-cyano-2-methylpiperidine-1- carboxylate (mixture of diastereomers)

[0104] Ammonium acetate (445 in one portion to a mixture of tert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate (490 g, 2.25 mol) in EtOH (5 L). Then KCN (225 g, 3.39 mol) was added to the reaction. The resulting 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 × 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: tert-Butyl (2S,4S)-4-amino-4-carbamoyl-2- methylpiperidine-1-carboxylate (Intermediate 2a) and tert-butyl (2S,4R)-4-amino-4-carbamoyl- 2-methylpiperidine-1-carboxylate (Intermediate 2b)

[0105] To a solution1-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. Na2SO3(2000 mL). The mixture was filtered, the filtrate was extracted withDCM / MeOH (10 / 1, 5 × 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: tert-Butyl (5R,7S)-7-methyl-4-oxo-2-(2- (trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate

[0106] A solution of 2- (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- 1-carboxylate (25.13 g, 97.66 mmol) in THF (450 mL) and TEA (26 mL, 190 mmol) with stirring, at RT under nitrogen in a RBF. After 45 min, sodium ethoxide (21% in EtOH, 140 mL, 380 mmol) was added and the mixture was stirred at 60 °C. After 45 min, water was added until the mixture volume reached 2 L and the pH was adjusted to 4 using solid citric acid. The mixture was stirred overnight at RT under a gentle sweep of nitrogen. The volume had been 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 MgSO4, filtered, and concentrated at 50 °C to give the title compound (36.44 g). ES-MS m / z 428 (M+H). Preparation of Intermediate 4: (5R,7S)-7-Methyl-2-(2-(trifluoromethoxy)phenyl)-1,3,8- triazaspiro[4.5]dec-1-en-4-one dihydrochloride

[0107] Hydrochloric acid (4.0mL, 317.2 mmol) was added to tert- butyl (5R,7S)-7-methyl-4-oxo-2-(2-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-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 5: (5R,7S)-7-Methyl-2-(2-(trifluoromethoxy)phenyl)-1,3,8- triazaspiro[4.5]dec-1-en-4-one

[0108] K3PO4(2 M aqueous, 300added to a 1 L conical flask with (5R,7S)-7-methyl-2-(2-(trifluoromethoxy)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 pH of the aqueous phase was adjusted with aq. K3PO4 (25 mL) to approx. pH 9.5. The phases were separated, and the aqueous extracted with further portions of EtOAc (4 × 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 RT 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 a solid. ES-MS m / z 328 (M+H). Preparation of Intermediate 6: (5R,7S)-8-(3-Bromophenyl)-7-methyl-2-(2- (trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0109] Lithium bis(trimethyls in THF) (63 mL, 1.00 molar, 63 mmol) was added to a mixture of (5R,7S)-7-methyl-2-(2-(trifluoromethoxy)phenyl)-1,3,8- triazaspiro[4.5]dec-1-en-4-one (8.20 g, 25.1 mmol) and THF (25 mL) under nitrogen. 1,3- Dibromobenzene (3.6 mL, 30 mmol) was added and the mixture was stirred at 78 °C. After 1.5 h, the reaction mixture was poured into stirred water (0.30 L), and the pH was adjusted to 3 using concentrated H3PO4. The resulting biphasic mixture was transferred to a separating funnel along with EtOAc (0.30 L), shaken and separated. The organics were washed with 2 M aq. K2HPO4 (0.10 L) with sat. aq. NaCl (50 mL), dried over MgSO4and filtered. The organics were concentrated under reduced pressure at 50 °C. The product mixture was purified by silica gel chromatography using a gradient of 0 to 20% EtOAc in DCM to give the title compound (4.9 g) as a solid. ES-MS m / z 482, 484 (M+H). Preparation of Intermediate 7: (5R,7S)-8-(3-Iodophenyl)-7-methyl-2-(2- (trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0110] Lithium bis20 mL, 20 mmol) was added to a solution of (5R,7S)-7-methyl-2-(2-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-4- one dihydrochloride (1.0 g, 2.5 mmol) in 1,4-dioxane (14 mL) and 1-bromo-3-iodo-benzene (1.6 mL, 12 mmol) at 20 °C. The mixture was heated to 80 °C and stirred for 4 h. The reaction was poured into water (2 mL) at 10 – 20 °C and extracted with EtOAc (2 × 3 mL). The combined organic phase was washed with sat. aq. NaCl (2 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase prep-HPLC using a gradient of 50 to 80% ACN in 10 mM aq. NH4HCO3to give the title compound (0.200 g) as a solid. ES-MS m / z 530 (M+H).Preparation of Intermediate 8: (5R,7S)-7-Methyl-8-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-2-(2-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0111] XPhos Pd(crotyl)Cl g, 0.352 mmol) was added to astirred solution of bis(pinacolato)diborane (2.31 g, 9.10 mmol), (5R,7S)-8-(3-bromophenyl)-7- methyl-2-(2-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (3.50 g, 6.97 mmol), potassium carbonate (2.43 g, 17.6 mmol) in 2-methyltetrahydrofuran (35 mL) and2-ethyl hexanoic acid (0.111 mL, 0.70 mmol) under nitrogen using a sub-surface needle for 10 min, then the needle was removed and mixture heated to 40 °C under a positive pressure of nitrogen. After the completion of the reaction, the mixture was diluted with MTBE to approx. 100 mL and stirred at RT. After 30 min, the resulting mixture was filtered through diatomaceous earth, and the cake was rinsed with 1:4 MeTHF / MTBE. The filtrate and wash were combined and washed with sat. aq. NaHCO3(70 mL) then with sat. aq. NaCl, dried over MgSO4and filtered. The organics were concentrated. The residue was triturated with heptane and a solid was collected by filtration, washed with 1:4 MTBE / heptane to give the title compound (2.82 g). ES-MS m / z 530 (M+H). Preparation of Intermediate 9: 2-Cyclopropylbenzoyl chloride

[0112] Oxalyl chloride (6.09 mL,added by a syringe to a stirred solution of 2-cyclopropyl-benzoic acid (10.0 g, 55.5 mmol) in DCM (100 mL) under nitrogen at RT. DMF (0.217 mL, 2.77 mmol) was added. After 3 h, the resulting mixture was concentrated under a stream of N2to give the title compound (10.7 g) as an oil, which was carried forward without further characterization.Preparation of Intermediate 10: tert-butyl (2S,4R)-4-Carbamoyl-4-(2-cyclopropylbenzamido)-2- methylpiperidine-1-carboxylate;

[0113] TEA (22 mL, 160 mmol) (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-1-carboxylate (14.42 g, 56.04 mmol) in DCM (100 mL) and stirred at RT under nitrogen 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 resulting in a thick mixture. After 30 min, the mixture was filtered, and the cake washed with water (200 mL) and heptane (100 m L). The solid was dried in a vacuum oven overnight to give the title compound (18.03 g). ES-MS m / z 402 (M+H). Preparation of Intermediate 11: tert-Butyl (5R,7S)-2-(2-cyclopropylphenyl)-7-methyl-4-oxo- 1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate

[0114] Sodium ethoxide (21%was added to a stirred suspension of tert-butyl (2S,4R)-4-carbamoyl-4-(2-cyclopropylbenzamido)-2-methylpiperidine-1- carboxylate (18.0 g, 43.5 mmol) in EtOH (0.25 L) in a 500 mL RBF, and the mixture was heated at 60 °C. After 4 h, the mixture was partially-concentrated under reduced pressure at 50 °C to approx. 0.1 L, then stirred at RT. Aqueous citric acid (5%; 0.50 L) was added and the mixture was extracted with EtOAc (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 MgSO4 and filtered. The organics were concentrated under reduced pressure at 50 °C to give the title compound (16.37 g) as a foam. ES-MS m / z 384 (M+H).Preparation of Intermediate 12: (5R,7S)-2-(2-Cyclopropylphenyl)-7-methyl-1,3,8- triazaspiro[4.5]dec-1-en-4-one dihydrochloride

[0115] 4M HCl in 1,4-dioxanes 137.9 mmol) was added to a 1 L RBFcontaining tert-butyl (5R,7S)-2-(2-cyclopropylphenyl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec- 1-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. Preparation of Intermediate 13: (5R,7S)-2-(2-Cyclopropylphenyl)-7-methyl-1,3,8- triazaspiro[4.5]dec-1-en-4-one

[0116] HCl (5-6 M in 2-propanol,was added to a solution of tert-butyl (5R,7S)-2-(2-cyclopropylphenyl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (8.15 g, 21.3 mmol) in 2-propanol (25 mL) at 60 °C. After stirring for 20 min, additional 2- propanol (20 mL) was added. After 6 h, the mixture was filtered and washed with 2-propanol (30 mL). The filter cake was diluted with 50 mL water. The mixture was stirred and 2 M aq. K3PO4solution (pH 11.7) was added and stirred. After 30 min, the solid was collected by filtration and washed extensively with water until the filtrate reached pH 8-9. The solid was dried in a vacuum oven overnight to give the title compound (7.63 g). ES-MS m / z 284. Preparation of Intermediate 14: (5R,7S)-8-(3-Bromophenyl)-2-(2-cyclopropylphenyl)-7-methyl- 1,3,8-triazaspiro[4.5]dec-1-en-4-oneO BrHN N

[0117] Lithium bis in THF, 16.7 mL, 16.7 mmol) wasadded to a mixture of (5R,7S)-2- - 1,3,8-triazaspiro[4.5]dec-1-en- 4-one (1.95 g, 6.67 mmol) in THF (30 mL) under nitrogen. After stirring for 5 min, 1,3- dibromobenzene (0.97 mL, 8.0 mmol) was added and the mixture was heated to 60 °C. After 4 h, the mixture was diluted with 5% aq citric acid until pH 3 and EtOAc (0.1 L) was added. The phases were separated, and the organics washed with water then with sat. aq. NaCl (each 25 mL), dried over MgSO4 and filtered. The organics were concentrated onto diatomaceous earth and purified by flash chromatography using a gradient of 0 to 60% EtOAc in cyclohexane to give the title compound (0.851 g). ES-MS m / z 438, 440 (M+H). Preparation of Intermediate 15: (5R,7S)-2-(2-Cyclopropylphenyl)-7-methyl-8-(3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0118] 2-Ethyl hexanoic acidadded to a solution of bis(pinacolato)diborane (0.468 g, 1.84 mmol), (5R,7S)-8-(3-bromophenyl)-2-(2- cyclopropylphenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.647 g, 1.42 mmol) and potassium carbonate (0.490 g, 3.55 mmol) in 2-methyltetrahydrofuran (20 mL). The reaction was gently purged with nitrogen for 5 min, then XPhos Pd(crotyl)Cl (CAS# 1798782-02-1, 0.067 g, 0.099 mmol) was added under nitrogen and stirred at 50 °C. After 5 h, reaction was diluted with of MTBE (50 mL), filtered through diatomaceous earth. The filtrate was diluted with MTBE, washed with NaHCO3, water and sat. aq. NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was suspended in (15 mL) of heptane and filtered to give the title compound (0.638 g). ES-MS m / z 486 (M+H).Preparation of Intermediate 16: 2-Bromo-6-chloro-3-methylphenol

[0119] NBS (100 g, 534 mmol) was to a 0 °C mixture of 2-chloro-5-methylphenol (100 g, 666 mmol) and (260 mL, 1800 mmol) in DCM (1000 mL). The mixture was then stirred at 20 °C. After 12 h, the reaction mixture was quenched with 1000 mL sat. Na2SO3solution. The aqueous phase was extracted with DCM (2 × 1000 mL). The combined organic phase was washed with sat. aq. NaCl (1000 mL), dried with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 1 to 50% EtOAc in petroleum ether, then re-purified by reverse phase prep-HPLC using a gradient of 30 to 60% ACN in aqueous HCl to give the title compound (27 g) as an oil. ES-MS m / z 221 (M+H). Preparation of Intermediate 17: 6-Chloro-3-methyl-2-(trimethylsilyl)phenol

[0120] Sodium hydride (9.0 g, 60%was added to a vigorously stirred mixture of THF (500 mL) and 2-bromo-6-chloro-3-methylphenol (43 g, 190 mmol) at 0 °C. After stirring 30 min at 0 °C, chlorotrimethylsilane (26 mL, 190 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C. After 2 h, n-butyllithium (2.5 M in hexane, 84 mL, 210 mmol) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C. After 30 min, the mixture was quenched with NH4Cl (500 mL) and extracted with EtOAc (3 × 500 mL). The organic layers were washed with sat. aq. NaCl (500 mL), dried over Na2SO4, 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 (32 g) as an oil. ES-MS m / z 215 (M+H). Preparation of Intermediate 18: 6-Chloro-3-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate

[0121] Trifluoromethanesulfonic anh mL, 220 mmol) was added in portions to a 0 °C mixture of 6-chloro-3-methyl-2-(trimethylsilyl)phenol (32 g, 150 mmol) and DIEA (52 mL, 290 mmol) in DCM (320 mL). The mixture was then stirred at 20 °C. After 2 h, the residue was diluted with DCM (300 mL). The organic layers were washed with NH4Cl (300 mL), NaHCO3(300 mL), sat. aq. NaCl (300 mL), dried over Na2SO4, 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 (50 g) as an oil. ES-MS m / z 345 (M-H). Preparation of Intermediate 19: (5R,7S)-8-(5-Chloro-2-methylphenyl)-7-methyl-2-(2- (trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0122] ACN (1.00 mL) was-7-methyl-2-(2- (trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.101 g, 0.296 mmol) and 2- cyclopropyl-6-(trifluoromethyl)nicotinic acid trifluoromethanesulfonate (0.198 g, 0.445 mmol). After stirring 5 min at RT, solid CsF (0.225 g, 1.48 mmol) was added. After 1 h, the mixture was loaded onto 5 g SCX resin and eluted first with water and then with MeOH. The water and MeOH eluates were discarded, then eluted, collected, and concentrated 2N NH3 in MeOH. The resulting residue was taken up in DCM, concentrated onto diatomaceous earth and purified by silica gel chromatography using a gradient of 0 to 30% EtOAc in DCM to give the title compound (0.086 g). ES-MS m / z 452 (M+H).

[0123] Intermediate 20 in the following table was prepared essentially as described in the Preparation of Intermediate 15 using (5R,7S)-8-(5-chloro-2-methylphenyl)-7-methyl-2-(2- (trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one.Intermediate ES-MS Chemical Name Structure number m / z ) P, yl-4- oxo-2-(2-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)phenyl)-1H-pyrazol-1- yl)acetic acid

[0124] Pd(dppf)Cl2added to a stirred solution of (5R,7S)-7-methyl-8-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(2- (trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.13 g, 0.24 mmol), K3PO4 (0.175 g, 0.82 mmol) and 2-(4-bromo-5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1-yl)acetic acid (0.105 g, 0. 36 mmol) in 1,4-dioxane (3.0 mL) and water (1.0 mL) under nitrogen and stirred at 100ºC. After 16 h, the reaction mixture was filtered, and the filtrate was concentrated under vacuum after acidification with a 2N solution of HCl. The residue was purified by reverse phase flash chromatography using a gradient of 0 to 50% ACN in aq. NH4HCO3to give the title compound (0.046 g). ES-MS m / z 618 (M+H). Preparation of Intermediate 22: N-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol- 7-yl) acetamide

[0125] Chloro[(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) (0.130 g, 0.216 mmol) was added to a solution of N-(4-bromo-1H-indazol-7-yl)acetamide (0.280 g, 1.07 mmol) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.000 g, 4.00 mmol) in 1,4-dioxane (2 mL) and K2CO3(0.600 g, 4.30 mmol) in one portion at 20 °C under N2and the mixture was stirred at 80 °C. Afte 2 h, the reaction mixture was poured into H2O (5 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with sat. aq. NaCl (5 mL), dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 35% EtOAc in petroleum ether to give the title compound (0.121 g) as a solid. ES-MS m / z 302 (M+H). Preparation of Intermediate 23: N-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-7- yl) acetamide

[0126] The title compound wasas described in the Preparation of Intermediate 22 using N-(4-chloro-1H-indol-7-yl)acetamide, heating the reaction at 100 °C for 12 h and purifying the product by silica gel chromatography using 15% EtOAc in petroleum ether. ES-MS m / z 301 (M+H). Preparation of Intermediate 24: 5-Bromo-N-cyclobutyl-4,6-dimethylpyridin-2-amine

[0127] Cyclobutanone (0.349 g, 4.98added to a solution of 5-bromo-4,6- dimethylpyridin-2-amine (0.500 g, 2.49 mmol) in DCM (15 mL) and acetic acid (0. 854 mL) and the mixture was stirred at RT for 1 h. Sodium triacetoxyborohydride (1.58 g, 7.45 mmol) was added portion-wise and the reaction mixture was stirred 16 h at RT. Additional cyclobutanone(0.349 g, 4.98 mmol) and sodium triacetoxyborohydride (1.58 g, 7.45 mmol) was added and the mixture was stirred. After 4 h, the reaction mixture was quenched with water and both layers were separated. The organic layer was washed twice with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in cyclohexane to give the title compound (0.419 g) as an oil. ES-MS m / z 255,257 (M+H). Preparation of Intermediate 25: N-(4-Bromo-1H-indazol-7-yl) acetamide

[0128] Acetyl chloride (0.189 mL, added to a solution of 4-bromo-1H-indazol-7-amine (0.450 g, 2.08 mmol) in DCM (6 mL) and DMAP (0.700 g, 5.62 mmol) in one portion at 20 °C under N2. After 2 h, the mixture was poured into H2O (10 mL) and stirred for 5 min. The aqueous phase was extracted with DCM (3 × 10 mL). The combined organic phase was washed with sat. aq. NaCl (3 × 10 mL), dried with anhydrous Na2SO4, 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 (0.300 g) as a solid. ES-MS m / z 254, 256 (M+H).

[0129] Intermediate 26 in the following table was prepared essentially as described in the Preparation of Intermediate 25 using the appropriate amine. Intermediate ES-MS Chemical Name StructurePreparation of Intermediate 27: N-(1,4-Dimethyl-1H-pyrazol-3-yl) acetamide

[0130] Acetyl chloride (0.466 mL, 6.48 mmol) was added dropwise to a solution of 1,4- dimethyl-1H-pyrazol-3-amine (0.655 g, 5.89 mmol) and TEA (1.64 mL, 11.8 mmol) in DCM (23 mL) at 0 ºC and stirred. After 5 min, the reaction mixture was concrentrated under reduced pressure. The residue was dissolved in EtOAc, and the suspension was filtered through 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).

[0131] The following intermediates were prepared essentially as described in the Preparation of Intermediate 27 using the appropriate amine. Intermediate Chemical Name Structure ES-MS number m / z 1 9Preparation of Intermediate 31: N-(5-Bromo-1,4-dimethyl-1H-pyrazol-3-yl) acetamide

[0132] NBS (1.28 g, 7.07 mmol)of N-(1,4-dimethyl-1H-pyrazol-3- yl) acetamide (0.925 g, 5.43 mmol) in DCM (27 mL) and stirred at RT. After 4 h, the reaction was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 50 to 100% EtOAc in DCM. The product dissolved in EtOAc, washed with sat. aq. NaHCO3, water and sat. aq. NaCl. The organic layer was dried over anhydrous Na2SO4, filtered and conccentrated to give the title compound (0.92 g) as a solid. ES-MS m / z 232, 234 (M+H).

[0133] Intermediate 32 in the following table was prepared essentially as described in the Preparation of Intermediate 31 using N-(1,4-dimethyl-1H-imidazol-2-yl)acetamide. Intermediate ES-MS number Chemical Name Structure m / z 4O

[0134] Bromine (4.46 mL; 86.82acid (5 mL) was added dropwise to p- acetanisidide, 2'-methyl- (5.003 g; 27.92 mmol) in acetic acid (25.24 mL) and stirred. After 18h, the reaction was treated with sodium bisulfite (40.99 g; 393.89 mmol) in water (100 mL) and cooled in an ice bath. Another 100 mL water was added. A solid was formed and isolated by filtration. The solid was washed with 300 mL water and dried, then recrystallized with 30 mL DCM and 25 mL EtOAc at 42 ℃. A small amount of MeOH was added to give a solution.20 mL Et2O was added, and the solution stirred as it cooled to RT. The mixture was filtered, and the filtrate was concentrated and the residue purified by silica gel chromatography using 10% ACN in DCM to give the title compound (1.05 g) as a solid. ES-MS m / z 258, 260 (M+H). Preparation of Intermediate 34: 7-Bromobenzo[d]thiazol-4-amine

[0135] To a mixture of benzo[d](0.503 g, 3.28 mmol) in DMF (10 mL) was added NBS (0.660 g, 3.63 mmol) and DIEA (0.638 mL, 3.66 mmol) at 20 °C. The mixture was stirred at 20 °C. After 2 h, the reaction was poured into water (5 mL) at 10-20 °C and then extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with sat. aq. NaCl (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduce pressure. Theresidue was purified by silica gel chromatography eluting with 15% EtOAc in petroleum ether to give the title compound (0.500 g) as a solid. ES-MS m / z 229, 231 (M+H). Preparation of Intermediate 35: N-(7-Bromobenzo[d]thiazol-4-yl) acetamide

[0136] Acetic anhydride (0.291 mL, was added to a solution of 7-bromobenzo[d]thiazol-4-amine (0.500 g, 1.96 mmol) in toluene (3 mL) at 20 °C. The mixture was stirred at 35 °C. After 4 h, the reaction was poured into water (3 mL) at 10-20 °C and then extracted with EtOAc (2 × 3 mL). The combined organic phase was washed with sat. aq. NaCl (3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduce pressure. The residue was purified by reverse-phase prep-HPLC (column: Waters Xbridge Prep OBD C18150 × 40 mm, 10 µm) using a gradient of 50 to 80% ACN in 10 mM aq. NH4HCO3) to give the title compound (0.400 mg) as a solid. ES-MS m / z 271, 273 (M+H). Preparation of Intermediate 36: N-(7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2- yl)benzo[d]thiazol-4-yl)acetamide

[0137] Chloro[]palladium(II) (0.120 g, 0.199 mmol) was added to a mixture of N-(7-bromobenzo[d]thiazol-4-yl) acetamide (0.250 g, 0.904 mmol) in 1,4-dioxane (10 mL), bis(pinacolato)diborane (0.940 g, 3.63 mmol), and K2CO3 (0.510 g, 3.65 mmol), under N2at 20 °C and the mixture was stirred at 80 °C. After 12 h, The reaction was poured into water (5 mL) at 10-20 °C and then extracted with EtOAc (3 × 5 mL). The combined organics were washed with sat. aq. NaCl (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduce pressure. The residue was purified by silica gelchromatography using 15% EtOAc in petroleum ether to give the title compound (0.160 g) as a solid. ES-MS m / z 319 (M+H). Preparation of Intermediate 37: N-(4-Bromo-3-methylpyridin-2-yl)acetamide

[0138] Acetic anhydride (0.108 mL, in 0.2 mL of DCM was added to 4-bromo-3-methylpyridin-2-amine (0.195 g, 1.04 mmol) in DCM (10 mL) and pyridine (0.253 mL, 3.12 mmol). The reaction was stirred for 18 h at 50 ℃. Additional acetic anhydride (0.054 mL, 0.575 mmol) and pyridine (0.337 mL, 4.16 mmol) were added and the mixture was stirred another 48 h at 50 ℃. The reaction was washed with sat. aq. NH4Cl, water and sat. aq. NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography isng a gradient of 30 to 100% EtOAc in cyclohexane to give the title compound (0.140 g). ES-MS m / z 229, 231 (M+H).

[0139] The compounds in the following table were prepared essentially as described in the Preparation of Intermediate 37 using the appropriate amine. Intermediate Chemical Name Structure ES-MS number m / z 1 1Preparation of Intermediate 40: N-(1,4-Dimethyl-5-(3-((5R,7S)-7-methyl-4-oxo-2-(2- (trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)phenyl)-1H-pyrazol-3- yl)acetamide

[0140] A mixture of (5R,7S methyl-1,3,2-dioxaborolan-2- yl)phenyl)-2-(2-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.101 g, 0.181 mmol), Pd(dppf)Cl2(complex with DCM, 0.018 g, 0.022 mmol), K3PO4(0.097 g, 0.451 mmol) and N-(5-bromo-1,4-dimethyl-1H-pyrazol-3-yl)acetamide (0.068 g, 0.26 mmol) was purged with nitrogen and 1,4-dioxane (1.91 mL) and water (0.638 mL) were added. The mixture was stirred at 100ºC. After 2 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 water and sat. aq. NaCl, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 10% EtOH in EtOAc to give the title compound (0.082 g) as a solid. ES-MS m / z 555 (M+H). Preparation of Intermediate 41: Methyl 2-cyclopropyl-6-(trifluoromethyl)nicotinate

[0141] To a 1 L RBF was charged(350 mL) and H2O (70 mL) was added methyl 2-chloro-6-(trifluoromethyl)nicotinate (60 g, 243 mmol), cyclopropaneboronic acid (51 g, 580 mmol) and K2CO3 (120 g, 864 mmol). The reaction mixture was de-gassed and backfilled with N23 times before and after adding chloro(crotyl)(tri-tert-butylphosphine)palladium(II) (CAS# 1334497-00-5, 6.2 g, 15 mmol). Then the reaction mixture was stirred at 90 °C for 12 h, cooled down to RT, and concentrated under reduced pressure to give a residue. The residue was dissolved into DCM (300 mL) to form a suspension, filtered to remove insoluble impurities, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 10% EtOAc in n-hexane to give the title compound (41.0 g) as oil. ES-MS m / z 245 (M+H).

[0142] Alternate procedure: Methyl 2-chloro-6-(trifluoromethyl)nicotinate (35.31 g, 140.0 mmol, CAS # 1073129-57-3) and potassium cyclopropyltrifluoroborate (29.8 g, 201 mmol) were mixed with toluene (0.30 L) and potassium carbonate (0.30 L, 2.0 M in water, 600 mmol). The mixture was purged with N2for 10 min and bis(triphenylphosphine)palladium(II) dichloride (9.75 g, 13.9 mmol) was added. The purge was continued for 5 min. The reaction mixture was heated at 75 °C for 13 h. The mixture was transferred to a separatory funnel, and the aqueous drained off. The organics were washed with 2 M aq. K2CO3(2 × 50 mL) then with sat. aq. NaCl (50 mL), dried over MgSO4 and filtered. The organic layer was eluted through a pad of silica gel eluting with toluene to give the desired product. (44.87 g, 70% purity). 1H NMR (400.13 MHz, CDCl3): 8.25 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 4.00 (s, 3H), 3.09-3.03 (m, 1H), 1.30- 1.26 (m, 2H), 1.13-1.09 (m, 2H). Preparation of Intermediate 42: 2-Cyclopropyl-6-(trifluoromethyl)nicotinic acid

[0143] To a 1 L one-neck RBF withbar was charged MeOH (400 mL), followed by the addition of methyl 2-cyclopropyl-6-(trifluoromethyl)nicotinate (41.0 g, 165 mmol) and NaOH (1.0 M in H2O, 282 mL, 282 mmol) at 0 °C. The reaction mixture was stirred at 24 °C for 12 h, concentrated under reduced pressure, and adjusted to pH = 2~3 with HCl (1.0 M in H2O, 300 mL). The mixture was extracted with EtOAc (100 mL × 2). The combined organic layer was washed with sat. aq. NaCl (100 mL × 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (32.0 g) as solid. ES-MS m / z 232 (M+H). Preparation of Intermediate 43: 2-cyclopropyl-6-(trifluoromethyl)nicotinoyl chloride

[0144] To a vigorous stirring DCMDMF (1 mL) solution of 2-cyclopropyl-6- (trifluoromethyl)nicotinic acid (20 g, 83 mmol) was added oxalyl chloride (26.9 g, 207 mmol)dropwise over 10 min at 0 °C. The reaction mixture was stirred at 25 °C for 2 h, then directly concentrated under reduced pressure to give the title compound (19.8 g, 89.3% purity) as solid. ES-MS m / z 246 (M+H, methyl ester from methanol in mass spec mobile phase). Preparation of Intermediate 44: tert-Butyl (2S,4R)-4-carbamoyl-4-(2-cyclopropyl-6- (trifluoromethyl)nicotinamido)-2-methylpiperidine-1-carboxylate

[0145] To a vigorous stirring tert-butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-1-carboxylate (17.0 g, 62 mmol) and TEA (20 g, 190 mmol) was added 2-cyclopropyl-6-(trifluoromethyl)nicotinoyl chloride (19.8 g, 89.3% purity, 70 mmol) in DCM (100 mL) dropwise over 2 min at 0 °C. The reaction mixture was stirred at 25 °C for 12 h, then poured into H2O (400 mL) at 20 °C, and extracted with DCM (100 mL × 3). The combined organic layer was washed with sat. aq. NaCl (250 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (34.7 g, 56.8% purity) as oil. ES-MS m / z 471 (M+H). Preparation of Intermediate 45: tert-Butyl (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin- 3-yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate

[0146] To a vigorous stirringtert-butyl (2S,4R)-4-carbamoyl-4- (2-cyclopropyl-6-(trifluoromethyl)nicotinamido)-2-methylpiperidine-1-carboxylate (34.7 g, 56.8% purity, 41.9 mmol) was added KOtBu (31 g, 270 mmol). The reaction mixture was stirred at 80 °C for 1 h, cooled to RT, diluted with H2O (500 mL), and extracted with EtOAc (300 mL × 3). The combined organic layer was washed with sat. aq. NaCl (500 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residuewas purified by silica gel chromatography using a gradient of 20 to 60% EtOAc in n-hexane to give the title compound (18.5 g) as solid. ES-MS m / z 453 (M+H). Preparation of Intermediate 46: (5R,7S)-2-(2-Cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0147] To a 500 mL RBF with a charged with EtOAc (100 mL),followed by the addition of tert-butyl (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)- 7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (18.5 g, 38.2 mmol) and HCl (4.0 M in EtOAc, 100 mL, 400 mmol) at 0 °C. Then the reaction mixture was stirred vigorously at 10 °C for 2 h, concentrated under reduced pressure directly to give a residue. The residue was diluted with water (80 mL) and adjusted to pH = 8~9 with NH3H2O (100 mL) at 10 °C and further purified by reverse phase prep-HPLC using a gradient of 1 to 60% ACN in 10 mM aq. NH4HCO3to give the title compound (12.8 g) as solid. ES-MS m / z 353 (M+H). Preparation of Intermediate 47: (5R,7S)-2-(2-Cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one dihydrochloride

[0148] A solution of 5M HClmmol) was added to a solution of tert-butyl (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-1,3,8- triazaspiro[4.5]dec-1-ene-8-carboxylate (12.6 g, 27.8 mmol) in 1,4-dioxane (250 mL) under N2 atmosphere and stirred at RT overnight. The reaction mixture was concentrated under reduced pressure to afford the title compound (12.5 g) as a solid. ES-MS m / z 352 (M+H). Preparation of Intermediate 48: tert-Butyl 4-carbamoyl-4-(2-cyclopropyl-6- (trifluoromethyl)nicotinamido)piperidine-1-carboxylate

[0149] tert-Butyl 4-amino-4-car rboxylate (22.35 g, 91.86 mmol, CAS [288154-18-7]) was mixed with THF (0.20 L) and sodium carbonate (1.0 M aqueous, 250 mL, 250 mmol). A solution of 2-cyclopropyl-6-(trifluoromethyl)nicotinoyl chloride (22.81 g, 87.72 mmol) in THF (0.10 L) was added. The mixture was stirred for 30 min then diluted with water (approximately 650 mL). The resulting slurry was stirred for 1 h then collected via filtration and the filter cake washed with additional water. The solid was dried in a vacuum oven to give the title compound (33.9 g, 98% purity) as solid. ES-MS m / z 457 (M+H). Preparation of Intermediate 49: tert-Butyl 2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-4- oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate

[0150] EtOH (0.17 L) was4-(2-cyclopropyl-6- (trifluoromethyl)nicotinamido)piperidine-1-carboxylate (33.90 g, 72.78 mmol) in a 500 mL RBF with stir bar. Sodium ethoxide (25% in EtOH, 90 mL, 0.29 mol) was added. The mixture was heated at 80 °C for 1.5 h. The reaction was cooled to RT and poured into a stirred mixture of water (0.50 L) and saturated aqueous NH4Cl (0.25 L). Stirred for 30 min, then the precipitate was collected by filtration. The precipitate was dissolved in EtOAc (0.40 L) then washed with sat. aq. NaCl (2 × 0.15 L), dried over MgSO4, filtered and partially concentrated to approximately 0.1 L. Heptane (approx. 0.2 L) was added, and the mixture was stirred at RT. A first crop of desired product was then obtained by filtration (washed with 50 mL each of 20% EtOAc / heptane then heptane). The filtrate was then further concentrated to approximately 0.15 L to give a second crop of desired product that was collected by filtration and washed with heptane (50 mL). The two crops of solid were combined and dried in a vacuum oven overnight to give the desired product as a cream solid (29.71 g). ES-MS m / z 439 (M+H), 383.0 (M-55).Preparation of Intermediate 50: 2-(2-Cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8- triazaspiro[4.5]dec-1-en-4-one dimethanesulfonate

[0151] tert-Butyl 2-(2- pyridin-3-yl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8- g, and 1-propanol (0.30 L) were charged to a 1 L flask with stir bar. The mixture was heated to 90 °C. Methanesulfonic acid (4.8 mL, 72 mmol) was added. After 4 h, additional methanesulfonic acid (4.1 mL, 61 mmol) was added. Th reaction was stirred for 10 min then removed from heat. The mixture was concentrated. Isopropyl acetate (0.40 L) was added and the mixture was stirred at 60 °C for 1.5 h. The heat was turned off and the mixture was stirred for 1 h. The solid was collected by filtration (6 cm porosity 3 glass frit, slow), washed with isopropyl acetate (0.1 L), then transferred to a vacuum oven for drying (10 mbar, 40 °C, from 2000 h) overnight to give the title compound (35.78 g) as solid. ES-MS m / z 339 (M+H). Preparation of Intermediate 51: 2-(2-Cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8- triazaspiro[4.5]dec-1-en-4-one

[0152] To a 500 mL RBF withcharged with 1,4-dioxane (120 mL), followed by the addition of tert-butyl 2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-4-oxo- 1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (15 g, 31 mmol) and HCl (4.0 M in 1,4-dioxane, 120 mL, 480 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 5 h, then concentrated under reduced pressure to a residue. The residue was dissolved in H2O (100 mL) and then adjusted to pH = 8~9 with sat. aq. Na2CO3 and extracted with EtOAc (200 mL × 3). The combined organic layer was washed with sat. aq. NaCl (100 mL × 2), dried over Na2SO4,filtered and the filtrate was concentrated under reduced pressure to give the title compound (10 g) as solid. ES-MS m / z 339 (M+H). Preparation of Intermediate 52: 4-Chloro-2-(2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-4- oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-6-fluorobenzaldehyde

[0153] To a 250 mL RBF DMSO (100 mL), followedby addition of 2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en- 4-one (10 g, 28 mmol), 4-chloro-2,6-difluorobenzaldehyde (5.2 g, 28 mmol) and DIEA (11 g, 84 mmol) at 15 °C. The reaction mixture was stirred at 100 °C for 12 h. The reaction was cooled to RT, poured into ice water (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with sat. aq. NaCl (100 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in n-hexane to give the title compound (8.5 g) as solid. ES-MS m / z 495, 497 (M+H). Preparation of Intermediate 53: 8-(5-Chloro-3-fluoro-2-(hydroxymethyl)phenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0154] To a 1 L RBF with a4-chloro-2-(2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-6-fluorobenzaldehyde (8.5 g, 16 mmol) and MeOH (430 mL). NaBH4 (2.3 g, 60 mmol) was added at 15 °C under N2 over 10 min. The mixture was stirred at 15 °C for 1 h, concentrated under reduced pressure to remove ~1 / 2 MeOH and then poured into sat. aq. NH4Cl (300 mL) at 0 ⁰C. The mixture wasextracted with DCM (150 mL × 3). The combined organic layer was washed with sat. aq. NaCl (100 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 60% EtOAc in n-hexane to give the title compound (5.6 g, 86.6% purity) as solid. ES-MS m / z 495, 497 (M-H). Preparation of Intermediate 54: 8-(2-(Bromomethyl)-5-chloro-3-fluorophenyl)-2-(2-cyclopropyl- 6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0155] To a 250 mL RBF with DCM (70 mL) and 8-(5-chloro-3-fluoro-2-(hydroxymethyl)phenyl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)- 1,3,8-triazaspiro[4.5]dec-1-en-4-one (5.6 g, 86.6% purity, 9.8 mmol) and triphenylphosphine (3.2 g, 12 mmol), followed by addition of NBS (2.2 g, 12 mmol) over 10 min at 0 °C. The reaction mixture was stirred at 15 °C for 1 h, then concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 70% EtOAc in n-hexane to give the title compound (4.2 g) as solid. ES-MS m / z 535, 537 (M+H). Preparation of Intermediate 55: 8-(5-Chloro-3-fluoro-2-(methoxymethyl)phenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0156] To a 500 mL RBF withcharged with MeOH (250 mL), followed by the addition of 8-(2-(bromomethyl)-5-chloro-3-fluorophenyl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (4.2 g, 6.8 mmol) and NaOMe (5.0 M in MeOH, 5.7 mL, 29 mmol) at 15 °C. The reaction mixture was stirred at 40 °C for 1 h. The reaction was cooled to RT and concentrated under reduced pressure to give a residueThe residue was diluted with ice water (100 mL) and extracted with DCM (50 mL × 3). The combined organic layer was washed with sat. aq. NaCl (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (20 g, 87.5% purity) as solid. ES-MS m / z 511, 513 (M+H).

[0157] Alternate Procedure: A 250 mL RBF with stir bar was charged 8-(5-chloro-3-fluoro- 2-(hydroxymethyl)phenyl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8- triazaspiro[4.5]dec-1-en-4-one (0.962 g, 1.94 mmol) in DCM (40 mL) under nitrogen. Methanesulfonyl chloride (0.190 mL, 2.44 mmol) was added, followed by TEA (0. 350 mL, 2.51 mmol) and the mixture was warmed to 40 °C. After 3 h, additional THF (10 mL), methanesulfonyl chloride (0.190 mL, 2.44 mmol) and TEA (0.350 mL, 2.51 mmol) were added. After 50 min, the reaction mixture was quenched with MeOH (20 mL). The mixture was stirred overnight at RT. The reaction mixture was concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in cyclohexanes, then re-purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in cyclohexanes to give the title compound (0.174 g). ES-MS m / z 511, 513 (M+H). Preparation of Intermediate 56: 2-(2-Cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-8-(3-fluoro-2- (methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,8- triazaspiro[4.5]dec-1-en-4-one

[0158] To a 100 mL RBFwith methoxycyclopentane (35 mL), followed by the addition of 8-(5-chloro-3-fluoro-2-(methoxymethyl)phenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (3.5 g, 87.5% purity, 6.0 mmol), KOAc (1.9 g, 18 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (1.9 g, 7.3 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i- propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81-5, 0.78 g, 0.90 mmol) at 15 °C. The reaction mixture was purgedwith N2for 20 seconds before vigorously stirring at 80 °C for 2 h. The reaction was cooled to RT and then concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in n-hexane to give the title compound (1.8 g, 82.5% purity) as solid. ES-MS m / z 603 (M+H). Preparation of Intermediate 57: (2-Bromo-4-chlorophenyl)(cyclopropyl)methanol (racemic mixture)

[0159] To a 2 L RBF with a magnetic charged with MeTHF (200 mL), followedby the addition of 2-bromo-4-chlorobenzaldehyde (30 g, 140 mmol). The reaction mixture was de-gassed and refilled with N23 times. Cyclopropylmagnesium bromide (1.0 M in THF, 270 mL, 270 mmol) was added dropwise to the mixture at -78 °C. The reaction mixture was warmed to 20 °C and stirred for 2 h. The reaction was quenched with sat. aq. NH4Cl (200 mL) at 0 °C, diluted with H2O (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (28 g, 87% purity) as oil. ES-MS m / z 243, 245 (M-OH). Preparation of Intermediate 58: 2-Bromo-4-chloro-1-(cyclopropylmethyl)benzene

[0160] To a 2 L RBF with a magneticcharged with DCM (560 mL), followed by the addition of (2-bromo-4-chlorophenyl)(cyclopropyl)methanol (racemic mixture, 28 g, 87% purity, 93 mmol), triethylsilane (18 g, 152 mmol) and TFA (72 g, 623 mmol) at 0 °C. The reaction mixture was purged with N2 for 2 min before vigorously stirring at 40 °C for 2 h. The mixture was cooled to RT and concentrated under reduced pressure to give the residue. The residue was purified by silica gel chromatography using a gradient of 0 to 10% EtOAc in n- hexane to give the title compound (20.0 g) as oil.1H-NMR (400 MHz, DMSO-d6) δ 7.70 (d, J =2.08 Hz, 1H), 7.54 - 7.34 (m, 2H), 2.58 (d, J = 6.97 Hz, 2H), 1.10 - 0.93 (m, 1H), 0.55 - 0.41 (m, 2H), 0.30 - 0.16 (m, 2H). Preparation of Intermediate 59: 8-(5-Chloro-2-(cyclopropylmethyl)phenyl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0161] To a 100 mL RBF with THF (3 mL), followedby the addition of 2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1- en-4-one (3.0 g, 8.0 mmol) and LiHMDS (1.0 M in THF, 22 mL, 22 mmol) at 20 °C. 2-Bromo- 4-chloro-1-(cyclopropylmethyl)benzene (3.6 g, 15 mmol) was added at 20 °C. The reaction mixture was stirred at 65 °C for 4 h. The reaction was cooled to RT and poured into H2O (50 mL) and then extracted with EtOAc (80 mL × 2). The combined organic layer was washed with sat. aq. NaCl (100 mL × 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase prep-HPLC using a gradient of 70 to 98% ACN in 0.2% FA to give the title compound (0.15 g) as solid. ES-MS m / z 503, 505 (M+H).

[0162] Alternate Procedure: 2-(2-Cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8- triazaspiro[4.5]dec-1-en-4-one (0.175 g, 0.517 mmol) was mixed with toluene (4.5 mL) in a microwave vial. 2-Bromo-4-chloro-1-(cyclopropylmethyl)benzene (0.19 g, 0.77 mmol) was added and the mixture degassed with N2 for 10 min. A solution of sodium 2-methylbutan-2-olate in 2-Me-THF (0.83 mL, 30% wt., 2.06 mmol) was added while continuing to bubble N2for 5 additional min. Methanesulfonato(2-bis(3,5-di(trifluoromethyl)phenylphosphino)-3,6- dimethoxy-2',6'-bis(dimethylamino)-1,1'-biphenyl )(2'-methylamino-1,1'-biphenyl-2- yl)palladium(II) (FrankenPhos Palladacycle Gen. 4, CAS# 1810068-35-9, 0.057 g, 0.050 mmol) was added and the reaction was heated via microwave irradiation at 90 °C for 5 h. The reation mixture was cooled to RT, poured into a separatory funnel containing sat. aq. NH4Cl and extracted with EtOAc (3 × 50 mL). The combined organic layer was washed with sat. aq. NaCland concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in n-heptanes to give the title compound (0.20 g). ES-MS m / z 503, 505 (M+H). Preparation of Intermediate 60: 2-(2-Cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-8-(2- (cyclopropylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,8- triazaspiro[4.5]dec-1-en-4-one

[0163] To a 40 mL vial methoxycyclopentane (15 mL),followed by the addition of 8-(5-chloro-2-(cyclopropylmethyl)phenyl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (1.2 g, 2.2 mmol), bis(pinacolato)diborane (1.3 g, 5.0 mmol), KOAc (0.80 g, 7.5 mmol) and methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2- yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81-5, 0.24 g, 0.27 mmol) at 20 °C. The reaction mixture was purged with N2 for 30 seconds before vigorously stirring at 80 °C for 2 h. The reaction was cooled to RT and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 20% EtOAc in n- hexane to give the title compound (0.75 g, 87% purity) as solid. ES-MS m / z 595 (M+H). Preparation of Intermediate 61: 5-Chloro-2-(trimethylsilyl)phenol

[0164] To a 2 L RBF with acharged with THF (500 mL), followed by the addition of 2-bromo-5-chlorophenol (50.0 g, 229 mmol) and HMDS (187 g, 1150 mmol) at 20 °C. The reaction mixture was stirred at 80 °C for 14 h. The reaction was cooled to RT and concentrated under reduced pressure to give a residue. The residue was dissolved in THF (500 mL) and the mixture was degassed and purged with N23 times. n-Butyllithium (2.5 M in n-hexane, 137 mL, 343 mmol) was added dropwise over 50 min at -70 °C. The reaction mixture was stirred at -70 °C for 1.5 h and warmed to RT. The reaction was poured into sat. aq. NH4Cl (1 L) at 0 °C and extracted with EtOAc (1 L × 3). The combined organic layer was washed with sat. aq. NaCl (1 L), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 15% EtOAc in n-hexane to give the title compound (34 g, 89% purity) as oil. ES-MS m / z 199, 201 (M-H). Preparation of Intermediate 62: 5-Chloro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate;

[0165] To a 2 L RBF with a charged with DCM (340 mL), followed bythe addition of 5-chloro-2-(trimethylsilyl)phenol (34.0 g, 89.4% purity, 151 mmol) and DIEA (39.3 g, 301 mmol) at 20 °C. Then trifluoromethanesulfonic anhydride (64.7 g, 227 mmol) was added dropwise over 20 min at 0 °C. The reaction mixture was stirred at 20 °C for 2 h, poured into water (600 mL) at 20 °C and extracted with DCM (600 mL × 3). The combined organic layer was washed with sat. aq. NaCl (600 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by reverse phase prep- HPLC using a gradient of 75 to 95% ACN in 10 mM aq. NH4HCO3 to give the title compound (30.5 g) as oil. ES-MS m / z 331 (M-H). Preparation of Intermediate 63: (5R,7S)-8-(5-Chloro-2-iodophenyl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0166] To a 250 mL RBFwith DME (50 mL), followed by the addition of (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (5.0 g, 14.0 mmol), 3-bromo-2-iodobenzo[b]thiophene (5.34 g, 15.4 mmol), potassium fluoride (1.65 g, 28.1 mmol) and 18-crown-6 (7.49 g, 28.1 mmol) at 20 °C. 5-Chloro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (5.14 g, 15.4 mmol) in DME (50 mL) was added dropwise over 10 min at 20 °C. The reaction mixture was degassed and purged with N23 times, then stirred at 20 °C for 2 h. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic layer was washed with sat. aq. NaCl (200 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase prep-HPLC using a gradient of 60 to 98% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.80 g) as solid. ES-MS m / z 589, 591 (M+H). Preparation of Intermediate 64: Diethyl 2-(5-bromo-4,6-dimethylpyrimidin-2-yl)malonate

[0167] To a 500 mL RBF with acharged with DME (240 mL), followed by the addition of diethyl malonate (30.5 g, 188 mmol), Cs2CO3(70.0 g, 212 mmol) and 5-bromo-2-chloro-4,6-dimethylpyrimidine (20.0 g, 85.7 mmol) at 16 °C. The reaction mixture was stirred at 90 °C for 16 h. The reaction was cooled down to RT and poured into sat. aq. NH4Cl (250 mL) at RT. The mixture was diluted with EtOAc (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layer was washed with sat. aq. NaCl (100 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 20% EtOAc in n-hexane to give the title compound (33.5 g, 80% purity) as oil. ES-MS m / z 345, 347 (M+H). Preparation of Intermediate 65: Ethyl 2-(5-bromo-4,6-dimethylpyrimidin-2-yl)acetate

[0168] To a 500 mL RBF with a magnetic stir bar was charged with DMSO (300 mL), followed by the addition of diethyl 2-(5-bromo-4,6-dimethylpyrimidin-2-yl)malonate (33.52 g, 80% purity, 77.68 mmol). A solution of sodium chloride (13.32 g, 225.6 mmol) in water (40 mL) was added at 16 °C. The reaction mixture was stirred at 130 °C for 32 h. The reaction was cooled to RT and poured into water (900 mL). The mixture was diluted with EtOAc (100 mL) and extracted with EtOAc (200 mL × 2). The combined organic layer was washed with sat. aq. NaCl (200 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 20% EtOAc in n-hexane to give the title compound (20.1 g, 75.4% purity) as oil. ES-MS m / z 273, 275 (M+H). Preparation of Intermediate 66: 2-(5-Bromo-4,6-dimethylpyrimidin-2-yl)acetamide

[0169] A solution of ethyl 2-(5-2-yl)acetate (26.6 g, 75.4% purity, 73.4 mmol) and ammonia (7.0 M in MeOH, 240 mL, 1680 mmol) was separated into three 100 mL sealed tubes, and then stirred under 15 psi at 80 °C for 32 h. The three reaction mixtures were cooled down to RT, combined and concentrated under reduced pressure to give a crude product. The crude product was triturated with MeOH (30 mL) at RT for 30 mins, filtered and the filter cake was washed with MeOH (10 mL) and n-hexane (40 mL). The filter cake was dried under reduced pressure to give the title compound. (15.1 g) as solid. ES-MS m / z 244, 246 (M+H). Preparation of Intermediate 67: (5R,7S)-8-(5-Chloro-2-cyclopropylphenyl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0170] To a 40 mL vial with a magnetic stir bar was charged with DMA (20 mL), followed by the addition of (5R,7S)-8-(5-chloro-2-iodophenyl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.40 g, 0.62 mmol), iodocyclopropane (0.64 g, 3.7 mmol), picolinimidamide hydrochloride (0.30 g, 1.87 mmol), tetrabutylammonium iodide (0.93 g, 2.49 mmol), nickel(II) chloride, dimethoxyethane adduct (0.14 g, 0.63 mmol) and zinc (0.41 g, 6.24 mmol) at 20 °C. The reaction mixture was purged with N2for 2 min before vigorously stirring at 50 °C for 2 h. The reaction was cooled to RT, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by reverse phase prep-HPLC using a gradient of 60 to 90% ACN in 10 mM aq. NH4HCO3to give the title compound (0.12 g) as solid. ES-MS m / z 503, 505 (M+H). Preparation of Intermediate 68: (5R,7S)-8-(2-Cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8- triazaspiro[4.5]dec-1-en-4-one

[0171] To an 8 mL vialwith methoxycyclopentane (2 mL), followed by the addition of (5R,7S)-8-(5-chloro-2-cyclopropylphenyl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.12 g, 0.22 mmol), bis(pinacolato)diborane (0.12 g, 0.45 mmol), KOAc (0.072 g, 0.67 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino- 1,1'-biphenyl-2-yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81-5, 0.020 g, 0.023 mmol) at 15 °C. The reaction mixture was purged with N2 for 30s before vigorously stirring at 80 °C for 3 h. The reaction was cooled to RT and concentrated under reduced pressure to give the crude product. The crude product was purified by prep-TLC (SiO2, 3:1 n-hexane : EtOAc, Rf= 0.4, UV), then the SiO2powder was soaked with EtOAc (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.12 g, 86% purity) as solid. ES-MS m / z 595 (M+H).Preparation of Intermediate 69: (5R,7S)-8-(5-Chloro-2-(cyclopropylmethyl)phenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0172] To a 100 mL RBF THF (35 mL), followed bythe addition of (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8- triazaspiro[4.5]dec-1-en-4-one (3.5 g, 9.9 mmol) and 2-bromo-4-chloro-1- (cyclopropylmethyl)benzene (5.2 g, 21 mmol). LiHMDS (1.0 M in THF, 62 mL, 62 mmol) was added dropwise over 10 min at 25 °C. The reaction mixture was purged with N2 for 30 seconds, then stirred at 80 °C for 2 h. The reaction was cooled to RT, poured into H2O (100 mL) and then extracted with EtOAc (30 mL × 3). The combined organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase prep-HPLC using a gradient of 65 to 90% ACN in 0.2% FA to give the title compound (2.0 g) as solid. ES-MS m / z 517, 519 (M+H). Preparation of Intermediate 70: (5R,7S)-2-(2-Cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-8-(2- (cyclopropylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7-methyl-1,3,8- triazaspiro[4.5]dec-1-en-4-one

[0173] To a 40 mL vialmethoxycyclopentane (20 mL), followed by the addition of (5R,7S)-8-(5-chloro-2-(cyclopropylmethyl)phenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (2.0 g, 3.8 mmol), bis(pinacolato)diborane (1.94 g, 7.49 mmol), KOAc (1.26 g, 11.8 mmol) andmethanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino- 1,1'-biphenyl-2-yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81-5, 0.40 g, 0.46 mmol) at 15 °C. The mixture was purged with N2 for 30s before vigorously stirring at 80 °C for 3 h. The reaction mixture was cooled to RT, and then concentrated under reduced pressure to give residue. The residue was purified by silica gel chromatography using a gradient of 0 to 40% EtOAc in n-hexane to give the title compound (1.5 g) as solid. ES-MS m / z 608 (M+H). Preparation of Intermediate 71: (5-Bromo-4,6-dimethylpyrimidin-2-yl)methanol

[0174] To a 1 L RBF with a magnetic charged with EtOH (500 mL), followed bythe addition of (4,6-dimethylpyrimidin-2-yl)methanol (43 g, 310 mmol) at 15 °C, then Br2(78 g, 460 mmol) was added dropwise over 10 min at 0 °C. The reaction mixture was stirred vigorously at 15 °C for 16 h. The reaction was filtered and the filter cake was washed with EtOH (500 mL). The filter cake was collected and dried under reduced pressure at 45 °C to give the title compound (34 g, 79.3% purity) as solid. ES-MS m / z 216, 218 (M-H). Preparation of Intermediate 72: 5-Bromo-4,6-dimethylpyrimidine-2-carbaldehyde

[0175] To a 1 L RBF with a magneticcharged with DCM (100 mL), followed by the addition of oxalyl chloride (35 g, 270 mmol) at 24 °C. Then a solution of DMSO (35 g, 440 mmol) in DCM (50 mL) was added dropwise at -78 °C over 20 min. The reaction was stirred at - 78 °C for 20 min. The reaction mixture was de-gassed and refilled with N23 times. (5-Bromo- 4,6-dimethylpyrimidin-2-yl)methanol (34 g, 79.3% purity, 120 mmol) in DCM (50 mL) was added dropwise to the reaction mixture at -78 °C over 30 min and the resulting mixture stirred at -78 °C for 20 min. The reaction mixture was de-gassed and refilled with N23 times. TEA (90 g, 870 mmol) was added dropwise at -78 °C over 20 min. The reaction was stirred at 0 °C for 30min. The reaction was poured into water (500 mL) at 20 °C and extracted with DCM (100 mL × 3). The combined organic layer was washed with sat. aq. NaCl (300 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 40% EtOAc in n-hexane to give the title compound (20.0 g, 48.8% purity) as solid. ES-MS m / z 214, 216 (M+H). Preparation of Intermediate 73: 2-(5-Bromo-4,6-dimethylpyrimidin-2-yl)-2-hydroxyacetonitrile (racemic mixture)

[0176] To a 100 mL RBF with a was charged with water (30 mL), followedby the addition of 5-bromo-4,6-dimethylpyrimidine-2-carbaldehyde (17 g, 48.8% purity, 39 mmol) at 25 °C. A solution of sodium bisulfite (16 g, 150 mmol) in water (10 mL) was added dropwise to the reaction mixture at 0 °C over 20 min and the reaction was stirred at 0 °C for 30 min. NaCN (8 g, 200 mmol) in water (10 mL) was added dropwise to the reaction mixture at 0 °C over 20 min. The reaction mixture was allowed to warm to RT and stirred for 3 h. The reaction mixture was extracted with EtOAc (30 mL × 4). The water layer was adjusted to pH >11 with NaOH (1.0 M in H2O), and aq. NaClO (10%, 500 mL) was added under stirring to quench the unreacted NaCN. The combined organic layer was washed with sat. aq. NaCl (100 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (12.0 g, 76.7% purity) as solid. ES-MS m / z 241, 243 (M+H). Preparation of Intermediate 74: 2-(5-Bromo-4,6-dimethylpyrimidin-2-yl)-2-hydroxyacetamide (racemic mixture)

[0177] To a 100 mL RBF with a magnetic stir bar was charged H2SO4(90% Wt in H2O, 40 mL, 680 mmol). 2-(5-Bromo-4,6-dimethylpyrimidin-2-yl)-2-hydroxyacetonitrile (racemic mixture, 12.0 g, 76.7% purity, 38 mmol) was added at 25 °C. The reaction mixture was stirred at 70 °C for 2 h. The reaction was allowed to cooled to RT and then poured into MeOH (40 mL) at -50 °C. The resulting solution was purified by reverse phase prep-HPLC directly using a gradient of 5 to 35% ACN in 0.2% aq. FA to give the title compound (3.1 g) as solid. ES-MS m / z 259, 261 (M+H). Preparation of Intermediate 75: 4-Amino-1,1,1-trifluorobut-3-en-2-one

[0178] A solution of 4-ethoxy-1,1,1- 3-en-2-one (80 g, 450 mmol), ammonia inMeOH (250 mL, 7 M, 1750 mmol) was stirred vigorously at 25 °C for 16 h. The mixture was concentrated under reduced pressure to obtain the title compound a yellow oil.1H-NMR (400 MHz, DMSO-d6) δ 9.42 (br s, 1H), 8.90 (br s, 1H), 7.44 (m, 1H), 5.28 (d, J = 6.8 Hz). Preparation of Intermediate 76: Ethyl 2-cyclobutyl-6-(trifluoromethyl)nicotinate

[0179] A solution of 4-amino-2-one (67 g, 80%, 390 mmol), ethyl 3- cyclobutyl-3-oxopropanoate (110 g, 633 mmol) and TFA (47 mL, 600 mmol) in toluene (500 mL) was stirred vigorously at 110 °C for 16 h. The reaction mixture was cooled to RT and concentrated to a residue. The residue was suspended in EtOAc (500 mL) and a 15% Na2CO3solution. After separation, the aqueous layer was extracted with EtOAc (3 × 500 mL). The combined organics were washed with sat. aq. NaCl (500 mL), dried over MgSO4, filtered and concentrated under reduced pressure to a residue. The residue was purified by flash chromatography on silica gel (0-40% EtOAc in n-hexane) to afford the title compound (44 g) as a liquid.Preparation of Intermediate 77: Methyl 2-cyclobutyl-6-(trifluoromethyl)nicotinate; (BVC- C01821-457-4D)

[0180] To a 1 L RBF with a charged with toluene (500 mL), followedby the addition of methyl 3-cyclobutyl- (130 g, 824 mmol), (E)-4-amino-1,1,1- trifluorobut-3-en-2-one (100 g, 683 mmol) and TFA (96 g, 842 mmol) at 20 °C. The reaction mixture was stirred at 110 °C for 16 h, cooled down to RT, and concentrated under reduced pressure to give a residue. The residue was poured into a mixture of EtOAc (500 mL) and sat. aq. Na2CO3 (15 wt% in water, 1 L). The reaction was extracted with EtOAc (500 mL × 3). The combined organic layer was washed with sat. aq. NaCl (500 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 40% EtOAc in n-hexane to give the title compound (60 g) as oil. ES-MS m / z 260 (M+H). Preparation of Intermediate 78: (1H-Imidazol-1-yl)(1-methylcyclopropyl)methanone

[0181] To a 500 mL (1-neck) RBFstir bar was charged with DCM (300 mL), followed by the addition of 1-methyl cyclopropanecarboxylic acid (20 g, 0.20 mol), TEA (56 mL, 0.40 mol) and CDI (42 g, 0.26 mol) at 20 °C. The reaction mixture was allowed to stir vigorously at 20 °C. After 2 h, the crude reaction mixture was concentrated under reduced pressure directly to give the title compound (33.6 g, 80% purity) as oil. Preparation of Intermediate 79: Methyl 3-(1-methylcyclopropyl)-3-oxopropanoate;

[0182] To a 3000 mL RBF with a magnetic stir bar was charged ACN (1500 mL), followed by addition of TEA (50.4 mL, 358 mmol), (1H-imidazol-1-yl)(1-methylcyclopropyl)methanone (33.6 g, 80% purity, 179 mmol), potassium 3-methoxy-3-oxopropanoate (56.5 g, 358 mmol) and magnesium chloride (34.4 g, 358 mmol) at 20 °C. The mixture was stirred at 80 °C for 12 h. The reaction mixture was allowed to cool to RT and adjusted to pH=1 with 1 N HCl aqueous solution (500 mL) with stirring at 15 °C. The mixture was diluted with H2O (500 mL) and extracted with EtOAc (1000 mL × 2). The combined organic layers were washed with sat. aq. NaCl (500 mL × 2), dried over anhydrous Na2SO4, the Na2SO4 was filtered off and further washed with EtOAc (200 mL). The obtained filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in n- hexane to give the title compound (21.7 g, 90% purity) as oil. ES-MS m / z 157 (M+H). Preparation of Intermediate 80: Methyl 2-(1-methylcyclopropyl)-6-(trifluoromethyl)nicotinate;

[0183] To a 500 mL RBF with awas charged with toluene (200 mL), followed by the addition of methyl 3-(1-methylcyclopropyl)-3-oxopropanoate (16.7 g, 90% purity, 96.2 mmol) ,(E)-4-amino-1,1,1-trifluorobut-3-en-2-one (10 g, 68 mmol), TFA (5.4 mL, 69 mmol) and ammonium trifluoroacetate (9.0 g, 68 mmol) at 20 °C. The reaction mixture was allowed to stir vigorously at 120 °C. After 12 h, the reaction mixture was allowed to cool down to RT, and poured into 250 mL H2O at 15 ⁰C. The mixture was extracted with EtOAc (500 mL × 2). The combined organic layer was washed with sat. aq. NaCl (100 mL) and dried over Na2SO4. The Na2SO4was filtered off and further washed with DCM (150 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in n-hexane to give the title compound (5.19 g, 28%,) as oil. ES-MS m / z 260 (M+H). Preparation of Intermediate 81: 2-(1-Methylcyclopropyl)-6-(trifluoromethyl)nicotinic acid;

[0184] To a 1 L RBF with a magnet charged with MeOH (170 mL) and THF (170 mL), followed by the addition of methyl 2-(1-methylcyclopropyl)-6- (trifluoromethyl)nicotinate (16.29 g, 59.38 mmol) and NaOH (1.0 M in H2O, 150 mL, 150 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 12 h. The reaction was concentrated under reduced pressure to remove MeOH and THF. The aq. phase was adjusted to pH = 2~3 with HCl (1.0 M in H2O) under stirring. The reaction mixture was filtered, and the filter cake was dried under reduced pressure to give the title compound (13.5 g) as solid. ES-MS m / z 246 (M+H). Preparation of Intermediate 82: 2-Cyclobutyl-6-(trifluoromethyl)nicotinic acid

[0185] NaOH (10 g, 240 mmol),of ethyl 2-cyclobutyl-6- (trifluoromethyl)nicotinate (44 g, 157 mmol) in THF (150 mL), MeOH (150 mL), water (150 mL) and the mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in water (200 mL), and the pH was adjusted to 3-4 by addition of 4 N HCl. The mixture was filtered and the filter cake rinsed with water (5 × 100 mL) to give the title compound (34 g) as a solid. ES-MS m / z 246 (M+H). Preparation of Intermediate 83: 2-Cyclobutyl-6-(trifluoromethyl)nicotinic acid

[0186] To a 2 L RBF wasnicotinic acid (30.0 g, 130 mmol) and cyclobutanecarboxylic acid (20.0 g, 196 mmol) in DMF (600 mL) was added 2-(tert-butyl)- 1,1,3,3-tetramethylguanidine (45.1 g, 261 mmol) and phthalimide (29.1 g, 196 mmol). Thereaction mixture was degassed and purged with N23 times. (4,4'-Di-t-butyl-2,2'- bipyridine)bis[3,5-difluoro-2-(5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (1.49 g, 1.30 mmol) and [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine] nickel (II) dichloride (2.65 g, 6.53 mmol) were added. The mixture was stirred at 55 °C for 2 h under irradiation with a 395 nm (200 W) LED. The reaction mixture was cooled to RT and poured into H2O (1 L). The mixture was extracted with EtOAc (1 L × 3). The combined organic layer was washed with sat. aq. NaCl (1 L), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase prep-HPLC using a gradient of 35 to 65% ACN in 0.2% FA to give the title compound (15.0 g, 80.6% purity) as solid. ES-MS m / z 246 (M+H). Preparation of Intermediate 84: Methyl 3-(2-oxabicyclo[2.2.2]octan-1-yl)-3-oxopropanoate

[0187] Step 1: A 40 mL RBF with abar was charged with DCM (8 mL), followed by the addition of 2-oxabicyclo[2.2.2]octane-1-carboxylic acid (CAS # 1447943-57-8, 800 mg, 5.07 mmol), N,N'-carbonyldiimidazole (2.00 g, 12.2 mmol), TEA (1.5 mL, 11 mmol) and DMAP (70 mg, 0.57 mmol) at RT and stirred vigorously for 1 h. The crude reaction mixture was concentrated under reduced pressure to give (2-oxabicyclo[2.2.2]octan-1-yl)(1H-imidazol-1- yl)methanone (1.20 g).

[0188] Step 2: A 100 mL RBF with a magnetic stir bar was charged with ACN (60 mL), followed by TEA (1.3 mL, 9.2 mmol), (2-oxabicyclo[2.2.2]octan-1-yl)(1H-imidazol-1- yl)methanone (1.20 g, 4.65 mmol), potassium 3-methoxy-3-oxopropanoate (1.47 g, 9.32 mmol) and magnesium chloride (900 mg, 9.36 mmol) at RT. The mixture was stirred at 80 °C for 12 h then cooled to RT. The mixture was adjusted to pH=1 with 1N HCl aqueous solution (10 mL) with stirring at 15 °C, diluted with H2O (5 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with sat. aq. NaCl (5 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in n-hexane to give the title compound (400 mg). ES-MS m / z 213 (M+H).Preparation of Intermediate 85: Methyl 2-(2-oxabicyclo[2.2.2]octan-1-yl)-6- (trifluoromethyl)nicotinate

[0189] A 40 mL vial with a with toluene (6 mL), followed bythe addition of methyl 3-(2-oxabicyclo[2.2.2]octan-1-yl)-3-oxopropanoate (0.30 g, 1.41 mmol), ammonium trifluoroacetate (180 mg, 1.36 mmol), (E)-4-amino-1,1,1-trifluoro-but-3-en-2-one (190 mg, 1.35 mmol) and TFA (0.1 mL, 1 mmol) at RT. The reaction mixture was stirred vigorously at 120 °C for 12 h. The reaction was cooled to RT and poured into a separatory funnel containing H2O (10 mL). The mixture was extracted with EtOAc (20 mL × 2). The combined organic layers were washed with sat. aq. NaCl (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in n-hexane to give the title compound (300 mg). ES-MS m / z 316 (M+H). Preparation of Intermediate 86: 2-(2-Oxabicyclo[2.2.2]octan-1-yl)-6-(trifluoromethyl)nicotinic acid

[0190] To a 100 mL flask with awas charged THF (6.5 mL) and MeOH (6.5 mL), followed by the addition of methyl 2-(2-oxabicyclo[2.2.2]octan-1-yl)-6- (trifluoromethyl)nicotinate (0.35 g, 1.04 mmol) and NaOH in H2O (6.5 mL, 1 molar, 6.5 mmol) at 20 °C. The reaction mixture was stirred vigorously at 20 °C for 16 h. The reaction was heated to 60 °C for an additional 16 h. The mixture was cooled to RT and concentrated under reduced pressure to give a residue. The residue was added to water (30 mL) and 1N HCl was added dropwise until pH=3. The mixture was extracted with EtOAc (50 mL × 4). The combinedorganic layer was dried over Na2SO4,filtered and concentrated under reduced pressure to give the title compound (0.31 g). ES-MS m / z 302 (M+H). Preparation of Intermediate 87: tert-Butyl 4-carbamoyl-4-(2-cyclobutyl-6- (trifluoromethyl)nicotinamido)piperidine-1-carboxylate

[0191] To a 1 L RBF with a DMF (250 mL), followed by theaddition of 2-cyclobutyl-6-(trifluoromethyl)nicotinic acid (15.0 g, 80.6% purity, 49.3 mmol), tert- butyl 4-amino-4-carbamoylpiperidine-1-carboxylate (12.5 g, 50.9 mmol), DIEA (12.6 g, 96.6 mmol) and HATU (36.5 g, 95.0 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 4 h, poured into H2O (300 mL) and extracted with EtOAc (500 mL × 3). The combined organic layer was washed with H2O (200 mL × 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (25.0 g, 81.9% purity) as solid. ES-MS m / z 469 (M-H). Preparation of Intermediate 88: tert-Butyl 4-carbamoyl-4-(2-(1-methylcyclopropyl)-6- (trifluoromethyl)nicotinamido)piperidine-1-carboxylate

[0192] To a 250 mL RBF withwith DMF (100 mL), followed by the addition of 2-(1-methylcyclopropyl)-6-(trifluoromethyl)nicotinic acid (7.0 g, 28 mmol), tert-butyl 4-amino-4-carbamoylpiperidine-1-carboxylate (8.5 g, 35 mmol), HATU (16.0 g, 41.7 mmol) and DIEA (11.1 g, 85.3 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 5 h, quenched by water (200 mL) and then extracted with EtOAc (100 mL × 3). The combined organic layer was washed with sat. aq. NaCl (100 mL), dried over Na2SO4, and filtered. The filtrate wasconcentrated under reduced pressure to give the title compound (21.5 g, 58.8% purity) as oil. ES- MS m / z 471 (M+H).

[0193] The following intermediate was prepared as described in the Preparation of Intermediate 88 by using appropriate carboxylic acid Intermediate Chemical name Structure ES-MS Number m / z ) )Preparation of Intermediate 90: tert-Butyl 2-(2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-4- oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate

[0194] To a 1 L RBF with aEtOH (300 mL), followed by the addition of tert-butyl 4-carbamoyl-4-(2-cyclobutyl-6-(trifluoromethyl)nicotinamido)piperidine- 1-carboxylate (25.0 g, 81.9% purity, 43.5 mmol), and KOtBu (25 g, 220 mmol) at 15 °C. The mixture was stirred at 80 °C for 4 h. The reaction was cooled to RT and concentrated under reduced pressure to remove ~3 / 4 EtOH. The solution was diluted with H2O (300 mL) and then extracted with EtOAc (200 mL × 2). The combined organic layer was washed with H2O (100 mL × 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 35% EtOAc in n-hexane to give the title compound (15.0 g) as solid. ES-MS m / z 451 (M-H).Preparation of Intermediate 91: tert-Butyl 2-(2-(1-methylcyclopropyl)-6- (trifluoromethyl)pyridin-3-yl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate

[0195] To a 500 mL RBF with with EtOH (220 mL),followed by the addition of tert-butyl 4-carbamoyl-4-(2-(1-methylcyclopropyl)-6- (trifluoromethyl)nicotinamido)piperidine-1-carboxylate (21.5 g, 58.8% purity, 26.9 mmol) and KOtBu (16.5 g, 146 mmol) at 20 °C. The reaction mixture was stirred vigorously at 80 °C for 12 h. The reaction was cooled to RT and concentrated under reduced pressure. The resulting mixture was poured into water (400 mL) at 20 °C and extracted with EtOAc (200 mL × 3). The combined organic layer was washed with sat. aq. NaCl (200 mL × 2), dried over Na2SO4, then filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in n-hexane to give the title compound (9.4 g) as solid. ES-MS m / z 453 (M+H).

[0196] The following intermediate was prepared in a similar manner as described in the Preparation of Intermediate 91 using appropriated amide Intermediate ES-MS Chemical name Structure N ) )Preparation of Intermediate 93: 2-(2-Cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8- triazaspiro[4.5]dec-1-en-4-one

[0197] To a 500 mL RBF with a charged with 1,4-dioxane (80 mL),followed by the addition of tert- pyridin-3-yl)-4-oxo- 1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (15.0 g, 33.1 mmol) and HCl (4.0 M in 1,4- dioxane, 80 mL, 320 mmol) at 20 °C. The reaction mixture was stirred vigorously at 20 °C for 2 h. The reaction was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (100 mL), adjusted to pH = 8~9 with sat. aq. Na2CO3and extracted with EtOAc (200 mL × 3). The combined organic layer was washed with H2O (150 mL × 2), dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to give the title compound (11.5 g) as solid. ES-MS m / z 353 (M+H).

[0198] Alternate Procedure: In a 500 mL RBF with stir bar, tert-butyl 2-(2-cyclobutyl-6- (trifluoromethyl)pyridin-3-yl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (3.92 g, 8.66 mmol) was dissolved in DCM (100 mL). TFA (20.0 mL, 260 mmol) was slowly added. The reaction was stirred overnight at RT. The reaction was concentrated under reduced pressure to a light-yellow oil. The oil was directly loaded onto a pre-washed (2 CV MeOH) 70 g SCX column (CV = 150 mL) and washed with 2 CV MeOH and elute with 3 CV NH3 MeOH (2N). The eluent was concentrated to profide a solid. The solid was dried in a vacuum oven at 45 °C overnight to give the title compound (3.013 g, 8.55 mmol) as foam. ES-MS m / z 353 (M+H).

[0199] The following intermediate was prepared in a similar manner as described in the Preparation of Intermediate 93 using appropriate Boc protected amine Intermediate ES-MS Chemical name Structure )(5R,7S)-2-(2-cyclobutyl-6- (trifluoromethyl)pyridin-3-yl)-7- 367 ), , triazaspiro[4.5]dec-1-en-4-one dihydrochloride

[0200] To a 3 L RBF with a 1,4-dioxane (600 mL), followedby the addition of tert-butyl 2-(2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-4-oxo-1,3,8- triazaspiro[4.5]dec-1-ene-8-carboxylate (60 g, 133 mmol) and HCl (4.0 M in 1,4-dioxane, 600 mL, 2400 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 2 h. The reaction was concentrated under reduced pressure to give the title compound (50 g) as solid. ES-MS m / z 353 (M+H). Preparation of Intermediate 96: 2-(2-(1-Methylcyclopropyl)-6-(trifluoromethyl)pyridin-3-yl)- 1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0201] To a 250 mL RBF with acharged with 1,4-dioxane (40 mL) and DCM (40 mL), followed by the addition of tert-butyl 2-(2-(1-methylcyclopropyl)-6- (trifluoromethyl)pyridin-3-yl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (9.4 g, 20 mmol) and HCl (4.0 M in 1,4-dioxane, 100 mL, 400 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 5 h. The reaction was concentrated under reduced pressure. The residue was quenched with water (100 mL) and THF (200 mL). The pH was adjusted to pH = 10 with sat. aq. Na2CO3 under stirring at 20 °C for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was dissolved into THF (100mL) and NaCl (2 g) to form a suspension. The suspension was filtered, and the filtrate was concentrated under reduced to give title compound (7.04 g) as solid. ES-MS m / z 353 (M+H). Preparation of Intermediate 97: 1-Bromo-5-chloro-3-fluoro-2-(methoxymethyl)benzene

[0202] To a 250 mL RBF with a was charged DMF (50 mL), followed bythe addition of (2-bromo-4-chloro-6-fluorophenyl)methanol; CAS [1449008-26-7] (5.0 g, 21 mmol). NaH (1.2 g, 60% Wt in mineral oil, 30 mmol) was added in portions over 2 min at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. MeI (4.4 g, 31 mmol) was added dropwise over 2 min at 0 °C. The reaction mixture was stirred at 17 °C for 2 h. The reaction was quenched by adding H2O (50 mL) at 0 °C and the resulting mixture was extracted with EtOAc (50 mL × 2). The combined organic layer was washed with sat. aq. NaCl (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 30% EtOAc in n- hexane to give the title compound (3.8 g) as oil.1H-NMR (400 MHz, CDCl3) δ 7.44 (t, J = 1.7 Hz, 1H), 7.10 (dd, J = 2.0, 8.9 Hz, 1H), 4.58 (d, J = 2.3 Hz, 2H), 3.41 (s, 3H). Preparation of intermediate 98: 5-Chloro-2-cyclopropoxy-1-fluoro-3-nitrobenzene

[0203] 5-Chloro-1,2-difluoro-3-g, 27.6 mmol) was dissolved in DMF (100 mL) and stirred under N2. Cyclopropanol (2.20 mL, 34 mmol) was added followed by potassium carbonate (7.61 g, 55.1 mmol). The reaction was heated at 100 °C for 3.5 h. The reaction was allowed to cool to RT and stirred overnight. The reaction was poured into 1M HCl (aq, 100 mL) and extracted with DCM (3 × 75 mL). The combined organic layer was washed with sat. aq. NaCl, dried over MgSO4, filtered and concentrated. The residue was purified bysilica gel chromatography using a gradient of 0 to 20% EtOAc in n-heptane to give the title compound (5.52 g).1H NMR (400.16 MHz, DMSO-d6): 7.97-7.92 (m, 2H), 4.36 (qd, J = 6.0, 3.0 Hz, 1H), 0.80-0.77 (m, 2H), 0.69-0.65 (m, 2H). Preparation of intermediate 99: 5-Chloro-2-cyclopropoxy-3-fluoroaniline

[0204] 5-Chloro-2-cyclopropoxy-1- (5.52 g, 23.8 mmol) wasdissolved in EtOH (150 mL) and water (50 mL). Iron (4.66 g, 83.4 mmol) was added followed by ammonium chloride (6.39 g, 119 mmol). The reaction was heated at 85 °C for 6 h. The reaction was cooled to RT and stirred for 16 h. The reaction was filtered through diatomaceous earth eluting with EtOAc. The filtrate was poured into a separatory funnel containing sat. aq. NaHCO3(100 mL). The layers were separated and the aqueous layer further extracted with EtOAc (100 mL). The combined organic layer was concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in n-heptane to give the title compound (4.25 g).1H NMR (400.13 MHz, DMSO-d6): 6.52 (dd, J = 1.6, 2.4 Hz, 1H), 6.48 (dd, J = 2.6, 10.7 Hz, 1H), 5.46 (s, 2H), 4.08-4.04 (m, 1H), 0.82-0.78 (m, 2H), 0.55-0.50 (m, 2H). Preparation of Intermediate 100: 1-Bromo-5-chloro-2-cyclopropoxy-3-fluorobenzene

[0205] In a 250 mL RBF was added(0.613 g, 4.28 mmol) and ACN (10 mL). The reaction mixture was cooled in an ice bath and tert-butyl nitrite (0.636 mL, 5.34 mmol) was added dropwise. After 10 min, 5-chloro-2-cyclopropoxy-3-fluoroaniline (0.431 g, 2.14 mmol) in ACN (10 mL) was added dropwise. The reaction was stirred for 4 h. The reaction was warmed to RT and stirred for 16 h. The reaction was then poured into sat. aq. NaHCO3and extracted with EtOAc (2 × 100 mL). The combined organic layer was washed with sat. aq. NaCl and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to50% EtOAc in n-heptane to give the title compound (359 mg).1H-NMR (400 MHz, CDCl3) δ 7.35 (t, J = 2.1 Hz, 1H), 7.13 (dd, J = 2.4, 10.4 Hz, 1H), 4.34-4.29 (m, 1H), 0.97-0.94 (m, 2H), 0.65-0.60 (m, 2H). Preparation of Intermediate 101: 1-Bromo-5-chloro-2-(cyclopropylmethoxy)-3-fluorobenzene

[0206] 2-Bromo-4-chloro-6- g, 4.49 mmol, CAS # 886499-88-3) wasdissolved in DMF (20 mL). Potassium carbonate (1.25 g, 9.04 mmol) was added and the mixture was stirred at RT for 3 min. (Bromomethyl)cyclopropane (0.57 mL, 5.88 mmol, CAS # 7051- 34-5) was added and the mixture was stirred at RT for 24 h. The reaction mixture was poured into a separatory funnel containing sat. aq. NaHCO3and extracted with EtOAc (3 × 100 mL). The combined organic layer was washed with sat. aq. NaCl, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in n-heptane to give the title compound (0.94 g).1H NMR (400.13 MHz, CDCl3): 7.35 (t, J = 2.2 Hz, 1H), 7.10 (dd, J = 2.5, 10.3 Hz, 1H), 3.94 (d, J = 7.2 Hz, 2H), 1.35-1.30 (m, 1H), 0.65-0.61 (m, 2H), 0.36-0.32 (m, 2H). Preparation of Intermediate 102: 8-(5-Chloro-3-fluoro-2-(methoxymethyl)phenyl)-2-(2- cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0207] To a 100 mL RBFtoluene (25 mL) and 2-(2- cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (1.50 g, 4.23 mmol), followed by addition of 1-bromo-5-chloro-3-fluoro-2-(methoxymethyl)benzene (1.15 g,.48 mmol), sodium 2-methylbutan-2-olate in THF (4.68 g, 30% Wt, 12.7 mmol) andmethanesulfonato(2-bis(3,5-di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',6'- bis(dimethylamino)-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (FrankenPhos Palladacycle Gen. 4, CAS# 1810068-35-9, 0.592 g, 0.514 mmol) at 15 °C. The mixture was purged with N2for 0.5 min before vigorously stirring at 100 °C for 12 h. The reaction was cooled to RT and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in n- hexane to give the title compound (0.48 g) as solid. ES-MS m / z 525, 527 (M+H).

[0208] The following intermediates were prepared in a similar manner as described in the Preparation of Intermediate 102 using the appropriate amine and bromide. Intermediate ES-MS Number Chemical name Structure m / z ) )Preparation of Intermediate 105: 2-(2-Cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-8-(3-fluoro-2- (methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,8- triazaspiro[4.5]dec-1-en-4-one

[0209] To a 40 mL vialmethoxycyclopentane (5 mL), followed by the addition of 8-(5-chloro-3-fluoro-2-(methoxymethyl)phenyl)-2-(2-cyclobutyl-6- (trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.46 g, 0.81 mmol),4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.29 g, 1.14 mmol), KOAc (0.27 g, 2.54 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'- biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81-5, 0.085 g, 0.097 mmol) at 15 °C. The reaction mixture was purged with N2for 0.5 min before vigorously stirring at 80 °C for 1 h. The reaction was cooled to RT and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in n-hexane to give the title compound (0.43 g) as solid. ES-MS m / z 617 (M+H). Preparation of Intermediate 106: 4-Bromo-2-(2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)- 4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-6-fluorobenzaldehyde

[0210] A 40 mL vial wasbenzaldehyde (1.24 g, 5.50 mmol), 2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (1.69 g, 5.00 mmol), DMSO (6 mL) and DIEA (2.50 mL, 14.5 mmol). The reaction was stirred at 85 °C for 2 h. The reaction mixture was cooled to RT and poured into EtOAc (100 mL). The organic solution was washed with water (5 × 20 mL), sat. aq. NaCl (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 60% EtOAc in n-hexane to give the title compound (2.46 g, 95% purity) as foam. ES-MS m / z 539, 541. Preparation of Intermediate 107: 8-(5-Bromo-3-fluoro-2-(hydroxymethyl)phenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0211] To a solution of 4-bromo 6-(trifluoromethyl)pyridin-3-yl)-4-oxo- 1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-6-fluorobenzaldehyde (1.65 g, 3.06 mmol) in MeOH (50 mL) at 0 °C was added NaBH4 (0.338 g, 8.93 mmol) in two potions over 10 min. The reaction was stirred for 2 h at 0 °C and then warmed to RT over 1 h. The reaction was concentrated to give a solid. The solid was partitioned between sat. aq. NH4Cl and EtOAc. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with sat. aq. NaCl, dried over Na2SO4, filtered and the filtrate concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 80% EtOAc in DCM to give the title compound (1.31 g, 95% purity) as foam. ES-MS m / z 540, 542. Preparation of Intermediate 108: 8-(5-Bromo-2-(bromomethyl)-3-fluorophenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0212] A 250 mL RBF was3-fluoro-2-(hydroxymethyl)phenyl)-2- (2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (1.3 g, 2.4 mmol) and DCM (15 mL). The reaction was cooled in a 0 °C ice bath. Triphenylphosphine (0.7995 g, 3.048 mmol) and NBS (0.580 g, 3.26 mmol) were added. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 65% EtOAc in cyclohexane to give the title compound (0.849 g) as solid.1H NMR (400 MHz, DMSO-d6) δ11.56 (d, J = 15.2 Hz, 1H), 8.19 (d, J = 7.7 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.36 (dd, J = 9.2, 1.8 Hz, 1H), 7.25 (t, J = 1.5 Hz, 1H), 5.39 (s, 0H), 4.70 (d, J = 1.7 Hz, 2H), 3.30 – 3.14 (m, 5H), 2.89 – 2.80 (m, 1H), 2.23 – 2.03 (m, 2H), 1.73 (d, J = 13.1 Hz, 2H), 1.18 – 1.02 (m, 4H). Preparation of Intermediate 109: 8-(5-Bromo-2-(cyclopropoxymethyl)-3-fluorophenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0213] Sodium hydride (0.217 was added to a 100 mL flask chargedwith a stir bar, and DMF (12 mL) at 0 °C. After five min, cyclopropanol (0.5 mL, 8 mmol) was added and the reaction mixture stirred at 0 °C for 5 min. 8-(5-Bromo-2-(bromomethyl)-3- fluorophenyl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en- 4-one (0.730 g, 1.21 mmol) in THF (12 mL) was added dropwise to the reaction mixture. After 5 min, the reaction mixture was diluted with ice-cold water (100 mL) and extracted with EtOAc (100 mL). The aq. layer was diluted with sat. aq. sodium bicarbonate (50 mL). The aq. layer was extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in n-hexane to give the title compound (0.338 g) as solid. ES-MS m / z 581, 583.

[0214] The following intermediates were prepared in a similar manner as described in the Preparation of Intermediate 109 using 8-(2-(bromomethyl)-5-chloro-3-fluorophenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one and the appropriate alcohol. Intermediate ES-MS Chemical name Structure8-(5-Chloro-2-(cyclobutoxymethyl)- ) ) ) ) ) )Preparation of Intermediate 116: (4-(Cyclopropoxymethyl)-3-(2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-5-fluorophenyl)boronic acid

[0215] A degassed (N2) (0.062 g, 0.24 mmol), 8-(5-bromo-2-(cyclopropoxymethyl)-3-fluorophenyl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3- yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.091 g, 0.16 mmol), potassium acetate (0.015 g, 0.15 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'- methylamino-1,1'-biphenyl-2-yl)palladium(II) (0.014 g, 0.016 mmol) in 1,4-dioxane (3.0 mL) was heated at 80 °C for 3 h. The reaction was diluted with EtOAc (100 mL) and filtered through diatomaceous earth. The filtrate was concentrated. The product was dissolved in MeOH (30 mL), split in three portions and loaded onto three separate 10 g SCX columns (10 mL each, pre- washed with MeOH). The loaded columns were each washed with excess MeOH and then the product was eluted from the columns using a 50 / 50 solution of (2N NH3 / MeOH) / DCM. The eluents were combined and concentrated to give the title compound (0.060 g, 40% purity) as solid. ES-MS m / z 547 (M+H). Preparation of Intermediate 117: 8-(5-Bromo-2-(cyclopropoxymethyl)-3-fluorophenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0216] To a 250 mL RBF with a magnetic stir bar was charged MeTHF (150 mL), followed by the addition of 8-(5-bromo-2-(bromomethyl)-3-fluorophenyl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (7 g, 27% purity, 3.13 mmol), cyclopropanol (2.5 g, 42 mmol) and KOH (1.0 g, 20 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layer was washed with sat. aq. NaCl (150 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in n-hexane to give the title compound (1.4 g, 76.6% purity) as solid. ES-MS m / z 581, 583 (M+H). Preparation of Intermediate 118: 8-(2-(Cyclopropoxymethyl)-3-fluoro-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8- triazaspiro[4.5]dec-1-en-4-one

[0217] To a 100 mL RBF withwith methoxycyclopentane (20 mL), followed by the addition of 8-(5-bromo-2-(cyclopropoxymethyl)-3-fluorophenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (1.4 g, 76.6% purity, 1.8 mmol), KOAc (0.70 g, 7.0 mmol), bis(pinacolato)diborane (0.91 g, 3.5 mmol) and methanesulfonato(tricyclohexylphosphine)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct (PCy3 Palladacycle Gen. 3, CAS# 1445086-12-3, 0.16 g, 0.24 mmol). The reaction mixture was purged with N2 before vigorously stirring at 90 °C for 2 h. The reaction was cooled to RT, filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 30% EtOAc in n-hexane to give the title compound (1.0 g, 84% purity) as solid. ES-MS m / z 629 (M+H).Preparation of Intermediate 119: 8-(5-Bromo-2-(cyclopropyl(hydroxy)methyl)-3-fluorophenyl)- 2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (racemic mixture)

[0218] A solution of (8.9 mL, 0.5 M, 4.5 mmol) wasadded dropwise to a -78 ºC cooled solution of 4-bromo-2-(2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-6-fluorobenzaldehyde (0.48 g, 0.89 mmol) in 2-MeTHF (4.5 mL). The resulting solution was allowed to warm to RT and stirred for 1 h. The reaction was quenched with a sat. aq. NH4Cl (20 mL) and extracted with EtOAc (20 mL × 3). The combined organics were washed with sat. aq. NaCl (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound (0.52 g, 0.89 mmol) as foam. ES-MS m / z 581, 583 (M+H). Preparation of Intermediate 120: 8-(5-Bromo-2-(cyclopropylmethyl)-3-fluorophenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one F Br

[0219] TFA (4.8 mL, 638-(5-bromo-2- (cyclopropyl(hydroxy)methyl)-3-fluorophenyl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3- yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (racemic mixture, 0.52 g, 0.89 mmol) and triethylsilane (9.8 mL, 61 mmol) in 2-MeTHF (1.0 mL). The reaction was stirred at 40 ºC for 2 h. The reaction mixture was concentrated under reduced pressure to a residue. The residue was purified by silicagel chromatography using a gradient of 0 to 50% EtOAc in cyclohexane to give the title compound (0.49 g) as foam. ES-MS m / z 564, 566 (M+H). Preparation of Intermediate 121: (3-(2-(2-Cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-4-oxo- 1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-4-(cyclopropylmethyl)-5-fluorophenyl)boronic acid

[0220] A suspension of 8- -3-fluorophenyl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.49 g, 0.87 mmol), bis(pinacolato)diborane (0.46 g, 1.80 mmol), KOAc (0.25 g, 2.52 mmol), methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino- 1,1'-biphenyl-2-yl)palladium(II) (0.04 g, 0.04 mmol) in CPME (9.8 mL) was sparged with N2for 10 min. The reaction mixture was warmed to 80 ºC and stirred for 24 h. The reaction mixture was cooled to RT and loaded onto a 20 g SCX column. The column was rinsed with MeOH and eluted with a 1N ammonia in MeOH solution. The ammonia solution was concentrated under reduced pressure to give the title compound (0.39 g) as solid. ES-MS m / z 530.6 (M+H). Preparation of Intermediate 122: 4-Bromo-2-fluoro-6-((5R,7S)-2,2,7-trimethyl-4-oxo-1,3,8- triazaspiro[4.5]decan-8-yl)benzonitrile

[0221] To a 500 mL RBF with acharged with DMSO (100 mL), followed by the addition of (5R,7S)-2,2,7-trimethyl-1,3,8-triazaspiro[4.5]decan-4-one dihydrochloride (10.0 g, 35.2 mmol), 4-bromo-2,6-difluorobenzonitrile (10.2 g, 44.4 mmol) and DIEA (45 g, 340 mmol) at 20 °C. The reaction mixture was stirred vigorously at 100 °C for 16 h. The reaction was cooled to 26 °C, poured into H2O (120 mL) and extracted with EtOAc (150 mL × 3). The combined organic layer was washed with sat. aq. NaCl (150 mL × 2), dried withNa2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in n- hexane to give the title compound (10.2 g) as solid. ES-MS m / z 395, 397 (M+H). Preparation of Intermediate 123: (2S,4R)-4-Amino-1-(5-bromo-2-cyano-3-fluorophenyl)-2- methylpiperidine-4-carboxamide

[0222] To a 500 mL RBF with a charged with AcOH (80 mL) and H2O(20 mL), followed by the addition of 4-bromo-2-fluoro-6-((5R,7S)-2,2,7-trimethyl-4-oxo-1,3,8- triazaspiro[4.5]decan-8-yl)benzonitrile (10.2 g, 24.8 mmol) at 15 °C. The reaction mixture was stirred at 100 °C for 15 h. The reaction was cooled to 0 °C and the pH was adjusted to 8 with sat. aq. NaHCO3. The resulting mixture was extracted with DCM (1 L × 3). The combined organic layer was washed with sat. aq. NaCl (1 L), dried over anhydrous Na2SO4, filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by reverse phase prep-HPLC using a gradient of 25 to 55% ACN in 10 mM aq. NH4HCO3to give the title compound (7.2 g) as solid. ES-MS m / z 355, 357 (M+H). Preparation of Intermediate 124: N-((2S,4R)-1-(5-Bromo-2-cyano-3-fluorophenyl)-4-carbamoyl- 2-methylpiperidin-4-yl)-2-cyclopropyl-6-(trifluoromethyl)nicotinamide

[0223] To a 500 mL RBF wasby the addition of 2- cyclopropyl-6-(trifluoromethyl)nicotinic acid (4.8 g, 20 mmol), HATU (8.5 g, 22 mmol) and DIEA (7.4 g, 56 mmol). (2S,4R)-4-Amino-1-(5-bromo-2-cyano-3-fluorophenyl)-2- methylpiperidine-4-carboxamide (7.0 g, 18 mmol) was added in one portion. The reaction mixture was de-gassed and refilled with N23 times before vigorously stirring at 30 °C for 1 h.The reaction was cooled to RT, quenched with H2O (150 mL) and extracted with EtOAc (150 mL × 2). The combined organic layer was washed with sat. aq. NaCl (200 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (8.2 g) as oil. ES-MS m / z 566, 568 (M-H). Preparation of Intermediate 125: 4-Bromo-2-((5R,7S)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-6- fluorobenzonitrile

[0224] To a 500 mL RBFtert-amyl alcohol (150 mL), followed by addition of N-((2S,4R)-1-(5-bromo-2-cyano-3-fluorophenyl)-4-carbamoyl-2- methylpiperidin-4-yl)-2-cyclopropyl-6-(trifluoromethyl)nicotinamide (8.2 g, 13 mmol), and KOtBu (2.2 g, 19 mmol) at 18 °C. The reaction mixture was stirred at 80 °C for 6 h. The reaction was cooled to RT, poured into H2O (200 mL) and extracted with EtOAc (150 mL × 2). The combined organic layer was washed with H2O (200 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 60% EtOAc in n-hexane to give the title compound (6.9 g) as solid. ES-MS m / z 550, 552 (M+H). Preparation of Intermediate 126: 2-((5R,7S)-2-(2-Cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)- 7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzonitrile

[0225] To a 500 mL RBF with a magnetic stir bar was charged methoxycyclopentane (100 mL), 4-bromo-2-((5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo- 1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-6-fluorobenzonitrile (6.9 g, 12 mmol), bis(pinacolato)diborane (5.8 g, 22 mmol) and KOAc (3 g, 30 mmol). The reaction mixture was purged with N2 for 2 min before and after adding methanesulfonato(2-dicyclohexylphosphino- 2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81-5, 1 g, 1 mmol). The reaction mixture was stirred at 80 °C for 3 h under N2. The reaction was cooled to RT and concentrated under reduced pressure to give the residue. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in n-hexane to give the title compound (6.5 g, 89% purity) as solid. ES-MS m / z 516 (boronic acid) (M+H), 598 (boronate ester) (M+H). Preparation of Intermediate 127: 4-Bromo-N,3-dimethyl-1H-pyrazol-5-amine

[0226] To a 40 mL vial with acharged with DMF (10 mL), followed by the addition of N,3-dimethyl-1H-pyrazol-5-amine (1.0 g, 8.9 mmol) and NBS (3.4 g, 19 mmol) at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction was poured into H2O (40 mL) and extracted with EtOAc (10 mL × 3). The combined organic layer was washed with sat. aq. NaCl (20 mL × 3), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (1.2 g, 64% purity) as solid. ES-MS m / z 190, 192 (M+H). Preparation of Intermediate 128: 2-(4-Bromo-3-methyl-5-(methylamino)-1H-pyrazol-1- yl)acetamide

[0227] To a 40 mL vial with acharged DMF (12 mL), followed by the addition of 4-bromo-N,3-dimethyl-1H-pyrazol-5-amine (1.2 g, 64% purity, 4.0 mmol), 2-bromoacetamide (2.4 g, 17 mmol) and K2CO3(1.8 g, 13 mmol) at 16 °C. The reaction mixture was purged with N2 for 2 min before vigorously stirring at 100 °C for 4 h. The reaction was cooled to RT, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase prep-HPLC using a gradient of 0 to 50% ACN in 0.2% FA to give the title compound (0.10 g, 60% purity) as solid. ES-MS m / z 247, 249 (M+H). Preparation of Intermediate 129: Ethyl 2-(4,5-dibromo-1H-imidazol-1-yl)acetate

[0228] To a 250 mL RBF with a was charged 4,5-dibromo-1H-imidazole(5.0 g, 22 mmol) and ACN (100 mL), followed by the addition of ethyl 2-bromoacetate (8.6 g, 50 mmol) and Cs2CO3 (22 g, 67 mmol) at 20 °C. The reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was cooled to RT, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was poured into water (150 mL) and extracted with EtOAc (50 mL × 3). The combined organic layer was washed with sat. aq. NaCl (30 mL), dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 25 to 30% EtOAc in n-hexane to give the title compound (4.0 g) as solid. ES-MS m / z 310, 312, 314 (M+H). Preparation of Intermediate 130: Ethyl 2-(4-bromo-5-cyclopropyl-1H-imidazol-1-yl)acetate

[0229] To a 100 mL RBF with awas charged with ethyl 2-(4,5-dibromo- 1H-imidazol-1-yl)acetate (4.0 g, 12 mmol), cyclopropylboronic acid (1.3 g, 15 mmol), tricyclohexylphosphane (0.80 g, 22 mmol), K2CO3 (6.3 g, 45 mmol), toluene (50 mL) and H2O (5 mL). The reaction mixture was de-gassed and refilled with N23 times. Palladium diacetate (0.70 g, 31 mmol) was added. The reaction mixture was stirred at 110 °C for 12 h. The reaction was cooled to RT, poured into water (40 mL) and extracted with EtOAc (30 mL × 3). The water layer was adjusted to pH = 2 with HCl (3.0 M in H2O, 20 mL) and extracted with EtOAc (30 mL × 4). The combined organic layer was washed with sat. aq. NaCl (20 mL), dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.40 g, 69.9% purity) as solid. ES-MS m / z 272, 274 (M+H). Preparation of Intermediate 131: 2-(4-Bromo-5-cyclopropyl-1H-imidazol-1-yl)acetamide

[0230] To a 40 mL vial with a charged ethyl 2-(4-bromo-5-cyclopropyl-1H-imidazol-1-yl)acetate (0.40 g, 69.9% purity, 1.0 mmol), followed by the addition of NH3 (7.0 M in MeOH) (5 mL, 35 mmol) at 20 °C (external temperature). The reaction mixture was stirred at 80 °C for 2 h. The reaction was cooled to RT and concentrated under reduced pressure to give the residue. The residue was purified by reverse phase prep-HPLC using a gradient of 1 to 40% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.11 g) as solid. ES-MS m / z 243, 245 (M+H). Preparation of Intermediate 132: 2-(5-Bromo-4,6-dimethylpyrimidin-2-yl)acetic acid

[0231] To a 250 mL RBF with awas charged MeOH (50 mL), followed by the addition of ethyl 2-(5-bromo-4,6-dimethylpyrimidin-2-yl)acetate (5.0 g, 80.6% purity, 15 mmol) and NaOH (3.0 g, 74 mmol) in water (50 mL) at 15 °C. The reaction mixture was stirred at 50 °C for 2 h. The reaction was cooled to RT, concentrated under reduced pressure to remove MeOH and extracted with MTBE (30 mL × 3). The aqueous phase was collected and acidified with HCl (1.0 M in H2O) to pH = 3. The mixture was filtered and the filter cake was dried under reduced pressure to give the title compound (3.6 g, 84.1% purity) as solid. ES-MS m / z 245, 247 (M+H). Preparation of Intermediate 133: 2-(5-Bromo-4,6-dimethylpyrimidin-2-yl)-N-(oxetan-3- yl)acetamide

[0232] To a 40 mL vial with a ma charged DMF (2 mL), followed by the addition of 2-(5-bromo-4,6-dimethylpyrimidin-2-yl)acetic acid (0.20 g, 84.1% purity, 0.686 mmol), oxetan-3-amine hydrochloride (0.116 g, 1.05 mmol), HATU (0.399 g, 1.04 mmol) and DIEA (0.358 g, 2.74 mmol) at 18 °C. The reaction mixture was stirred at 18 °C for 2 h. Then the reaction mixture was purified by reverse phase prep-HPLC directly using a gradient of 1 to 35% ACN in 10 mM aq. NH4HCO3to give the title compound (0.10 g) as solid. ES-MS m / z 300, 302 (M+H). Preparation of Intermediate 134: 2-(4,6-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrimidin-2-yl)acetamide

[0233] To a 100 mL RBF withcharged methoxycyclopentane (40 mL), 2-(5-bromo-4,6-dimethylpyrimidin-2-yl)acetamide (1.90 g, 7.61 mmol), bis(pinacolato)diborane (3.92 g, 15.3 mmol) and KOAc (2.44 g, 22.9 mmol). The reaction mixture was de-gassed and refilled with N23 times before and after adding methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2- yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81-5, 0.66 g, 0.758 mmol). The reaction mixture was stirred at 80 °C for 12 h. The reaction was cooled down to RT, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by normal phase prep-HPLC using a gradient of 5 to 55% EtOH in heptane to give the title compound (0.49 g) as oil. ES-MS m / z 292 (M+H). Preparation of Intermediate 135: 2-Oxabicyclo[2.1.1]hexan-1-yl)(1H-imidazol-1-yl)methanone

[0234] To a 100 mL RBF with a magn ar was charged DCM (50 mL), followed by the addition of 2-oxabicyclo[2.1.1]hexane-1-carboxylic acid (5.00 g, 38.6 mmol), CDI (12.7 g, 77.5 mmol) and TEA (11.8 g, 116 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 2 h. The reaction was concentrated under reduced pressure to give the title compound (8.0 g, 80% purity) as oil. TLC (2: 1, n-hexane : EtOAc, stained with bromocresol green), Rf= 0.4. Preparation of Intermediate 136: Methyl 3-(2-oxabicyclo[2.1.1]hexan-1-yl)-3-oxopropanoate

[0235] To a 500 mL RBF with a was charged ACN (350 mL), followed byaddition of TEA (7.3 g, 71 mmol), (2-oxabicyclo[2.1.1]hexan-1-yl)(1H-imidazol-1-yl)methanone (8.0 g, 80% purity, 36 mmol), potassium 3-methoxy-3-oxopropanoate (11 g, 70 mmol) and MgCl2 (6.9 g, 72 mmol) at 20 °C. The reaction mixture was stirred at 80 °C for 12 h. The reaction was cooled down to RT, concentrated under reduced pressure to give the residue. The residue was diluted with H2O (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic layer was washed with sat. aq. NaCl (50 mL × 2), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in n-hexane to give the title compound (5.56 g) as oil. ES-MS m / z 185 (M+H). Preparation of Intermediate 137: Methyl 2-(2-oxabicyclo[2.1.1]hexan-1-yl)-6- (trifluoromethyl)nicotinate

[0236] To a 100 mL RBF with acharged toluene (50 mL), followed by the addition of methyl 3-(2-oxabicyclo[2.1.1]hexan-1-yl)-3-oxopropanoate (5.10 g, 26.4 mmol),(E)-4-amino-1,1,1-trifluorobut-3-en-2-one (3.51 g, 24.0 mmol), TFA (1.9 mL, 24 mmol) and ammonium trifluoroacetate (3.17 g, 23.9 mmol) at 20 °C. Then the reaction mixture was stirred at 120 °C for 12 h. The reaction was cooled down to RT, poured into H2O (250 mL) at 15 °C and then extracted with EtOAc (500 mL × 2). The combined organic layer was washed with sat. aq. NaCl (100 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in n-hexane to give the title compound (3.77 g) as oil. ES-MS m / z 288 (M+H). Preparation of Intermediate 138: 2-(2-Oxabicyclo[2.1.1]hexan-1-yl)-6-(trifluoromethyl)nicotinic acid

[0237] To a 250 mL RBF with acharged with MeOH (40 mL) and THF (40 mL), followed by addition of methyl 2-(2-oxabicyclo[2.1.1]hexan-1-yl)-6- (trifluoromethyl)nicotinate (3.77 g, 12.3 mmol) and NaOH (1.0 M in H2O, 30.7 mL, 30.7 mmol) at 20 °C. The reaction mixture was stirred vigorously at 20 °C for 3 h, The reaction was concentrated under reduced pressure to remove MeOH. The mixture was adjusted to pH = 2~3 with HCl (1.0 M in H2O), then extracted with EtOAc (200 mL × 2). The combined organic layer was washed with sat. aq. NaCl (100 mL), dried over Na2SO4,filtered and the filtrate was concentrated under reduced pressure to give the title compound (3.37 g) as oil. ES-MS m / z 274 (M+H). Preparation of Intermediate 139: tert-Butyl (2S,4R)-4-(2-(2-oxabicyclo[2.1.1]hexan-1-yl)-6- (trifluoromethyl)nicotinamido)-4-carbamoyl-2-methylpiperidine-1-carboxylate

[0238] To a 100 mL RBF with a magnetic stir bar was charged DMF (30 mL), followed by addition of 2-(2-oxabicyclo[2.1.1]hexan-1-yl)-6-(trifluoromethyl)nicotinic acid (1.60 g, 5.76 mmol), tert-butyl (2S,4R)-4-amino-4-carbamoyl-2-methylpiperidine-1-carboxylate (1.80 g, 6.92 mmol), HATU (3.32 g, 8.64 mmol) and DIEA (2.30 g, 17 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 4 h. The reaction was poured into H2O (50 mL) and then extracted with EtOAc (100 mL × 2). The combined organic layer was washed with sat. aq. NaCl (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (3.0 g) as solid. ES-MS m / z 513 (M+H). Preparation of Intermediate 140: tert-Butyl (5R,7S)-2-(2-(2-oxabicyclo[2.1.1]hexan-1-yl)-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate

[0239] To a 100 mL RBFwith EtOH (50 mL), followed by the addition of tert-butyl (2S,4R)-4-(2-(2-oxabicyclo[2.1.1]hexan-1-yl)-6- (trifluoromethyl)nicotinamido)-4-carbamoyl-2-methylpiperidine-1-carboxylate (3.00 g, 5.36 mmol) and KOtBu (3.10 g, 27.4 mmol) at 15 °C. The reaction mixture was stirred vigorously at 80 °C for 12 h. The reaction was cooled down to RT, poured into H2O (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic layer was washed with sat. aq. NaCl (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in n-hexane to give the title compound (2.64 g) as solid. ES-MS m / z 495 (M+H). Preparation of Intermediate 141: (5R,7S)-2-(2-(2-Oxabicyclo[2.1.1]hexan-1-yl)-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0240] To a 100 mL RBF with a magnetic stir bar was charged DCM (45 mL), followed by addition of tert-butyl (5R,7S)-2-(2-(2-oxabicyclo[2.1.1]hexan-1-yl)-6-(trifluoromethyl)pyridin-3- yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (2.64 g, 5.19 mmol) and TFA (15 mL, 190 mmol) at 25 °C. The reaction mixture was stirred vigorously at 25 °C for 2 h. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase prep-HPLC using a gradient of 5 to 55% ACN in 10 mM aq. NH4HCO3to give the title compound (1.2 g) as solid. ES-MS m / z 395 (M+H). Preparation of Intermediate 142: (5R,7S)-2-(2-(2-Oxabicyclo[2.1.1]hexan-1-yl)-6- (trifluoromethyl)pyridin-3-yl)-8-(5-chloro-2-(cyclopropylmethyl)phenyl)-7-methyl-1,3,8- triazaspiro[4.5]dec-1-en-4-one;

[0241] To a 40 mL vial withTHF (2 mL), followed by addition of (5R,7S)-2-(2-(2-oxabicyclo[2.1.1]hexan-1-yl)-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.26 g, 0.66 mmol), LiHMDS (1.0 M in hexane, 3.3 mL, 3.3 mmol) and 2-bromo-4-chloro-1-(cyclopropylmethyl)benzene (0.25 g, 0.99 mmol) at 20 °C. The mixture was stirred at 65 °C for 16 h. The reaction was cooled down to RT, quenched with H2O (10 mL), and diluted with EtOAc (5 mL). The mixture was extracted with EtOAc (5 mL × 3). The combined organic layer was washed with sat. aq. NaCl (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase prep-HPLC using a gradient of 65 to 95% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.10 g, 83.7% purity) as solid. ES-MS m / z 559, 561 (M+H). Preparation of Intermediate 143: 2-((5R,7S)-2-(2-(2-Oxabicyclo[2.1.1]hexan-1-yl)-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-4-bromo-6- fluorobenzonitrile

[0242] To a 40 mL vial with ged with DMSO (4 mL), followed by addition of (5R,7S)-2-(2-(2-oxabicyclo[2.1.1]hexan-1-yl)-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.30 g, 0.76 mmol), 4-bromo-2,6- difluorobenzonitrile (0.18 g, 0.82 mmol) and DIEA (0.30 g, 2.0 mmol) at 20 °C. The mixture was stirred at 110 °C for 16 h. The reaction was cooled to RT and quenched with H2O (20 mL). The mixture was diluted with EtOAc (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layer was washed with sat. aq. NaCl (30 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in n-hexane to give the title compound (0.16 g, 89.1% purity) as solid. ES-MS m / z 592, 594 (M+H). Preparation of Intermediate 144: (3-((5R,7S)-2-(2-(2-Oxabicyclo[2.1.1]hexan-1-yl)-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-4-cyano-5- fluorophenyl)boronic acid

[0243] To a 40 mL vial1,4-dioxane (2 mL), followed by the addition of 2-((5R,7S)-2-(2-(2-oxabicyclo[2.1.1]hexan-1-yl)-6-(trifluoromethyl)pyridin-3- yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-4-bromo-6-fluorobenzonitrile (0.15 g, 89.1% purity, 0.226 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.18 g, 0.45 mmol), KOAc (0.068 g, 0.69 mmol) and 1,1'-bis(diphenylphosphino)ferrocene- palladium(II) dichloride (CAS# 72287-26-4, 0.034 g, 0.046 mmol) at 18 °C. The reaction mixture was purged with N2for 30 seconds before vigorously stirring at 80 °C for 3 h. The reaction was cooled to RT and concentrated under reduced pressure to give a residue. Theresidue was purified by reverse phase prep-HPLC using a gradient of 30 to 70% ACN in 0.2% FA to give the title compound (0.10 g, 87.3% purity) as solid. ES-MS m / z 558 (M+H). Preparation of Intermediate 145: 4-Bromo-5-cyclopropyl-3-methyl-1H-pyrazole

[0244] To a 500 mL RBF with a was charged with DMF (150 mL),followed by the addition of 5- 1H-pyrazole (10.0 g, 81.6 mmol) and NBS (21.0 g, 117 mmol) at 20 °C. Tthe reaction mixture was stirred vigorously at 20 °C for 2 h. The reaction was poured into H2O (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layer was washed with H2O (500 mL × 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 35% EtOAc in n-hexane to give the title compound (10.1 g) as solid. ES-MS m / z 201, 203 (M+H). Preparation of Intermediate 146: Ethyl 2-(4-bromo-5-cyclopropyl-3-methyl-1H-pyrazol-1- yl)acetate

[0245] To a 500 mL RBF with acharged DMF (150 mL), followed by addition of 4-bromo-5-cyclopropyl-3-methyl-1H-pyrazole (10.0 g, 49.3 mmol), ethyl bromoacetate (16.5 g, 96.8 mmol) and K2CO3(20.0 g, 143 mmol) at 20 °C. The mixture was purged with N2 for 2 min before vigorously stirring at 100 °C for 2 h. The reaction was cooled to RT. The mixture was poured into H2O (500 mL) and extracted with EtOAc (500 mL × 2). The combined organic layer was washed sat. aq. NaCl (300 mL × 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase prep-HPLC using a gradient of 40 to 60% ACN in 0.2% FA to give the title compound (2.2 g) as solid. ES-MS m / z 287, 289 (M+H).Preparation of Intermediate 147: 2-(4-Bromo-5-cyclopropyl-3-methyl-1H-pyrazol-1- yl)acetamide

[0246] To a 250 mL RBF with a was charged MeOH (10 mL), followed byaddition of ethyl 2-(4-bromo-5- pyrazol-1-yl)acetate (2.2 g, 7.5 mmol) and ammonia (7.0 M in MeOH, 20 mL) at 20 °C. The mixture was purged with N2 for 2 min before vigorously stirring at 60 °C for 6 h. The reaction was cooled to RT. The mixture was concentrated under reduced pressure to give a residue, which was triturated with n-hexane (50 mL) at 20 ⁰C for 0.5 h. The mixture was filtered and the filter cake was dried under reduced pressure to give the title compound (1.85 g) as solid. ES-MS m / z 258, 260 (M+H). Preparation of Intermediate 148: Ethyl 2-(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)acetate

[0247] To a 40 mL vial with acharged DMF (5 mL), followed by addition of 4-bromo-3,5-dimethyl-1H-pyrazole (0.50 g, 2.83 mmol), ethyl 2-bromoacetate (0.96 g, 5.70 mmol) and K2CO3 (0.80 g, 5.77 mmol) at 15 °C. The mixture was stirred at 80 °C for 2 h. The reaction was cooled to RT and poured into ice water (30 mL). The mixture was filtered and the filter cake was concentrated under reduced pressure to give the title compound (0.52 g) as solid. ES-MS m / z, 261, 263 (M+H). Preparation of Intermediate 149: 2-(4-Bromo-3,5-dimethyl-1H-pyrazol-1-yl)acetamide

[0248] To a 100 mL RBF with awas charged ethyl 2-(4-bromo-3,5-dimethyl- 1H-pyrazol-1-yl)acetate (0.52 g, 1.92 mmol) and MeOH (3 mL), followed by addition of ammonia (7.0 M in MeOH, 5 mL, 35 mmol) at 15 °C. The reaction mixture was stirred at 15 °C for 12 h.The reaction was concentrated under reduced pressure to give the title compound (0.44 g) as solid. ES-MS m / z, 232, 234 (M+H). Preparation of Intermediate 150: 4-Chloro-2-((5R,7S)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-6- fluorobenzaldehyde

[0249] To a 250 mL RBF with a magnetic stir bar was charged DMSO (70 mL), followed by the addition of (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8- triazaspiro[4.5]dec-1-en-4-one (7.0 g, 20 mmol), 4-chloro-2,6-difluoro-benzaldehyde (4.0 g, 22 mmol) and DIEA (7.9 g, 61 mmol) at 15 °C. The reaction mixture was stirred at 100 °C for 12 h. The reaction was cooled to 15 °C, poured into ice H2O (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layer was washed with sat. aq. NaCl (70 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in n- hexane gradient to give the title compound (6.1 g) as solid. ES-MS m / z 509, 511 (M+H). Preparation of Intermediate 151: (5R,7S)-8-(5-Chloro-3-fluoro-2-(hydroxymethyl)phenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0250] To a 100 mL RBFwith 4-chloro-2-((5R,7S)-2- (2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en- 8-yl)-6-fluorobenzaldehyde (3.0 g, 5.69 mmol) and MeOH (30 mL). NaBH4 (0.53 g, 13.7 mmol)was added at 0 °C under N2over 0.5 h. The mixture was stirred at 15 °C for 1 h. The reaction was poured into sat. aq. NH4Cl (100 mL) at 0 °C and extracted with DCM (40 mL × 3). The combined organic layer was washed with sat. aq. NaCl (60 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in n-hexane to give the title compound (2.2 g) as solid. ES-MS m / z, 511, 513 (M+H). Preparation of Intermediate 152: (5R,7S)-8-(2-(Bromomethyl)-5-chloro-3-fluorophenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0251] To a 100 mL RBFDCM (30 mL), (5R,7S)-8-(5- chloro-3-fluoro-2-(hydroxymethyl)phenyl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (2.20 g, 4.24 mmol) and triphenylphosphine (1.45 g, 5.42 mmol). NBS (0.92 g, 5.12 mmol) was added at 0 °C over 15 min. The mixture was stirred at 15 °C for 0.5 h. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in n- hexane to give the title compound (1.5 g) as solid.1H-NMR (400 MHz, CDCl3) δ 9.21 (br s, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.18 (s, 1H), 6.99 (dd, J = 1.8, 9.2 Hz, 1H), 4.88 (dd, J = 1.8, 9.2 Hz, 1H), 4.63 (d, J = 9.0 Hz, 1H), 3.54 (ddd, J = 2.3, 6.0, 10.9 Hz, 1H), 3.28 - 3.11 (m, 2H), 2.56 - 2.48 (m, 1H), 2.40 (dt, J = 4.7, 12.7 Hz, 1H), 2.11 - 2.02 (m, 1H), 1.74 - 1.60 (m, 2H), 1.42 - 1.35 (m, 2H), 1.19 - 1.12 (m, 2H), 0.89 (d, J = 6.1 Hz, 3H). Preparation of Intermediate 153: (5R,7S)-8-(5-Chloro-3-fluoro-2-(methoxymethyl)phenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0252] To a 100 mL one-nec bar was charged MeOH (60 mL), followed by addition of (5R,7S)-8-(2-(bromomethyl)-5-chloro-3-fluorophenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (1.20 g, 1.99 mmol) and NaOMe (5.0 M in MeOH, 1.5 mL, 7.5 mmol) at 15 °C. The reaction mixture was stirred at 45 °C for 1 h. The reaction was cooled to RT and concentrated under reduced pressure to give a residue. The residue was diluted with ice water (20 mL) and extracted with DCM (15 mL × 3). The combined organic layer was washed with sat. aq. NaCl (20 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (0.86 g) as solid. ES-MS m / z, 525, 527 (M+H). Preparation of Intermediate 154: (5R,7S)-2-(2-Cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-8- (3-fluoro-2-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7-methyl- 1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0253] To a 40 mL vialmethoxycyclopentane (15 mL), followed by addition of (5R,7S)-8-(5-chloro-3-fluoro-2-(methoxymethyl)phenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.86 g, 1.49 mmol), KOAc (0.52 g, 4.88 mmol), bis(pinacolato)diborane (0.51 g, 1.97 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'- methylamino-1,1'-biphenyl-2-yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81- 5, 0.21 g, 0.24 mmol) at 15 °C. The reaction mixture was purged with N2 for 0.5 min before vigorously stirring at 80 °C for 1 h. The reaction was cooled to RT and then concentrated underreduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in n-hexane to give the title compound (0.63 g) as solid. ES-MS m / z 617 (M+H). Preparation of Intermediate 155: (4-Chloro-2-((5R,7S)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-6- fluorobenzyl)triphenylphosphonium bromide

[0254] To a 100 mL RBFtoluene (28 mL), followed by the addition of (5R,7S)-8-(2-(bromomethyl)-5-chloro-3-fluorophenyl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (2.8 g, 4.4 mmol) and triphenylphosphine (1.2 g, 4.4 mmol) at 16 °C. The reaction mixture was purged with N2for 2 min and stirred at 80 °C for 8 h. The reaction mixture was cooled down to RT, filtered and the filter cake was washed with n-hexane (20 mL). The filter cake was dried under reduced pressure to give the title compound (3.0 g, 82% purity) as solid. ES-MS m / z 754, 756 (M). Preparation of Intermediate 156: (5R,7S)-8-(5-Chloro-3-fluoro-2-(oxetan-3- ylidenemethyl)phenyl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8- triazaspiro[4.5]dec-1-en-4-one

[0255] To a 100 mL RBFTHF (30 mL), followed by the addition of (4-chloro-2-((5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-6-fluorobenzyl)triphenylphosphonium bromide (3.0 g, 82% purity, 3.3 mmol). KOtBu (1.0 M in THF, 3.4 mL, 3.4 mmol) was added dropwise at 0 °C. Oxetan-3-one (0.48 g, 6.6 mmol) in THF (3 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 24 °C for 12 h. The reaction was poured into water (100 mL) and extracted with EtOAc (30 mL × 3). The combined organic layer was washed with sat. aq. NaCl (60 mL × 3), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 60% EtOAc in n-hexane to give the title compound (1.1 g, 81% purity) as solid. ES-MS m / z 549, 551 (M+H). Preparation of Intermediate 157: (5R,7S)-8-(5-Chloro-3-fluoro-2-(oxetan-3-ylmethyl)phenyl)-2- (2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0256] To a 35 mLstir bar was charged rhodium on carbon (5% Wt, 0.68 g, 0.33 mmol) under an Ar atmosphere, followed by the addition of THF (10 mL) and (5R,7S)-8-(5-chloro-3-fluoro-2-(oxetan-3-ylidenemethyl)phenyl)-2-(2-cyclopropyl- 6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (1.1 g, 81% purity, 1.6 mmol). The reaction mixture was degassed and purged with H23 times. The reaction was stirred under H2(30 PSI) at 20 °C for 24 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC using a gradient of 50 to 90% ACN in 10 mM aq. NH4HCO3 to give the title compound (0.53 g) as solid. ES-MS m / z 551, 553 (M+H). Preparation of Intermediate 158: 1-Bromo-5-chloro-3-fluoro-2-methoxybenzene

[0257] To a 500 mL RBF with a magnetic stir bar was charged DMF (300 mL), followed by the addition of 2-bromo-4-chloro-6-fluorophenol (30.0 g, 130 mmol), K2CO3 (36.6 g, 264 mmol) and MeI (22.4 g, 157 mmol) at 0 °C. The reaction mixture was de-gassed and refilled with N23 times and stirred at 25 °C for 2 h. The reaction was poured into water (250 mL) and then extracted with EtOAc (100 mL × 3). The combined organic layer was washed with sat. aq. NaCl (150 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 30% EtOAc in n-hexane to give the title compound (27.9 g) as oil.1H-NMR (400 MHz, DMSO- d6) δ 7.64 - 7.56 (m, 2H), 3.86 (d, J = 1.22 Hz, 3H). Preparation of Intermediate 159: (5R,7S)-8-(5-Chloro-3-fluoro-2-methoxyphenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0258] To a 100 mL RBF wasmL), followed by the addition of (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1- en-4-one (1.0 g, 2.8 mmol), 1-bromo-5-chloro-3-fluoro-2-methoxybenzene (0.79 g , 3.1 mmol), sodium 2-methylbutan-2-olate (30% Wt in THF, 3.1 g, 8.5 mmol) and methanesulfonato(2- bis(3,5-di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',6'-bis(dimethylamino)-1,1'- biphenyl )(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (FrankenPhos Palladacycle Gen. 4, CAS# 1810068-35-9, 0.33 g, 0.29 mmol) at 15 °C. The reaction mixture was de-gassed and refilled with N23 times, then stirred at 100 °C for 16 h. The reaction was cooled to RT, poured into water (10 mL), and extracted with EtOAc (10 mL × 2). The combined organic layer was washed with sat. aq. NaCl (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 30% EtOAc in n-hexane to give the title compound (0.270 g) as solid. ES-MS m / z 511, 513 (M+H).Preparation of Intermediate 160: (5R,7S)-2-(2-Cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-8- (3-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7-methyl-1,3,8- triazaspiro[4.5]dec-1-en-4-one

[0259] To a 40 mL vial methoxycyclopentane (2.7 mL),followed by the addition of (5R,7S)-8-(5-chloro-3-fluoro-2-methoxyphenyl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.27 g, 0.478 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.245 g, 0.955 mmol), KOAc (0.142 g, 1.43 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'- biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81-5, 0.042 g, 0.048 mmol) at 15 °C. The mixture was purged with N2for 0.2 min before vigorously stirring at 80 °C for 2 h. The reaction was cooled to RT, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, 2:1 n-hexane : EtOAc, Rf= 0.4, UV), then the SiO2powder was soaked with EtOAc (50 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.25 g) as solid. ES-MS m / z 603 (M+H). Preparation of Intermediate 161: (1H-Imidazol-1-yl)(1-methylcyclobutyl)methanone

[0260] To a 1 L RBF with a magneticcharged DCM (540 mL), followed by the addition of 1-methylcyclobutane-1-carboxylic acid (45 g, 386 mmol), TEA (79.9 g, 781 mmol) and CDI (84 g, 513 mmol) at 15 °C. The reaction mixture was stirred vigorously at 15 °C for 2 h. The reaction was concentrated under reduced pressure to give the title compound (75.4 g, 80% purity) as oil. TLC (SiO2, 2:1 n-hexane : EtOAc, stained with bromocresol green), Rf = 0.8. Preparation of Intermediate 162: methyl 3-(1-methylcyclobutyl)-3-oxopropanoate

[0261] To a 5 L RBF with a magnetic s charged ACN (3.6 L), followed by addition of TEA (77 g, 753 mmol), (1H-imidazol-1-yl)(1-methylcyclobutyl)methanone (75.4 g, 80% purity, 367 mmol), potassium 3-methoxy-3-oxopropanoate (116 g, 735.3 mmol) and MgCl2 (71 g, 738 mmol) at 15 °C. The reaction mixture was stirring at 80 °C for 12 h. The reaction was cooled to RT and concentrated under reduced pressure to give the residue. The residue was diluted with water (1 L) and extracted with EtOAc (800 mL × 4). The combined organic layer was washed with sat. aq. NaCl (600 mL × 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 20% EtOAc in n-hexane to give the title compound (55 g) as oil. ES-MS m / z 171 (M+H). Preparation of Intermediate 163: Methyl 2-(1-methylcyclobutyl)-6-(trifluoromethyl)nicotinate

[0262] To a 1 L RBF with acharged toluene (500 mL), followed by the addition of methyl 3-(1-methylcyclobutyl)-3-oxopropanoate (55 g, 291 mmol), (E)-4-amino- 1,1,1-trifluorobut-3-en-2-one (35.0 g, 251 mmol), ammonium trifluoroacetate (34 g, 254 mmol) and TFA (29.9 g, 260 mmol) at 18 °C. The reaction mixture was stirred at 120 °C for 12 h. The reaction was cooled down to RT, poured into water (500 mL) and extracted with EtOAc (200 mL × 3). The combined organic layer was washed with sat. aq. NaCl (500 mL × 2), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 20% EtOAc in n-hexane to give the title compound (20 g) as oil. ES-MS m / z 274 (M+H). Preparation of Intermediate 164: 2-(1-Methylcyclobutyl)-6-(trifluoromethyl) nicotinic acid

[0263] To a 1 L RBF with a magneti charged MeOH (160 mL) and THF (160 mL), followed by the addition of methyl 2-(1-methylcyclobutyl)-6-(trifluoromethyl)nicotinate (16.2 g, 55.9 mmol) and NaOH (1.0 M in H2O, 260 mL, 260 mmol) at 15 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction was concentrated under reduced pressure to remove MeOH and THF. The aq. phase was adjusted to pH = 2~3 with HCl (1.0 M in H2O) under stirring. The reaction mixture was filtered, and the filter cake was rinsed with water (50 mL). The filter cake was dried under reduced pressure to give title compound (14.5 g) as solid. ES-MS m / z 260 (M+H). Preparation of Intermediate 165: tert-Butyl 4-carbamoyl-4-(2-(1-methylcyclobutyl)-6- (trifluoromethyl)nicotinamido)piperidine-1-carboxylate

[0264] To a 250 mL RBFwith DMF (100 mL), followed by the addition of 2-(1-methylcyclobutyl)-6-(trifluoromethyl)nicotinic acid (7.0 g, 27 mmol), tert-butyl 4-amino-4-carbamoylpiperidine-1-carboxylate (8.0 g, 33 mmol), HATU (15 g, 39.1 mmol) and DIEA (11.1 g, 85.3 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 12 h. The reaction was quenched with water (200 mL) and then extracted with EtOAc (100 mL × 3). The combined organic layer was washed with sat. aq. NaCl (100 mL), dried over Na2SO4, then filtered. The filtrate was concentrated under reduced pressure to give the title compound (19.5 g, 61.9% purity). ES-MS m / z 485 (M+H). Preparation of Intermediate 166: tert-Butyl 2-(2-(1-methylcyclobutyl)-6- (trifluoromethyl)pyridin-3-yl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate

[0265] To a 500 mL RBF wit harged with EtOH (200 mL), followed by the addition of tert-butyl 4-carbamoyl-4-(2-(1-methylcyclobutyl)-6- (trifluoromethyl)nicotinamido)piperidine-1-carboxylate (19.5 g, 61.9% purity, 24.9 mmol) and KOtBu (15.0 g, 132 mmol) at 20 °C. The reaction mixture was stirred vigorously at 80 °C for 12 h. The reaction was cooled to RT, concentrated under reduced pressure to give a mixture. The mixture was poured into water (150 mL) at 20 °C and then extracted with EtOAc (100 mL × 3). The combined organic layer was washed with sat. aq. NaCl (100 mL × 2), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in n-hexane to give the title compound (7.96 g, 87.3% purity) as solid. ES-MS m / z 467 (M+H). Preparation of Intermediate 167: 2-(2-(1-Methylcyclobutyl)-6-(trifluoromethyl)pyridin-3-yl)- 1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0266] To a 250 mL RBF with acharged 1,4-dioxane (30 mL) and DCM (30 mL), followed by the addition of tert-butyl 2-(2-(1-methylcyclobutyl)-6- (trifluoromethyl)pyridin-3-yl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (7.96 g, 87.3% purity, 14.9 mmol) and HCl (4.0 M in 1,4-dioxane, 80 mL, 320 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 5 h. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase prep-HPLC using a gradient of 5 to 62% ACN in 10 mM aq. NH4HCO3to give the title compound (4.79 g) as solid. ES-MS m / z 367 (M+H).Preparation of Intermediate 168: 8-(5-Chloro-3-fluoro-2-(methoxymethyl)phenyl)-2-(2-(1- methylcyclobutyl)-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0267] To a 40 mL vial with 1,4-dioxane (10 mL), followedby the addition of 2-(2-(1- - pyridin-3-yl)-1,3,8- triazaspiro[4.5]dec-1-en-4-one (0.60 g, 1.61 mmol), 1-bromo-5-chloro-3-fluoro-2- (methoxymethyl)benzene (0.65 g, 69.5% purity, 1.78 mmol), sodium 2-methylpropan-2-olate (0.48 g, 4.94 mmol), BINAP (0.20 g, 0.318 mmol) and tris((1E,4E)-1,5-diphenylpenta-1,4-dien- 3-one)dipalladium (0.15 g, 0.161 mmol) at 15 °C. The reaction mixture was purged with N2 for 2 min before vigorously stirring at 110 °C for 12 h. The reaction was cooled to RT, poured into water (20 mL) at 15 °C and then extracted with EtOAc (10 mL × 3). The combined organic layer was washed with sat. aq. NaCl (10 mL × 2), dried over Na2SO4, then filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (SiO2, 2:1 n-hexane : EtOAc, Rf= 0.5, UV) to give the title compound (0.65 g, 88.2% purity) as solid. ES-MS m / z 539 (M+H). Preparation of Intermediate 169: 4-Bromo-2-fluoro-6-(2-(2-(1-methylcyclobutyl)-6- (trifluoromethyl)pyridin-3-yl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)benzaldehyde

[0268] To a 100 mL flask withDMSO (30 mL), followed by the addition of 2-(2-(1-methylcyclobutyl)-6-(trifluoromethyl)pyridin-3-yl)-1,3,8- triazaspiro[4.5]dec-1-en-4-one (4.0 g, 9.0 mmol), 4-bromo-2,6-difluorobenzaldehyde (2.5 g, 11 mmol) and DIEA (5.9 g, 45 mmol) at 20 °C (external temperature). The reaction mixture was stirred at 100 °C for 5 h. The reaction was cooled to RT, quenched with water (50 mL), and extracted with EtOAc (50 mL × 2). The combined organic layer was washed with sat. aq. NaCl(50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in n-hexane to give the title compound (4.2 g) as solid. ES-MS m / z 567, 569 (M+H). Preparation of Intermediate 170: 8-(5-Bromo-3-fluoro-2-(hydroxymethyl)phenyl)-2-(2-(1- methylcyclobutyl)-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0269] To a 100 mL bottom was charged EtOH (20 mL) andTHF (20 mL), followed by the addition of 4-bromo-2-fluoro-6-(2-(2-(1-methylcyclobutyl)-6- (trifluoromethyl)pyridin-3-yl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)benzaldehyde (4.1 g, 6.8 mmol) at 0 °C. NaBH4 (0.13 g, 3.4 mmol) was added at 0 °C under N2 in portions. The reaction mixture was stirred at 25 °C for 1 h. The reaction was quenched with sat. aq. NH4Cl (20 mL) at 20 ⁰C, diluted with water (30 mL) and extracted with DCM (20 mL × 3). The combined organic layer was washed with sat. aq. NaCl (20 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (3.5 g) as solid. ES-MS m / z 569, 571 (M+H). Preparation of Intermediate 171: 8-(5-Bromo-2-(bromomethyl)-3-fluorophenyl)-2-(2-(1- methylcyclobutyl)-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0270] To a 100 mL RBFwith THF (30 mL), followed by the addition of 8-(5-bromo-3-fluoro-2-(hydroxymethyl)phenyl)-2-(2-(1-methylcyclobutyl)-6- (trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (2.9 g, 4.8 mmol) at 0 °C.PBr3(2.0 g, 7.3 mmol) was added at 0 °C in portions. The reaction mixture was stirred at 0 °C for 1 h. The reaction was quenched with sat. aq. Na2S2O3 (20 mL), and extracted with EtOAc (50 mL × 3). The combined organic layer was washed with sat. aq. NaCl (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (3.0 g, 74.7% purity) as solid. A sample was quenched by MeOH, and the MeOH solution was used for LCMS detection. ES-MS m / z 583, 585 (M+H, methyl ether). Preparation of Intermediate 172: 8-(5-Bromo-2-(cyclopropoxymethyl)-3-fluorophenyl)-2-(2-(1- methylcyclobutyl)-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0271] To a 100 mL RBFwith cyclopropanol (21 g, 362 mmol), followed by the addition of 8-(5-bromo-2-(bromomethyl)-3-fluorophenyl)-2-(2-(1- methylcyclobutyl)-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (3.0 g, 74.7% purity, 3.5 mmol) and KOH (0.35 g, 85% purity, 5.30 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. The reaction was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layer was washed with sat. aq. NaCl (30 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 25% EtOAc in n-hexane to give the title compound (1.4 g, 87.5% purity) as solid. ES-MS m / z 609, 611 (M+H). Preparation of Intermediate 173: 8-(2-(Cyclopropoxymethyl)-3-fluoro-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)-2-(2-(1-methylcyclobutyl)-6-(trifluoromethyl)pyridin-3-yl)- 1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0272] To a 100 mL three n bar was charged 1,4-dioxane (20 mL), followed by the addition of 8-(5-bromo-2-(cyclopropoxymethyl)-3-fluorophenyl)-2-(2-(1- methylcyclobutyl)-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (1.5 g, 87.5% purity, 2.2 mmol), bis(pinacolato)diborane (1.1 g, 4.3 mmol), KOAc (0.650 g, 6.56 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (CAS# 72287-26-4, 0.30 g, 0.406 mmol) at 20 °C. The reaction mixture was purged with N2 for 1 min before vigorously stirring at 80 °C for 2 h. The reaction was cooled to RT and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 30% EtOAc in n-hexane to give the title compound (1.2 g) as solid. ES-MS m / z 675 (M+H). Preparation of Intermediate 174: 4-Bromo-2-((5R,7S)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)benzaldehyde

[0273] To a 100 mL RBFDMSO (50 mL), followed by addition of (5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8- triazaspiro[4.5]dec-1-en-4-one (3.0 g, 8.4 mmol), 4-bromo-2-fluorobenzaldehyde (2.13 g, 10.4 mmol) and K2HPO4(2.95 g, 16.8 mmol) at 18 °C. The reaction mixture was stirred at 120 °C for 40 h. The reaction was cooled to RT and poured into water (200 mL) at 18 °C and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with sat. aq. NaCl (100 mL × 2), dried over Na2SO4, then filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in n-hexane to give the title compound (1.4 g) as solid. ES-MS m / z 535, 537 (M+H).Preparation of Intermediate 175: Ethyl 2-(4-bromo-2-((5R,7S)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)phenyl)acetate

[0274] To a 100 mL RBF with THF (15 mL), followedby the addition of 4-bromo-2-((5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)benzaldehyde (0.679 g, 1.21 mmol), methyl((methylsulfinyl)methyl)sulfane (0.23 g, 1.83 mmol) and NaOH (0.10 g, 2.48 mmol) at 20 °C. The mixture was stirred at 70 °C for 8 h. The reaction was cooled down to RT, poured into water (30 mL) and extracted with EtOAc (20 mL × 2). The combined organic layer was washed with sat. aq. NaCl (30 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue. EtOH (30 mL) and HCl (4.0 M in EtOAc, 10 mL, 40 mmol) were added to the residue at 20 °C. The mixture was stirred at 80 °C for 1 h. The reaction was cooled to RT poured into water (20 mL) and extracted with EtOAc (10 mL × 2). The combined organic layer was washed with sat. aq. NaCl (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in n-hexane to give the title compound (0.423 g) as solid. ES-MS m / z 593, 595 (M+H). Preparation of Intermediate 176: (5R,7S)-8-(5-Bromo-2-(2-hydroxy-2-methylpropyl)phenyl)-2- (2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0275] To a 40 mL vial with a magnetic stir bar was charged THF (5 mL) and ethyl 2-(4- bromo-2-((5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-1,3,8- triazaspiro[4.5]dec-1-en-8-yl)phenyl)acetate (0.423 g, 0.649 mmol). The reaction mixture was purged with N2for 1 min. Methylmagnesium bromide (3.0 M in 2-MeTHF, 1.3 mL, 3.9 mmol) was added dropwise over 0.3 min at -70 °C. The reaction mixture was stirred at 20 °C for 1 h under a N2 atmosphere. MeOH (5 mL) was added dropwise to the reaction mixture at 0 °C. The reaction was the mixture was poured into water (10 mL) at RT and extracted with EtOAc (10 mL × 2). The combined organic layer was washed with sat. aq. NaCl (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, 1:1 n-hexane : EtOAc, Rf= 0.4, UV), then the SiO2powder was soaked with DCM (30 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.325 g, 83.2% purity) as solid. ES-MS m / z 579, 581 (M+H). Preparation of Intermediate 177: (5R,7S)-8-(5-Bromo-2-(2-fluoro-2-methylpropyl)phenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0276] To a 40 mL vialwith toluene (3 mL) and (5R,7S)-8-(5-bromo-2-(2-hydroxy-2-methylpropyl)phenyl)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.305 g, 83.2% purity, 0.438 mmol). DAST (0.10 g, 0.61 mmol) was added over 10 second at 0 °C. The reaction mixture was stirred at 18 °C for 2 h. The reaction was poured into sat. aq. NaHCO3(10 mL) at RT and extracted with EtOAc (10 mL × 2). The combined organic layer was washed with sat. aq. NaCl (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, 1:2 n-hexane : EtOAc, Rf= 0.5, UV), then the SiO2powder was soaked with DCM (30 mL) and filtered. The filtratewas concentrated under reduced pressure to give the title compound (0.092 g) as solid. ES-MS m / z 581, 583 (M+H). Preparation of Intermediate 178: 5-bromo-2-chloro-4-methoxy-6-methylpyrimidine

[0277] To a 100 mL RBF with a was charged THF (500 mL) and 5-bromo-2,4-dichloro-6-methylpyrimidine (40 g, 168 mmol). NaOMe (5.0 M in MeOH, 35 mL, 175 mmol) was added over 10 min at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction was quenched with water (500 mL) and extracted with EtOAc (300 mL × 3). The combined organic layer was washed with sat. aq. NaCl (300 mL × 2), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give title compound (35 g) as solid. ES-MS m / z 237, 239 (M+H). Preparation of Intermediate 179: tert-Butyl 2-(5-bromo-4-methoxy-6-methylpyrimidin-2-yl)-2-(racemic mixture)

[0278] To a 1 L RBF with acharged with THF (350 mL) and tert-butyl 2-cyanoacetate (60 g, 425 mmol). NaH (8 g, 60% Wt in mineral oil, 450 mmol) was added in portions into the mixture at 0 °C. The mixture was stirred at 0 °C for 0.5 h. 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 reaction was cooled to RT, poured into sat. aq. NH4Cl (500 mL) at 20 °C and then extracted with EtOAc (200 mL × 3). The combined organic layer was washed with sat. aq. NaCl (200 mL × 3), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was triturated with MTBE (100 mL) at 15 °C for 10 min. The mixture was filtered, and the filter cake wasdried under reduced pressure to give the title compound (33 g) as solid. ES-MS m / z 342, 344 (M+H). Preparation of Intermediate 180: 2-(5-Bromo-4-methoxy-6-methylpyrimidin-2-yl)acetonitrile;

[0279] To a 1 L RBF with a charged DCM (350 mL) and tert-butyl 2-(5-bromo-4-methoxy-6-methylpyrimidin-2-yl)-2-cyanoacetate (racemic mixture, 33 g, 90 mmol), followed by the addition of TFA (178 g, 1537 mmol) dropwise over 5 min at 15 °C. The reaction mixture was stirred at 15 °C for 2 h. The reaction was concentrated under reduced pressure to give the title compound (31 g, 62.7% purity) as oil. ES-MS m / z 242, 244 (M+H). Preparation of Intermediate 181: 2-(5-Bromo-4-methoxy-6-methylpyrimidin-2-yl)acetamide;

[0280] To a 500 mL RBF with acharged H2O (30 mL) and 2-(5- bromo-4-methoxy-6-methylpyrimidin-2-yl)acetonitrile (31.0 g, 62.7% purity, 80.3 mmol), followed by the addition of 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 reaction was cooled down to RT and poured into water (1 L). The pH was adjusted to 10~11 with NaOH (2.0 M in H2O) and the mixture extracted with EtOAc (500 mL × 3). The combined organic layer was washed with sat. aq. NaCl (500 mL × 3), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was triturated with DCM (50 mL) for 15 min to get a mixture. The mixture was filtered and the filter cake was rinsed with DCM (10 mL). The filter cake was dried under reduced pressure to give the title compound (13 g) as solid. ES-MS m / z 260, 262 (M+H).Preparation of Intermediate 182: 4-Bromo-2-((5R,7S)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-6- fluorobenzaldehyde

[0281] A 250 mL RBF was 6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (1.90 g, 5.39 mmol), 4-bromo-2,6-difluoro- benzaldehyde (1.19 g, 5.39 mmol), DMSO (25 mL) and DIEA (2.82 g, 18 mmol). The reaction was stirred at 80 °C for 12 h. Additional 4-bromo-2,6-difluorobenzaldehyde (0.15 g) was added and the reaction mixture stirred at 90 ºC for 4 h. The reaction mixture was cooled to RT, poured into 200 mL of water and extracted with EtOAc (3 × 60 mL). The combined organic layer was washed with sat. aq. NaCl (60 mL × 3), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to obtain a crude material. The residue was purified by flash silica gel chromatography using a gradient of 0 to 50% EtOAc in cyclohexane to give the title compound (1.92 g). ES-MS m / z 553, 555 (M+H). Preparation of Intermediate 183: (5R,7S)-8-(5-Bromo-3-fluoro-2-(hydroxymethyl)phenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0282] NaBH4(0.13 g, 3.43to a 0 ºC cooled solution of 4-bromo-2-((5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-1,3,8- triazaspiro[4.5]dec-1-en-8-yl)-6-fluorobenzaldehyde (1.90 g, 3.43 mmol) in MeOH (20 mL) under N2atmosphere and stirred for 1 h. The reaction mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was poured into sat. aq. NH4Cl (100 mL) and extracted with DCM (50 mL × 3). The combined organics were washed with sat. aq. NaCl (60 mL), dried overanhydrous Na2SO4, filtered and concentrated under reduced pressure to a residue. The residue was purified by flash silica gel chromatography using a gradient of 0 to 50% EtOAc in n-hexane to give the title compound (1.35 g, 2.44 mmol). ES-MS m / z 555, 557 (M+H). Preparation of Intermediate 184: (5R,7S)-8-(5-Bromo-2-(bromomethyl)-3-fluorophenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0283] NBS (0.11 g, 0.63 solution of (5R,7S)-8-(5-bromo-3-fluoro-2-(hydroxymethyl)phenyl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl- 1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.23 g, 0.41 mmol) and triphenylphosphine (0.13 g, 0.49 mmol) in DCM (3.0 mL) and stirred for 1 h. The reaction mixture was allowed to warm to RT and stirred for 5 h. The reaction mixture was concentrated under reduced pressure to a yellow residue. The residue was purified by silica gel chromatography using a gradient of 0 to 65% EtOAc in n-hexane to give the title compound (0.21 g, 0.34 mmol).1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.19 (d, J = 7.9 Hz, 1H), 7.94 – 7.78 (m, 1H), 7.48 (dd, J = 9.2, 1.8 Hz, 1H), 7.43 (t, J = 1.6 Hz, 1H), 4.85 (dd, J = 9.4, 1.7 Hz, 1H), 4.76 – 4.69 (m, 1H), 3.49 (t, J = 9.4 Hz, 1H), 3.09 (t, J = 11.6 Hz, 1H), 3.03 – 2.94 (m, 1H), 2.79 (td, J = 8.1, 4.1 Hz, 1H), 2.11 (td, J = 12.7, 4.4 Hz, 1H), 1.79 (dd, J = 13.0, 11.0 Hz, 1H), 1.67 (d, J = 13.1 Hz, 1H), 1.63 – 1.54 (m, 1H), 1.40 (s, 1H), 1.26 – 1.06 (m, 3H), 1.07 (q, J = 4.1 Hz, 2H), 0.81 (d, J = 6.0 Hz, 3H). Preparation of Intermediate 185: (5R,7S)-8-(5-Bromo-3-fluoro-2-(methoxymethyl)phenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0284] Sodium methoxide (0.07 g, 1.36 mmol) was added to a solution of (5R,7S)-8-(5- bromo-2-(bromomethyl)-3-fluorophenyl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7- methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.21 g, 0.33 mmol) in MeOH (12 mL) and stirred at 45 ºC for 5 h. Additional sodium methoxide (0.05 g, 0.94 mmol) was added and the reaction mixture stirred for an additional 2 h. The reaction mixture was cooled to RT, diluted with DCM (30 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to a yellow oil. The oil was purified by flash silica gel chromatography using a gradient of 0 to 65% EtOAc in cyclohexane to give the title compound (0.12 g, 0.19 mmol) as a colorless foam. ES-MS m / z 569, 571 (M+H). Preparation of Intermediate 186: (5R,7S)-8-(5-Bromo-2-(cyclopropoxymethyl)-3-fluorophenyl)- 2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0285] A solution of (5R,7S)-3-fluorophenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.28 g, 0.45 mmol) in THF (2 mL) was added to a stirring suspension of sodium hydride (0.06 g, 60% wt, 2.56 mmol) in cyclopropanol (0.15 mL, 2.0 mmol). The reaction was stirred at 45 ºC for 2 h. The reaction mixture was diluted with DCM (20 mL) and washed with sat. aq. NaCl (20 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to a yellow oil. The oil was purified by silica gel chromatography using a gradient of 0 to 65% EtOAc in cyclohexane to give the title compound (0.10 g, 0.17 mmol). ES-MS m / z 595, 597 (M+H). Preparation of Intermediate 187: (3-((5R,7S)-2-(2-Cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)- 7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-5-fluoro-4-(methoxymethyl)phenyl)boronic acid

[0286] A suspension of (5R ethoxymethyl)phenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.12 g, 0.21 mmol), bis(pinacolato)diborane (0.11 g, 0.44 mmol), KOAc (0.06 g, 0.64 mmol) and methanesulfonato(tricyclohexylphosphine)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct (0.03 g, 0.04 mmol) in CPME (3.6 mL) was sparged with nitrogen for 10 min. The reaction was stirred at 90 ºC for 1 h. The reaction mixture was cooled to RT and loaded onto a 20 g SCX cartridge. The cartridge was rinsed with MeOH and eluted with a 1N ammonia in MeOH solution. The ammonia solution was concentrated under reduced pressure to afford the title compound (0.1 g, 0.16 mmol). ES-MS m / z 535 (M+H). Preparation of Intermediate 188: (4-(Cyclopropoxymethyl)-3-((5R,7S)-2-(2-cyclopropyl-6- (trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-5- fluorophenyl)boronic acid

[0287] A suspension of-3-fluorophenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.09 g, 0.14 mmol), bis(pinacolato)diborane (0.08 g, 0.30 mmol), KOAc (0.04 g, 0.43 mmol) and methanesulfonato(tricyclohexylphosphine)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct (0.007 g, 0.008 mmol) in CPME (3.0 mL) was sparged with nitrogen for 10 min. The reaction was stirred at 80 ºC for 6 h. The reaction mixture was cooled to RT and loaded onto a 20 g SCX cartridge. The cartridge was rinsed with MeOH and eluted with a 1Nammonia in MeOH solution. The ammonia solution was concentrated under reduced pressure to afford the title compound (0.05 g, 0.07 mmol). ES-MS m / z 561 (M+H). Preparation of Intermediate 189: (5R,7S)-8-(5-Chloro-2-(cyclopropyl(hydroxy)methyl)-3- fluorophenyl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8- triazaspiro[4.5]dec-1-en-4-one (mixture of isomers)

[0288] To a 100 mL RBF with MeTHF (20 mL),followed by the addition of 4-chloro-2-((5R,7S)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3- yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-6-fluorobenzaldehyde (2.80 g, 62% purity, 3.41 mmol). The reaction mixture was de-gassed and refilled with N23 times. Cyclopropylmagnesium bromide (1.0 M in THF, 6.9 mL, 6.9 mmol) was added dropwise to the mixture at -78 °C. The reaction mixture was warmed to 20 °C and stirred at 20 °C for 2 h. The reaction was quenched with sat. aq. NH4Cl (40 mL) at 0 °C, diluted with H2O (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (0.80 g) as oil. ES-MS m / z 551, 553 (M+H). Preparation of Intermediate 190: (5R,7S)-8-(5-Chloro-2-(cyclopropylmethyl)-3-fluorophenyl)-2- (2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0289] To a 40 mL vial with awith triethylsilane (12 g, 99 mmol), followed by the addition of (5R,7S)-8-(5-chloro-2-(cyclopropyl(hydroxy)methyl)-3- fluorophenyl)-2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (mixture of isomers, 0.80 g, 1.35 mmol) and TFA (8 mL) at 16 °C. The reaction was stirred at 40 °C for 2 h. The reaction was concentrated under reduced pressure to give a residue. The crude product was purified by silica gel chromatography using a gradient of 0 to 60% EtOAc in n-hexane to give the title compound (0.74 g) as solid. ES-MS m / z 535, 537 (M+H). Preparation of Intermediate 191: (5R,7S)-2-(2-Cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-8- (2-(cyclopropylmethyl)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7- methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0290] To a 40 mL vialmethoxycyclopentane (7 mL), followed by the addition of (5R,7S)-8-(5-chloro-2-(cyclopropylmethyl)-3-fluorophenyl)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-1,3,8-triazaspiro[4.5]dec-1-en-4-one (0.74 g, 1.33 mmol), bis(pinacolato)diborane (0.688 g, 2.66 mmol), KOAc (0.426 g, 3.99 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'- methylamino-1,1'-biphenyl-2-yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81- 5, 0.12 g, 0.135 mmol) at 15 °C. The mixture was purged with N2 for 30 seconds, then stirred at 80 °C for 2 h. The reaction was cooled to RT and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, 1: 3 EtOAc: n-hexane, Rf= 0.4, UV), then the SiO2powder was soaked with EtOAc (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.75 g, 89% purity) as solid. ES-MS m / z 627 (M+H). Preparation of Intermediate 192: 5-Bromo-2-(methoxycarbonyl)-4-methylpyridine 1-oxide

[0291] To a 5 L RBF with a magnetic as charged DCM (2 L), followed by the addition of methyl 5-bromo-4-methylpicolinate (200 g, 826 mmol), carbamide peroxide (125 g, 1312 mmol) and trifluoroacetic anhydride (271 g, 1265 mmol) at 10 °C. The reaction mixture was de-gassed and refilled with N23 times before vigorously stirring at 10 °C for 4 h. The reaction was quenched by sat. aq. Na2SO3 (2 L) at 10 °C and extracted with DCM (1 L × 3). The combined organic layer was washed with sat. aq. NaCl (1 L × 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (199 g) as solid. ES-MS m / z 246, 248 (M). Preparation of Intermediate 193: Methyl 5-bromo-6-chloro-4-methylpicolinate

[0292] To a vigorous stirring DCE (2of 5-bromo-2-(methoxycarbonyl)-4- methylpyridine 1-oxide (199 g, 747 mmol) in a 3 L RBF was added POCl3 (362 g, 2342 mmol) dropwise over 30 min at 10 °C. The reaction mixture was stirred at 50 °C for 6 h. The reaction was cooled to RT and then concentrated under reduced pressure directly to give a residue. The residue was dissolved in DCM (1 L), quenched by sat. aq. Na2CO3 (2 L) at 0 °C and then extracted with DCM (1 L × 2). The combined organic layer was washed with sat. aq. NaCl (1 L × 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 30% EtOAc in n-hexane to give the title compound (120 g) as solid. ES-MS m / z 264, 266 (M+H). Preparation of Intermediate 194: 5-Bromo-6-methoxy-4-methylpicolinic acid

[0293] To a vigorous stirring MeOH (500 mL) solution of methyl 5-bromo-6-chloro-4- methylpicolinate (100 g, 371 mmol) in a 3L RBF was added NaOMe (5.0 M in MeOH, 1 L, 5000 mmol) at 10 °C. The reaction mixture was stirred at 80 °C for 6 h. The reaction was cooled to RT and concentrated under reduced pressure to give a residue. The residue was adjusted to pH = 3~5 with HCl (6.0 M in H2O) under stirring at 10 °C, then extracted with EtOAc (1 L × 3). The combined organic layer was washed with sat. aq. NaCl (1 L), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (90 g) as solid. ES- MS m / z 246, 248 (M+H). Preparation of Intermediate 195: (5-Bromo-6-methoxy-4-methylpyridin-2-yl)methanol

[0294] To a vigorous stirring THFof 5-bromo-6-methoxy-4- methylpicolinic acid (30 g, 117 mmol) in a 500 mL RBF was added BH3(10.0 M in dimethyl sulfide, 110 mL, 1100 mmol) dropwise over 30 min at 0 °C. The reaction mixture was stirred at 20 °C for 12 h. The reaction was quenched with MeOH (50 mL) and stirred vigorously at 50 °C for 30 min. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 20% EtOAc in n- hexane to give the title compound (22 g, 86.5% purity) as solid. ES-MS m / z 232, 234 (M+H). Preparation of Intermediate 196: 3-Bromo-6-(chloromethyl)-2-methoxy-4-methylpyridine

[0295] To a vigorous stirring DCMDMF (0.1 mL) solution of (5-bromo-6- methoxy-4-methylpyridin-2-yl)methanol (22 g, 86.5% purity, 82 mmol) in a 500 mL RBF was added SOCl2 (29 g, 244 mmol) dropwise over 5 min at 0 °C. The reaction mixture was stirred at 10 °C for 4 h. The reaction was quenched with sat. aq. NaHCO3 (250 mL) at 0 °C, then extracted with DCM (200 mL × 3). The combined organic layer was washed with sat. aq. NaCl (300 mL),dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (21 g, 88.6% purity) as solid. ES-MS m / z 250, 252 (M+H). Preparation of Intermediate 197: 2-(5-Bromo-6-methoxy-4-methylpyridin-2-yl)acetonitrile

[0296] To a 500 mL RBF with a was charged DMSO (200 mL), followedby the addition of 3-bromo-6-(chloromethyl)-2-methoxy-4-methylpyridine (20 g, 88.6% purity, 71 mmol) and NaCN (12.3 g, 239 mmol) at 25 °C. The reaction mixture was stirred vigorously at 25 °C for 12 h. The reaction was poured into sat. aq. NaHCO3(600 mL) at 20 ⁰C and extracted with EtOAc (200 mL × 3). The combined organic layer was washed with sat. aq. NaCl (300 mL × 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 20% EtOAc in n-hexane to give the title compound (15.8 g) as solid. ES-MS m / z 241, 243 (M+H). Preparation of Intermediate 198: 2-(5-Bromo-6-methoxy-4-methylpyridin-2-yl)acetamide

[0297] To a 500 mL RBF with awas charged H2O (19 mL), followed by the addition of 2-(5-bromo-6-methoxy-4-methylpyridin-2-yl) acetonitrile (15.8 g, 62.0 mmol) and H2SO4(98%, 184 g, 1846 mmol). Then the reaction mixture was stirred at 50 °C for 0.5 h. The reaction was cooled to RT, poured into water (1 L) at 0 °C and adjusted to pH = 9~10 with NaOH (5.0 M in H2O) under stirring at 25 °C. The mixture was filtered, and the filter cake was triturated with DCM (20 mL) at 20 °C for 2 min, and dried under reduced pressure to give the title compound (12.5 g) as solid. ES-MS m / z 259, 261 (M+H). Preparation of Intermediate 199: 3,6-Dibromo-2,4-dimethylpyridine

[0298] To a 1000 mL RBF with a mag bar was charged CH2Br2(100 mL), followed by the addition of cupric bromide (112.00 g, 491.43 mmol) at 20 °C. tert-Butyl nitrite (70.8 mL, 588.5 mmol) was added dropwise over 10 min at 20 °C. 5-Bromo-4,6-dimethylpyridin-2-amine (100.00 g, 487.39 mmol) in CH2Br2(100 mL) was added dropwise over 20 min at 20 °C. The reaction mixture was allowed to stir vigorously at 20 °C for 2 h. The reaction mixture was poured into H2O (400 mL) at 20 °C and extracted with DCM (400 mL × 3). The combined organic layers were washed with sat. aq. NaCl (400 mL), dried over Na2SO4, filtered and the filter cake further washed with DCM (400 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography using a gradient of 0 to 10% EtOAc in n-hexane to give the title compound (75.06 g, 91.9% purity) as a yellow solid. ES-MS m / z 264, 266 (M+H). Preparation of Intermediate 200: Ethyl 2-(5-bromo-4,6-dimethylpyridin-2-yl)acetate

[0299] To a 3000 mL three-neckstir bar was charged DMSO (2000 mL) and EtOH (124 mL), followed by the addition of 3,6-dibromo-2,4-dimethylpyridine (100.06 g, 91.9% purity, 347.07 mmol), ethyl 3-oxobutanoate (273.64 g, 2082 mmol), potassium phosphate, tribasic (446.44 g, 2082 mmol), picolinic acid (34.80 g, 279.8 mmol) and cuprous iodide (40.04 g, 208.1 mmol) at 20 °C. The reaction was de-gassed and refilled with N2three times. The reaction mixture was allowed to stir vigorously at 80 °C for 12 h. The reaction mixture was allowed to cool to RT. The reaction was filtered through a pad of diatomaceous earth under reduced pressure and the filter cake was rinsed with EtOAc (500 mL). The filtrate was quenched with H2O (5000 mL) at RT and diluted with EtOAc (1000 mL). The resultant mixture was extracted with EtOAc (1000 mL × 2). The combined organic layer was washed with sat. aq. NaCl (800 mL × 2), dried over Na2SO4. The Na2SO4was filtered off and the filter cakefurther washed with EtOAc (500 mL). The filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography using a gradient of 0 to 20% EtOAc in n-hexane to give the title compound (100.50 g, 64.4% purity) was obtained as an oil. ES-MS m / z 271.8, 273.8 (M+H). Preparation of Intermediate 201: 2-(5-Bromo-4,6-dimethylpyridin-2-yl)acetamide

[0300] A mixture of ethyl 2-(5- 2-yl)acetate (100.05 g, 64.4%purity, 236.76 mmol) and 7N ammonia in MeOH (1000 mL, 7.0 mol) saturated with N2was split into 14 equal portions. Each portion was stirred under 15 PSI at 80 °C in 14 separate 100 mL sealed tubes for 16 h. The reactions were cooled to RT. The reaction mixtures were combined and the mixture concentrated under reduced pressure to give a crude. The crude was triturated with MeOH (150 mL) at RT for 30 min to get a mixture. The mixture was filtered and the filter cake was rinsed with MeOH (50 mL) and n-hexane (30 mL). The filter cake was dried under reduced pressure to give the title compound (39.50 g, 98.5% purity) as solid. ES-MS m / z 243, 245. Preparation of Intermediate 202: 2-(4,6-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2-yl)acetamide

[0301] To a 250 mL RBF (with awith a magnetic stir bar was charged 1,4-dioxane (150 mL), 2-(5-bromo-4,6-dimethylpyridin-2-yl)acetamide (15.50 g, 62.80 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (32.12 g, 125.2 mmol), potassium acetate (18.73 g, 188.9 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride(4.69 g, 6.28 mmol) at 20 °C. The system was de-gassed and backfilled with N2three times before vigorously stirring at 100 °C for 12 h. The reaction mixture was allowed to cool to RT and filtered through a pad of diatomaceous earth and the filter cake rinsed with EtOAc (300 mL). The filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography using a gradient of 0 to 10% MeOH in DCM to give the title compound (9.85 g, 69.1% purity). The product was further purified by prep- HPLC using a gradient of 1 to 22% heptane in EtOH to give the title compound (5.82 g, 100% purity) as solid. ES-MS m / z 291.1 (M+H). Preparation of Intermediate 203: 4-Bromo-2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid

[0302] To a vigorous stirring THF2,2-difluorobenzo[d][1,3]dioxole-5- carboxylic acid (250 g, 1224 mmol) in a 10 L RBF was added n-butyllithium (2.5 M in THF, 1.2 L, 3000 mmol) dropwise over 30 min at -70 °C. The mixture was stirred at -70 °C for 10 min and then warmed to 0 °C. The reaction was 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. The reaction was warmed to RT and poured into H2O (800 mL) at 15 °C. The mixture was adjusted to pH = 2 with HCl (2.0 M in H2O) and extracted with EtOAc (500 mL × 3). The combined organic layer was washed with sat. aq. NaCl (500 mL × 2), dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 35 to 65% EtOAc in n-hexane to give the title compound (151 g) as solid. ES-MS m / z 279, 281. (M-H). Preparation of Intermediate 204: Methyl 4-bromo-2,2-difluorobenzo[d][1,3]dioxole-5- carboxylate

[0303] To a vigorous stirring(760 mL) solution of 4-bromo-2,2- difluorobenzo[d][1,3]dioxole-5-carboxylic acid (151 g, 525 mmol) in a 5 L RBF was added(trimethylsilyl)diazomethane (2.0 M in n-hexane, 1 L, 2000 mmol) dropwise over 1 h at 0 °C. The mixture was stirred at 18 °C for 16 h. The reaction was quenched with AcOH (100 mL) at 5 °C until no bubbles were produced and the pH was between 2 and 3. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 10 to 65% EtOAc in n-hexane to give the title compound (101 g) as solid.1H-NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 3.75 (s, 3H). Preparation of Intermediate 205: Methyl 4-cyclopropyl-2,2-difluorobenzo[d][1,3]dioxole-5- carboxylate

[0304] To a 3 L RBF with a with 1,4-dioxane (1 L) and H2O (200 mL), followed by the addition of methyl 4-bromo-2,2-difluorobenzo[d][1,3]dioxole-5- carboxylate (101 g, 329 mmol), K2HPO4(150 g, 671 mmol), cyclopropylboronic acid (45 g, 513 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (CAS# 95464-05-4, 35 g, 41 mmol) at 16 °C. The reaction mixture was de- gassed and backfilled with N23 times and vigorously stirred at 100 °C for 8 h. The reaction was cooled to RT, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in n- hexane to give the title compound (51 g) as solid. ES-MS m / z 257 (M+H). Preparation of Intermediate 206: 4-Cyclopropyl-2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid

[0305] To a vigorous stirringof methyl 4-cyclopropyl-2,2- difluorobenzo[d][1,3]dioxole-5-carboxylate (51 g, 191 mmol) in a 2 L RBF was added NaOH (24 g, 597 mmol) in H2O (110 mL) dropwise over 30 min at 5 °C. The reaction mixture wasstirred at 25 °C for 8 h. The reaction was concentrated under reduced pressure and diluted with water (1 L) and EtOAc (500 mL). The mixture was extracted with EtOAc (500 mL). The combined organic layer was discarded. The water phase was adjusted to pH = 3~4 with HCl (2.0 M in H2O, 300 mL) and extracted with EtOAc (500 mL × 3). The combined organic layer was washed with sat. aq. NaCl (300 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was triturated with EtOAc : n-hexane (1:30, 500 mL) at 15 °C for 30 min and filtered. The filter cake was dried under reduced pressure to give the title compound (34.3 g) as solid. ES-MS m / z 241 (M-H). Preparation of Intermediate 207: (2S,4R)-1-(5-Bromo-2-cyano-3-fluorophenyl)-4-(4- cyclopropyl-2,2-difluorobenzo[d][1,3]dioxole-5-carboxamido)-2-methylpiperidine-4- carboxamide

[0306] To 100 mL RBF withwith DMF (30 mL), followed by the addition of 4-cyclopropyl-2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid (2.8 g, 11 mmol), DIEA (4 g, 30 mmol), HATU (7 g, 18 mmol) and (2S,4R)-4-amino-1-(5-bromo-2-cyano- 3-fluorophenyl)-2-methylpiperidine-4-carboxamide (4.1 g, 11 mmol) at 13 °C. The reaction mixture was de-gassed and refilled with N23 times and stirred at 40 °C for 16 h under N2. The reaction was cooled to RT, poured into H2O (150 mL) at 5 °C and extracted with EtOAc (50 mL × 3). The combined organic layer was washed with sat. aq. NaCl (50 mL), dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to give the title compound (5.5 g, 85.3% purity) as solid. ES-MS m / z 577, 579 (M-H). Preparation of Intermediate 208: 4-Bromo-2-((5R,7S)-2-(4-cyclopropyl-2,2- difluorobenzo[d][1,3]dioxol-5-yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-6- fluorobenzonitrile

[0307] To a 100 mL RBF wit harged tert-amyl alcohol (60 mL), followed by the addition of (2S,4R)-1-(5-bromo-2-cyano-3-fluorophenyl)-4-(4-cyclopropyl-2,2- difluorobenzo[d][1,3]dioxole-5-carboxamido)-2-methylpiperidine-4-carboxamide (5.5 g, 85.3% purity, 8.1 mmol) and KOtBu (1.1 g, 9.7 mmol) at 15 °C. The mixture was stirred at 60 °C for 4 h. The reaction was cooled to RT and concentrated under reduced pressure to get a residue. The residue was purified by silica gel chromatography using a gradient of 0 to 60% EtOAc in n- hexane to give the title compound (1.9 g) as solid. ES-MS m / z 561, 563 (M+H). Preparation of Intermediate 209: 2-((5R,7S)-2-(4-Cyclopropyl-2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzonitrile N O F

[0308] To a 100 mL one-was charged with methoxycyclopentane (20 mL), followed by the addition of 4-bromo-2-((5R,7S)-2-(4- cyclopropyl-2,2-difluorobenzo[d][1,3]dioxol-5-yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1- en-8-yl)-6-fluorobenzonitrile (1.9 g, 3.3 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (1.6 g, 6.2 mmol), KOAc (1 g, 9.9 mmol) and methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2- yl)palladium(II) (XPhos Palladacycle Gen. 4, CAS# 1599466-81-5, 0.29 g, 0.33 mmol) at 11 °C. The reaction mixture was de-gassed and refilled with N22 times. The reaction was stirred at 80 °C for 4 h. The reaction was cooled to RT and filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.2 g, 83.2% purity) as a solid. ES-MS m / z 527 (boronic acid) (M+H).Preparation of Intermediate 210: 2-(3,5-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazol-1-yl)acetamide

[0309] Combined 3,5- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole(3.406 g, 15.34 mmol) in a 250 mL and cooled to 0 °C under nitrogen. A solution of 2-bromoacetamide (2.539 g, 18.40 mmol) in DMF (10 mL) was added dropwise over 1 min. The ice water bath was removed and the reaction allowed to slowly warm to RT over 2 h. The reaction was poured into water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layer was washed with saturated sat. aq. NaCl solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to a residue. The residue was purified by flash silica gel chromatography using a gradient of 0 to 10% MeOH in DCM to give the product. The product was dried in a vacuum oven at 45 °C for 1 h to give the title compound (2.452 g). ES-MS m / z 280 (M+H). Preparation of Intermediate 211: Mixture of 2-(4-bromo-3-cyclopropyl-5-methyl-1H-pyrazol-1- yl)acetamide and 2-(4-bromo-5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)acetamide

[0310] A mixture of 4-bromo-pyrazole (2.9 g, 14 mmol), 2- bromoacetamide (2.45 g, 17.4 mmol) and potassium carbonate (3.04 g, 21.8 mmol) in ACN (48 mL) was stirred under nitrogen atmosphere at 90 ºC for 16 h. Additional 2-bromoacetamide (1.02 g, 7.39 mmol) was added and mixture was stirred at 90 ºC for16 h. The reaction mixture was cooled to RT and the solvent was removed. Water was added. The mixture was filtered and the filter cake washed with water and EtOAc to give the title compound (2.06 g) as a solid, estimated 3:1 mixture of isomers. ES-MS m / z 259 (M+H). Preparation of Intermediate 212: 2-(2-Cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8- triazaspiro[4.5]dec-1-en-4-one

[0311] In a 500 mL RBF with stir bar clobutyl-6-(trifluoromethyl)pyridin- 3-yl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (3.92 g, 8.66 mmol) was dissolved in DCM (100 mL) and then TFA (20.0 mL, 260 mmol) was slowly added. The reaction was stirred overnight at RT. The mixture was concentrated under reduced pressure. The residue was loaded onto a 70 g SCX column (CV = 150 mL, pre-washed with 2 CV MeOH) and washed with 2 CV MeOH. The column was eluted with 3 CV NH3MeOH (2N) and the eluent concentrated to give the product. The product was dried in a vacuum oven at 45 °C overnight to give the title compound (3.013 g, 8.55 mmol) as foam. ES-MS m / z 353 (M+H).

[0312] The following intermediate was prepared in a similar manner as described in the Preparation of Intermediate 212 with the appropriate Boc protected amine Intermediate ES-MS Chemical Name Structure number m / z )Preparation of Intermediate 214: 8-(5-Bromo-3-fluoro-2-(methoxymethyl)phenyl)-2-(2- cyclobutyl-6-(trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one

[0313] In a 40 mL reaction2-(2-cyclobutyl-6- (trifluoromethyl)pyridin-3-yl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (1.506 g, 4.274 mmol) , DMSO (12 mL) and 5-bromo-1,3-difluoro-2-(methoxymethyl)benzene (2.026 g, 8.548 mmol). DIEA (1.49 mL, 8.548 mmol) was added. The reaction was heated at 80 °C for 30 h. Additional5-bromo-1,3-difluoro-2-(methoxymethyl)benzene (1.013 g, 4.274 mmol) was added, and the reaction mixture was heated at 100 °C for 48 h. The reaction mixture was allowed to cool down to RT. The reaction mixture was poured into water (50 mL) at 20 ⁰C and extracted with EtOAc (60 mL × 3). The combined organic layer was washed with sat. aq. NaCl (60 mL), dried over Na2SO4. The Na2SO4 was filtered off and the filter cake further washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to give a crude product. The residue was purified by flash silica gel chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give the product. The product was dried in a vacuum oven at 45 °C to give the title compound (546.2 mg). ES-MS m / z 571 (M+H). Preparation of Intermediate 215: Ethyl 2-(5-amino-3-methyl-1H-pyrazol-1-yl)acetate

[0314] In a 1000 mL RBF with stir bar(E)-3-aminobut-2-enenitrile (6.685 g, 81.42 mmol) and ethyl aminoglycinate (9.619 g, 81.42 mmol) in EtOH (250 mL). The reaction was purged with nitrogen for 5 min. The reaction was heated at 80 °C for 14 h. The reaction was cooled to RT and concentrated under reduced pressure to a beige solid. The product was dried in a vacuum oven at 45 °C to give the title compound (15.001 g) as solid. ES-MS m / z 184 (M+H). Preparation of Intermediate 216: Ethyl 2-(5-acetamido-3-methyl-1H-pyrazol-1-yl)acetate

[0315] In a 500 mL RBF with stir barethyl 2-(5-amino-3-methyl-1H-pyrazol- 1-yl)acetate (4.312 g, 23.54 mmol) dissolved in EtOAc (30 mL) and added potassium acetate (2.541 g, 25.89 mmol) followed by cooling in an ice water bath. Acetic anhydride (2.443 mL, 25.89 mmol) was added slowly to the mixture. After the addition was complete, the ice bath was removed and was allowed to slowly warm to RT. The reaction was stirred at RT for 2 h. Thereaction was quenched with sat. aq. sodium bicarbonate and diluted with EtOAc. The mixture was extracted with EtOAc (× 3). The combined organic layer was washed with sat. aq. NaCl solution, dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to provide a residue. The residue was purified by flash silica gel chromatography using a gradient of 0 to 100% EtOAc in heptane to give the product. The product was dried in a vacuum oven at 45 °C to give the title compound (2.8034 g). ES-MS m / z 226 (M+H). Preparation of Intermediate 217: Ethyl 2-(5-acetamido-4-bromo-3-methyl-1H-pyrazol-1- yl)acetate

[0316] In a 100 mL RBF with stir barethyl 2-(5-acetamido-3-methyl-1H- pyrazol-1-yl)acetate (1.0364 g, 4.6011 mmol) dissolved in DCM (20 mL) and cooled in an ice water bath. A suspension of NBS (1.2284 g, 6.9017 mmol) in DCM (10 mL) was added dropwise. The reaction was stirred for 30 min and the water bath was removed. The mixture was quenched with sat. aq. sodium bicarbonate solution, diluted with EtOAc and extracted with EtOAc (× 2). The combined organic layer was washed with sat. aq. NaCl, dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 20 to 100% EtOAc in heptane to give the title compound (486 mg) as a solid. ES-MS m / z 305.8 (M+H). Preparation of Intermediate 218: Ethyl 2-(4-bromo-3-methyl-5-(N-methylacetamido)-1H- pyrazol-1-yl)acetate

[0317] To a solution of ethyl 2-(5-3-methyl-1H-pyrazol-1-yl)acetate (486.02 mg, 1.5980 mmol) in DMF (10 mL) at 0 °C was added NaH (96.15 mg, 4.006 mmol) slowly in portions. The reaction was stirred for 1 h at 0 °C. MeI (199.8 μL, 3.1960 mmol) wasadded dropwise. The ice bath was removed and the mixture allowed to slowly warm to RT. The reaction was cooled to 0 °C and quenched with sat. aq. sodium bicarbonate solution. The mixture was diluted with EtOAc and extracted with EtOAc (×3). The combined organic layer was washed with sat. aq. NaCl solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by flash silica gel chromatography using a gradient of 0 to 80% EtOAc in heptane to give the title compound (309 mg). ES-MS m / z 320 (M+H). Preparation of Intermediate 219: Ethyl 2-(3-methyl-5-(2,2,2-trifluoroacetamido)-1H-pyrazol-1- yl)acetate

[0318] In a 1 L RBF with stir bar2-(5-amino-3-methyl-1H-pyrazol-1- yl)acetate (7.45 g, 40.7 mmol) suspended in DCM (150 mL) and TEA (11.3 mL, 81.4 mmol). The mixture was cooled to 0 °C and a solution of trifluoroacetic anhydride (8.52 mL, 61.0 mmol) in DCM (50 mL) was added dropwise over about 30 min. After the addition was complete, the ice bath was removed and the reaction allowed to warm slowly to RT. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 50 to 100% EtOAc in heptane to give the title compound (7.45 g) as oil. ES-MS m / z 280 (M+H). Preparation of Intermediate 220: Ethyl 2-(4-bromo-3-methyl-5-(2,2,2-trifluoroacetamido)-1H- pyrazol-1-yl)acetate

[0319] The title compound was prepared in a similar manner as described in the Preparation of Intermediate 217 using ethyl 2-(3-methyl-5-(2,2,2-trifluoroacetamido)-1H-pyrazol-1- yl)acetate. ES-MS m / z 358, 360 (M+H).

[0320] The following intermediates were prepared in a similar manner as described in the Preparation of Intermediate 218 using ethyl 2-(4-bromo-3-methyl-5-(2,2,2-trifluoroacetamido)- 1H-pyrazol-1-yl)acetate and the appropriate alkyl iodide. Intermediate ES-MS Chemical name Structure Number m / z ) )Preparation of Intermediate 223: 2-(4-Bromo-3-methyl-5-(methylamino)-1H-pyrazol-1- yl)acetamide

[0321] A solution of ethyl 2-(4-(2,2,2-trifluoro-N-methylacetamido)-1H- pyrazol-1-yl)acetate (4.331 g, 11.64 mmol) in ammonia in MeOH (99.76 mL, 7 molar, 698.3 mmol) was heated at 60 °C for 1 h. The reaction was cooled to RT. The mixture was concentrated under reduced pressure to provide a white solid that was dried in the vacuum oven at 45 °C. The residue was dissolved in minimal DCM with <5% MeOH. The solution was purified by flash silica gel chromatography using a gradient of 20 to 50% (10%MeOH / DCM) in DCM to give the title compound (910 mg) as a solid. ES-MS m / z 247, 249 (M+H).

[0322] The following intermediate was prepared in a similar manner as described in the Preparation of Intermediate 223 using ethyl 2-(4-bromo-5-(N-ethyl-2,2,2-trifluoroacetamido)-3- methyl-1H-pyrazol-1-yl)acetate. Intermediate ES-MS Chemical name Structure Number m / z )p y , y p py (trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)-5- fluorophenyl)boronic acid

[0323] In a 5 mL vial withbromo-2-((5R,7S)-2-(2- cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)-7-methyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8- yl)-6-fluorobenzonitrile (0.967 g, 1.49 mmol) and 1,4-dioxane (10 mL). The solvent was purged with nitrogen while adding sequentially, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (759 mg, 2.99 mmol), potassium carbonate (619 mg, 4.48 mmol) and 2-ethyl hexanoic acid (238 μL, 1.49 mmol). The nitrogen purge was continued, and heating began. After reaching 50 °C, [(1,2,3-eta)-2-buten-1-yl]chloro[dicyclohexyl[2',4',6'-tris(1- methylethyl)[1,1'-biphenyl]-2-yl]phosphine]palladium (201 mg, 299 μmol) was added. The reaction was sealed and the vessel was heated at 50 °C for 16 h. The reaction was poured into water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organics were washed with sat. aq. NaCl solution, dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to provide a residue. The residue was dried in a vacuum oven for 1 h to provide the product. purified by reverse phase reversed phase flash chromatography using a gradient of 5 to 35% ACN in (10 mM aq. NH4HCO3 + 5% MeOH) to give the title compound (471.0 mg). ES-MS m / z 516 (M+H).Preparation of Intermediate 226: Ethyl 2-(5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)acetate

[0324] In a 1 L RBF with stir bar aminoglycinate (3.933 g, 37.78mmol) suspended, EtOH (100 mL) 1,3-dione (4.333 g, 34.35 mmol). The reaction was heated at 80 °C for 16 h. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in EtOAc and washed with water. The aqueous layer was extracted again with EtOAc. The combined organic layer was washed with sat. aq. NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give the title compound as the second-eluting regioisomer, which was re-purified by silica gel chromatography using a gradient of 40 to 70% EtOAc in cyclohexane to give the title compound (3.9 g) as oil. ES-MS m / z 209 (M+H). Preparation of Intermediate 227: Ethyl 2-(4-bromo-5-cyclopropyl-3-methyl-1H-pyrazol-1- yl)acetate Br

[0325] In a 250 mL RBF, to acyclopropyl-3-methyl-1H-pyrazol-1- yl)acetate (1.205 g, 5.786 mmol) in EtOAc (20 mL). NBS (2.060 g, 11.57 mmol) was added in one portion at RT. The mixture was sonicated at 25 °C for 30 min. The reaction was poured into a 125 mL separatory funnel and rinsed in with EtOAc. A solution of sodium sulfite (10% in water) was added, and the mixture extracted with EtOAc (× 2). The combined organic layer was washed with sat. aq. NaCl, dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to provide the title compound (1.662 g). ES-MS m / z 287, 289 (M+H). Preparation of Intermediate 228: 2-(4-Bromo-5-cyclopropyl-3-methyl-1H-pyrazol-1- yl)acetamide

[0326] In a 20 mL vial with stir bar w ed ethyl 2-(4-bromo-5-cyclopropyl-3- methyl-1H-pyrazol-1-yl)acetate (1.662 g, 5.788 mmol) with ammonia in MeOH (16.54 mL, 7 molar, 115.8 mmol) at RT. The vessel was sealed and heated to 50 °C for 2 h in a heating block, then concentrated under reduced pressure and the residue was dried under vacuum at RT to give the title compound (1.5 g) as a solid. ES-MS m / z 258, 260 (M+H). Preparation of Intermediate 229: Ethyl 2-(5-hydr...

Claims

CLAIMS 1. A compound of the following formula, or a pharmaceutically acceptable salt thereof: ; wherein: each of RA1, RA2, RA3, and(1) H, (2) -C1-10 alkyl, optionally substituted with 1 to 4 substituents independently selected from: (a) halogen, (b) -OR11, wherein R11is selected from: (i) H, (ii) -C1-10alkyl, optionally substituted with 1 to 4 substituents independently selected from halogen, -C1-10alkoxy and -C3-10cycloalkyl optionally substituted with 1 to 4 halogens, (iii) -C3-10cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from halogen and -C1-10alkyl, and (iv) 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from halogen, -OH, and -C1-10alkyl optionally substituted with 1 to 4 halogens, (c) -C3-10 cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from (i) halogen and (ii) -C1-10alkoxy, optionally substituted with 1 to 4 halogens, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-10alkyl, optionally substituted with -C1-10alkoxy, and (iii) -C3-10cycloalkyl, optionally substituted with 1 to 4 halogens, and(e) 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from: (i) halogen, (ii) -OH, and (iii) -C1-10 alkyl, optionally substituted with 1 to 4 halogens, (3) -CN, (4) -C1-10 alkoxy, optionally substituted with 1 to 4 halogens, (5) -NRa1Rb1, wherein each of Ra1and Rb1is independently selected from (a) H and (b) -C1-10 alkyl, (6) -C(O)R8, wherein R8is selected from (a) H, (b) -C1-10alkyl, and (c) -NH2, (7) -SO2R9; wherein R9is selected from (a) H and (b) -C1-10 alkyl, (8) -O-C3-10 cycloalkyl, optionally substituted with 1 to 4 halogens, (9) halogen, (10) -C3-10 cycloalkyl, optionally substituted with 1 to 4 halogens, and (11) C2-10 alkenyl, optionally substituted with 1 to 4 halogens; B ring is a 5 to 10 membered heteroaryl or 4 to 10 membered 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) -C1-10alkyl, optionally substituted with 1 to 4 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-10alkyl, optionally substituted with 1 to 4 halogens, (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-10alkyl, optionally substituted with 1 to 4 halogens, (iii) -C3-10 cycloalkyl, optionally substituted with 1 to 4 halogens, and (iv) 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from:(i) H, (ii) -C1-10 alkyl, optionally substituted with 1 to 4 halogens, and (iii) -C(O)C1-10 alkyl, optionally substituted with 1 to 4 halogens, (2) halogen, (3) -C3-10 cycloalkyl, optionally substituted with 1 to 4 halogens, (4) -C1-10 alkoxy, optionally substituted with 1 to 4 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-10 alkyl, optionally substituted with 1 to 4 halogens, (c) -C3-10cycloalkyl, optionally substituted with 1 to 4 halogens, and (d) -C(O)C1-10alkyl, optionally substituted with 1 to 4 halogens, (6) oxo, and (7) -CN; and each of R4, R4’, R5, and R5’is independently selected from: (1) H, (2) -C1-10alkyl, optionally substituted with 1 to 4 substituents independently selected from (a) -OH and (b) halogen, (3) -C3-10 cycloalkyl, and (4) halogen; R6is selected from: (1) an aryl, (2) a 5 to 10 membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O, and S, and (3) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 4 substituents independently selected from: (a) halogen,(b) -C1-10alkyl, optionally substituted with 1 to 4 substituents independently selected from (i) halogen and (ii) -OH, (c) -C1-10 alkoxy, optionally substituted with 1 to 4 halogens, (d) -C3-10cycloalkyl, optionally substituted with 1 to 4 substituents independently selected from (i) halogen and (ii) -C1-10 alkyl, (e) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (i) -C1-10 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-10 alkoxy, and (f) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from (i) -C1-10alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-10alkoxy; and R7is selected from: (1) H, (2) -C1-10 alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen, and (3) halogen.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (Ia): ; wherein:each of RA1and RA2is independently selected from: (1) H, (2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OR11, wherein R11is selected from:(i) H, (ii) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -C1-6 alkoxy and -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (iii) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6 alkyl, and (iv) 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6alkoxy, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-6 alkyl, optionally substituted with -C1-6 alkoxy, and (iii) -C3-6cycloalkyl, and (e) 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) -OH, and (iii) -C1-6alkyl, optionally substituted with 1 to 3 halogens, (3) -CN, (4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa1Rb1, wherein each of Ra1and Rb1is independently selected from (a) H, and (b) -C1-6 alkyl, (6) -C(O)R8, wherein R8is selected from (a) H, (b) -C1-6 alkyl, and (c) -NH2, (7) -SO2R9; wherein R9is selected from (a) H and (b) -C1-6 alkyl, (8) -O-C3-6cycloalkyl, (9) halogen, and (10) -C2-6 alkenyl;the B ring is a 5 to 10 membered heteroaryl or 5 to 10 membered 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) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-6alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6alkyl, (iii) -C3-6cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6 alkyl, (2) halogen, (3) -C3-6 cycloalkyl, (4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6 alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-6alkyl, (6) oxo, and (7) -CN; R4is selected from: (1) H, (2) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) -OH and (b) halogen, and(3) -C3-6cycloalkyl; R6is selected from: (1) an aryl, (2) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (3) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH, (c) -C1-6alkoxy, optionally substituted with 1 to 3 halogens, (d) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -C1-6 alkyl, (e) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-6 alkyl, (b) halogen, (c) -OH, and (d) -C1-6 alkoxy, and (f) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-6 alkyl, (b) halogen, (c) -OH, and (d) -C1-6 alkoxy; and R7is selected from: (1) H, and (2) -C1-6 alkyl, optionally substituted with a substituent selected from (a) -OH and (b) halogen.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (Ib):b), wherein: W1is -CR1or -NR1; W2is -CR2or -NR2; W3is -CR3or -NR3; W4is -CR4aor -NR4a; and W5is -CR5aor -NR5a; wherein each partial dashed bond “ ” is a single bond or a double bond, provided thatwhen it is a single bond, an extra H is present on each carbon to which it is attached to satisfy the valency of those carbons; or alternatively, when it is a double bond, R1, R2, R3, R4aor R5ais absent from -NR1, -NR2, -NR3, -NR4a, or -NR5ato satisfy the valency of that N; and each of R1, R2, R3, R4aand R5ais independently selected from: (1) H, (2) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-6alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6 alkyl, (iii) -C3-6cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from:(i) H, and (ii) -C(O)C1-6 alkyl, (3) halogen, (4) -C3-6cycloalkyl, (5) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6 alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-6alkyl, (7) oxo, and (8) -CN; or alternatively, when W2is -CR2= and W5is -CR5a=, R2and R5a, together with the carbon atoms to which they are attached form a 4 to 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -C1-6alkyl, and (c) oxo.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (Ic): , wherein:W3is -CR3or -NR3; W5is -CR5aor -NR5a; wherein each partial dashed bond “ ” is a single bond or a double bond, provided that whenit is a single bond, an extra H is present on each carbon to which it is attached to satisfy thevalency of those carbons; or alternatively, when it is a double bond, R3or R5ais absent from -NR3or -NR5ato satisfy the valency of that N; and each of R2, R3, R4aand R5ais independently selected from: (1) H, (2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-6 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6 alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6 alkyl, (3) halogen, (4) -C3-6cycloalkyl, (5) -C1-6alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-6 alkyl, (7) oxo, and (8) -CN; or alternatively, when W5is -CR5a=, R2and R5a, together with the carbon atoms to which they are attached form a 4 to 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatomsindependently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -C1-6 alkyl, and (c) oxo.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (Id): , wherein:W4is -CR4a= or -N=; W5is -CR5a= or -N=; and each of R1, R2, R3, R4aand R5ais independently selected from: (1) H, (2) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-6alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6 alkyl, (iii) -C3-6cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6 alkyl, (3) halogen,(4) -C3-6cycloalkyl, (5) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6 alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-6alkyl, (7) oxo, and (8) -CN; or alternatively, when W5is -CR5a=, R2and R5a, together with the carbon atoms to which they are attached form a 4 to 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -C1-6alkyl, and (c) oxo.

6. The compound of any one of claims 3-5, or a pharmaceutically acceptable salt thereof, wherein, when present: W4is -N=; W5is -N=; each of RA1and RA2is independently selected from: (1) H, (2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OR11, wherein R11is selected from: (i) H, (ii) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -C1-6alkoxy and -C3-6cycloalkyl, optionally substituted with 1 to 3 halogens, (iii) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6 alkyl, and(iv) 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6alkoxy, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-6alkyl, optionally substituted with -C1-6alkoxy, and (iii) -C3-6 cycloalkyl, and (e) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) -OH and (iii) -C1-6alkyl, optionally substituted with 1 to 3 halogens, (3) -CN, (4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (5) -O-C3-6cycloalkyl, (6) halogen, and (7) -C2-6 alkenyl; when present, each of R1, R2, and R3is independently selected from: (1) H, (2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-6 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6 alkyl, (iii) -C3-6cycloalkyl, and(iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6 alkyl, (3) halogen, (4) -C3-6cycloalkyl, (5) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-6 alkyl, (7) oxo, and (8) -CN; when present, each of R4aand R5ais H; each of R4, R4’, R5, and R5’is independently selected from: (1) H, (2) -C1-6alkyl, (3) -C3-6 cycloalkyl, and (4) halogen; R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (3) a 5 to 10 membered monocyclic or fused bicyclic heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,wherein each of the phenyl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH, (c) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (d) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, (e) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-6alkoxy, and (f) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-6alkoxy; and R7is selected from: (1) H, and (2) -C1-6 alkyl.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein: each of RA1and RA2is independently selected from: (1) H, (2) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OR11, wherein R11is selected from: (i) H, (ii) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -C1-4alkoxy and -C3-6cycloalkyl, optionally substituted with 1 to 3 halogens, (iii) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-4 alkyl, and(iv) 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-4alkoxy, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-4alkyl, optionally substituted with -C1-4alkoxy, and (iii) -C3-6 cycloalkyl, and (e) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) -OH and (iii) -C1-4alkyl, optionally substituted with 1 to 3 halogens, (3) -CN, and (4) halogen; R1is selected from: (1) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-4 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-4 alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-4alkyl,(2) halogen, (3) -C3-6 cycloalkyl, and (4) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens; each of R2and R3is independently selected from: (1) H, (2) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-4alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-4 alkyl, (iii) -C3-6cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-4 alkyl, (3) -C1-4alkoxy, and (4) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, and (b) -C1-6 alkyl; each of R4, R4’, R5, and R5’is independently selected from: (1) H, and (2) -C1-4alkyl; R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl selected from pyridyl, pyridazinyl, and pyrimidyl, and(3) a 5 to 10 membered heterocyclyl selected fro , wherein each of the phenyl of (1), heteroaryl of ( ) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH, (c) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (d) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-4alkyl; and R7is selected from: (1) H, and (2) -C1-4alkyl.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (Ie): , wherein:W1is -CR1or -NR1, W2is -CR2or -NR2, W3is -CR3or -NR3, and W4is -CR4aor -NR4a, wherein each partial dash bond “ ” is a single bond or a double bond, provided that whenit is a single bond, anon each carbon to which it is attached to satisfy the valency of those carbons; or alternatively, when it is a double bond, R1, R2, R3, or R4ais absent from -NR1, -NR2, -NR3or -NR4ato satisfy the valency of that N; and wherein each of R1, R2, R3, and R4ais independently selected from: (1) H, (2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-6 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6alkyl, (3) halogen, (4) -C3-6 cycloalkyl, (5) -C1-6alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6 alkyl, (c) -C3-6cycloalkyl, and (d) -C(O)C1-6 alkyl, (7) oxo, and (8) -CN; or alternatively, when W1is -CR1= and W2is -CR2or -NR2-, R1and R2, together with the carbon and / or nitrogen atoms to which they are attached form a 4 to 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S,optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -C1-6 alkyl, and (c) -NH2, optionally substituted with 1 to 2 substituents independently selected from C1-6 alkyl and .

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (If): , wherein:W2is -CR2or -NR2, W3is -CR3or -NR3, and W4is -CR4aor -NR4a, wherein each partial dash bond “ ” is a single bond or a double bond, provided that whenit is a single bond, an extra H is present on each carbon to which it is attached to satisfy the valency of those carbons; or alternatively, when it is a double bond, R2, R3, or R4ais absent from -NR2, -NR3, or -NR4ato satisfy the valency of that N; and wherein, when present, each of R1, R2, R3, and R4ais independently selected from: (1) H, (2) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-6alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6alkyl, (iii) -C3-6cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and(e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6 alkyl, (3) halogen, (4) -C3-6 cycloalkyl, (5) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6 alkyl, (c) -C3-6cycloalkyl, and (d) -C(O)C1-6alkyl, (7) oxo, and (8) -CN; or alternatively, when W2is -CR2or -NR2, R1and R2, together with the carbon and / or nitrogen atoms to which they are attached form a 4 to 6 membered heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -C1-6 alkyl, and (c) -NH2, optionally substituted with 1 to 2 C1-6 alkyl groups.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (Ig): , wherein:each of R1, R2, and R3is independently selected from: (1) H, (2) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from:(a) halogen, (b) -OH, (c) -O-C(O)C1-6 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6 alkyl, (iii) -C3-6cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6 alkyl, (3) halogen, (4) -C3-6cycloalkyl, (5) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6 alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-6alkyl, (7) oxo, and (8) -CN.

11. The compound of any one of claims 8-10, or a pharmaceutically acceptable salt thereof, wherein: each of RA1and RA2is independently selected from: (1) H, (2) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OR11, wherein R11is selected from: (i) H,(ii) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -C1-6 alkoxy and -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (iii) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6 alkyl, and (iv) 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6 alkoxy, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-6 alkyl, optionally substituted with -C1-6 alkoxy, and (iii) -C3-6 cycloalkyl, and (e) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) -OH and (iii) -C1-6 alkyl, optionally substituted with 1 to 3 halogens, (3) -CN, (4) -C1-6alkoxy, optionally substituted with 1 to 3 halogens, (5) -O-C3-6 cycloalkyl, (6) halogen, and (7) -C2-6alkenyl; each of R1, R2, and R3is independently selected from: (1) H, (2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-6alkyl, and(d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6 alkyl, (iii) -C3-6cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6 alkyl, (3) halogen, (4) -C3-6cycloalkyl, (5) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6 alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-6alkyl, (7) oxo, and (8) -CN; when present, each of R4aand R5ais H; each of R4, R4’, R5, and R5’is independently selected from: (1) H, (2) -C1-6 alkyl, (3) -C3-6 cycloalkyl, and (4) halogen; R6is selected from: (1) a phenyl,(2) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (3) a 5 to 10 membered monocyclic or fused bicyclic heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein each of the phenyl of (1), heteroaryl of (2), and heterocyclyl of (3) 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 (i) halogen and (ii) -OH, (c) -C1-6alkoxy, optionally substituted with 1 to 3 halogens, (d) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, (e) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-6 alkoxy, and (f) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-6 alkoxy; and R7is selected from: (1) H, and (2) -C1-6 alkyl.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein: each of RA1and RA2is independently selected from: (1) H, (2) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OR11, wherein R11is selected from: (i) H,(ii) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -C1-4 alkoxy and -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (iii) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-4 alkyl, and (iv) 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-4 alkoxy, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-4 alkyl, optionally substituted with -C1-4 alkoxy, and (iii) -C3-6 cycloalkyl, and (e) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) -OH and (iii) -C1-4 alkyl, optionally substituted with 1 to 3 halogens, (3) -CN, and (4) halogen; R1is selected from: (1) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-4alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-4alkyl, (iii) -C3-6cycloalkyl, and(iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-4 alkyl, (2) halogen, (3) -C3-6cycloalkyl, and (4) -C1-4 alkoxy; each of R2and R3is independently selected from: (1) H, (2) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-4 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-4 alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-4alkyl, (3) -C1-4 alkoxy, and (4) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, and (b) -C1-6 alkyl; each of R4, R4’, R5, and R5’is independently selected from: (1) H, and(2) -C1-4alkyl; R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl selected from pyridyl, pyridazinyl, and pyrimidyl, and (3) a 5 to 10 membered heterocyclyl selected , wherein each of the phenyl of (1), heteroaryl ofis optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH, (c) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (d) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-4 alkyl; and R7is selected from: (1) H, and (2) -C1-4 alkyl.

13. The compound of any one of claims 1-5 and 8-10, or a pharmaceutically acceptable salt thereof, wherein each of RA1and RA2is independently selected from: (1) H, (2) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OR11, wherein R11is selected from: (i) H, (ii) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -C1-6alkoxy and -C3-6cycloalkyl, optionally substituted with 1 to 3 halogens,(iii) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6 alkyl, and (iv) 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6 alkoxy, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-6 alkyl, optionally substituted with -C1-6 alkoxy, and (iii) -C3-6cycloalkyl, and (e) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) -OH and (iii) -C1-6 alkyl, optionally substituted with 1 to 3 halogens, (3) -CN, (4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (5) -O-C3-6 cycloalkyl, (6) halogen, and (7) -C2-6alkenyl.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein RA1is selected from: (1) H, (2) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OR11, wherein R11is selected from: (i) H,(ii) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -C1-4 alkoxy and -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (iii) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-4 alkyl, and (iv) 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-4 alkoxy, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-4 alkyl, optionally substituted with -C1-4 alkoxy, and (iii) -C3-6 cycloalkyl, and (e) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) -OH and (iii) -C1-4 alkyl, optionally substituted with 1 to 3 halogens, (3) -CN, (4) -C1-4alkoxy, optionally substituted with 1 to 3 halogens, (5) -O-C3-6 cycloalkyl, (6) halogen, and (7) -C2-4alkenyl; and RA2is selected from: (2) H, (2) halogen, and (3) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, and (c) -C3-6cycloalkyl.

15. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein: the B ring is a 5 to 10 membered monocyclic or fused bicyclic heteroaryl or heterocyclyl 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)C1-6 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6 alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6 alkyl, (2) halogen, (3) -C3-6cycloalkyl, (4) -C1-6alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-6 alkyl, (6) oxo, and (7) -CN.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein:the B ring is a 5 to 6 membered monocyclic heteroaryl or heterocyclic ring selected from azetidinyl, imidazolyl, morpholinyl, oxetanyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and triazolyl; or the B ring is an 8 to 10 membered bicyclic heteroaryl or heterocyclic ring selected from benzoimidazolyl, benzothiazolyl, benzothiophenyl, benzoxazole, cinnolinyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridyl, imidazopyrimidinyl, indazolyl, indolyl, isoindolyl, isoquinolyl, pyrazolopyrazinyl, pyrazolopyridazinyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrrolopyridyl, quinazolinyl, quinolyl, and quinoxalinyl; wherein the B ring is optionally substituted with 1 to 4 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)C1-4 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-4 alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-4alkyl, (2) halogen, (3) -C3-6 cycloalkyl, (4) -C1-4alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-4alkyl, (c) -C3-6cycloalkyl, and(d) -C(O)C1-4alkyl, (6) oxo, and (7) -CN.

17. The compound of any one of claims 1-5, 8-10 and 13-16, or a pharmaceutically acceptable salt thereof, wherein: R4is selected from: (1) H, and (2) -C1-6 alkyl; and when present, each of R4’, R5, R5’is H.

18. The compound of any one of claims 1-5, 8-10 and 13-17, or a pharmaceutically acceptable salt thereof, wherein: R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (3) a 5 to 10 membered monocyclic or fused bicyclic heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein each of the phenyl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH, (c) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (d) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -C1-6 alkyl, (e) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-6alkoxy, and(f) a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-6 alkoxy.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein: R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and thiazolyl, and (3) a 5 to 10 membered monocyclic or fused bicyclic heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein each of the phenyl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH, (c) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (d) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -C1-4alkyl, (e) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-4 alkyl, (b) halogen, (c) -OH, and (d) -C1-4 alkoxy, and (f) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-4 alkyl, (b) halogen, (c) -OH, and (d) -C1-4 alkoxy.

20. The compound of any one of claims 1-5, 8-10, and 13-19, or a pharmaceutically acceptable salt thereof, wherein: R7is selected from: (1) H, and(2) -C1-6alkyl.

21. The compound of any one of claims 3-5, 8-10, and 13-20, or a pharmaceutically acceptable salt thereof, wherein: when present, each of R1, R2, R3, R4a, and R5ais independently selected from: (1) H, (2) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-4alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-4alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-4alkyl, (3) halogen, (4) -C3-6 cycloalkyl, (5) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-4 alkyl, (c) -C3-6cycloalkyl, and (d) -C(O)C1-4 alkyl, (7) oxo, and (8) -CN.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein, when present, R1is selected from: (1) H, (2) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-4alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-4alkyl, (iii) -C3-6cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-4 alkyl, (3) halogen, (4) -C3-6 cycloalkyl, (5) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (6) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-4 alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-4alkyl, (7) oxo, and (8) -CN; and wherein, when present, each of R2, R3, R4a, and R5ais independently selected from: (1) H, (2) -C1-4 alkyl, optionally substituted with 1 to 3 halogens, (3) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens,(4) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from (a) H and (b) -C1-4alkyl, and (5) oxo.

23. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein, when present, R1is selected from: (1) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-4 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-4 alkyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-4alkyl, (2) halogen, (3) -C3-6 cycloalkyl, (4) -C1-4alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-4alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-4 alkyl; and wherein, when present, each of R2, R3, R4a, and R5ais independently selected from: (1) H, (2) -C1-4 alkyl, optionally substituted with 1 to 3 halogens,(3) -C1-4alkoxy, and (4) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from (a) H and (b) -C1-4 alkyl.

24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: each of RA1and RA2is independently selected from: (1) H, (2) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OR11, wherein R11is selected from: (i) H, (ii) -C1-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -C1-6 alkoxy and -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (iii) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6 alkyl, and (iv) 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (c) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-6 alkoxy, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-6 alkyl, optionally substituted with -C1-6 alkoxy, and (iii) -C3-6cycloalkyl, and (e) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) -OH and (iii) -C1-6 alkyl, optionally substituted with 1 to 3 halogens,(3) -CN, (4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (5) -O-C3-6 cycloalkyl, (6) halogen, and (7) -C2-6 alkenyl; the B ring is a 5 to 10 membered monocyclic or fused bicyclic heteroaryl or heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 4 substituents independently selected from: (1) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-6 alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-6 alkyl, (iii) -C3-6cycloalkyl, and (iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-6 alkyl, (2) halogen, (3) -C3-6cycloalkyl, (4) -C1-6 alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-6 alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-6alkyl, (6) oxo, and(7) -CN; when present, each of RA3and RA4is H; R4is selected from: (1) H, and (2) -C1-6alkyl; when present, each of R4’, R5, and R5’is H; R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (3) a 5 to 10 membered monocyclic or fused bicyclic heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein each of the phenyl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C1-6alkyl, optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -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) -C1-6alkyl, (e) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-6alkoxy, and (f) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -C1-6alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-6alkoxy; andR7is selected from: (1) H, and (2) -C1-6 alkyl.

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein: RA1is selected from: (1) H, (2) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OR11, wherein R11is selected from: (i) H, (ii) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -C1-4 alkoxy and -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens, (iii) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-4 alkyl, and (iv) 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (c) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-4 alkoxy, (d) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (i) H, (ii) -C1-4 alkyl, optionally substituted with -C1-4 alkoxy, and (iii) -C3-6 cycloalkyl, and (e) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from: (i) halogen, (ii) -OH and(iii) -C1-4alkyl, optionally substituted with 1 to 3 halogens, (3) -CN, (4) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (5) -O-C3-6cycloalkyl, (6) halogen, and (7) -C2-4 alkenyl; RA2is selected from: (2) H, (2) halogen, and (3) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) -OH, and (c) -C3-6 cycloalkyl; the B ring is a 5 to 6 membered monocyclic heteroaryl or heterocyclyl selected from azetidinyl, imidazolyl, morpholinyl, oxetanyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and triazolyl; or the B ring is an 8 to 10 membered bicyclic heteroaryl or heterocyclic ring selected from benzoimidazolyl, benzothiazolyl, benzothiophenyl, benzoxazole, cinnolinyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridyl, imidazopyrimidinyl, indazolyl, indolyl, isoindolyl, isoquinolyl, pyrazolopyrazinyl, pyrazolopyridazinyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrrolopyridyl, quinazolinyl, quinolyl, and quinoxalinyl, wherein the B ring is optionally substituted with 1 to 3 substituents independently selected from: (1) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)C1-4alkyl, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from: (i) H, (ii) -C1-4alkyl, (iii) -C3-6cycloalkyl, and(iv) 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and (e) -NRa5Rb5, wherein each of Ra5and Rb5is independently selected from: (i) H, and (ii) -C(O)C1-4 alkyl, (2) halogen, (3) -C3-6cycloalkyl, (4) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) -C1-4alkyl, (c) -C3-6 cycloalkyl, and (d) -C(O)C1-4 alkyl, (6) oxo, and (7) -CN; R4is selected from: (1) H, and (2) -C1-4 alkyl; R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and thiazolyl, and (3) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein each of the phenyl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH,(c) -C1-4alkoxy, optionally substituted with 1 to 3 halogens, (d) -C3-6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -C1-4 alkyl, (e) a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-4 alkyl, (b) halogen, (c) -OH, and (d) -C1-4 alkoxy and (f) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-4 alkyl, (b) halogen, (c) -OH, and (d) -C1-4 alkoxy; and R7is selected from: (1) H, and (2) -C1-4 alkyl.

26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: RA1is selected from: (1) H, (2) -C1-4 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -OCH3, optionally substituted with -C3-4 cycloalkyl, wherein the -C3-4 cycloalkyl is optionally substituted with 1 to 3 halogens, (d) -OCH2CH3, (e) -OCH(CH3)2, (f) -O-C3-5 cycloalkyl, (g) -C3-5cycloalkyl, optionally substituted with 1 to 3 halogens, (h) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: H, -CH3, -CH2CH3, cyclopropyl, and cyclobutyl, and(i) 5 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from -CH3, CHF2, CF3, -OH, and halogen, (3) -CN, (4) - halogen, and (5) -C2-4 alkenyl; RA2is selected from: (2) H, (2) halogen, and (3) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH; the B ring is optionally substituted with 1 to 3 substituents independently selected from: (1) -C1-2 alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)CH3, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from (i) H, (ii) methyl, (iii) ethyl, (iv) -C3-6cycloalkyl, and (v) 4 to 6 membered heterocyclyl selected from oxetanyl, tetrahydro-2H-pyranyl, piperidinyl, and piperidinyl, (2) halogen, (3) -C3-6 cycloalkyl, (4) -C1-2alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) methyl, (c) ethyl, (d) -C3-6 cycloalkyl, and (e) -C(O)CH3, (6) oxo, and(7) -CN; R4is selected from: (1) H, (2) methyl, and (3) ethyl; R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and thiazolyl, and (3) a 5 to 10 membered heterocyclyl selected , wherein each of the phenyl of (1), heteroaryl ofis optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C1-4 alkyl, optionally substituted with 1 to 3 halogens, (c) -C1-4 alkoxy, optionally substituted with 1 to 3 halogens, (d) -C3-6cycloalkyl, optionally substituted with 1 to 3 halogens, (e) a 5 to 6 membered heteroaryl selected from furanyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, and thiophenyl, optionally substituted with 1 to 3 halogens, and (f) a 5 to 10 membered heterocyclyl selected ,R7is selected from: (1) H, (2) methyl, and (3) ethyl.

27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein: the B ring is a 5 to 6 membered monocyclic heteroaryl or heterocyclic ring selected from imidazolyl, morpholinyl, pyrazolyl, pyridyl, pyridazinyl, and pyrimidyl; or the B ring is an 8 to 10 membered bicyclic heteroaryl or heterocyclic ring selected from ,hetero portion of the B ring that is suitable for attachment, and wherein the B ring is optionally substituted with 1 to 3 substituents independently selected from: (1) -C1-4alkyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -OH, (c) -O-C(O)CH3, and (d) -C(O)NRa2Rb2, wherein each of Ra2and Rb2is independently selected from (i) H and (ii) methyl, (iii) -C3-6 cycloalkyl, and (iv) 4 to 6 membered heterocyclyl selected from oxetanyl, tetrahydro-2H-pyranyl, piperidinyl, and piperidinyl, (2) halogen, (3) -C3-6 cycloalkyl, optionally substituted with 1 to 3 halogens,(4) -C1-4alkoxy, optionally substituted with 1 to 3 halogens, (5) -NRa3Rb3, wherein each of Ra3and Rb3is independently selected from: (a) H, (b) methyl, (c) -C3-6 cycloalkyl, and (d) -C(O)CH3, and (6) oxo; R4is selected from: (1) H and (2) methyl; R6is selected from: (1) a phenyl, (2) a 5 to 6 membered heteroaryl selected from imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, and thiazolyl, and (3) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein each of the phenyl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C1-3alkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) -OH, (c) -C1-3 alkoxy, optionally substituted with 1 to 3 halogens, (d) -C3-6cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from (a) halogen and (b) methyl, (e) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-2 alkyl, (b) halogen, (c) -OH, and (d) -C1-2 alkoxy, and (f) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-2alkyl, (b) halogen, (c) -OH, and (d) -C1-2alkoxy; andR7is selected from: (1) H and (2) methyl.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein: the B ring is a 5 to 6 membered monocyclic heteroaryl or heterocyclic ring selected from imidazolyl, morpholinyl, pyrazolyl, pyridyl, pyridazinyl, and pyrimidinyl; or the B ring is an 8 to 10 membered bicyclic heteroaryl or heterocyclic ring selected from , ,29. A pharmaceutical composition comprising a compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

30. 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 1-28, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

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

32. A compound of any one of claims 1-28, 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.

33. A compound or a pharmaceutically acceptable salt thereof, for use of claim 32, in the treatment of a type 2 diabetes.

34. A compound or a pharmaceutically acceptable salt thereof, for use of claim 32, in the treatment of obesity.

35. 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.

36. A compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with one or more of a glucagon-like peptide-1 (GLP-1) receptor agonist, an amylin receptor agonist, a glucose- dependent insulinotropic polypeptide (GIP) agonist, and a peptide tyrosine-tyrosine (PYY) agonist, or a pharmaceutically acceptable salt thereof, in the treatment of a type 2 diabetes, obesity, or overweight with at least one weight related comorbidity selected from diabetes, high blood pressure, high cholesterol, obstructive sleep apnea and heart disease.

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