Liver x receptor agonists, compositions and methods

Abstract

The present invention provides compounds of Formula (I) and pharmaceutically acceptable salts thereof. The compounds described herein are selective agonists of LXRβ and / or can be used to treat a disease or condition described herein, including Alzheimer's Disease.

Description

[0001] LIVER X RECEPTOR AGONISTS, COMPOSITIONS AND METHODS

[0002] RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 737,366, filed on December 20, 2024 and U.S. Provisional Application No. 63 / 866,342, filed on August 19, 2024. The entire teachings of the above applications are incorporated herein by reference.

[0004] FIELD OF THE INVENTION

[0005] Provided herein are compounds that are liver X receptor p (LXRP) selective agonists for the treatment of pathologies including diseases in which alterations in cholesterol and lipid metabolism and inflammation play a role.

[0006] BACKGROUND OF THE INVENTION

[0007] Alzheimer’s disease (AD) is an age-related multifactorial neurodegenerative disorder with complex etiology, including disruptions of brain lipid homeostasis, neuroinflammation and other factors, leading to amyloidogenesis and other disease processes1. Ap peptides 1-40 and 1-42 are released from oligodendrocytes and neurons and bind to extracellular lipoprotein particles (LPs). These lipoproteins are secreted by astrocytes and contain apolipoprotein E as well as cholesterol, which is transported out of cells by the ABCA1 and ABCG1 efflux transporters. Ap containing LPs are subsequently cleared by LDLR and LRP1 cell surface receptors on glial cells. AD brains have impaired clearance of Ap leading to their accumulation in parenchymal cells and formation of neurotoxic Ap oligomers and amyloid plaques. The binding of Ap oligomers and fibrils to microglial cell receptors triggers the release of pro-inflammatory cytokines resulting in neuroinflammation and neurodegeneration (summarized in Molecular Psychiatry (2021) 26:5481 - 55032). Accordingly, disrupted cholesterol homeostasis leading to decreased production of Ap acceptor LPs and neurotoxic inflammation are hallmarks of AD pathophysiology, among others.

[0008] The liver X receptors, LXRa and LXRP, are oxy sterol -activated nuclear hormone receptors3that control the transcription of genes involved in all major phases of reverse cholesterol transport(4,5), a process whereby excess cholesterol is effluxed out of cells via ABC transporters on to acceptor lipoproteins for subsequent removal. LXRa is expressed primarily in tissues that metabolize large amounts of lipid such as liver, intestine, adipose tissue and macrophages, while LXRP expression is ubiquitous and is the predominant isoform in brain. Dual LXR agonists have undesirable effects in liver, causing increased plasma LDL-C and TG and elevated liver TG in rodent models and humans6. LXRa mediates most if not all of hepatic agonist responses and, thus, LXRP-selective agonists have been sought to avoid the lipid effects.

[0009] LXRs bind and are transactivated by oxysterol cholesterol metabolites, resulting in the induction of ABCA1, ABCG1, and apoE, which, together, help determine Ap acceptor levels, and other target genes. Thus, LXR activity is a key determinant of the concentration of extracellular apoE and cholesterol-containing Ap acceptors. Ligand activated LXRs also decrease inflammation and, in AD models, act to suppress microglial inflammatory genes, by a variety of mechanisms(7,8). LXR agonists such as T091317 can increase the concentration of apoE containing LPs, elevate Ap clearance, and improve brain function in mouse AD models. For example, T091317 treatment of the AD mouse model Tg2576 induced the expression of apoE and ABCA1, downregulated inflammation and cell death genes, and decreased beta-amyloid deposits9. Multiple studies also show cognitive improvements with LXR agonist treatment across a range of mouse models and treatment paradigms10. For example, treatment of high fat-fed APP23 mice with the LXR agonist T0901317 reduced memory deficits which correlated with decreased AD-like morphological and biochemical parameters such as amyloid plaque load, insoluble Ap and soluble Ap oligomers11.

[0010] There remains a need in the art for LXRP selective agonists that can be used to treat diseases and disorders characterized by defects in cholesterol and lipid metabolism, such as Alzheimer’s Disease.

[0011] SUMMARY OF THE INVENTION

[0012] The present invention provides compounds of Formula (I) and pharmaceutically acceptable salts thereof. The compounds described herein are selective agonists of LXRP and / or can be used to treat a disease or condition described herein, including Alzheimer’s Disease. Provided herein are compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein:

[0013] X is a bond or a linker, such as a substituted or unsubstituted alkylene, -C(R)2-, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, -SO2-, -NRSO2-, -CO-, -NRCO-, -C=NR-, or -OCO-; preferably, X is a bond or a linker, such as a substituted or unsubstituted alkylene, -C(R)2-, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, -SO2-, -NRSO2-, -CO-, -NRCO-, or -OCO-;

[0014] R is independently selected from H, D, halogen, OH, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two Rs together with the carbon to which they are attached to form a substituted or unsubstituted 3 to 7-membered ring, preferably a substituted or unsubstituted C3-C7 cycloalkyl;

[0015] Ri is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; preferably, Ri is a substituted aryl, an unsubstituted aryl, a substituted heteroaryl, or an unsubstituted heteroaryl;

[0016] R2 is selected from F, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; preferably, R2 is an unsubstituted C1-C7 alkyl; more preferably, R2 is a branched C3-C5 alkyl, such as isopropyl or t-butyl. In another embodiment, R2 is Si(R)3 wherein each R can independently be a substituted or unsubstituted alkyl, preferably methyl or ethyl;

[0017] R3 is selected from hydrogen, deuterium, F, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R2 and R3 together with the carbon to which they are attached form a substituted or unsubstituted spiro 3 to 7-membered substituted or unsubstituted ring, preferably a substituted or unsubstituted C3-C7 cycloalkyl; R.4 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; preferably, R.4 is a substituted aryl or a substituted heteroaryl; R.4 can also be substituted or unsubstituted -CO-aryl or -CFk-aryl; each Rs is independently selected from H, D, F, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or the two Rs are taken together with the carbon to which they are attached form a spiro, substituted or unsubstituted 3 to 6 membered ring; and n is 0 or 1; preferably n is 0.

[0018] Each preferred group stated above and herein can be taken in combination with one, any or all other preferred groups.

[0019] Also provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, wherein the composition further comprises a pharmaceutically acceptable carrier or diluent.

[0020] Also encompassed is a method of treating a subject with a disease or disorder that is treatable by upregulating LXR activity comprising administering to the subject an effective amount of the compound described herein. In a preferred aspect, the subject is a human patient.

[0021] Also provided herein is a method of treating a condition selected from the group consisting of Alzheimer's Disease, Neimann-Pick disease type Cl, Parkinson's Disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis, age-related macular degeneration, schizophrenia, depression, Stargardt's disease, cardiovascular disease, obesity and diabetes in a subject in need thereof, said method comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0022] DETAILED DESCRIPTION

[0023] A description of the preferred embodiments of the invention follows.

[0024] As used herein, the words “a” and “an” are meant to include one or more unless otherwise specified.

[0025] As discussed above, provided herein are compounds of Formula (I) and pharmaceutically acceptable salts thereof. Also provided herein are compositions comprising compounds having Formula (I) or pharmaceutically acceptable salts thereof, for example, pharmaceutical compositions comprising an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0026] In certain aspects, the compound has the Formula (I), or a pharmaceutically acceptable salt thereof, wherein X is C1-C7 alkylene, -C(R)2-, substituted or unsubstituted C3- C7 cycloalkylene, substituted or unsubstituted 3 to 7- membered- heterocycle with one, two or three heteroatoms, substituted or unsubstituted aryl, -SO2-, -NRSO2-, -CO-, -NRCO-, or - OCO-. In certain specific aspects, X is a bond, unsubstituted C1-C7 alkylene, -C(R)2, -SO2-, - NRSO2-, -CO-, -NRCO-, or -OCO-. In additional embodiments, X is a bond, -SO2-, - NRSO2-, -CO-, or -NRCO-. In yet further aspects, X is a bond, -CO-, -OCO-, -SO2-, -C(R)2-, or -NHSO2-. In yet further aspects, X is a bond or -CO-.

[0027] In certain embodiments, the compound has the Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, unsubstituted C1-C7 alkyl, or C1-C7 alkyl substituted by one or more halogen, deuterium, CF3, OH, C1-C7 alkoxy, or substituted or unsubstituted aryl. In certain specific aspects, Ri is substituted aryl, unsubstituted aryl, substituted heteroaryl, or unsubstituted heteroaryl. In certain additional aspects, Ri is substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, or substituted or unsubstituted pyrazine.

[0028] In certain aspects, the compound has the Formula (I), or a pharmaceutically acceptable salt thereof, wherein R2 is fluoro, unsubstituted C1-C7 alkyl, C1-C7 alkyl substituted with one or more R, or substituted or unsubstituted C3-C7 cycloalkyl. In further aspects, R2 is substituted or unsubstituted C1-7 alkyl. In additional embodiments, R2 is unsubstituted C1-7 alkyl. In yet additional aspects, R2 is an unsubstituted branched C3-5 alkyl. In yet further aspects, R2 is isopropyl or t-butyl. In yet additional aspects, R2 is isopropyl.

[0029] In certain embodiments, the compound has the Formula (I), or a pharmaceutically acceptable salt thereof, wherein R3 is H, D, fluoro, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, unsubstituted C1-C7 alkyl, or C1-C7 alkyl substituted by one or more halo, deuterium, OH, or alkoxy. In certain aspects, R3 is H or unsubstituted C1-C7 alkyl. In yet further aspects, R3 is H.

[0030] In certain aspects, the compound has the Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4 is unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl. In certain additional aspects, R4 is an aryl or heteroaryl substituted by a CON(R)2, SO2R, CN, or SO2N(R)2, and optionally further substituted. In yet further aspects, R4 is an aryl or heteroaryl substituted by CON(R)2, such as CON(CH3)2, and optionally further substituted. In other aspects, R4 is an aryl or heteroaryl substituted by CON(R)2, wherein the two R are taken together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocyclic ring.

[0031] In yet further aspects, the compound has the Formula (I), or a pharmaceutically acceptable salt thereof, wherein Rs is selected from the group consisting of H, D, F, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, unsubstituted C1-C7 alkyl, or C1-7 alkyl substituted with one or more D, halogen, OH, or C1-C7 alkoxy. In certain embodiments, Rs is H or unsubstituted C1-C7 alkyl.

[0032] In certain aspects, the compound has the Formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0033] In additional aspects, the compound has the Formula (I), or a pharmaceutically acceptable salt thereof, wherein n is i.

[0034] In certain embodiments, the compound has the Formula (la): or a pharmaceutically acceptable salt thereof, wherein Re is CON(R)2, SO2R, CN, or SO2N(R)2; and R7 is H, halogen, alkyl or haloalkyl; and the other substituents (e.g., X, Ri, Rs, R2, R3, R and n) are as defined for Formula (I). In certain aspects, Re is CON(R)2. In additional aspects, the compound has the Formula (la), wherein Re is CON(CH3)2. In further aspects, the compound has the Formula (la), wherein R7 is halo. In yet additional aspects, the compound has the Formula (la), wherein R7 is chloro. In yet further aspects, the compound has the Formula (la), wherein Re is CON(R)2 and R7 is halo. In additional embodiments, the compound has the Formula (la), wherein Re is CON(CH3)2 and R7 is chloro. In further aspects, the compound has the Formula (la) wherein X is a bond, -CO-, -O-CO-, -SO2-, - C(R)2, -NHCO-, or -NHSO2-; and Ri is a substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain additional embodiments, the compound has the Formula (la) wherein X is a bond, -CO-, -O-CO-, -SO2-, -C(R)2-, or -NHSO2-; and Ri is a substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain aspects, the compound has the Formula (la), wherein n is 0. In additional aspects, the compound has the Formula (la), wherein n is 1.

[0035] In certain embodiments, the compound has the Formula (la-1):

[0036] (la-1); or a pharmaceutically acceptable salt thereof, wherein Re is CON(R)2, SO2R, CN, or SO2N(R)2,; and R7 is H, halogen, alkyl or haloalkyl; and the other substituents (e.g., X, Ri, Rs, R2, R3, R and n) are as defined for Formula (I). In certain aspects, the compound has the Formula (la-1), wherein Re is CON(R)2. In additional aspects, the compound has the Formula (la-1), wherein Re is CON(CH3)2. In further aspects, the compound has the Formula (la-1), wherein R7 is halo. In yet additional aspects, the compound has the Formula (la-1), wherein R7 is chloro. In yet further aspects, the compound has the Formula (la-1), wherein Re is CON(R)2 and R7 is halo. In additional embodiments, the compound has the Formula (la-1), wherein Re is CON(CH3)2 and R7 is chloro. In certain additional embodiments, the compound has the Formula (la-1) wherein X is a bond, -CO-, -O-CO-, -SO2-, -C(R)2-, or -NHSO2-; and Ri is a substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In yet additional aspects, the compound has the Formula (la-1), wherein Re is CON(CH3)2 ; R7 is chloro; and X is bond, -CO-, -O-CO-, -SO2-, -C(R)2-, or -NHSO2-; and Ri is a substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl In certain aspects, the compound has the Formula (la-1), wherein n is 0. In additional aspects, the compound has the Formula (la-1), wherein n is 1. In certain specific aspects, the compound has the Formula (lb): or a pharmaceutically acceptable salt thereof, wherein Re is CON(R)2, SO2R, CN, or SO2N(R)2; and R7 is H, halogen, alkyl or haloalkyl; and the other substituents (e.g., X, Ri, Rs, R2, R3, and R) are as defined for Formula (I). In certain aspects, the compound has the Formula (lb), wherein Re is CON(R)2. In additional aspects, the compound has the Formula (lb), wherein Re is CON(CH3)2. In further aspects, the compound has the Formula (lb), wherein R7 is halo. In yet additional aspects, the compound has the Formula (lb), wherein R7 is chloro. In yet further aspects, the compound has the Formula (lb), wherein Re is CON(R)2 and R7 is halo. In additional embodiments, the compound has the Formula (lb), wherein Re is CON(CH3)2 and R7 is chloro. In further aspects, the compound has the Formula (lb), wherein each Rs is H; R3 is H; and R2 is an unsubstituted C1-C7 alkyl. In further aspects, the compound has the Formula (lb), wherein each Rs is H; R3 is H; and R2 is unsubstituted, branched C3-5 alkyl. In yet further aspects, the compound has the Formula (lb), wherein each Rs is H; R3 is H; and R2 is unsubstituted isopropyl or unsubstituted t-butyl. In certain additional embodiments, the compound has the Formula (lb) wherein X is a bond, -CO-, -O- CO-, -SO2-, -C(R)2-, or -NHSO2-; and Ri is a substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0037] In some embodiments, the compound has the Formula (Ic):

[0038] (Ic); or a pharmaceutically acceptable salt thereof, wherein each R is a substituted or unsubstituted alkyl; R7 is H or halogen; R2 is alkyl, preferably isopropyl; Ri is a substituted or unsubstituted phenyl, pyridine, pyrimidine, pyridazine or pyrazine; and X is a bond or -CO-. In certain aspects, the compound has the Formula (Ic), wherein R2 is isopropyl.

[0039] In yet further aspects, the compound has the Formula (Ic-i):

[0040] (ic-i); or a pharmaceutically acceptable salt thereof, wherein each R is a substituted or unsubstituted alkyl; R7 is H or halogen; R2 is alkyl, preferably isopropyl; Ri is a substituted or unsubstituted phenyl, pyridine, pyrimidine, pyridazine or pyrazine; and X is a bond or -CO-. In certain aspects, the compound has the Formula (Ic), wherein R2 is isopropyl.

[0041] In additional aspects, the compound has the Formula (Ic-ii):

[0042] (ic-ii); or a pharmaceutically acceptable salt thereof, wherein each R is a substituted or unsubstituted alkyl; R7 is H or halogen; R2 is alkyl, preferably isopropyl; Ri is a substituted or unsubstituted phenyl, pyridine, pyrimidine, pyridazine or pyrazine; and X is a bond or -CO-. In certain aspects, the compound has the Formula (Ic), wherein R2 is isopropyl.

[0043] In certain additional aspects, the compound has the Formula (Ic-1), (Ic-2), (Ic-3), (Ic- 4), (Ic-5), (Ic-6), or (Ic-7):

[0044] (Ic-1)

[0045]

[0046] (Ic-7); or a pharmaceutically acceptable salt of any of thereof, wherein each R is a substituted or unsubstituted alkyl; R7 is H or halogen; R2 is alkyl (preferably isopropyl); each Rs is independently selected from halogen, substituted or unsubstituted alkyl; and m is 0, 1 or 2.

[0047] In certain aspects, the compound has the Formula (Ic-1), or a pharmaceutically acceptable salt thereof. In additional embodiments, the compound has the Formula (Ic-1), wherein R2 is isopropyl. In further aspects, the compound has the Formula (Ic-1), wherein each Rs is independently selected from F, methyl, CF3 or CHF2. In yet further aspects, the compound has the Formula (Ic-1), wherein R2 is isopropyl and each Rs is independently selected from F, methyl, CF3 or CHF2. In yet additional embodiments, the compound has the Formula (Ic-1), wherein each R is methyl. In yet further embodiments, the compound has the Formula (Ic-1), wherein R2is isopropyl; each Rs is independently selected from F, methyl, CF3 or CHF2; and each R is methyl. In certain embodiments, the compound has the Formula (Ic-1), wherein at least one Rs is CF3. In yet other aspects, the compound has the Formula (Ic-

[0048] 1), wherein R2is isopropyl; at least one Rs is CF3; and each R is methyl.

[0049] In certain aspects, the compound has the Formula (Ic-2), or a pharmaceutically acceptable salt thereof. In additional embodiments, the compound has the Formula (Ic-2), wherein R2 is isopropyl. In further aspects, the compound has the Formula (Ic-2), wherein each Rs is independently selected from F, methyl, CF3 or CHF2. In yet further aspects, the compound has the Formula (Ic-2), wherein R2 is isopropyl and each Rs is independently selected from F, methyl, CF3 or CHF2. In yet additional embodiments, the compound has the Formula (Ic-2), wherein each R is methyl. In yet further embodiments, the compound has the Formula (Ic-2), wherein R2is isopropyl; each Rs is independently selected from F, methyl, CF3 or CHF2; and each R is methyl. In certain embodiments, the compound has the Formula (Ic-2), wherein at least one Rs is CF3. In yet other aspects, the compound has the Formula (Ic-

[0050] 2), wherein R2is isopropyl; at least one Rs is CF3; and each R is methyl.

[0051] In certain aspects, the compound has the Formula (Ic-3), or a pharmaceutically acceptable salt thereof. In additional embodiments, the compound has the Formula (Ic-3), wherein R2 is isopropyl. In further aspects, the compound has the Formula (Ic-3), wherein each Rs is independently selected from F, methyl, CF3 or CHF2. In yet further aspects, the compound has the Formula (Ic-3), wherein R2 is isopropyl and each Rs is independently selected from F, methyl, CF3 or CHF2. In yet additional embodiments, the compound has the Formula (Ic-3), wherein each R is methyl. In yet further embodiments, the compound has the Formula (Ic-3), wherein R2is isopropyl; each Rs is independently selected from F, methyl, CF3 or CHF2; and each R is methyl. In certain embodiments, the compound has the Formula (Ic-3), wherein at least one Rs is CF3. In yet other aspects, the compound has the Formula (Ic-

[0052] 3), wherein R2is isopropyl; at least one Rs is CF3; and each R is methyl.

[0053] In certain aspects, the compound has the Formula (Ic-4), or a pharmaceutically acceptable salt thereof. In additional embodiments, the compound has the Formula (Ic-4), wherein R2 is isopropyl. In further aspects, the compound has the Formula (Ic-4), wherein each Rs is independently selected from F, methyl, CF3 or CHF2. In yet further aspects, the compound has the Formula (Ic-4), wherein R2 is isopropyl and each Rs is independently selected from F, methyl, CF3 or CHF2. In yet additional embodiments, the compound has the Formula (Ic-4), wherein each R is methyl. In yet further embodiments, the compound has the Formula (Ic-4), wherein R2is isopropyl; each Rs is independently selected from F, methyl, CF3 or CHF2; and each R is methyl. In certain embodiments, the compound has the Formula (Ic-4), wherein at least one Rs is CF3. In yet other aspects, the compound has the Formula (Ic-

[0054] 4), wherein R2is isopropyl; at least one Rs is CF3; and each R is methyl.

[0055] In certain aspects, the compound has the Formula (Ic-5), or a pharmaceutically acceptable salt thereof. In additional embodiments, the compound has the Formula (Ic-5), wherein R2 is isopropyl. In further aspects, the compound has the Formula (Ic-5), wherein each Rs is independently selected from F, methyl, CF3 or CHF2. In yet further aspects, the compound has the Formula (Ic-5), wherein R2 is isopropyl and each Rs is independently selected from F, methyl, CF3 or CHF2. In yet additional embodiments, the compound has the Formula (Ic-5), wherein each R is methyl. In yet further embodiments, the compound has the Formula (Ic-5), wherein R2is isopropyl, each Rs is independently selected from F, methyl, CF3 or CHF2; and each R is methyl. In certain embodiments, the compound has the Formula (Ic-5), wherein at least one Rs is CF3. In yet other aspects, the compound has the Formula (Ic-

[0056] 5), wherein R2is isopropyl; at least one Rs is CF3; and each R is methyl.

[0057] In certain aspects, the compound has the Formula (Ic-6), or a pharmaceutically acceptable salt thereof. In additional embodiments, the compound has the Formula (Ic-6), wherein R2 is isopropyl. In further aspects, the compound has the Formula (Ic-6), wherein each Rs is independently selected from F, methyl, CF3 or CHF2. In yet further aspects, the compound has the Formula (Ic-6), wherein R2 is isopropyl and each Rs is independently selected from F, methyl, CF3 or CHF2. In yet additional embodiments, the compound has the Formula (Ic-6), wherein each R is methyl. In yet further embodiments, the compound has the Formula (Ic-6), wherein R2is isopropyl; each Rs is independently selected from F, methyl, CF3 or CHF2, and each R is methyl. In certain embodiments, the compound has the Formula

[0058] (Ic-6), wherein at least one Rs is CF3. In yet other aspects, the compound has the Formula (Ic- 6), wherein R2is isopropyl; at least one Rs is CF3; and each R is methyl.

[0059] In certain aspects, the compound has the Formula (Ic-7), or a pharmaceutically acceptable salt thereof. In additional embodiments, the compound has the Formula (Ic-7), wherein R2 is isopropyl. In further aspects, the compound has the Formula (Ic-7), wherein each Rs is independently selected from F, methyl, CF3 or CHF2. In yet further aspects, the compound has the Formula (Ic-7), wherein R2 is isopropyl and each Rs is independently selected from F, methyl, CF3 or CHF2. In yet additional embodiments, the compound has the

[0060] Formula (Ic-7), wherein each R is methyl. In yet further embodiments, the compound has the Formula (Ic-7), wherein R2is isopropyl; each Rs is independently selected from F, methyl,

[0061] CF3 or CHF2; and each R is methyl. In certain embodiments, the compound has the Formula (Ic-7), wherein at least one Rs is CF3. In yet other aspects, the compound has the Formula (Ic- 7), wherein R2is isopropyl; at least one Rs is CF3; and each R is methyl.

[0062] In certain additional embodiments, the compound has the Formula (Ic-8), (Ic-9), (Ic- 10), (Ic-11), (Ic-12), (Ic-13) or (Ic-14):

[0063] or a pharmaceutically acceptable salt of any of thereof, wherein each R is a substituted or unsubstituted alkyl; R? is H or halogen; R2is alkyl (preferably isopropyl); each Rs is independently selected from halogen, substituted or unsubstituted alkyl; and m is 0, 1 or 2. In certain aspects, the compound has the Formula (Ic-8), or a pharmaceutically acceptable salt thereof. In additional embodiments, the compound has the Formula (Ic-8), wherein R2 is isopropyl. In further aspects, the compound has the Formula (Ic-8), wherein each Rs is independently selected from F, methyl, CF3 or CHF2. In yet further aspects, the compound has the Formula (Ic-8), wherein R2 is isopropyl and each Rs is independently selected from F, methyl, CF3 or CHF2. In yet additional embodiments, the compound has the Formula (Ic-8), wherein each R is methyl. In yet further embodiments, the compound has the Formula (Ic-8), wherein R2 is isopropyl; each Rs is independently selected from F, methyl, CF3 or CHF2; and each R is methyl. In certain embodiments, the compound has the Formula (Ic-8), wherein at least one Rs is CF3. In yet other aspects, the compound has the Formula (Ic-

[0064] 8), wherein R2is isopropyl; at least one Rs is CF3; and each R is methyl.

[0065] In certain aspects, the compound has the Formula (Ic-9), or a pharmaceutically acceptable salt thereof. In additional embodiments, the compound has the Formula (Ic-7), wherein R2 is isopropyl. In further aspects, the compound has the Formula (Ic-9), wherein each Rs is independently selected from F, methyl, CF3 or CHF2. In yet further aspects, the compound has the Formula (Ic-9), wherein R2 is isopropyl and each Rs is independently selected from F, methyl, CF3 or CHF2. In yet additional embodiments, the compound has the Formula (Ic-9), wherein each R is methyl. In yet further embodiments, the compound has the Formula (Ic-9), wherein R2is isopropyl; each Rs is independently selected from F, methyl, CF3 or CHF2; and each R is methyl. In certain embodiments, the compound has the Formula (Ic-9), wherein at least one Rs is CF3. In yet other aspects, the compound has the Formula (Ic-

[0066] 9), wherein R2is isopropyl; at least one Rs is CF3; and each R is methyl.

[0067] In certain aspects, the compound has the Formula (Ic-10), or a pharmaceutically acceptable salt thereof. In additional embodiments, the compound has the Formula (Ic-10), wherein R2 is isopropyl. In further aspects, the compound has the Formula (Ic-10), wherein each Rs is independently selected from F, methyl, CF3 or CHF2. In yet further aspects, the compound has the Formula (Ic-10), wherein R2 is isopropyl and each Rs is independently selected from F, methyl, CF3 or CHF2. In yet additional embodiments, the compound has the Formula (Ic-10), wherein each R is methyl. In yet further embodiments, the compound has the Formula (Ic-10), wherein R2is isopropyl; each Rs is independently selected from F, methyl, CF3 or CHF2; and each R is methyl. In certain embodiments, the compound has the Formula (Ic-10), wherein at least one Rs is CF3. In yet other aspects, the compound has the Formula (Ic-10), wherein R2is isopropyl; at least one Rs is CF3; and each R is methyl. In certain aspects, the compound has the Formula (Ic-11), or a pharmaceutically acceptable salt thereof. In additional embodiments, the compound has the Formula (Ic-11), wherein R2 is isopropyl. In further aspects, the compound has the Formula (Ic-11), wherein each Rs is independently selected from F, methyl, CF3 or CHF2. In yet further aspects, the compound has the Formula (Ic-11), wherein R2 is isopropyl and each Rs is independently selected from F, methyl, CF3 or CHF2. In yet additional embodiments, the compound has the Formula (Ic-11), wherein each R is methyl. In yet further embodiments, the compound has the Formula (Ic-11), wherein R2is isopropyl; each Rs is independently selected from F, methyl, CF3 or CHF2; and each R is methyl. In certain embodiments, the compound has the Formula (Ic-11), wherein at least one Rs is CF3. In yet other aspects, the compound has the Formula (Ic-11), wherein R2is isopropyl; at least one Rs is CF3; and each R is methyl.

[0068] In certain aspects, the compound has the Formula (Ic-12), or a pharmaceutically acceptable salt thereof. In additional embodiments, the compound has the Formula (Ic-12), wherein R2 is isopropyl. In further aspects, the compound has the Formula (Ic-12), wherein each Rs is independently selected from F, methyl, CF3 or CHF2. In yet further aspects, the compound has the Formula (Ic-12), wherein R2 is isopropyl and each Rs is independently selected from F, methyl, CF3 or CHF2. In yet additional embodiments, the compound has the Formula (Ic-12), wherein each R is methyl. In yet further embodiments, the compound has the Formula (Ic-12), wherein R2is isopropyl; each Rs is independently selected from F, methyl, CF3 or CHF2; and each R is methyl. In certain embodiments, the compound has the Formula (Ic-12), wherein at least one Rs is CF3. In yet other aspects, the compound has the Formula (Ic-12), wherein R2is isopropyl; at least one Rs is CF3; and each R is methyl.

[0069] In certain aspects, the compound has the Formula (Ic-13), or a pharmaceutically acceptable salt thereof. In additional embodiments, the compound has the Formula (Ic-13), wherein R2 is isopropyl. In further aspects, the compound has the Formula (Ic-13), wherein each Rs is independently selected from F, methyl, CF3 or CHF2. In yet further aspects, the compound has the Formula (Ic-13), wherein R2 is isopropyl and each Rs is independently selected from F, methyl, CF3 or CHF2. In yet additional embodiments, the compound has the Formula (Ic-13), wherein each R is methyl. In yet further embodiments, the compound has the Formula (Ic-13), wherein R2is isopropyl; each Rs is independently selected from F, methyl, CF3 or CHF2; and each R is methyl. In certain embodiments, the compound has the Formula (Ic-13), wherein at least one Rs is CF3. In yet other aspects, the compound has the Formula (Ic-13), wherein R2is isopropyl; at least one Rs is CF3; and each R is methyl. In certain aspects, the compound has the Formula (Ic-14), or a pharmaceutically acceptable salt thereof. In additional embodiments, the compound has the Formula (Ic-14), wherein R2 is isopropyl. In further aspects, the compound has the Formula (Ic-14), wherein each Rs is independently selected from F, methyl, CF3 or CHF2. In yet further aspects, the compound has the Formula (Ic-14), wherein R2 is isopropyl and each Rs is independently selected from F, methyl, CF3 or CHF2. In yet additional embodiments, the compound has the Formula (Ic-14), wherein each R is methyl. In yet further embodiments, the compound has the Formula (Ic-14), wherein R2is isopropyl; each Rs is independently selected from F, methyl, CF3 or CHF2; and each R is methyl. In certain embodiments, the compound has the Formula (Ic-14), wherein at least one Rs is CF3. In yet other aspects, the compound has the Formula (Ic-14), wherein R2is isopropyl; at least one Rs is CF3; and each R is methyl.

[0070] It is to be understood that the specific embodiments described herein can be taken in combination with other specific embodiments delineated herein. For example, X in Formula (I) is described as a bond, CO, O-CO, SO2, -C(R)2, or NHSO2 in certain embodiments, and R2 is described as a branched C3-C5 alkyl in certain embodiments. The present invention thus encompasses a compound of Formula (I) wherein X is a bond, -CO-, -O-CO-, -SO2-, -C(R)2-, or -NHSO2-, and R2 is a branched C3-C5 alkyl.

[0071] In certain aspects, the compound has the Formula (Ic-14):

[0072] (Ic-14); or a pharmaceutically acceptable salt thereof, wherein: each R is independently a H or substituted or unsubstituted alkyl;

[0073] R7 is halogen;

[0074] R2 is alkyl or substituted alkyl, SiMes, preferably isopropyl or t-Butyl; each Rs is independently H or halogen; m is 0, 1, 2, or 3. Preferably, the compound has the Formula: or a pharmaceutically acceptable salt thereof, wherein: each R is independently a H or substituted or unsubstituted alkyl;

[0075] R7 is halogen;

[0076] R2 is alkyl or substituted alkyl, SiMes, preferably isopropyl or t-Butyl; and

[0077] In certain specific aspects, the compound is selected from those set forth in Table A below or a pharmaceutically acceptable salt thereof. “PK1” and “PK2” as used herein are abbreviations for “Peak 1” and “Peak 2,” and compounds labeled “PK1” and “PK2” refer to specific enantiomers that are separated by chiral HPLC but are undefined. In the following table, the PK1 and PK2 are assigned putative chiral designations (R or S). Structures in Table A can be annotated with the characters “orl” adjacent to a chiral carbon. The “orl” is intended to convey that the actual peak may be the alternative enantiomer. In other words, PK1 may be drawn as an R enantiomer in Table A. However, the actual enantiomer associated with the biological activity in Table C may be associated with the S enantiomer. The confirmation of the enantiomer associated with either PK1 or PK2 biological activity can be confirmed using routine experimentation, including for example, the synthesis of the isolated enantiomer and repeating the assay.

[0078] Compounds labeled with a configuration in the compound number were synthesized using the appropriate chiral starting material to set the stereochemistry. For example, compound number 2-S and 2-R were confirmed by synthesis of the desired chiral form starting with the defined chiral amino acid and carried through Synthetic Scheme 1.

[0079] TABLE A

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086] In certain specific embodiments, the compound is selected from: Compounds 2, 37, 45, 56 and 57, or a pharmaceutically acceptable salt thereof. In certain aspects, the compound is selected from Compounds 2-PK2, 37-PK2, 45-PK2, 56-PK2 and 57-PK2, or a pharmaceutically acceptable salt thereof. In further aspects, the compound is selected from Compounds 2-PK1, 37-PK1, 45-PK1, 56-PK1 and 57-PK1, or a pharmaceutically acceptable salt thereof.

[0087] Also provided herein are the compounds, compositions and methods described in the Enumerated Embodiments section below.

[0088] Definitions

[0089] The term “alkyl” as used herein, refers to saturated, straight- or branched-chain hydrocarbon radicals. By “Ci-z alkyl” or “Cl-Cz alkyl” is meant an alkyl group having 1 to z number of carbon atoms (z is an integer such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12). For example, “C1-C3 alkyl,” “Ci-Ce alkyl,” “C1-C7 alkyl” refer to alkyl groups containing from one to three, one to six, one to seven carbon atoms, respectively. Examples of C1-C7 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, and heptyl radicals. An alkyl group can be substituted or unsubstituted.

[0090] The term “alkenyl” as used herein, refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond by the removal of a single hydrogen atom. “C2-C7 alkenyl,” “C2-C6 alkenyl,” or “C2-C4 alkenyl,” refer to alkenyl groups containing from two to seven, two to eight, or two to four carbon atoms respectively. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2- buten-l-yl, heptenyl, and the like. An alkenyl group can be substituted or unsubstituted.

[0091] The term “alkynyl” as used herein, refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. “C2-C7 alkynyl,” “C2-C6 alkynyl,” “C2-C4 alkynyl,” refer to alkynyl groups containing from two to seven, two to six, or two to four carbon atoms, respectively. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, and the like. An alkynyl group can be substituted or unsubstituted.

[0092] The term “cycloalkyl”, as used herein, refers to a monocyclic or polycyclic saturated carbocyclic ring, and the carbon atoms may be optionally oxo- substituted. A polycyclic cycloalkyl can comprise a fused, bridged or spiro system. Non-limiting examples of cycloalkyl groups include C3-C12 cycloalkyl, C3-C6 cycloalkyl, C3-C8 cycloalkyl and C4-C7 cycloalkyl. Examples of C3-C12 cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, and the like. A cycloalkyl group can be substituted or unsubstituted.

[0093] The term “cycloalkenyl”, as used herein, refers to monocyclic or polycyclic carbocyclic ring having at least one carbon-carbon double bond and the carbon atoms may be optionally oxo-substituted.. Non-limiting examples of cycloalkenyl groups include C3-C12 cycloalkenyl, C3-C8 cycloalkenyl or C5-C7 cycloalkenyl groups. Examples of cycloalkenyl groups, e.g., C3-C12 cycloalkenyl include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-l-enyl, bicyclo[4.2.1]non-3-en- 9-yl, and the like. A cycloalkenyl can be substituted or unsubstituted.

[0094] The term “aryl,” as used herein, refers to a mono- or polycyclic carbocyclic ring system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system that comprises more than one aromatic ring. Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof. An aryl group can be substituted or unsubstituted.

[0095] The term “heteroaryl,” as used herein, refers to a mono- or polycyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized. Nonlimiting examples of heteroaryl include pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, triazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl. A polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof. A heteroaryl can be substituted or unsubstituted.

[0096] The terms “heterocyclic,” “heterocycloalkyl,” or “heterocycle” can be used interchangeably and referred to a non-aromatic ring or a 3-12-membered ring or a bi- or tri- cyclic group fused, bridged or spiro system, wherein (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quatemized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo- substituted. Non-limiting examples of heterocyclic groups include 1,3 -di oxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyl, 8- azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl, l-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4- yl, and tetrahydrofuryl. A heterocyclic group can be substituted or unsubstituted.

[0097] Heteroaryl or heterocyclic groups can be C-attached or N-attached (where possible). As used herein, the term “arylalkyl” means a functional group wherein an alkylene chain is attached to an aryl group, e.g., — CH2CH2-phenyl. The arylalkyl group can be substituted or un substituted. Similarly, the term “heteroarylalkyl” means a functional group wherein an alkylene chain is attached to a heteroaryl group. The heteroarylalkyl group can be substituted or unsubstituted.

[0098] As used herein, the term “alkoxy” means, unless otherwise stated, an alkyl group having connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1 -propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers. Non-limiting examples of alkoxy are C1-C3 alkoxy and Ci-Ce alkoxy. An alkoxy group can be substituted or unsubstituted.

[0099] It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, or the like, described herein can also be a divalent or multivalent group when used as a linker or linkage to connect two or more groups or substituents, which can be at the same or different atom(s). One of skill in the art can readily determine the valence of any such group from the context in which it occurs. An “alkylene” is a divalent radical derived from an alkyl group. Similarly, a “cycloalkylene” is a divalent radical derived from a cycloalkyl group.

[0100] A substituted group can be referred to herein as “substituted,” for example, a substituted C1-C7 alkyl or a substituted aryl. An unsubstituted group can be referred to herein as “unsubstituted” or without the term “substituted,” for example, “unsubstituted C1-C7 alkyl,” “unsubstituted C3-C5 alkyl,” “isopropyl” or “t-butyl” all refer to unsubstituted groups. The term “substituted” refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, — D, — F, — Cl, — Br, — I, — OH, Ci-Ci2-alkyl; C2-Ci2-alkenyl, C2-Ci2-alkynyl, protected hydroxy, — NO2, — N3, — CN, — NH2, protected amino, oxo, thioxo, — NH — Ci-Ci2-alkyl, — NH — C2-Cs-alkenyl, — NH — C2-Cs-alkynyl, — NH — C3-Ci2-cycloalkyl, — NH-aryl, — NH-heteroaryl, — NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, — O — Ci-Ci2-alkyl, — O — C2-Cs-alkenyl, — O — C2-Cs-alkynyl, — O — C3-Ci2-cycloalkyl, — O- aryl, — O-heteroaryl, — O-heterocycloalkyl, — C(O) — Ci-Ci2-alkyl, — C(O) — C2-Cs-alkenyl, — C(O) — C2-Cs-alkynyl, — C(O) — C3-Ci2-cycloalkyl, — C(O)-aryl, — C(O)-heteroaryl, — C(O)-heterocycloalkyl, — CONH2, — CONH — Ci-Ci2-alkyl, — CONH — C2-Cs-alkenyl, — CONH — C2-Cs-alkynyl, — CONH — C3-Ci2-cycloalkyl, — CONH-aryl, — CONH-heteroaryl, — CONH-heterocycloalkyl, — OCO2 — Ci-Ci2-alkyl, — OCO2 — C2-Cs-alkenyl, — OCO2 — C2- Cs-alkynyl, — OCO2 — C3-Ci2-cycloalkyl, — OCO2-aryl, — OCO2-heteroaryl, — OCO2- heterocycloalkyl, — CO2 — C1-C12 alkyl, — CO2 — C2-C8 alkenyl, — CO2 — C2-C8 alkynyl, CO2 — C3-Ci2-cycloalkyl, — CO2 — aryl, CO2-heteroaryl, CO2-heterocyloalkyl, — OCONH2, — OCONH— Ci-Ci2-alkyl, — OCONH— C2-C8-alkenyl, — OCONH— C2-C8-alkynyl, — OCONH— C3-Ci2-cycloalkyl, — OCONH-aryl, —OCONH— heteroaryl, —OCONH— heterocyclo-alkyl, — NHC(O)H, — NHC(O) — Ci-Ci2-alkyl, — NHC(O) — C2-C8-alkenyl, — NHC(O)— C2-C8-alkynyl, — NHC(O)— C3-Ci2-cycloalkyl, — NHC(O)-aryl, — NHC(O)— heteroaryl, — NHC(O)-heterocyclo-alkyl, — NHCO2 — Ci-Ci2-alkyl, — NHCO2 — C2-C8- alkenyl, — NHCO2 — C2-C8-alkynyl, — NHCO2 — C3-Ci2-cycloalkyl, — NHCO2-aryl, — NHCO2-heteroaryl, — NHCO2— heterocycloalkyl, — NHC(O)NH2, — NHC(O)NH— C1-C12- alkyl, — NHC(O)NH— C2-C8-alkenyl, — NHC(O)NH— C2-C8-alkynyl, — NHC(O)NH— C3- Ci2-cycloalkyl, — NHC(O)NH-aryl, — NHC(O)NH-heteroaryl, — NHC(O)NH- heterocycloalkyl, NHC(S)NH2, — NHC(S)NH— Ci-Ci2-alkyl, — NHC(S)NH— C2-C8- alkenyl, — NHC(S)NH— C2-C8-alkynyl, — NHC(S)NH— C3-Ci2-cycloalkyl, — NHC(S)NH- aryl, — NHC(S)NH-heteroaryl, — NHC(S)NH-heterocycloalkyl, — NHC(NH)NH2, — NHC(NH)NH— Ci-Ci2-alkyl, — NHC(NH)NH— C2-C8-alkenyl, — NHC(NH)NH— C2-C8- alkynyl, — NHC(NH)NH— C3-Ci2-cycloalkyl, — NHC(NH)NH-aryl, — NHC(NH)NH— heteroaryl, — NHC(NH)NH-heterocycloalkyl, — NHC(NH)— Ci-Ci2-alkyl, — NHC(NH)— C2-C8-alkenyl, — NHC(NH) — C2-C8-alkynyl, — NHC(NH) — C3-Ci2-cycloalkyl, — NHC(NH)-aryl, — NHC(NH)-heteroaryl, — NHC(NH)-heterocycloalkyl, — C(NH)NH— Ci- Ci2-alkyl, — C(NH)NH— C2-C8-alkenyl, — C(NH)NH— C2-C8-alkynyl, — C(NH)NH— C3- Ci2-cycloalkyl, — C(NH)NH-aryl, — C(NH)NH-heteroaryl, — C(NH)NH-heterocycloalkyl, — S(O)X— Ci-Ci2-alkyl, — S(O)x— C2-C8-alkenyl, — S(O)x— C2-C8-alkynyl, — S(O)X— C3- Ci2-cycloalkyl, — S(O)X-aryl, — S(O)X-heteroaryl, — S(O)X— heterocycloalkyl, — SO2NH2, — SO2NH— Ci-Cn-alkyl, — SO2NH— C2-C8-alkenyl, — SO2NH— C2-C8-alkynyl, — SO2NH — Cs-Cn-cycloalkyl, — SO2NH-aryl, — SO2NH-heteroaryl, — SO2NH — heterocycloalkyl, — NHSO2 — Ci-Ci2-alkyl, — NHSO2 — C2-C8-alkenyl, — NHSO2 — C2-C8- alkynyl, — NHSO2 — Cs-Cn-cycloalkyl, — NHSO2-aryl, — NHSO2-heteroaryl, — NHSO2- heterocycloalkyl, — CH2NH2, — CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, - heterocycloalkyl, — Cs-Cn-cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, - methoxyethoxy, — SH, — S — Ci-Cn-alkyl, — S — C2-C8-alkenyl, — S — C2-C8-alkynyl, — S — Cs-Cn-cycloalkyl, — S-aryl, — S — heteroaryl, — S-heterocycloalkyl, or methylthio-methyl. X can be 0, 1 or 2. It is understood that the aryls, heteroaryls, alkyls, cycloalkyls and the like can be further substituted.

[0101] The term “optionally substituted”, as used herein, means that the referenced group may be substituted or unsubstituted. A “substituted” group means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.

[0102] The term “halo” or halogen” alone or as part of another substituent, as used herein, refers to a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. The terms “halo” and “halogen” are used interchangeably herein.

[0103] “H” is hydrogen. Deuterium is “2H.” The term “deuterium” and “D” are used interchangeably herein. Deuterium can replace one or more hydrogens in the compounds described herein. The compounds of the invention can be understood to include deuterated forms of the compounds described.

[0104] The compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S). The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Centers of asymmetry that are present in the compounds described herein can all independently of one another have (R) or (S) configuration. When bonds to a chiral carbon are depicted as straight lines in the structural formulae described herein, or when a compound name is recited without an (R) or (S) chiral designation for a chiral carbon, it is understood that both the (R) and (S) configurations of each such chiral carbon, and hence each enantiomer or diastereomer and mixtures thereof, are embraced within the formula or by the name. Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques, which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.

[0105] Certain compounds described herein may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers. The present invention includes each conformational isomer of these compounds and mixtures thereof.

[0106] As used herein, the term “pharmaceutically acceptable salt” refers to those salts of the compounds formed by the process of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0107] Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts e.g., salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate. Pharmaceutically acceptable salts can also be prepared by deprotonation of the parent compound with a suitable base, thereby forming the anionic conjugate base of the parent compound. In such salts the counter ion is a cation. Suitable cations include ammonium and metal cations, such as alkali metal cations, including Li+, Na+, K+and Cs+, and alkaline earth metal cations, such as Mg2+and Ca2+.

[0108] Also encompassed herein are pharmaceutically acceptable prodrugs of the compounds described herein. The term “pharmaceutically acceptable prodrugs” as used herein refers to those prodrugs of the compounds formed by the process of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention. “Prodrug”, as used herein means a compound, which is convertible in vivo by metabolic means (e.g. by hydrolysis) to afford any compound delineated by the formulae of the instant invention. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, Vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed.). “Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter s, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8: 1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002). Additionally, the compounds of the present invention, including the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc. “Solvates” means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrate.

[0109] In another embodiment, the compounds described herein, and / or compositions comprising them, are present in isolated and / or purified form. The term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction), or natural source or combination thereof. Thus, the term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound (or a tautomer thereof, or pharmaceutically acceptable salt of said compound or said tautomer) after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be suitable for in vivo or medicinal use and / or characterizable by standard analytical techniques described herein or well known to the skilled artisan.

[0110] When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.

[0111] Another embodiment which may be useful include isotopically-labelled compounds described herein. Such compounds are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as2H,3H,nC,13C,14C,15N,18O,170,31P,32P,35S,18F, and36C1, respectively.

[0112] In the compounds described herein, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds described herein. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the schemes and examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0113] The compounds encompassed herein may exist in multiple crystalline (polymorphs) or amorphous forms. In general, any physical forms can be used in the present invention and are intended to be within the scope of the invention. Stable crystalline forms are preferred.

[0114] The terms “subject” and “patient” are used interchangeably herein and mean human and non-human animals. In one embodiment, the subject is a human. Other animals that can be treated include, but are not limited to, non-human primates (e.g., monkeys, gorillas, chimpanzees), domesticated animals (e.g., horses, pigs, goats, rabbits, sheep, cattle), and companion animals (e.g., guinea pigs, rats, mice, dogs, cats). In preferred aspects, the patient is a human patient.

[0115] “Effective amount” or “therapeutically effective amount” describes an amount of compound or a composition described herein, alone or in combination with another active agent, that is sufficient to achieve a specific effect or result, e.g., that is effective in treating the disease or condition and / or the symptoms, for example, alleviating, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition, and / or provides selective LXR0 agonism.

[0116] The terms "treat", "treating" and "treatment," as used herein, refers to ameliorating one or more symptoms associated with a disease, condition, or disorder described herein including inhibiting the progress of the disease or disorder, reducing the rate of progression of disease or disorder, reducing the severity of the disease or disorder or a symptom thereof, and / or lessening the severity or frequency of symptoms of the disease, condition, or disorder.

[0117] Pharmaceutical Compositions

[0118] The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term “pharmaceutically acceptable carrier” means a non-toxic, inert solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intraci stemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, ocularly, or as an oral or nasal spray.

[0119] The pharmaceutical compositions of this invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, ocularly, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrastemal, intrathecal, intralesional, ocular and intracranial injection or infusion techniques.

[0120] Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18thEdition, (1990), Mack Publishing Co., Easton, PA.

[0121] Liquid form preparations include solutions, suspensions and emulsions. Non-limiting examples which may be useful include water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Liquid form preparations may also include solutions for ocular administration.

[0122] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.

[0123] Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

[0124] Another embodiment which may be useful includes compositions comprising a compound described herein formulated for transdermal delivery. The transdermal compositions can take the form of creams, lotions, aerosols and / or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

[0125] Other embodiment which may be useful includes compositions comprising a compound described herein formulated for subcutaneous delivery or for oral delivery. In some embodiments, it may be advantageous for the pharmaceutical preparation comprising one or more compounds described herein be prepared in a unit dosage form. In such forms, the preparation may be subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. Each of the foregoing alternatives, together with their corresponding methods of use, are considered as included in the various embodiments of the invention.

[0126] Methods of Treatment

[0127] As discussed above, also encompassed herein are methods of a disease or disorder that is treatable by upregulating LXR activity comprising administering to the subject an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof. In certain aspects, the compound or pharmaceutically acceptable salt thereof that is administered is a LXR0 selective agonist.

[0128] Also encompassed are methods of treating a disease or disorder characterized by defects in cholesterol or lipid metabolism in a patient in need thereof. Diseases for which the compounds described herein may be useful include those characterized by disturbances in cholesterol or lipid metabolism and / or by a pro-inflammatory state. The compounds described herein may have utility in treating Alzheimer's disease, Neimann-Pick disease type Cl, Parkinson's Disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis, age-related macular degeneration, psychiatric disorders such as schizophrenia and depression, and metabolic disorders such as cardiovascular disease, obesity and diabetes. Potential cardiovascular conditions or disorders for which the compounds described herein may be useful include atherosclerosis, myocardial infarction and coronary heart disease, and hypertension. The compounds described herein may also be useful for the treatment of Type 2 diabetes and its complications. The compounds described herein may also have utility in treating certain kinds of cancers which are affected by the LXR mechanism. Such cancers include, but are not limited to, prostate, breast, ovarian, melanoma, pancreas, lung, colon and hematological malignancy.

[0129] In additional aspects, the compounds described herein may have utility in treating Alzheimer's disease, Neimann-Pick disease type Cl, Parkinson's Disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis, age-related macular degeneration, psychiatric disorders such as schizophrenia and depression, and metabolic disorders such as cardiovascular disease, obesity and diabetes. Potential cardiovascular conditions or disorders for which the compounds described herein may be useful include atherosclerosis, hypertension, hyperlipidemia, coronary heart disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, vascular complications of diabetes, obesity (including abdominal obesity) and endotoxemia. The compounds described herein may also be useful in the treatment of the metabolic syndrome. According to one widely used definition, a patient having metabolic syndrome is characterized as having three or more symptoms selected from the following group of five symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low high-density lipoprotein cholesterol (HDL); (4) high blood pressure; and (5) elevated fasting glucose, which may be in the range characteristic of Type 2 diabetes if the patient is also diabetic. Each of these symptoms is defined clinically in the recently released Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III), National Institutes of Health, 2001, NIH Publication No. 01-3670. Patients with metabolic syndrome have an increased risk of developing the macrovascular and microvascular complications that are listed above, including atherosclerosis and coronary heart disease. The compounds described herein can also be useful for the treatment of Type 2 diabetes, and conditions and disorders related to Type 2 diabetes, such as hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, irritable bowel syndrome, inflammatory bowel disease, including Crohn's disease and ulcerative colitis, other inflammatory conditions, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Syndrome X, ovarian hyperandrogenism (polycystic ovarian syndrome), and other disorders where insulin resistance is a component. The compounds described herein may also be useful for treating steatotic fatty liver diseases including metabolic associated steatotic liver disease (MASLD or MASH and metabolic and alcohol associated liver disease (MetALD). The compounds described herein may also have utility in treating certain kinds of cancers which are affected by the LXR mechanism. Such cancers include, but are not limited to, prostate, breast, ovarian, melanoma, pancreas, lung, colon and hematological malignancy. (Lin, C — Y and Gustafsson, J-A, (2015) Nature Reviews Cancer 15, 216-224).

[0130] The compounds described herein may have utility in treating ocular diseases or conditions including Stargardt disease, Dry age-related macular degeneration, Wet age- related macular degeneration, Choroidal neovascularization (CNV), Glaucoma, Uveitis, Uveitic glaucoma, Diabetic retinopathy, Dry eye disease, Optic neuropathies and Meibomian gland dysfunction. In a preferred embodiment, the compounds are useful in the treatment of Alzheimer’s disease.

[0131] Enumerated Embodiments

[0132] In certain aspects, the present invention is directed to the following non-limiting embodiments:

[0133] Embodiment 1 : A compound having the Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0134] X is a bond or a linker, such as a substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, -SO2-, -NRSO2-, -CO-, -NRCO-, or -OCO-; each R is independently selected from H, D, halogen, OH, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two Rs together with the carbon to which they are attached form a 3 to 7 membered ring, preferably cycloalkyl;

[0135] Ri is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0136] R2 is selected from F, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl;

[0137] R3 is selected from H, D, F, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R2 and R3 together with the carbon to which they are attached form a substituted or unsubstituted spiro 3 to 7 membered substituted or unsubstituted ring, preferably a substituted or unsubstituted cycloalkyl;

[0138] R4 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rs is independently selected from H, D, F, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or the two Rs are taken together with the carbon to which they are attached form a substituted or unsubstituted, spiro 3 to 7-membered ring; and n is 0 or 1, preferably 0.

[0139] Embodiment la: The compound of Embodiment 1, wherein X is C1-C7 alkylene or - C(R)2-.

[0140] Embodiment lb: The compound of Embodiment 1, wherein X is substituted or unsubstituted C3-C7 cycloalkylene.

[0141] Embodiment 1c: The compound of Embodiment 1, wherein X is substituted or unsubstituted 3 to 7-membered- heterocycle with one, two or three heteroatoms.

[0142] Embodiment ld-1 : The compound of Embodiment 1, wherein X is substituted or unsubstituted aryl.

[0143] Embodiment ld-2: The compound of Embodiment 1, wherein X is -SO2-, -NRSO2-, -CO-, -NRCO-, or -OCO-.

[0144] Embodiment le: The compound of Embodiment 1, la or ld-2, wherein each R is independently selected from H, D, F, Cl, Br, I, OH, unsubstituted C1-C7 alkyl, or C1-C7 alkyl substituted by one or more of halo, D, OH, and substituted or unsubstituted C1-C7 alkoxy, for example unsubstituted C1-C7 alkoxy.

[0145] Embodiment If: The compound of any of the Embodiment 1 or la-le (Embodiments “la-le” is inclusive of Embodiment ld-1 and ld-2), wherein Ri is unsubstituted C1-7 alkyl or C1-7 alkyl substituted by one or more halogen, D, CF3, OH, substituted or unsubstituted alkoxy, or substituted or unsubstituted aryl.

[0146] Embodiment 1g: The compound of Embodiment 1 or la-le, wherein Ri is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0147] Embodiment Ih: The compound of Embodiment 1 or la-lg, wherein R2 is unsubstituted C1-C7 alkyl or C1-C7 alkyl substituted with one or more R.

[0148] Embodiment li: The compound of Embodiment 1 or la-lg, wherein R2 is unsubstituted C3-C5 alkyl or C3-C5 alkyl substituted with one or more R.

[0149] Embodiment Ij : The compound of Embodiment 1 or la-li, wherein R3 is unsubstituted C1-7 alkyl or C1-7 alkyl substituted by one or more halogen, deuterium, OH, and substituted or unsubstituted alkoxy, for example unsubstituted C1-C7 alkoxy.

[0150] Embodiment Ik: The compound of Embodiment 1 or la-li, wherein R3 is H. Embodiment 11: The compound of Embodiment 1 or la-lk, wherein each Rs is independently unsubstituted C1-7 alkyl or C1-7 alkyl substituted with one or more D, halogen (e.g., F, Cl, Br, I), OH, or alkoxy, for example unsubstituted C1-C7 alkoxy.

[0151] Embodiment Im: The compound of Embodiment 1 or la-lk, wherein each Rs is H.

[0152] Embodiment 2: The compound of Embodiment 1, la-lg, or Ij-lm, wherein R2 is a Ci- 7 alkyl.

[0153] Embodiment 2a: The compound of Embodiment 2, wherein R2 is a branched C3-5 alkyl; preferably isopropyl or t-butyl.

[0154] Embodiment 2b: The compound of Embodiment 2a, wherein R2 is isopropyl.

[0155] Embodiment 2c: The compound of Embodiment 2a, wherein R2 is t-butyl.

[0156] Embodiment 3: The compound of Embodiment 1, la-lm, 2, or 2a, wherein R4 is a substituted aryl or a substituted heteroaryl.

[0157] Embodiment 4: The compound of Embodiment 3, wherein R4 is an aryl or heteroaryl substituted by a CON(R)2, SO2R, CN, or SC>2N(R)2, and optionally further substituted.

[0158] Embodiment 4a: The compound of Embodiment 4, wherein R4 is an aryl or heteroaryl substituted by CON(R)2 and optionally further substituted.

[0159] Embodiment 4b: The compound of Embodiment 4a, wherein R4 is aryl or heteroaryl substituted by CON(CHs)2 and optionally further substituted.

[0160] Embodiment 5: The compound of Embodiment 4, 4a or 4b having the formula (la): or a pharmaceutically acceptable salt thereof, wherein:

[0161] R6is CON(R)2, SO2R, CN, or SO2N(R)2,; and

[0162] R7 is H, halogen, alkyl or haloalkyl, preferably Cl.

[0163] Embodiment 5a: The compound of Embodiment 5, wherein Re is CON(R)2.

[0164] Embodiment 5b: The compound of Embodiment 5a, wherein Re is CON(CH3)2.

[0165] Embodiment 5c: The compound of Embodiment 5, 5a or 5b, wherein R7 is Cl. Embodiment 6: The compound of Embodiment 5 or 5a-5c, wherein the compound has the Formula (la-1):

[0166] (la-1), or a pharmaceutically acceptable salt thereof.

[0167] Embodiment 7: The compound of any one of the preceding Embodiments (Embodiments 1, la-lm, 2, 2a, 2b, 2c, 3, 4, 4a, 4b, 5, 5a, 5b, 5c or 6), wherein n is 0.

[0168] Embodiment 8: The compound of Embodiment 1 or la-lm having the Formula (lb): or a pharmaceutically acceptable salt thereof, wherein:

[0169] R6is CON(R)2, SO2R, CN, or SO2N(R)2; and

[0170] R7 is H, halogen, alkyl or haloalkyl.

[0171] Embodiment 8a: The compound of Embodiment 8, wherein Re is CON(R)2.

[0172] Embodiment 8b: The compound of Embodiment 8a, wherein Re is CON(CH3)2.

[0173] Embodiment 8c: The compound of Embodiment 8, 8a or 8b, wherein R7 is Cl.

[0174] Embodiment 9: The compound of Embodiment 8 or 8a-8c, wherein each Rs is H, R3 is H and R2 is a C1-C7 alkyl.

[0175] Embodiment 9a: The compound of Embodiment 9, wherein R2 is a branched C3-5 alkyl.

[0176] Embodiment 9b: The compound of Embodiment 9a, wherein R2 is isopropyl or t- butyl. Embodiment 10: The compound of any one of the preceding embodiments (Embodiment 1, la-lm, 2, 2a, 2b, 2c, 3, 4, 4a, 4b, 5, 5a, 5b, 5c, 6, 7, 8, 8a-8c, 9, 9a or 9b), wherein X is a bond, -CO-, -O-CO-, -SO2-, -C(R)2-, -NHCO-, or -NHSO2-.

[0177] Embodiment 11 : The compound of any one of Embodiments 1, la-le, Ih-lm, 2, 2a, 2b, 2c, 3, 4, 4a, 4b, 5, 5a, 5b, 5c, 6, 7, 8, 8a-8c, 9, 9a or 9b, wherein Ri is a substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0178] Embodiment 12: The compound of Embodiment 1 having the Formula (Ic): or a pharmaceutically acceptable salt thereof, wherein: each R is a substituted or unsubstituted alkyl;

[0179] R7 is H or halogen;

[0180] R2 is alkyl, preferably isopropyl;

[0181] Ri is a substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine or substituted or unsubstituted pyrazine; and X is a bond or -CO-.

[0182] Embodiment 12a: The compound of Embodiment 12, wherein R2 is isopropyl.

[0183] Embodiment 13: The compound of Embodiment 1 having the Formula (Ic- 1):

[0184] (Ic-1); or a pharmaceutically acceptable salt thereof, wherein: each R is a substituted or unsubstituted alkyl;

[0185] R7 is H or halogen;

[0186] R2 is alkyl, preferably isopropyl; each Rs is independently selected from halogen, substituted or unsubstituted alkyl; and m is 0, 1 or 2.

[0187] Embodiment 13a: The compound of Embodiment 13, wherein R2 is isopropyl.

[0188] Embodiment 13b: The compound of Embodiment 13 or 13a, wherein m is 1 or 2, and each Rs is independently selected from F, methyl, CF3 or CHF2.

[0189] Embodiment 13c: The compound of Embodiment 13, 13a, or 13c, wherein each R is methyl.

[0190] Embodiment 14: The compound of Embodiment 1 having the Formula (Ic-2):

[0191] (Ic-2); or a pharmaceutically acceptable salt thereof, wherein: each R is a substituted or unsubstituted alkyl;

[0192] R7 is H or halogen;

[0193] R2 is alkyl, preferably isopropyl; each Rs is independently selected from halogen, substituted or unsubstituted alkyl; and m is 0, 1 or 2.

[0194] Embodiment 14a: The compound of Embodiment 14, wherein R2 is isopropyl.

[0195] Embodiment 14b: The compound of Embodiment 14 or 14a, wherein m is 1 or 2, and each Rs is independently selected from F, methyl, CF3 or CHF2.

[0196] Embodiment 14c: The compound of Embodiment 14, 14a, or 14c, wherein each R is methyl.

[0197] Embodiment 15: The compound of Embodiment 1 having the Formula (Ic-3):

[0198] (Ic-3); or a pharmaceutically acceptable salt thereof, wherein: each R is a substituted or unsubstituted alkyl;

[0199] I l l R7 is H or halogen;

[0200] R2 is alkyl, preferably isopropyl; and each Rs is independently selected from H, halogen, substituted or unsubstituted alkyl; and m is 0, 1 or 2.

[0201] Embodiment 15a: The compound of Embodiment 15, wherein R2 is isopropyl.

[0202] Embodiment 15b: The compound of Embodiment 15 or 15a, wherein m is 1 or 2, and each Rs is independently selected from F, methyl, CF3 or CHF2.

[0203] Embodiment 15c: The compound of Embodiment 15, 15a, or 15c, wherein each R is methyl.

[0204] Embodiment 16: The compound of Embodiment 1 having the Formula (Ic-4):

[0205] (Ic-4); or a pharmaceutically acceptable salt thereof, wherein: each R is a substituted or unsubstituted alkyl;

[0206] R7 is H or halogen;

[0207] R2 is alkyl, preferably isopropyl; each Rs is independently selected from H, halogen, substituted or unsubstituted alkyl; and m is 0, 1 or 2.

[0208] Embodiment 16a: The compound of Embodiment 16, wherein R2 is isopropyl.

[0209] Embodiment 16b: The compound of Embodiment 16 or 16a, wherein m is 1 or 2, and each Rs is independently selected from F, methyl, CF3 or CHF2.

[0210] Embodiment 16c: The compound of Embodiment 16, 16a, or 16c, wherein each R is methyl. Embodiment 17: The compound of Embodiment 1 having the Formula (Ic-5):

[0211] (Ic-5) or a pharmaceutically acceptable salt thereof, wherein: each R is a substituted or unsubstituted alkyl;

[0212] R? is H or halogen;

[0213] R2 is alkyl, preferably isopropyl; each Rs is independently selected from H, halogen, substituted or unsubstituted alkyl; and m is 0, 1 or 2.

[0214] Embodiment 17a: The compound of Embodiment 17, wherein R2 is isopropyl.

[0215] Embodiment 17b: The compound of Embodiment 17 or 17a, wherein m is 1 or 2, and each Rs is independently selected from F, methyl, CF3 or CHF2.

[0216] Embodiment 17c: The compound of Embodiment 17, 17a, or 17c, wherein each R is methyl.

[0217] Embodiment 18: The compound of Embodiment 1 having the Formula (Ic-6):

[0218] (Ic-6) or a pharmaceutically acceptable salt thereof, wherein: each R is a substituted or unsubstituted alkyl;

[0219] R7 is H or halogen;

[0220] R2 is alkyl, preferably isopropyl; each Rs is selected from H, halogen, substituted or unsubstituted alkyl; and m is 0, 1 or 2.

[0221] Embodiment 18a: The compound of Embodiment 18, wherein R2 is isopropyl. Embodiment 18b: The compound of Embodiment 18 or 18a, wherein m is 1 or 2, and each Rs is independently selected from F, methyl, CF3 or CHF2.

[0222] Embodiment 18c: The compound of Embodiment 18, 18a, or 18c, wherein each R is methyl.

[0223] Embodiment 19: The compound of Embodiment 1 having the Formula (Ic-7):

[0224] (Ic-7); or a pharmaceutically acceptable salt thereof, wherein: each R is a substituted or unsubstituted alkyl;

[0225] R7 is H or halogen;

[0226] R2 is alkyl, preferably isopropyl; each Rs is independently selected from halogen, substituted or unsubstituted alkyl; and m is 0, 1 or 2.

[0227] Embodiment 19a: The compound of Embodiment 19, wherein R2 is isopropyl.

[0228] Embodiment 19b: The compound of Embodiment 19 or 19a, wherein m is 1 or 2, and each Rs is independently selected from F, methyl, CF3 or CHF2.

[0229] Embodiment 19c: The compound of Embodiment 19, 19a, or 19c, wherein each R is methyl.

[0230] Embodiment 20: The compound of Embodiments 13, 13a-13c, 14, 14a-14c, 15, 15a- 15c, 16, 16a-16c, 17, 17a-17c, 18, 18a-18c, 19 or 19a-19c, wherein at least one Rs is CF3.

[0231] Embodiment 21 : The compound of Embodiment 1 having the Formula (Ic-8):

[0232] (Ic-8); or a pharmaceutically acceptable salt thereof, wherein: each R is a substituted or unsubstituted alkyl; R7 is H or halogen;

[0233] R2 is alkyl, preferably isopropyl; each Rs is independently selected from halogen, substituted or unsubstituted alkyl; and m is 0, 1 or 2.

[0234] Embodiment 21a: The compound of Embodiment 19, wherein R2 is isopropyl.

[0235] Embodiment 21b: The compound of Embodiment 19 or 19a, wherein m is 1 or 2, and each Rs is independently selected from F, methyl, CF3 or CHF2.

[0236] Embodiment 21c: The compound of Embodiment 21, 21a, or 21c, wherein each R is methyl.

[0237] Embodiment 22: The compound of Embodiment 1 having the Formula (Ic-9): or a pharmaceutically acceptable salt thereof, wherein: each R is a substituted or unsubstituted alkyl;

[0238] R7 is H or halogen;

[0239] R2 is alkyl, preferably isopropyl; each Rs is independently selected from halogen, substituted or unsubstituted alkyl; and m is 0, 1 or 2.

[0240] Embodiment 22a: The compound of Embodiment 19, wherein R2 is isopropyl.

[0241] Embodiment 22b: The compound of Embodiment 19 or 19a, wherein m is 1 or 2, and each Rs is independently selected from F, methyl, CF3 or CHF2.

[0242] Embodiment 22c: The compound of Embodiment 22, 22a, or 22c, wherein each R is methyl.

[0243] Embodiment 23: The compound of Embodiment 1 having the Formula (Ic-10):

[0244] (Ic-10); or a pharmaceutically acceptable salt thereof, wherein: each R is a substituted or unsubstituted alkyl;

[0245] R7 is H or halogen;

[0246] R2 is alkyl, preferably isopropyl; each Rs is independently selected from halogen, substituted or unsubstituted alkyl; and m is 0, 1 or 2.

[0247] Embodiment 23a: The compound of Embodiment 19, wherein R2 is isopropyl.

[0248] Embodiment 23b: The compound of Embodiment 19 or 19a, wherein m is 1 or 2, and each Rs is independently selected from F, methyl, CF3 or CHF2.

[0249] Embodiment 23c: The compound of Embodiment 23, 23a, or 23c, wherein each R is methyl.

[0250] Embodiment 24: The compound of Embodiment 1 having the Formula (Ic-11):

[0251] (Ic-11); or a pharmaceutically acceptable salt thereof, wherein: each R is a substituted or unsubstituted alkyl;

[0252] R7 is H or halogen;

[0253] R2 is alkyl, preferably isopropyl; each Rs is independently selected from halogen, substituted or unsubstituted alkyl; and m is 0, 1 or 2.

[0254] Embodiment 24a: The compound of Embodiment 19, wherein R2 is isopropyl. Embodiment 24b: The compound of Embodiment 19 or 19a, wherein m is 1 or 2, and each Rs is independently selected from F, methyl, CF3 or CHF2.

[0255] Embodiment 24c: The compound of Embodiment 24, 24a, or 24c, wherein each R is methyl.

[0256] Embodiment 25: The compound of Embodiment 1 having the Formula (Ic-12):

[0257] (Ic-12); or a pharmaceutically acceptable salt thereof, wherein: each R is a substituted or unsubstituted alkyl; R7 is H or halogen;

[0258] R2 is alkyl, preferably isopropyl; each Rs is independently selected from halogen, substituted or unsubstituted alkyl; and m is 0, 1 or 2.

[0259] Embodiment 25a: The compound of Embodiment 19, wherein R2 is isopropyl.

[0260] Embodiment 25b: The compound of Embodiment 19 or 19a, wherein m is 1 or 2, and each Rs is independently selected from F, methyl, CF3 or CHF2.

[0261] Embodiment 25c: The compound of Embodiment 25, 25a, or 25c, wherein each R is methyl.

[0262] Embodiment 26: The compound of Embodiment 1 having the Formula (Ic-13):

[0263] (Ic-13); or a pharmaceutically acceptable salt thereof, wherein: each R is a substituted or unsubstituted alkyl;

[0264] R7 is H or halogen; R2 is alkyl, preferably isopropyl; each Rs is independently selected from halogen, substituted or unsubstituted alkyl; and m is 0, 1 or 2.

[0265] Embodiment 26a: The compound of Embodiment 19, wherein R2 is isopropyl.

[0266] Embodiment 26b: The compound of Embodiment 19 or 19a, wherein m is 1 or 2, and each Rs is independently selected from F, methyl, CF3 or CHF2.

[0267] Embodiment 26c: The compound of Embodiment 26, 26a, or 26c, wherein each R is methyl.

[0268] Embodiment 27: The compound of Embodiment 1 having the Formula (Ic-14): or a pharmaceutically acceptable salt thereof, wherein: each R is a substituted or unsubstituted alkyl;

[0269] R7 is H or halogen;

[0270] R2 is alkyl, preferably isopropyl; each Rs is independently selected from halogen, substituted or unsubstituted alkyl; and m is 0, 1, 2 or 3.

[0271] Embodiment 27a: The compound of Embodiment 19, wherein R2 is isopropyl.

[0272] Embodiment 27b: The compound of Embodiment 19 or 19a, wherein m is 1 or 2, and each Rs is independently selected from F, methyl, CF3 or CHF2.

[0273] Embodiment 27c: The compound of Embodiment 27, 27a, or 27c, wherein each R is methyl.

[0274] Embodiment 28: The compound of Embodiments 21, 2 la-21 c, 22, 22a-22c, 23, 23 a- 23c, 24, 24a-24c, 25, 25a-25c, 26, 26a-26c, 27 or 27a-27c, wherein at least one Rs is CF3.

[0275] Embodiment 29a: The compound of Embodiment 1, wherein the compound is selected from those shown in Table A, or a pharmaceutically acceptable salt thereof. Embodiment 29b: The compound of Embodiment 1, wherein the compound is selected from: Compounds 2, 37, 45, and 56-57, or a pharmaceutically acceptable salt thereof.

[0276] Embodiment 30: A pharmaceutical composition comprising a compound according to any one of the preceding Embodiments (Embodiment 1, la-lm, 2, 2a, 2b, 2c, 3, 4, 4a, 4b, 5, 5a, 5b, 5c, 6, 7, 8, 8a-8c, 9, 9a or 9b, 10, 11, 12, 12a, 13, 13a-13c, 14, 14a-14c, 15, 15a-15c, 16, 16a- 16c, 17, 17a- 17c, 18, 18a- 18c, 19, 19a- 19c, 20, 21, 21a-21c, 22, 22a-22c, 23, 23a-23c, 24, 24a-24c, 25, 25a-25c, 26, 26a-26c, 27 or 27a-27c, 28, 29a or 29b) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0277] Embodiment 31 : A method of treating a subject with a disease or disorder that is treatable by upregulating LXR activity comprising administering to the subject an effective amount of the compound of any one of the preceding Embodiments (Embodiments 1, la-lm, 2, 2a, 2b, 2c, 3, 4, 4a, 4b, 5, 5a, 5b, 5c, 6, 7, 8, 8a-8c, 9, 9a or 9b, 10, 11, 12, 12a, 13, 13a- 13c, 14, 14a-14c, 15, 15a-15c, 16, 16a-16c, 17, 17a-17c, 18, 18a-18c, 19,19a-19c, 20, 21, 21a-21c, 22, 22a-22c, 23, 23a-23c, 24, 24a-24c, 25, 25a-25c, 26, 26a-26c, 27 or 27a-27c, 28, 29a or 29b), or the pharmaceutical composition of Embodiment 30.

[0278] Embodiment 32: A method for the treatment of Alzheimer's Disease, Neimann-Pick disease type Cl, Parkinson's Disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis, age-related macular degeneration, schizophrenia, depression, cardiovascular disease, obesity or diabetes in a patient in need thereof, said method comprising administering to the patient an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of the preceding embodiments (Embodiments 1, la-lm, 2, 2a, 2b, 2c, 3, 4, 4a, 4b, 5, 5a, 5b, 5c, 6, 7, 8, 8a-8c, 9, 9a or 9b, 10, 11, 12, 12a, 13, 13a-13c, 14, 14a-14c, 15, 15a-15c, 16, 16a- 16c, 17, 17a- 17c, 18, 18a- 18c, 19, 19a- 19c, 20, 21, 21a-21c, 22, 22a-22c, 23, 23a-23c, 24, 24a-24c, 25, 25a-25c, 26, 26a-26c, 27 or 27a-27c, 28, 29a or 29b), or the pharmaceutical composition of Embodiment 30.

[0279] Embodiment 33: A compound according to any one of the preceding embodiments (Embodiments 1, la-lm, 2, 2a, 2b, 2c, 3, 4, 4a, 4b, 5, 5a, 5b, 5c, 6, 7, 8, 8a-8c, 9, 9a or 9b, 10, 11, 12, 12a, 13, 13a-13c, 14, 14a-14c, 15, 15a-15c, 16, 16a-16c, 17, 17a-17c, 18, 18a-18c, 19,19a-19c, 20, 21, 21a-21c, 22, 22a-22c, 23, 23a-23c, 24, 24a-24c, 25, 25a-25c, 26, 26a-26c, 27 or 27a-27c, 28, 29a or 29b), or pharmaceutically acceptable salt thereof, for use as a medicament.

[0280] Embodiment 34: Use of a compound according to any one of the preceding embodiments (Embodiments 1, la-lm, 2, 2a, 2b, 2c, 3, 4, 4a, 4b, 5, 5a, 5b, 5c, 6, 7, 8, 8a-8c, 9, 9a or 9b, 10, 11, 12, 12a, 13, 13a-13c, 14, 14a-14c, 15, 15a-15c, 16, 16a-16c, 17, 17a-17c, 18, 18a-18c, 19,19a-19c, 20, 21, 21a-21c, 22, 22a-22c, 23, 23a-23c, 24, 24a-24c, 25, 25a-25c, 26, 26a-26c, 27 or 27a-27c, 28, 29a or 29b), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of Alzheimer's Disease, Neimann-Pick disease type Cl, Parkinson's Disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis, age-related macular degeneration, schizophrenia, depression, cardiovascular disease, obesity or diabetes.

[0281] Embodiment 35: A compound having the Formula (I): and pharmaceutically acceptable salts thereof, wherein:

[0282] X is a bond or a linker, such as a substituted or unsubstituted alkylene (e.g., C1-7 alkylene or -C(R)2), substituted or unsubstituted cycloalkylene (e.g., C3-7 cycloalkylene), substituted or unsubstituted heterocycle (e.g., 3 to 7 membered ring with one, two or three heteroatoms (O, S, or N)), substituted or unsubstituted aryl, -SO2-, -NRSO2-, -CO-, -C(=NH)-, -NRCO-, or -OCO-; each R is independently selected from H, D, halogen (e.g., F, Cl, Br, I), OH, substituted or unsubstituted alkyl (preferably C1-7 alkyl substituted by one or more halogen, deuterium, OH, alkoxy), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two Rs together with the carbon to which they are attached form a 3 to 7 membered ring, preferably cycloalkyl;

[0283] Ri is selected from substituted or unsubstituted alkyl (preferably C1-7 alkyl substituted by one or more halogen, deuterium, CF3, OH, alkoxy, or substituted or unsubstituted aryl), substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0284] R2 is selected from F, substituted or unsubstituted alkyl (such as a C1-7 alkyl or C1-7 alkyl substituted with one or more R), substituted or unsubstituted cycloalkyl or Si(R)3 wherein each R can independently be a substituted or unsubstituted alkyl, preferably methyl or ethyl.;

[0285] R3 is selected from H, D, F, substituted or unsubstituted alkyl (such as unsubstituted C1-7 alkyl, C1-7 alkyl substituted by one or more halogen (e.g., F, Cl, Br, I), deuterium, OH, alkoxy), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl); or R2 and R3 together with the carbon to which they are attached form a substituted or unsubstituted spiro 3 to 7-membered substituted or unsubstituted ring, preferably a substituted or unsubstituted cycloalkyl;

[0286] R4 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted -COaryl or CH2aryl; each Rs is independently selected from H, D, F, substituted or unsubstituted alkyl (such as unsubstituted C1-7 alkyl or C1-7 alkyl substituted by one or more halogen, deuterium, OH, alkoxy), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or wherein the two Rs are taken together with the carbon to which they are attached form a substituted or unsubstituted spiro 3 to 6 membered ring; and n is 0 or 1, preferably 0.

[0287] Embodiment 36: The compound of Embodiment 1 having the Formula (Ic-14):

[0288] (Ic-14); or a pharmaceutically acceptable salt or deuterated form thereof, wherein: each R is independently a H or substituted or unsubstituted alkyl;

[0289] R7 is halogen;

[0290] R2 is alkyl or substituted alkyl, preferably isopropyl or t-Butyl; each Rs is independently H or halogen; m is 0, 1, 2, or 3. Embodiment 37: The compound of Embodiment 1 having the Formula (Ic-14): or a pharmaceutically acceptable salt or deuterated form thereof, wherein: each R is independently a H or substituted or unsubstituted alkyl;

[0291] R? is halogen;

[0292] R2 is alkyl or substituted alkyl, preferably isopropyl or t-Butyl.

[0293] EXAMPLES

[0294] The following examples are offered by way of illustration and are not to be construed as limiting the invention as claimed in any way.

[0295] The compounds and procedures for preparing the compounds will be better understood in connection with the following examples, which are intended as an illustration only and not limiting of the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and / or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.

[0296] Although the invention has been described with respect to various specific or preferred embodiments, it is not intended to be limited thereto, but rather those skilled in the art will recognize that variations and modifications may be made therein which are within the spirit of the invention and the scope of the claims.

[0297] Abbreviations

[0298] ACN - Acetonitrile

[0299] DCC - N,N'-dicyclohexylcarbodiimide

[0300] DCM - Dichloromethane

[0301] DIPEA - 7V,7V-diisopropylethylamine

[0302] DMAP - 4-dimethylaminopyridine

[0303] 1,2-DME - 1,2-dimethoxy ethane

[0304] DMF - N,N-dimethylformamide

[0305] DMF-DMA - N,N-dimethylformamide dimethyl acetal

[0306] DMP - Dess-Martin periodinane equiv. - equivalent

[0307] HATU - l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, N-[(Dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l-ylmethylene]- N-methylmethanaminium hexafluorophosphate N-oxide iPA - 2-Propanol

[0308] Lawesson reagent - 2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-l,3,2,4-dithiadiphosphetane, 2,4-

[0309] Bis-(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane 2,4-disulfide, 4-

[0310] Methoxyphenylthiophosphoric cyclic di(thioanhydride) mCPBA - 3 -Chloroperbenzoic acid

[0311] MTBE - Methyl t-butyl ether pTSA - p-Toluenesulfonic acid monohydrate

[0312] PCC - Pyridinium chlorochromate

[0313] PYBOP® - (Benzotri azol- l-yloxy)tripyrrolidinophosphonium hexafluorophosphate

[0314] RT - Room temperature

[0315] T3P® - Propanephosphonic acid anhydride

[0316] TBAF - Trifluoromethyltrimethylsilane

[0317] TEA - Triethyl amine

[0318] V - volumes

[0319] Analytical

[0320] Proton and F NMRs were taken on 400 MHz Instrument. Some proton NMRs show broad peaks or multiple distinct peaks likely due to restricted rotation. Increasing the NMR temperature sharpened the peaks, sometimes the peaks moved to coalesce the peaks as expected.

[0321] EXAMPLE 1: SCHEME 1 - CORE

[0322] Step 1: Synthesis of tert-butyl (l-(2,2-dimethyl-4,6-dioxo-l,3-dioxan-5-ylidene)-l- hydroxy-3-methylbutan-2-yl) carbamate

[0323] To a stirred solution of (tert-butoxycarbonyl) valine (50 g, 230.13 mmol) and 2,2- dimethyl 1,3 -dioxane-4, 6-dione (39.80 g, 276.16 mmol) in DCM (250 mL, 5 V) were added N,N'-dicyclohexylcarbodiimide (71.2 g, 345.20 mmol) and 4-dimethylaminopyridine (36.55 g, 299.19 mmol) at 0 °C. The reaction was allowed to RT and stirred at same temperature for 16 rt. The reaction was filtered and the filtrate was washed with 1 N HC1 solution (3 X 300 mL) followed by water (3 x 300 mL) and brine solution (300 mL). The organic layer was dried over anhydrous MgSCU, filtered and concentrated under reduced pressure of tertbutyl ( 1 -(2,2-dimethyl-4,6-dioxo- 1 ,3 -dioxan-5-ylidene)- 1 -hydroxy-3 -methylbutan-2-yl) carbamate (70 g crude).

[0324] LC-MS (m / z): 344.44 [M+H]+

[0325] Step 2: Synthesis of tert-butyl 3-hydroxy-2-isopropyl-5-oxo-2,5-dihydro-lH-pyrrole-l- carboxylate

[0326] To a stirred solution of tert-butyl (l-(2,2-dimethyl-4,6-dioxo-l,3-dioxan-5-ylidene)-l- hydroxy-3-methylbutan-2-yl) carbamate (70 g crude, 203.8 mmol) in ethyl acetate (1400 mL, 20 V) was refluxed under N2 for 2 h. The volatiles were concentrated under reduced pressure. The product was triturated with Et2O (50 mL) and dried under reduced pressure to give tertbutyl 3-hydroxy-2-isopropyl-5-oxo-2,5-dihydro-lH-pyrrole-l-carboxylate (50 g crude). LC-MS (m / z): 242.33 [M+H]+ Step 3: Synthesis of tert-butyl 3-hydroxy-2-isopropyl-5-oxopyrrolidine-l-carboxylate To a stirred solution of tert-butyl 3-hydroxy-2-isopropyl-5-oxo-2,5-dihydro-lH-pyrrole-l- carboxylate (50 g, 207.22 mmol) in DCM (500 mL, 10 V) was added acetic acid (125 mL, 2.5 V) and sodium borohydride (23.52 g, 621.67 mmol) at -15 °C stirred at -15 °C for 6 h. The reaction was warmed RT and maintained for 16 h. The reaction was quenched with 10% citric acid solution (500 mL) and extracted with DCM (2 x 250 mL). The combined organic layer washed with saturated NaCl solution (250 mL). The organic layer dried over anhydrous MgSCU, filtered and concentrated under reduced pressure. Purification by silica gel T(230- 400 mesh) column chromatography using 80% ethyl acetate in petroleum ether afforded tertbutyl 3-hydroxy-2-isopropyl-5-oxopyrrolidine-l-carboxylate (15 g, 22% yield over 3 steps). LC-MS (m / z): 244.37 [M+H]+

[0327] Step 4: Synthesis of tert-butyl 3-hydroxy-2-isopropylpyrrolidine-l-carboxylate

[0328] To a stirred solution of tert-butyl 3-hydroxy-2-isopropyl-5-oxopyrrolidine-l-carboxylate (15 g, 61.65 mmol) in tetrahydrofuran, (150 mL, 10 V) was added borane dimethyl sulphide (92 mL, 184 mmol, 2M solution in THF) at RT. The reaction heated to reflux and stirred at same temperature for 1 h. The reaction was quenched with saturated ammonium chloride solution 250 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic layer washed with saturated NaCl solution (150 mL). The organic layer dried over anhydrous MgSCU, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (230-400 mesh) column chromatography using 30% ethyl acetate in petroleum ether to afford a tert-butyl 3-hydroxy-2-isopropylpyrrolidine-l-carboxylate (10 g, 71% yield).

[0329] LC-MS (m / z): 228.31 [M-H]’

[0330] Step 5: Synthesis of tert-butyl 2-isopropyl-3-oxopyrrolidine-l-carboxylate

[0331] To a stirred solution of tert-butyl 3-hydroxy-2-isopropylpyrrolidine-l-carboxylate (10 g, 43.61 mmol) in dichloromethane (100 mL, 10 V) was added Dess-Martin periodinane (18.5 g, 43.61 mmol) at 0 °C. The reaction was allowed to RT and stirred for 8 h. The reaction was quenched with saturated sodium thiosulfate solution (150 mL) and extracted with DCM (2x100 mL). The combined organic layer was washed with saturated sodium bicarbonate solution (50 mL) followed by saturated NaCl solution (50 mL). The organic layer dried over anhydrous MgSCU, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (230-400 mesh) column chromatography using 15% ethyl acetate in petroleum ether to afford tert-butyl 2-isopropyl-3-oxopyrrolidine-l -carboxylate (6.5 g, 62% yield). LC-MS (m / z): 227.36 [M+H]+

[0332] Step 6 & 7: Synthesis of tert-butyl 6-isopropyl-2,6-dihydropyrrolo[3,4-c] pyrazole- 5(4H)-carboxylate

[0333] A stirred solution of tert-butyl 2-isopropyl-3-oxopyrrolidine-l-carboxylate (6.5 g, 28.59 mmol) in N,N-dimethylformamide dimethyl acetal (22.7 mL 3.5 V) was heated to 75 °C and stirred at 75 °C for 4 h. The volatiles are concentrated and proceeded to next step. Added acetic acid (9.7 mL 1.5 V) and hydrazine monohydrate (16.2 mL, 2.5 V) to the crude reaction. The reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer washed with saturated NaCl solution (50 mL) and dried over anhydrous MgSCh, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (230-400 mesh) column chromatography using 50% ethyl acetate in petroleum ether to afford tert-butyl 6-isopropyl-2,6-dihydropyrrolo[3,4-c] pyrazole- 5 (decarboxylate (3.2 g, 45% yield).

[0334] LC-MS (m / z): 252.24 [M+H]+

[0335] EXAMPLE 2: SCHEME 2 - CORE

[0336] Step-1: Synthesis of methyl l-(3-methoxy-3-oxopropanamido)cyclobutane-l-carboxylate

[0337] To a stirred solution of methyl 1 -aminocyclobutane- 1 -carboxylate hydrochloride (25 g, 150.951 mmol, 1.0 equiv.) and triethylamine (21.385 g, 211.33 mmol, 1.4 equiv.) in DCM (250.0 mL) at 0 °C under N2 was dropwise added methyl 3-chloro-3-oxopropanoate (24.732 g, 181.141 mmol, 1.2 equiv.) and stirred at RT for 12 h. The reaction was concentrated under reduced pressure to afford methyl 1 -(3 -m ethoxy-3 -oxopropanamido)cy cl obutane-1- carboxylate (27.0 g, 78% yield) as a light brown solid. The crude product was used in the next step without purification.

[0338] LC-MS (ESI): m / z= 230.20 [M+H]+ Step-2: Synthesis of 5-azaspiro [3.4] octane-6, 8-dione

[0339] To a stirred solution of methyl 1 -(3 -methoxy-3-oxopropanamido)cyclobutane-l -carboxylate (27 g, 117.785 mmol, 1.0 equiv.) in MeOH (270.0 mL) was added sodium methoxide (46.66 mL, 259 mmol, 2.2 equiv.) and stirred at 65 °C for 12h. The reaction was concentrated under reduced pressure. The crude product was taken in in acetonitrile (270 mL) and water (27 mL) and refluxed for 12h. The mixture was concentrated under reduced pressure and the residue was triturated with MTBE (50 mL) to afford 5-azaspiro[3.4]octane-6, 8-dione (12.0 g, 73% yield) as a brown solid.

[0340] LC-MS (ESI): m / z= 138.10 [M-H]’

[0341] Step-3: Synthesis of 8-hydroxy-5-azaspiro[3.4]octan-6-one

[0342] To a stirred solution of 5-azaspiro[3.4]octane-6, 8-dione (8 g, 57.49 mmol, 1.0 equiv.) in MeOH (120) at 0 °C was added sodium borohydride (4.350 g, 114.981 mmol, 2 equiv.) in portions and the reaction was stirred at RT for 16h. The reaction was concentrated under reduced pressure to afford 8-hydroxy-5-azaspiro[3.4]octan-6-one (8 g) as an off-white solid. LC-MS (ESI): m / z= 142.03 [M+H]+

[0343] Step-4: Synthesis of 5-azaspiro [3.4] octan-8-ol

[0344] To a stirred solution of lithium aluminum hydride, IM solution (172.471 mL, 172.471 mmol, 3.0 equiv.) in tetrahydrofuran (dry) (80 mL) at 0 °C was dropwise added trimethyl silyl chloride (21.889 mL, 172.471 mmol, 3.0 equiv.) and the mixture was stirred for 30 min. 8- hydroxy-5-azaspiro[3.4]octan-6-one (8.0 g, 56.67 mmol, 1.0 equiv.) was added in portions maintaining temperature <5 °C. The resultant mixture was stirred at 65 °C for 30 h. The reaction was cooled to 0 °C and quenched by dropwise addition of 30% KOH aq. solution (25 mL). The mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel (230-400 mesh) flash column using 0-10% MeOH in DCM to afford 5-azaspiro[3.4]octan-8-ol (4.6 g, 63% yield) as a colourless sticky solid.

[0345] LC-MS (ESI): m / z= 127.99 [M+H]+

[0346] Step-5: Synthesis of tert-butyl 8-hydroxy-5-azaspiro[3.4]octane-5-carboxylate

[0347] To a stirred solution of 5-azaspiro[3.4]octan-8-ol (4.6 g, 36.191 mmol, 1.0 equiv.) in MeOH (46 mL) at 0 °C was added di-tert-butyl dicarbonate (9.97 mL, 43.4 mmol, 1.2 equiv.). The reaction was stirred at RT for 16 h. The reaction was diluted with water (100 mL) and washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) flash column using 0-50% ethyl acetate in petroleum ether to afford tert-butyl 8- hydroxy-5-azaspiro[3.4]octane-5-carboxylate (2.1 g, 25% yield) as a white solid. LC-MS (ESI): m / z= 228.3 [M+H]+

[0348] Step-6: Synthesis of tert-butyl 8-oxo-5-azaspiro[3.4]octane-5-carboxylate

[0349] To a solution of oxalyl chloride (1.3 mL, 15.12 mmol, 1.5 equiv.) in DCM (23.0 mL) at -60 °C under N2 was added dimethyl sulfoxide (2.18 mL, 30.36 mmol, 3.0 equiv.). The reaction was stirred at 60 °C for 30 min. tert-butyl 8-hydroxy-5-azaspiro[3.4]octane-5-carboxylate (2.3 g, 10.12 mmol, 1.0 equiv.) was added and stirring was continued for additional 1.5 h. Triethyl amine (7.01 mL, 50.60 mmol, 5.0 equiv.) was added, stirred at -60 °C for 30 min and was slowly brought to RT. The reaction was diluted with water (50 mL) and extracted with DCM (2 x 250 mL). The combined organic layer was washed with brine (100 mL). The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (230-400 mesh) flash column by using 0-50% ethyl acetate in petroleum ether to afford tert-butyl 8-oxo-5-azaspiro[3.4]octane-5- carboxylate (1.2 g, 52% yield) as a white solid.

[0350] LC-MS (ESI): m / z= 2AH [M-H]’

[0351] Step-7: Synthesis of tert-butyl (Z)-7-((dimethylamino)methylene)-8-oxo-5- azaspiro[3.4]octane-5-carboxylate

[0352] A solution of tert-butyl 8-oxo-5-azaspiro[3.4]octane-5-carboxylate (1.2 g, 5.327 mmol, 1.0 equiv.) in A Mdi methyl form am ide dimethyl acetal (4.2 mL) was refluxed for 6 h. The reaction was cooled to RT and concentrated under reduced pressure to get tert-butyl (Z)-7- ((dimethylamino)methylene)-8-oxo-5-azaspiro[3.4]octane-5-carboxylate (1.2 g, 80% yield) as an off white solid.

[0353] LC-MS (ESI): m / z= 281.20 [M+H]+

[0354] Step-8: Synthesis of 2',4'-dihydro-5'H-spiro[cyclobutane-l,6'-pyrrolo[3,4-c]pyrazole]-5'- carboxylate

[0355] To a stirred solution of tert-butyl (Z)-7-((dimethylamino)methylene)-8-oxo-5- azaspiro[3.4]octane-5-carboxylate (1.2 g, 4.28 mmol, 1.0 equiv.) in acetic acid (1.8 mL) was added hydrazine monohydrate (3 mL) and the mixture was stirred at rt for 30 min. Then the mixture was refluxed for 16 h. The reaction was cooled to RT and water (25 mL) was added. The resulting mixture was extracted with ethyl acetate (2 x 25 mL) and the combined organic layer was washed with brine (25 mL). The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (230-400 mesh) flash column using 0-50% ethyl acetate in petroleum ether to afford tertbutyl 2',4'-dihydro-5'H-spiro[cyclobutane-l,6'-pyrrolo[3,4-c]pyrazole]-5'-carboxylate (0.98 g, 91% yield) as an off white solid. LC-MS (ESI): m / z= 248.2 [M-H]’

[0356] EXAMPLE 3: SCHEME 3

[0357] Cui, K2CO3, 1 ,4-dioxane

[0358] With or without Nal

[0359] Step 1: Synthesis of tert-butyl 2-(3-chloro-4-(methoxycarbonyl)phenyl)-6-isopropyl-2,6- d ihy dr opyrrolo|3.4-c|pyrazole-5(4 / / )-car boxy late

[0360] To a stirred solution of tert-butyl 6-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4Z / )- carboxylate (4.0 g, 15.92 mmol, 1.0 equiv.) and methyl 4-bromo-2-chlorobenzoate (4.77 g, 19.1 mmol, 1.2 equiv.) in 1,4 dioxane (40 mL) were added potassium carbonate (6.6 g, 47.75 mmol, 3.0 equiv.) and copper(I) iodide (1.5 g, 7.96 mmol, 0.5 equiv.). The mixture was purged with N2 for 10 min and (±)-traws-l,2-diaminocyclohexane (0.91 g, 7.96 mmol, 0.5 equiv.) was added. The resulting mixture was heated at 100 °C for 16 h. The mixture was filtered through a celite bed and concentrated under reduced pressure. The compound was purified by flash column (davisil silica) using 0-20% EtOAc in petroleum ether to afford tert-butyl 2-(3-chloro-4-(methoxycarbonyl)phenyl)-6-isopropyl-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4J7)-carboxylate (3.6 g, 54%) as an off white solid.

[0361] LC-MS (ESI): m / z= 420.68 [M+H]+

[0362] Step 2: Synthesis of methyl 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol- 2(4 / / )-yl)benzoate hydrochloride

[0363] To solution of tert-butyl 2-(3-chloro-4-(methoxycarbonyl)phenyl)-6-isopropyl-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4J7)-carboxylate (3.6 g, 8.57 mmol, 1.0 equiv.) in DCM (18 mL) at 0 °C was added 4M HC1 in dioxane (18 mL). The reaction was allowed to stir at RT for 2 h. The reaction was dried under vacuum and the crude compound was triturated with diethyl ether (3 X 50 mL) to afford methyl 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4- c]pyrazol-2(4J7)-yl)benzoate hydrochloride (2.7 g, crude) as an off white solid.

[0364] LC-MS (ESI): m / z= 320.72 [M+H]+ EXAMPLE 4: SCHEME 4 with or without microwave

[0365] Step 1: Synthesis of 2-chloro-4-(6-isopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)-5,6- diliydropyrrolo|3.4-c|pyrazol-2(4H)-yl)- \. \-diinethylbenzamide (racemic) (Compound 2)

[0366] To a stirred solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)- 7V,7V-dimethylbenzamide hydrochloride (0.25 g, 0.677 mmol, 1.0 eq.) and 4-chloro-2- (trifluoromethyl)pyrimidine (0.185 g, 1.02 mmol, 1.5 eq.) in 2-propanol (2.5 mL) was added / f-diisopropylethylamine (0.59 mL, 3.385 mmol, 5.0 eq.) at RT. The reaction was heated to 130 °C in microwave for 4 h. The reaction was concentrated under reduced pressure and the crude product was purified by silica gel (230-400 mesh) column chromatography using 0-5% MeOH in dichloromethane to afford 2-chloro-4-(6-isopropyl-5-(2- (trifluoromethyl)pyrimidin-4-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-7V,7V- dimethylbenzamide (150 mg, 46%) as an off-white solid.

[0367] LC-MS (ESI): / « z = 479.78 [M+H]+

[0368] Step-2: Chiral SEC separation of enantiomers

[0369] The racemic material was separated by chiral prep-SFC to give 103.90 mg of Peak 1 and 98.99 mg of Peak 2 as white solids.

[0370] Chiral SFC method: Column / dimensions: Chiralpak H4 (30x250) mm,5p; % CO2: 65%; % Co solvent: 35% (0.1% DEA in MeOH); Flow: 100 mL / min; Back Pressure: 100 bar;

[0371] Temperature: 30 °C; UV: 270 nm; Solubility: MeOH + MeCN + THF.

[0372] Compound 2-PK1:

[0373] HPLC: 99.16%; Chiral HPLC: 99.99%

[0374] LC-MS (ESI): m / z: = 479.29 [M+H]+

[0375] 'H NMR (400 MHz, DMSO-d6): 8 8.56-8.52 (m, 1H), 8.45-8.40 (m, 1H), 8.03 (d, J= 2.0 Hz, 1H), 7.93 (dd, J= 8.4 & 2.0 Hz, 1H), 7.50 (d, J= 8.4 Hz,lH), 7.06-6.91 (m,lH), 5.21-5.15 (m, 1H), 4.83-4.62 (m, 2H), 3.03 (s, 3H), 2.82 (s, 4H), 1.25-1.19 (m, 3H), 0.53 (d, J= 6.8 Hz, 3H). Compound 2-PK2:

[0376] HPLC: 99 22%; Chiral HPLC: 99 98%

[0377] LC-MS (ESI): m / z: = 479.29 [M+H]+

[0378] 'H NMR (400 MHz, DMSO-d6): 6 8.56-8.52 (m, 1H), 8.45-8.40 (m, 1H), 8.03 (d, J= 2.0 Hz, 1H), 7.93 (dd, J= 8.4 & 2.0 Hz, 1H), 7.50 (d, J= 8.4 Hz,lH), 7.07-6.91 (m,lH), 5.21-5.15 (m, 1H), 4.83-4.62 (m, 2H), 3.03 (s, 3H), 2.82 (s, 4H), 1.25-1.16 (m, 3H), 0.53 (d, J= 6.8 Hz, 3H).

[0379] EXAMPLE 5: SCHEME 5

[0380] Step 1: Synthesis of 4-chloro-2,6-bis(trifluoromethyl)pyrimidine

[0381] To a stirred solution of 2,6-bis(trifluoromethyl)pyrimidin-4-ol (0.3 g, 1.293 mmol, 1.0 equiv.) in toluene (3 mL) at 0 °C were added thionyl chloride (0.188 mL, 2.585 mmol, 2 equiv.) and DMF (0.020 mL, 0.259 mmol, 0.2 equiv.). Reaction was stirred for 3 h at 80 °C. The reaction was cooled to RT and water (10 mL) was added. The mixture was extracted with MTBE (3 mL). The combined organic layer washed with sodium bicarbonate solution (3 mL) and brine (3 mL). The organic layer dried over anhydrous MgSC>4, filtered and the filtrate was used for next step directly.

[0382] Step 2: Synthesis of 4-(5-(2,6-bis(trifluoromethyl)pyrimidin-4-yl)-6-isopropyl-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4Z7)-yl)-2-chloro-7V,7V-dimethylbenzamide (Racemic) (Compound 43)

[0383] To a stirred solution of 4-chloro-2,6-bis(trifluoromethyl)pyrimidine in MTBE (3.0 mL) were added 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)-7V,7V- dimethylbenzamide hydrochloride (0.31 g, 0.838 mmol, 0.7 equiv.) and DIPEA (0.835 mL, 5.99 mmol, 5.0 equiv.). The reaction was stirred at 40 °C for 2h. Reaction was concentrated under reduced pressure and the crude material was purified by flash column using 0-40% EtOAc in petroleum ether to afford 4-(5-(2,6-bis(trifluoromethyl)pyrimidin-4-yl)-6- isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)-2-chloro-7V,7V-dimethylbenzamide (0.29 g, 44%) as a white solid.

[0384] LC-MS (ESI): m / z = 547.79 [M+H]+ Step 3: Synthesis of Compound 43-PK1 and Compound 43-PK2

[0385] The racemate compound (0.290 g) was separated by chiral prep-SFC into Compound 43- PK1 (111.1 mg) and Compound 43-PK2 (110.8 mg) as white solids.

[0386] Chiral Purification Method:

[0387] Column / dimensions: Lux Cellulose (30 x 250) mm, 5 p, %CO2: 75; %Co solvent: 25% (MEOH), Flow: 100 mL / min; Back Pressure: 100 bar, Temperature: 30 °C, UV: 265 nm, Solubility: MeOH + MeCN.

[0388] Compound 43-PK1:

[0389] LC-MS (ESI): m / z = 547.38 [M+H]+

[0390] 'H NMR (400 MHz, DMSO-< / 6): d 8.61-8.54 (m, 1H), 8.05 (d, J= 2.0 Hz, 1H), 7.95-7.92 (m, 1H), 7.52-7.36 (m, 2H), 5.43-5.27 (m, 1H), 4.90-4.70 (m, 2H), 3.03 (s, 3H), 2.83-2.77 (m, 4H), 1.26-1.21 (m, 3H), 0.55 (d, J= 6.8 Hz, 3H).

[0391] Compound 43-PK2:

[0392] LC-MS (ESI): m / z = 547.34 [M+H]+

[0393] 'H NMR (400 MHz, DMSO-< / 6): d 8.61-8.54 (m, 1H), 8.05 (d, J= 2.0 Hz, 1H), 7.95-7.92 (m, 1H), 7.52-7.37 (m, 2H), 5.43-5.27 (m, 1H), 4.90-4.70 (m, 2H), 3.03 (s, 3H), 2.83-2.77 (m, 4H), 1.26-1.21 (m, 3H), 0.55 (d, J= 6.8 Hz, 3H).

[0394] EXAMPLE 6: SCHEME 6

[0395] Step-1: Synthesis of 2-chloro-4-(6-isopropyl-5-(2-(trifluoromethyl)pyridin-4-yl)-5,6- dihydropyrrolo[3,4-c] pyrazol-2(4H)-yl)-7V,7V-dimethylbenzamide (Compound 86; Racemic)

[0396] To a stirred solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c] pyrazol-2(4J7)-yl)- Wdimethylbenzamide (0.6 g, 1.630 mmol, 1.0 equiv.) and 4-chloro-2- (trifluoromethyl)pyridine (0.439 g, 2.45 mmol, 1.5 equiv.) in DMSO (6 mL) were added and triethylamine (0.79 mL, 5.71 mmol, 3.5 equiv.) and cesium fluoride (0.49 g, 3.26 mmol, 2.0 equiv.). The resulting mixture was stirred at 110 °C for 16 h. The reaction was concentrated under reduced pressure and purified by silica gel (100-200) flash column using 0-40% ethyl acetate in petroleum ether to afford 2-chloro-4-(6-isopropyl-5-(2-(trifluoromethyl)pyridin-4- yl)-5,6-dihydropyrrolo[3,4-c] pyrazol-2(4H)-yl)-7V,7V-dimethylbenzamide (0.28 g, 95% yield) as an off white solid.

[0397] The racemate (0.28 g) was separated by chiral prep-SFC into Compound 86-PK1 (0.043 g) and Compound 86-PK2 (0.049 g) as off-white solids.

[0398] Preparative SFC Conditions: Column / dimensions: Chiralpak -IF (30 x 250) mm, 5 p;

[0399] %CO2: 60; %Co solvent: 40 (MeOH); Flow: 100 mL / min; Back Pressure: 100 bar;

[0400] Temperature: 30 °C; UV: 250 nm.

[0401] Compound 86-PK1:

[0402] LC-MS (ESI): m / z = &. l [M+H]+

[0403] 'H NMR (400 MHz, DMSO-d6): 8 8.55 (s, 1H), 8.31 (d, J= 5.6 Hz, 1H), 8.03 (d, J= 2.0 Hz, 1H), 7.92 (dd, J= 2.0 & 8.4 Hz, 1H), 7.50 (d, J= 8.4 Hz, 1H), 7.07 (d, J= 2.0 Hz, 1H), 6.94 (d, J = 3.6 Hz, 1H), 5.14 (d, J= 2.0 Hz, 1H), 4.70-4.51 (m, 2H), 3.03 (s, 3H), 2.83 (s, 3H), 2.47-2.44 (m, 1H), 1.24 (d, J = 6.8 Hz, 3H), 0.48 (d, J = 6.4 Hz, 3H).

[0404] Compound 86-PK2:

[0405] LC-MS (ESI): m / z = &. 1 [M+H]+

[0406] 'H NMR (400 MHz, DMSO-d6): 6 8.55 (s, 1H), 8.31 (d, J= 5.6 Hz, 1H), 8.03 (d, J= 2.0 Hz, 1H), 7.92 (dd, J= 2.0 & 8.4 Hz, 1H), 7.50 (d, J= 8.4 Hz, 1H), 7.07 (d, J= 2.0 Hz, 1H), 6.94 (d, J = 4.4 Hz, 1H), 5.15 (s, 1H), 4.70-4.51 (m, 2H), 3.03 (s, 3H), 2.83 (s, 3H), 2.46-2.42 (m, 1H), 1.24 (d, J = 6.8 Hz, 3H), 0.48 (d, J = 6.4 Hz, 3H).

[0407] EXAMPLE 7: SCHEME 7

[0408] Step-1: Synthesis of (2-chloro-4-(5-(2-cyanopyrimidin-4-yl)-6-isopropyl-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,N-dimethylbenzamide) Racemate (Compound 109)

[0409] To a stirred solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)- N,N-dimethylbenzamide hydrochloride (350 mg, 0.95 mmol; 1 eq) and 4-chloropyrimidine- 2-carbonitrile (159 mg, 1.14 mmol; 1.2 eq) in DMF (3.5 mL) was added potassium carbonate (262 mg, 1.896 mmol; 2 eq) and sodium iodide (142 mg, 0.95 mmol, 1 eq) at RT. The reaction was warmed to 80 °C and stirred for 2 h. The reaction was cooled to rt and quenched into water and filtered the solid. Crude purified by silica column and elution with 0-100% ethyl acetate with petroleum ether afforded 2-chloro-4-(5-(2-cyanopyrimidin-4-yl)-6- isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,N-dimethylbenzamide (280 mg, 68% yield) as off white solid.

[0410] LC-MS (ESI): m / z = 436.73 [M+H]+

[0411] Step-2: Synthesis of Compound 109-PK1 and Compound 109-PK2

[0412] The Racemate (280 mg) was separated by chiral prep-SFC into Compound 109-PK1 (0.058 g) as an off white solid and Compound 109-PK2 (0.054 g) as an off white solid.

[0413] Chiral Purification Method:

[0414] Column / dimensions: Chirapak AS-H (30x250) mm, 5p; % CO2: 50%; % Co solvent: 50% (MeOH); Flow: lOOmL / min; Back Pressure: 100 bar Temperature: 30 ° C; UV: 274 nm; Solubility: MeOH + THF

[0415] Compound 109-PK1:

[0416] LC-MS (ESI): m / z = 436.38 [M+H]+

[0417] 'H NMR (400 MHz, DMSO-< / 6): 8 8.56 (d, J= 6.6 Hz, 1H), 8.39-8.34 (m,lH), 8.03 (d, J= 2.0 Hz, 1H), 7.92 (dd, J= 8.4 Hz, & 2.0 Hz, 1H), 7.50 (d, J= 6.6 Hz, 1H), 7.12-6.95 (m, 1H), 5.19 (d, J= 19.6 Hz, 1H), 4.81-4.59 (m, 2H), 3.02 (s, 3H), 2.82 (s, 3H), 1.22 (d, J = 6.4 Hz, 3H), 0.52 (d, J = 6.8 Hz, 3H).

[0418] Compound 109-PK2:

[0419] LC-MS (ESI): m / z = 436.42 [M+H]+

[0420] 'H NMR (400 MHz, DMSO-< / 6): 6 8.56 (d, J= 6.6 Hz, 1H), 8.39-8.34 (m,lH), 8.03 (d, J= 2.0 Hz, 1H), 7.92 (dd, J= 8.4 Hz, & 2.0 Hz, 1H), 7.50 (d, J= 6.6 Hz, 1H), 7.12-6.95 (m, 1H), 5.19 (d, J= 19.6 Hz, 1H), 4.81-4.59 (m, 2H), 3.02 (s, 3H), 2.82 (s, 3H), 1.22 (d, J = 6.4 Hz, 3H), 0.52 (d, J = 6.8 Hz, 3H).

[0421] Step-1: Synthesis of 4-(6-(tert-butyl)-5-(2-methoxypyridin-4-yl)-5,6-dihydropyrrolo[3,4- c|pyrazol-2(4 / / )-yl)-2-chloro- \. \ diniethylbenz:imide (Compound 84 Racemic)

[0422] To a stirred solution of 4-(6-(tert-butyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)-2- chloro-A,A-dimethylbenzamide hydrochloride (0.3 g, 0.783 mmol, 1.0 equiv.) in THF (3.0 mL) was added 4-bromo-2-methoxypyridine (0.16 g, 0.86 mmol, 1.1 equiv.) and cesium carbonate (0.51 g, 1.565 mmol, 2.0 equiv.). Reaction was purged with nitrogen gas for 10 min with vigorous stirring. RuPhos (0.037 g, 0.078 mmol, 0.1 equiv.) and RuPhos Pd G2 (0.061 g, 0.078 mmol, 0.1 equiv.) were added and the reaction was stirred at 80 °C for 12 h. The reaction was concentrated under reduced pressure and purified by silica gel (100-200) flash column using 0-45% EtOAc in petroleum ether to afford 4-(6-( / c / 7-butyl)-5-(2- methoxypyridin-4-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)-2-chloro-7V,7V- dimethylbenzamide (0.15 g, 42%) as a white solid.

[0423] LC-MS (ESI): m / z = 454.79 [M+H]+

[0424] The racemate (0.15 g) was separated by chiral prep-SFC into Compound 84-PK1 (0.0537 g) and Compound 84-PK2 (0.0310 g) as off-white solids.

[0425] Chiral Purification Method:

[0426] Column / dimensions: Chirapak IH (4.6 x 250) mm, 5 p, % CO2: 60; % Co solvent: 40 (MeOH); Flow: 3 mL / min; Back Pressure: 100 bar; Temperature: 30 °C; UV: 271 nm Compound 84-PK1:

[0427] LC-MS (ESI): m / z = 454.31 [M+H]+

[0428] 'H NMR (400 MHz, DMSO-d6): <5 8.45 (s, IH), 8.00 (d, J= 2.0 Hz, IH), 7.89 (dd, J= 2.0 & 8.4 Hz, IH), 7.79 (d, J= 6.0 Hz, IH), 7.49 (d, J= 8.4 Hz, IH), 6.63-6.62 (m, IH), 6.18 (d, J = 1.6 Hz, IH), 5.02 (s, IH), 4.68 (d, J= 13.6 Hz, IH), 4.38 (d, J= 13.6 Hz, IH), 3.79 (s, 3H), 3.03 (s, 3H), 2.83 (s, 3H), 0.94 (s, 9H).

[0429] Compound 84-PK2:

[0430] LC-MS (ESI): m / z = 454.35 [M+H]+

[0431] 'H NMR (400 MHz, DMSO-d6): 3 8.45 (s, IH), 8.00 (d, J= 2.0 Hz, IH), 7.89 (dd, J= 2.0 & 8.4 Hz, IH), 7.79 (d, J= 6.4 Hz, IH), 7.49 (d, J= 8.4 Hz, IH), 6.64-6.62 (m, IH), 6.18 (d, J = 1.6 Hz, IH), 5.01 (s, IH), 4.68 (d, J= 13.6 Hz, IH), 4.38 (d, J= 13.6 Hz, IH), 3.79 (s, 3H), 3.03 (s, 3H), 2.83 (s, 3H), 0.94 (s, 9H).

[0432] EXAMPLE 9: SCHEME 9

[0433] Synthesis of Compound 119

[0434] Step 1 : To a stirred solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol- 2(4J7)-yl)-7V,7V-dimethylbenzamide hydrochloride (1.0 g, 2.708 mmol, 1.0 equiv.) and 3- bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole (1.255 g, 5.434 mmol, 2.0 equiv.) in 1,4- dioxane (10 mL) was added sodium tert-butoxide (0.31 g, 3.249 mmol, 1.2 equiv.). The mixture was purged with nitrogen for 5 min and Peppsi-iHept-Cl (0.21 g, 0.217 mmol, 0.08 equiv.) was added. The reaction was stirred at 100 °C for 16 h. The reaction was concentrated under reduced pressure and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 X 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by flash column (silica gel 100-200) chromatography using 0-40% EtOAc in pet-ether to afford 2-chloro-4-(6-isopropyl-5-(l-(tetrahydro-2J / -pyran-2-yl)-U / -pyrazol-3-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)-7V,7V-dimethylbenzamide (0.4 g, 31%) as an off-white solid.

[0435] LC-MS (ESI): m / z= 487.47 [M+H]+

[0436] 'H NMR (400 MHz, DMSO-d6): <5 8.43 (s, 1H), 7.99 (d, J= 2.0 Hz, 1H), 7.88 (dd, J= 2.0 &

[0437] 8.4 Hz, 1H), 7.66 (t, J= 2.0 Hz, 1H), 7.47 (d, J= 8.4 Hz, 1H), 5.74 (t, J= 2.4 Hz, 1H), 5.19 (dd, = 2.4 & 10.0 Hz, 1H), 4.65-4.64 (m, 1H), 4.50-4.31 (m, 2H), 3.91-3.88 (m, 1H), 3.61- 3.59 (m, 1H), 3.02 (s, 3H), 2.82 (s, 3H), 2.04-1.85 (m, 3H), 1.54-1.47 (m, 4H), 1.19 (d, J = 7.2 Hz, 3H), 0.59 (d, J= 6.8 Hz, 3H).

[0438] Step 2: Synthesis of Compound 120

[0439] To a stirred solution of 2-chloro-4-(6-isopropyl-5-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol- 3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,N-dimethylbenzamide (0.05 g, 0.104 mmol, ) in Ethanol (0.5 mL) was added Hydrochloric acid (0.25 mL) drop wise at 0 °C. The reaction was stirred at rt for 16 h. The reaction was concentrated under reduced pressure to get crude. The crude was purified by flash column using 50% EtOAc in pet-ether to obtain 2- chloro-4-(6-isopropyl-5-(lH-pyrazol-3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,N- dimethylbenzamide (0.04 g) as an off-white solid.

[0440] LC-MS (ESI): m / z = 399.77 [M+H]+

[0441] The racemate (0.04 g) was separated by chiral prep-SFC into Compound 120-PK1 (1.5 mg) and Compound 120-PK2 (2.3 mg) as off-white solids.

[0442] Preparative SFC Conditions: Column / dimensions: Chirapak IH (30x250) mm, 5p; %CC>2: 75; %Co solvent: 25 (MeOH), Flow rate: 100 mL / min; Back Pressure: 100 bar, Temperature: 30 °C, UV: 274 nm, Solubility: MeOH +THF

[0443] Compound 120-PK1:

[0444] LC-MS (ESI): m / z = 399.37 [M+H]+

[0445] 'H NMR (400 MHz, DMSO-d6): <5 11.75 (s, IH), 8.42 (s, IH), 7.99 (d, J= 2.40 Hz, IH), 7.88 (dd, J= 2.00, 8.40 Hz, IH), 7.51-7.46 (m, 2H), 5.66 (s, IH), 4.65-4.64 (m, IH), 4.50 (d, J= 12.80 Hz, IH), 4.30 (d, J= 12.80 Hz, IH), 3.02 (s, 3H), 2.82 (s, 3H), 2.54-2.53 (m, IH), 1.23-1.18 (m, 3H), 0.59 (d, J= 6.40 Hz, 3H).

[0446] Compound 120-PK2:

[0447] LC-MS (ESI): m / z = 399.37 [M+H]+

[0448] 'H NMR (400 MHz, DMSO-d6): 3 11.74 (s, IH), 8.42 (s, IH), 7.99 (d, J= 2.40 Hz, IH), 7.88 (dd, J= 2.00, 8.40 Hz, IH), 7.49-7.46 (m, 2H), 5.65 (s, IH), 4.65-4.64 (m, IH), 4.52- 4.49 (m, IH), 4.30 (d, J= 13.20 Hz, IH), 3.02 (s, 3H), 2.82 (s, 3H), 2.51-2.50 (m, IH), 1.19 (d, J= 7.20 Hz, 3H), 0.59 (d, J = 6.80 Hz, 3H).

[0449] Step 3: Synthesis of Compound 99-Racemic

[0450] To a stirred solution of 2-chloro-4-(6-isopropyl-5-(lH-pyrazol-3-yl)-5,6-dihydropyrrolo[3,4- c]pyrazol-2(4H)-yl)-N,N-dimethylbenzamide (0.15 g, 0.376 mmol, 1 equiv.) in Acetonitrile (1.5 mL) was added diethyl (bromodifluoromethyl)phosphonate (0.1 g, 0.376 mmol, 1 equiv.), Potassium fluoride, 98% (0.044 g, 0.752 mmol, 2 equiv.). The reaction was stirred at RT for 12 h. The reaction was concentrated under reduced pressure to get crude. The crude was purified by flash column using 50% EtOAc in pet-ether to obtain 2-chloro-4-(5-(l- (difluoromethyl)-lH-pyrazol-3-yl)-6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-

[0451] N,N-dimethylbenzamide (0.1 g) as an off-white solid.

[0452] LC-MS (ESI): m / z = 449.74 [M+H]+

[0453] The Racemate (0.1 g) was separated by chiral prep-SFC into Compound 99-PK1 (5.92 mg), Compound 99-PK2 (4.12 mg), Compound 132-PK1 (6.55 mg) and Compound 132-PK2 (11.09 mg) as off-white solids.

[0454] Preparative SFC Conditions: Column / dimensions: Chirapak AD-H (30x250) mm, 5p;

[0455] %CC>2: 80; %Co solvent: 20 (0.2% isopropyl amine in IP A), Flow rate: 100 mL / min; Back Pressure: 100 bar, Temperature: 30 °C, UV: 273 nm, Solubility: MeOH +THF

[0456] Compound 99-PK1:

[0457] LC-MS (ESI): m / z = 449.42 [M+H]+

[0458] 'H NMR (400 MHz, DMSO-< / 6): 8 8.46 (s, 1H), 8.00-7.98 (m, 2H), 7.89 (dd, J= 2.00, 8.40 Hz, 1H), 7.70-7.41 (m, 2H), 6.06 (d, J= 2.80 Hz, 1H), 4.75-4.74 (m, 1H), 4.55-4.52 (m, 1H), 4.40 (d, J=13.2 Hz, 1H), 3.02 (s, 3H), 2.82 (s, 3H), 2.50-2.49 (m, 1H), 1.20-1.19 (m, 3H),

[0459] O.58 (d, J= 6.40 Hz, 3H).

[0460] Compound 99-PK2:

[0461] LC-MS (ESI): m / z = 449.27 [M+H]+

[0462] 'H NMR (400 MHz, DMSO-< / 6): d 8.46 (s, 1H), 8.00-7.98 (m, 2H), 7.89 (dd, J= 2.40, 8.40 Hz, 1H), 7.70-7.41 (m, 2H), 6.06 (d, J= 2.80 Hz, 1H), 4.75-4.73 (m, 1H), 4.55-4.52 (m, 1H), 4.40 (d, J=13.2 Hz, 1H), 3.02 (s, 3H), 2.82 (s, 3H), 2.50-2.49 (m, 1H), 1.23-1.18 (m, 3H), 0.58 (d, J= 6.40 Hz, 3H).

[0463] Compound 132-PK1:

[0464] LC-MS (ESI): m / z = 449.27 [M+H]+

[0465] 'H NMR (400 MHz, DMSO-< / 6): d 8.43 (s, 1H), 7.99 (d, J= 2.40 Hz, 1H), 7.94-7.64 (m, 3H), 7.48 (d, J= 8.40 Hz, 1H), 6.22 (d, J= 1.60 Hz, 1H), 4.78-4.75 (m, 2H), 4.13 (d, J = 12.00 Hz, 1H), 3.02 (s, 3H), 2.82 (s, 3H), 1.94-1.93 (m, 1H), 1.07 (d, J= 6.80 Hz, 3H), 0.75 (d, J = 6.40 Hz, 3H).

[0466] Compound 132-PK2:

[0467] LC-MS (ESI): m / z = 449.41 [M+H]+

[0468] 'H NMR (400 MHz, DMSO-< / 6): d 8.43 (s, 1H), 7.99 (d, J= 2.00 Hz, 1H), 7.94-7.64 (m, 3H), 7.48 (d, J= 8.40 Hz, 1H), 6.22 (d, J= 1.60 Hz, 1H), 4.78-4.75 (m, 2H), 4.13 (d, J = 12.00 Hz, 1H), 3.02 (s, 3H), 2.82 (s, 3H), 1.99-1.91 (m, 1H), 1.07 (d, J= 6.80 Hz, 3H), 0.75 (d, = 6.80 Hz, 3H). EXAMPLE 10: SCHEME 10

[0469] Synthesis of Compound 17-Racemic

[0470] To a stirred solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)- A-dimethylbenzamide hydrochloride (0.15 g, 0.406 mmol, 1.0 equiv.) in DCM (1.50 mL) was added N, A-diisopropylethylamine (0.22 mL, 1.219 mmol, 3.0 equiv.) followed by 2,6- dichlorobenzenesulfonyl chloride (0.100 g, 0.406 mmol, 1.0 equiv.) at 0 °C. The reaction was stirred for 6 h, concentrated under reduced pressure and purified by flash column(SiC>2, 100- 200 mesh; 0-60 % EtOAc in pet. ether) to afford 2-chloro-4-(5-((2,6- dichlorophenyl)sulfonyl)-6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)-7V,7V- dimethylbenzamide (0.2 g 91% yield) as a white solid.

[0471] LC-MS (ESI): m / z = 540.99 [M+H]+

[0472] Step-2: Prep-SFC chiral separation of Compound 17-Racemic to Compound 17-PK1 and Compound 17-PK2

[0473] Racemic 2-chloro-4-(5-((2,6-dichlorophenyl)sulfonyl)-6-isopropyl-5,6-dihydropyrrolo[3,4- c]pyrazol-2(4J7)-yl)-7V,7V-dimethylbenzamide (0.4 g), was separated by chiral prep-SFC to give Compound 17-PK1 (138 mg) and Compound 17-PK2 (129 mg) as white solids.

[0474] Compound 17-PK1 and Compound 17-PK2 Chiral SFC purification Conditions:

[0475] Preparative SFC Conditions Column / dimensions: Lux Cellulose-4 (30*250mm) 5p; % CO2: 53; % Co solvent: 47 (0.1% DEA in MeOH); Flow: 100 mL / min; Back Pressure: 100 bar; Temperature: 30 °C; UV: 272 nm; Solubility: MeOH

[0476] Compound 17-PK1:

[0477] LC-MS (ESI): m / z = 541.20 [M+H]+

[0478] 'H NMR (400 MHz, DMSO-< / 6): 8 8.43 (s, 1H), 7.97 (d, J= 2.0 Hz, 1H), 7.87-7.84 (m,lH), 7.71-7.69 (m, 2H), 7.62-7.58 (m, 1H), 7.47 (d, J= 8.0 Hz, 1H), 4.99-4.98 (m, 1H), 4.71-4.61 (m, 2H), 3.01 (s, 3H), 2.80 (s, 3H), 2.29-2.27 (m, 1H), 1.11 (d, J= 7.2 Hz, 3H), 0.63 (d, J = 6.8 Hz, 3H).

[0479] Compound 17-PK2:

[0480] LC-MS (ESI): m / z = 541.20 [M+H]+ 'H NMR (400 MHz, DMSO-< / 6): 6 8.43 (s, 1H), 7.97 (d, J= 2.0 Hz, 1H), 7.87-7.84 (m,lH), 7.71-7.69 (m, 2H), 7.62-7.58 (m, 1H), 7.47 (d, J= 8.4 Hz, 1H), 4.99-4.98 (m, 1H), 4.71-4.61 (m, 2H), 3.01 (s, 3H), 2.80 (s, 3H), 2.31-2.27 (m, 1H), 1.11 (d, J= 6.8 Hz, 3H), 0.63 (d, J = 6.8 Hz, 3H).

[0481] EXAMPLE 11: SCHEME 11

[0482] Synthesis of Compound 57-Racemic

[0483] To a stirred solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)- 7V,7V-dimethylbenzamide hydrochloride (0.4 g, 1.084 mmol, 1.0 equiv.) and DIPEA (0.94 mL, 5.416 mmol, 5.0 equiv.) in dimethylformamide (4.0 mL) was at 0 °C was added 2,6- di chlorobenzoyl chloride (0.254 g, 1.625 mmol, 1.5 equiv.) and the resulting mixture was stirred at 120° C for 4 h, concentrated under reduced pressure and purified by silica gel (100- 200) flash column using 0-40% ethyl acetate in petroleum ether to afford 2-chloro-4-(5-(2,6- dichlorobenzoyl)-6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,N- dimethylbenzamide (0.35 g, 76% yield) as an off white solid.

[0484] LC-MS (ESI): m / z = 507.63 [M+H]+

[0485] The racemate (0.35 g) was separated by chiral prep-SFC into Compound 57-PK1 (0.101 g) and Compound 57-PK2 (0.102 g) as off-white solids.

[0486] Preparative SEC Conditions: Preparative SFC Conditions Column / dimensions: Chiralpak AD-H (30 x 250) mm, 5 p; % CO2: 70; % Co solvent: 30 (0.1% MeOH ammonia in MeOH); Flow: 100 mL / min; Back Pressure: 100 bar; Temperature: 30 °C; UV: 276 nm.

[0487] Compound 57-PK1:

[0488] LC-MS (ESI): m / z = 505.32 [M+H]+

[0489] 'H NMR (400 MHz, DMSO-d6): 8 8.53-8.38 (m, 1H), 8.01-7.99 (m, 1H), 7.90-7.87 (m, 1H), 7.65-7.61 (m, 2H), 7.57-7.47 (m, 2H), 5.17 (d, J= 3.6 Hz, 1H), 4.35-4.20 (m, 2H), 3.02 (s, 3H), 2.81-2.76 (m, 4H), 1.21-0.89 (m, 3H), 0.70-0.60 (m, 3H).

[0490] Compound 57-PK2:

[0491] LC-MS (ESI): m / z = 505.32 [M+H]+ 'H NMR (400 MHz, DMSO-d6): 6 8.53-8.38 (m, 1H), 8.01-7.99 (m, 1H), 7.90-7.87 (m, 1H), 7.65-7.61 (m, 2H), 7.57-7.47 (m, 2H), 5.17 (d, J= 3.6 Hz, 1H), 4.35-4.20 (m, 2H), 3.02 (s, 3H), 2.81-2.76 (m, 4H), 1.24-0.89 (m, 3H), 0.70-0.60 (m, 3H).

[0492] EXAMPLE 12: SCHEME 12

[0493] Synthesis of Compound 56-Racemic

[0494] A stirred solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)- 7V,7V-dimethylbenzamide hydrochloride (0.4 g, 1.083 mmol, 1.0 equiv.) and 2-chlorobenzoic acid (0.254 g, 1.625 mmol, 1.5 equiv.) in dimethylformamide (4.0 mL) was cooled to 0 °C and DIPEA (1.1 mL, 5.416 mmol, 5.0 equiv.) and propylphosphonic anhydride 50% in DMF (1.3 mL, 2.166 mmol, 2.0 equiv.) was added and the resulting mixture was stirred at RT for 2 H. The reaction was concentrated under reduced pressure and purified by silica gel (100- 200) flash column using 0-40% ethyl acetate in petroleum ether to afford 2-chloro-4-(5-(2- chlorobenzoyl)-6-isopropyl-5,6-dihydropyrrolo[3,4-c] pyrazol-2(4J7)-yl)-7V,7V- dimethylbenzamide (0.35 g, 69% yield) as an off white solid.

[0495] LC-MS (ESI): m / z = 471.53 [M+H]+

[0496] The racemate (0.35 g) was separated by chiral prep-SFC into Compound 56-PK1 (0.101 g) and Compound 56-PK2 (0.100 g) as off-white solids.

[0497] Preparative SEC Conditions: Column / dimensions: (R, R) WHELK-01 (30x250mm), 5p % CO2: 60; % Co-solvent: 40% (0.2% 7N MeOH ammonia in ACN: IP A) (1 : 1) Flow: 100 mL / min; Back Pressure: 100 bar; Temperature: 30 °C; UV: 275 nm.

[0498] Compound 56-PK1:

[0499] LC-MS (ESI): m / z = 471.31 [M+H]+

[0500] 'H NMR (400 MHz, DMSO-d6): 8 8.52-8.35 (m, 1H), 7.99-7.98 (m, 1H), 7.89-7.86 (m, 1H), 7.61-7.45 (m, 5H), 5.16 (d, J= 3.6 Hz, 1H), 4.88-4.19 (m, 2H), 3.02 (s, 3H), 2.81 (s, 3H), 2.70-2.69 (m, 1H), 1.20-0.83 (m, 3H), 0.72-0.55 (m, 3H).

[0501] Compound 56-PK2:

[0502] LC-MS (ESI): m / z = 471.31 [M+H]+ 'H NMR (400 MHz, DMSO-d6): 6 8.52-8.35 (m, 1H), 8.00-7.98 (m, 1H), 7.89-7.86 (m, 1H), 7.61-7.45 (m, 5H), 5.16 (d, J= 3.6 Hz, 1H), 4.88-4.19 (m, 2H), 3.02 (s, 3H), 2.81 (s, 3H), 2.76-2.67 (m, 1H), 1.20-0.83 (m, 3H), 0.72-0.55 (m, 3H).

[0503] EXAMPLE 13: SCHEME 13

[0504] Synthesis of racemic Compound 7

[0505] To a stirred solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c] pyrazol-2(4H)-yl)- N, N-dimethylbenzamide hydrochloride (300 mg, 0.812 mmol) in N, N-dimethylformamide (1.5 mL, 5 V) were added 1 -phenylcyclobutane- 1 -carboxylic acid (286.3 mg, 1.625 mmol), PYBOP® (507.3 mg, 0.975 mmol) and N, N-diisopropylethylamine (1.1 mL, 6.499 mmol) at RT and stirred at same temperature for 16 h. The reaction was diluted with water (5 mL) and extracted with ethyl acetate (2 x 5 mL). The combined organic layer was washed with saturated NaCl solution (5 mL). The organic layer dried over anhydrous MgSC>4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (230-400 mesh) column chromatography using 50% ethyl acetate in petroleum ether followed by preparative Reverse Phase HPLC and lyophilisation to give 2-Chloro-4-(6-isopropyl-5-(l- phenylcyclobutane-l-carbonyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,N- dimethylbenzamide (90 mg, 23% yield) as a white solid.

[0506] Prep-HPLC purification Conditions:

[0507] Column / dimensions: X-B ridge Cl 8 (19*250), 5pm; Mobile phase A: 10mm Ammonium Bicarbonate in water; Mobile phase B: CAN; Gradient (Time / %B): 0 / 25, 1 / 25, 8 / 65,1 7.5 / 65, 17.6 / 100, 20 / 100, 20.1 / 25, 22 / 25; Flow rate: 17 ml / min; Solubility: ACN +THF+H2O LC-MS (m / z): 491.38 [M+H]+

[0508] 'H NMR (400 MHz, DMSO-< / 6): 8 8.23 (s, 1H), 7.90 (d, J= 2.0 Hz, 1H), 7.79 (dd, J= 8.4, 2.0 Hz, 1H), 7.46-7.38 (m, 5H), 7.27 (t, J= 7.2 Hz, 1H), 4.99 (d, J= 3.6 Hz, 1H), 4.08 (d, J = 13.6 Hz, 1H), 3.91 (d, J= 13.2 Hz, 1H), 3.00 (s, 3H), 2.87-2.67 (m, 5H), 2.65-2.61 (m, 1H), 2.44-2.35 (m, 2H), 1.96-1.94 (m, 1H), 1.83-1.81 (m, 1H), 1.10 (d, J= 7.2 Hz, 3H), 0.40 (d, J = 6.8 Hz, 3H). EXAMPLE 14: SCHEME 14

[0509] Synthesis of Compound 115-Racemic

[0510] To a stirred solution of 2-chloro-6-fluorobenzoic acid (0.165 g, 0.948 mmol, 1 equiv.) in DMF (10.5 mL) were added HATU (0.721 g, 1.896 mmol, 2 equiv.) and DIPEA (0.66 mL, 3.791 mmol, 4 equiv.) at 0 °C. The reaction was stirred for 5 min then 2-chloro-4-(6- isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,N-dimethylbenzamide hydrochloride (0.35 g, 0.948 mmol, 1 equiv.) was added. The reaction stirred at rt for 16 h. The reaction was diluted with water (25 mL). The mixture was extracted with ethyl acetate (50 mL x 2) filtered, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by silica gel (100-200) flash column using 0-70% EtOAc in petroleum ether to afford 2-chloro-4-(5-(2-chloro-6-fluorobenzoyl)-6-isopropyl-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,N-dimethylbenzamide (0.23 g, 49% yield) as a white solid.

[0511] LC-MS (ESI): m / z = 489.75 [M+H]+

[0512] Synthesis of Compound 115-PK1 and Compound 115-PK2

[0513] The Racemate (0.230 g) was separated by chiral prep-SFC into Compound 115-PK1 (0.06465 g) and Compound 115-PK2 (0.04690 g) as white solids.

[0514] Chiral Purification Method:

[0515] Column / dimensions: Conditions Column / dimensions: Chirapak AD-H (30x250) mm, 5p % CO2 : 70% % Co solvent : 30% (MeOH Ammonia in ACN: MeOH)(l : l) Flow : lOOmL / min Back Pressure : 100 bar Temperature : 30 0 C UV : 274 nm Solubility: MeOH +CAN 89.36 [M+H]+MSO-d6): d 8.53-8.39 (m, 1H), 8.01-7.99 (m, 1H), 7.90-7.86 (m, 1H), 2-7.39 (m, 3H), 5.18-4.89 (m, 1H), 4.62-4.25 (m, 2H), 3.02 (s, 3H), 0-0.89 (m, 3H), 0.70-0.58 (m, 3H).

[0516] LC-MS (ESI): m / z = 489.36 [M+H] 'H NMR (400 MHz, DMSO-d6): 3 8.53-8.39 (m, 1H), 8.01-7.99 (m, 1H), 7.90-7.86 (m, 1H), 7.61-7.55 (m, 1H), 7.52-7.39 (m, 3H), 5.18-4.89 (m, 1H), 4.62-4.25 (m, 2H), 3.02 (s, 3H), 2.81 (s, 3H), 2.69 (s, 1H), 1.20-0.89 (m, 3H), 0.70-0.58 (m, 3H).

[0517] EXAMPLE 15: SCHEME 15

[0518] Synthesis of 2-chloro-4-(6-isopropyl-5-(3-methyl-2-oxobutanoyl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,N-dimethylbenzamide

[0519] To a stirred solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)- N,N-dimethylbenzamide hydrochloride (0.5 g, 1.354 mmol) in N,N-dimethylformamide (2.5 mL, 5 V) were added 3-methyl-2-oxobutanoic acid (0.314 g, 2.708 mmol) and N,N- diisopropylethylamine (1.9 mL, 10.832 mmol) at RT. The reaction was maintained at RT for 5 minutes. PYBOP® (0.845 g, 1.625 mmol) was added to the reaction and stirred for 5 h. The reaction was quenched with ice cold water (10 mL) extracted with EtOAc (2 X 20 mL). The organic layer dried over anhydrous MgSCh, filtered, and concentrated. The crude product was purified by silica gel (230-400 mesh) column chromatography using 3% MeOH in DCM to get product. The product was triturated with 10% diethyl ether in pentane (5 mL) to give 2- chloro-4-(6-isopropyl-5-(3-methyl-2-oxobutanoyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)- yl)-N,N-dimethylbenzamide (0.4 g, 68%).

[0520] LC-MS (m / z): 431.49 [M+H]+

[0521] Synthesis of 2-chloro-4-(5-(2-hydroxy-3-methyl-2-(trifluoromethyl)butanoyl)-6- isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,N-dimethylbenzamide

[0522] To a solution of 2-chloro-4-(6-isopropyl-5-(3-methyl-2-oxobutanoyl)-5,6-dihydropyrrolo[3,4- c]pyrazol-2(4H)-yl)-N,N-dimethylbenzamide (0.34 g, 0.789 mmol) in tetrahydrofuran (3.4 mL, 10 V) at 0°C was added trifluorom ethyltrimethylsilane (2.24 g, 15.779 mmol) and maintained at same temperature for 1 h. Tetrabutylammonium fluoride (4.0 mL, 3.945 mmol, IM solution in THF) was added drop by drop at -5 °C. The reaction allowed stirring at -5 °C to 0 °C for 1 h. The reaction was cooled to -10 °C and quenched by adding saturated aqueous NH4CI (15 mL) over 5 minutes. The product extracted with EtOAc (2 x 25 mL). The combined organic layer was washed with water, dried over anhydrous MgSO4 and concentrated under reduced pressure to get 2-chloro-4-(5-(2-hydroxy-3-methyl-2- (trifluoromethyl)butanoyl)-6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,N- dimethylbenzamide (0.39 g, 99%).

[0523] LC-MS (m / z): 501.51 [M+H]+

[0524] Synthesis of Compound 1-PK1, Compound 1-PK2, Compound l-PK-3 and Compound l-PK-4

[0525] Compound 1 racemic compound isomers separated by chiral SFC. Obtained four peaks were concentrated separately and lyophilized to get Compound 1-PK1, Compound 1- PK2, Compound l-PK-3 and Compound l-PK-4.

[0526] Preparative chiral SFC Conditions:

[0527] Column / dimensions: Chiral Pak IH (30x250)mm,5p; % CO2 : 85%; % Co solvent : 15% (MeOH); Flow : lOOml / min; Back Pressure : 100 bar; Temperature: 30 °C; UV : 275 nm; Solubility: MeOH+THF

[0528] Obtained four isomers Compound 1-PK1, Compound 1-PK2, Compound l-PK-3 and Compound l-PK-4 re-purified using achiral SFC to remove aliphatic impurities. Four peaks were concentrated separately and lyophilized to give products Compound 1-PK1 (17 mg), Compound 1-PK2 (59 mg), Compound l-PK-3 (60 mg) and Compound l-PK-4 (15 mg) as a white solid. 1-PK1 preparative achiral SFC Condition:

[0529] Column / dimensions : DCPAK P4VP (30x250)mm,5p; % CO2 : 80%; % Co solvent : 20% (MeOH); Flow : lOOml / min; Back Pressure : 100 bar; Temperature : 30 °C; UV : 210 nm Solubility: MeOH+THF

[0530] Compound 1-PK2 and Compound 1-PK3 preparative achiral SFC Condition:

[0531] Column / dimensions : DCPAK P4VP (30x250)mm,5p; % CO2 : 80%; % Co solvent : 20% (MeOH); Flow : lOOml / min; Back Pressure : 100 bar; Temperature : 30 °C; UV : 220 nm; Solubility: MeOH+THF

[0532] Compound 1-PK4 preparative achiral SFC Condition:

[0533] Column / dimensions: DCPAK P4VP (30x250)mm,5p; % CO2 : 77%; % Co solvent : 23% (MeOH); Flow : lOOml / min; Back Pressure : 100 bar; Temperature : 30 °C; UV : 215 nm; Solubility: MeOH

[0534] Compound 1-PK1:

[0535] 1H-NMR (400 MHz, DMSO-< / 6): 8 8.41 (s, IH), 7.98 (d, J= 2.0 Hz, IH), 7.87 (dd, J= 8.4, 2.4 Hz, IH), 7.48 (d, J= 8.4 Hz, IH), 6.77 (brs, IH), 5.63-4.41 (m, 3H), 3.02 (s, 3H), 2.82 (s, 3H), 2.48-2.44 (m, 2H), 1.11 (d, J= 7.2 Hz, 3H), 1.00 (d, J= 6.8 Hz, 3H), 0.93 (d, J= 6.8 Hz, 3H), 0.56 (d, J= 6.8 Hz, 3H). LC-MS (m / z): 501.44 [M+H]+

[0536] Compound 1-PK2:

[0537] 1H-NMR (400 MHz, DMSO-< / 6): 6 8.42 (s, 1H), 7.98 (d, J= 2.0 Hz, 1H), 7.87 (dd, J= 8.4, 2.0 Hz, 1H), 7.48 (d, J= 8.4 Hz, 1H), 6.59 (brs, 1H), 5.62-4.44 (m, 3H), 3.02 (s, 3H), 2.82 (s, 3H), 2.70-2.63 (m, 1H), 2.47-2.44 (m, 1H), 1.12 (d, J= 7.2 Hz, 3H), 1.01 (d, J= 6.4 Hz, 3H), 0.94 (d, J= 6.8 Hz, 3H), 0.83 (d, J= 6.8 Hz, 3H)

[0538] LC-MS (m / z): 501.33 [M+H]+

[0539] Compound l-PK-3:

[0540] 1H-NMR (400 MHz, DMSO-< / 6): 6 8.42 (s, 1H), 7.98 (d, J= 2.0 Hz, 1H), 7.87 (dd, J= 8.4, 2.0 Hz, 1H), 7.48 (d, J= 8.4 Hz, 1H), 6.59 (brs, 1H), 5.62-4.44 (m, 3H), 3.02 (s, 3H), 2.82 (s, 3H), 2.70-2.63 (m, 1H), 2.47-2.44 (m, 1H), 1.12 (d, J= 7.2 Hz, 3H), 1.01 (d, J= 6.4 Hz, 3H), 0.94 (d, J= 6.8 Hz, 3H), 0.83 (d, J= 6.8 Hz, 3H)

[0541] LC-MS (m / z): 501.30 [M+H]+

[0542] Compound l-PK-4:

[0543] 1H-NMR (400 MHz, DMSO-< / 6): 6 8.41 (s, 1H), 7.98 (d, J= 2.0 Hz, 1H), 7.87 (dd, J= 8.4,

[0544] 2.4 Hz, 1H), 7.48 (d, J= 8.4 Hz, 1H), 6.77 (brs, 1H), 5.63-4.41 (m, 3H), 3.02 (s, 3H), 2.82 (s, 3H), 2.48-2.44 (m, 2H), 1.11 (d, J= 7.2 Hz, 3H), 1.00 (d, J= 6.8 Hz, 3H), 0.93 (d, J= 6.8 Hz, 3H), 0.56 (d, J= 6.8 Hz, 3H)

[0545] LC-MS (m / z): 501.30 [M+H]+

[0546] EXAMPLE 16: SCHEME 16

[0547] Step-1: Synthesis of 2-chloro-4-(6-isopropyl-5-(3-methyl-2-oxobutanoyl)-5,6- dihydropyrrolo[3,4-c] pyrazol-2(4H)-yl)-N, N-dimethylbenzamide:

[0548] To a stirred solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c] pyrazol-2(4H)-yl)- N, N-dimethylbenzamide hydrochloride (1.0 g, 2.708 mmol) in N, N-dimethylformamide (5.0 mL, 5 V) were added 3-methyl-2-oxobutanoic acid (629 mg, 5.416 mmol), PYBOP® (4.23 g, 8.124 mmol) and N, N-diisopropylethylamine (3.8 mL, 21.663 mmol) at RT and stirred at same temperature for 16 h. The reaction mass was diluted with water (5 mL) and the reaction was extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with saturated NaCl solution (5 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (230- 400 mesh) column chromatography using 70% ethyl acetate in petroleum ether to give 2- chloro-4-(6-isopropyl-5-(3-methyl-2-oxobutanoyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)- yl)-N,N-dimethylbenzamide (800 mg 75% yield) as a white solid.

[0549] LC-MS (m / z): 431.70 [M+H]+

[0550] Step-2: Synthesis of Compound 9 racemic

[0551] To the solution of 2-chloro-4-(6-isopropyl-5-(3-methyl-2-oxobutanoyl)-5,6- dihydropyrrolo[3,4-c] pyrazol-2(4H)-yl)-N, N-dimethylbenzamide (0.880 mg, 2.042 mmol) in tetrahydrofuran (8.8 mL, 10 V) was added Isopropyl magnesium bromide (1.5M solution in tetrahydrofuran) (8.3 mL, 14.295 mmol) at 0° C. The reaction was allowed to RT and stirred for 2 h. The reaction was quenched with ammonium chloride solution (10 mL) and the reaction was extracted with DCM (2 x 10 mL). The combined organic layer was washed with saturated NaCl solution (5 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (230- 400 mesh) column chromatography using 50% ethyl acetate in petroleum ether followed by achiral SFC purification to give 2-chloro-4-(5-(2-hydroxy-2-isopropyl-3-methylbutanoyl)-6- isopropyl-5,6-dihydropyrrolo [3,4-c]pyrazol-2(4H)-yl)-N, N-dimethylbenzamide (330 mg, 34% yield) as a white solid.

[0552] LC-MS (m / z): 475.82 [M+H]+

[0553] Preparative achiral SFC purification Conditions:

[0554] Column / dimensions: DCPAK P4VP (30x250) mm,5p; % CO2: 73%; % Co solvent: 27% (MeOH); Flow: 100 ml / min; Back Pressure: 100 bar; Temperature: 30 °C; UV: 220 nm; Solubility: MeOH + THF

[0555] Step-3: Synthesis of Compound-9-PKl and Compound-9-PK2:

[0556] The crude product was purified by chiral SFC purification.

[0557] Compound 9-PK1 and Compound 9-PK2 Chiral SFC purification Conditions:

[0558] Column / dimensions: Chiral Pak AD H (30x250) mm,5p% CO2: 65%; % CO2: 80; % Co solvent: 20 % (MeOH); Flow: 100 ml / min; Back Pressure: 100 bar; Temperature: 30 °C; UV: 28 0 nm; Solubility: MeOH + THF

[0559] LC-MS (m / z): 475.42 [M+H]+ 1H NMR (400 MHz, DMSO-d6): 6 1H-NMR (400 MHz, ) 6 8.41-8.38 (m, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.4, 2.0 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 5.66-5.10 (m, 2H), 4.85- 4.81 (m, 1H), 4.67-4.56 (m, 1H), 3.02 (s, 3H), 2.82 (s, 3H), 2.57-2.50 (m, 1H), 2.17-2.02 (m, 2H), 1.13-1.08 (m, 3H), 0.94-0.83 (m, 12H), 0.53-0.46 (m, 3H).

[0560] Compound 9-PK2:

[0561] LC-MS (m / z): 475.42 [M+H]+

[0562] 'H NMR (400 MHz, DMSO-d6): 6 8.41-8.38 (m, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.4, 2.0 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 5.66-5.10 (m, 2H), 4.85-4.81 (m, 1H), 4.67-4.56 (m, 1H), 3.02 (s, 3H), 2.82 (s, 3H), 2.57-2.50 (m, 1H), 2.17-2.02 (m, 2H), 1.13-1.08 (m, 3H), 0.94-0.83 (m, 12H), 0.53-0.46 (m, 3H).

[0563] EXAMPLE 17: SCHEME 17

[0564] Synthesis of Compound 69-Racemic

[0565] To a stirred solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c] pyrazol-2(4J7)-yl)- V, 7V-dimethylbenzamide (0.35 g, 0.948 mmol, 1.0 equiv.) in DCM (3.5 mL) and 1,3- dichloro-2-isocyanobenzene (0.36 g, 1.896 mmol, 2.0 equiv.) was added triethylamine (0.40 mL, 2.843 mmol, 3.0 equiv.) was added and the resulting mixture was stirred at RT for 16 h. The reaction was diluted with water (25 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure. The crude was purified by flash column (Davisil) chromatography using 0-100% ethyl acetate in petroleum ether to afford 2-(3-chloro-4- (dimethylcarbamoyl)phenyl)-7V-(2,6-dichlorophenyl)-6-isopropyl-2,6-dihydropyrrolo[3,4- c]pyrazole-5(4J7)-carboxamide (0.35 g, 71% yield) as a white solid.

[0566] The racemate (0.35 g) was separated by chiral prep-SFC into Compound 69-PK1 (0.109 g) and Compound 69-PK2 (0.103 g) as white solids.

[0567] Preparative SEC Conditions: Column / dimensions: Chirapak IH (30 x 250) mm, 5 p; %CC>2: 50; % Co solvent: 50 (MeOH); Flow: 100 mL / min; Back Pressure: 100 bar;

[0568] Temperature: 30 °C; UV: 275 nm. Compound 69-PK1:

[0569] LC-MS (ESI): m / z = 520.33 [M+H]+

[0570] 'H NMR (400 MHz, DMSO-d6): <5 8.50 (s, 1H), 8.41 (s, 1H), 8.00 (d, J= 2.0, 1H), 7.91-7.88 (m, 1H), 7.71-7.55 (d, J= 8.0 Hz, 2H), 7.50 (d, J= 8.4 Hz, 1H), 7.33 (d, J= 8.4 Hz, 1H), 4.98 (s, 1H), 4.65-4.55 (m, 2H), 3.03 (s, 3H), 2.83 (s, 3H), 2.60 (bs, 1H), 1.14 (d, J = 6.8 Hz, 3H), 0.64 (d, J = 6.8 Hz, 3H).

[0571] Compound 69-PK2:

[0572] LC-MS (ESI): m / z = 520.34 [M+H]+

[0573] 'H NMR (400 MHz, DMSO-d6): <5 8.49 (s, 1H), 8.41 (s, 1H), 8.00 (d, J= 2.0, 1H), 7.90-7.88 (m, 1H), 7.71-7.54 (d, J= 8.0 Hz, 2H), 7.49 (d, J= 8.4 Hz, 1H), 7.33 (d, J= 8.4 Hz, 1H), 4.97 (s, 1H), 4.65-4.55 (m, 2H), 3.02 (s, 3H), 2.82 (s, 3H), 2.59 (bs, 1H), 1.13 (d, J= 6.8 Hz, 3H), 0.64 (d, J = 6.8 Hz, 3H).

[0574] EXAMPLE 18: SCHEME 18

[0575] Step 1: Synthesis of 7V-(2,6-dichlorophenyl)-2-oxooxazolidine-3-sulfonamide

[0576] To a stirred solution of chlorosulfonyl isocyanate (0.87 g, 6.172 mmol, 1.0 equiv.) in dichloromethane (15 mL) at 0 °C was added a solution of 2-bromoethanol (0.76 g, 6.172 mmol, 1.0 equiv.) in dichloromethane (2.5 mL) over 5 min maintaining reaction temperature between 0-10 °C. The mixture was stirred for 30 min at same temperature and a mixture of 2,6-dichloroaniline (1.0 g, 6.172 mmol, 1.0 equiv.) and triethylamine (3.67 mL,18.516 mmol, 3.0 equiv.) in dichloromethane (2.5 mL) was added maintaining reaction temperature between 0-10 °C. The solution was warmed to RT and stirred at rt for 5 h. The reaction was diluted with water (30 mL) and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layer washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography using 0-40% ethyl acetate in petroleum ether to get7V-(2,6-dichlorophenyl)-2-oxooxazolidine-3-sulfonamide (1.0 g, 52%) as an off- white solid.

[0577] LC-MS (ESI): m / z = 309.32 [M-H]' Step 2: Synthesis of 2-chloro-4-(5-(7V-(2,6-dichlorophenyl)sulfamoyl)-6-isopropyl-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4Z7)-yl)-7V,7V-dimethylbenzamide

[0578] To a stirred solution of A-(2,6-dichlorophenyl)-2-oxooxazolidine-3-sulfonamide (0.350 g, 1.125 mmol, 1.0 equiv.) in pyridine (7.0 mL) was added 2-chloro-4-(6-isopropyl-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)-A,A-dimethylbenzamide (0.300 g, 0.900 mmol, 0.8 equiv.). The reaction was stirred at 80 °C for 3 h. Reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography in 0-40% EtOAc in petroleum ether to afford 2-chloro-4-(5-(7V-(2,6-dichlorophenyl)sulfamoyl)-6-isopropyl-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)-A,A-dimethylbenzamide (110 mg) as a pale brown solid.

[0579] LC-MS (ESI): m / z = 556.62 [M+H]+

[0580] Step 3: Synthesis of Compound 18-PK1 and Compound 18-PK2

[0581] The racemate compound (0.190 g) was separated by chiral prep SFC Compound 18-PK1 (59 mg) and Compound 18-PK2 (62 mg) as white solids.

[0582] Chiral SFC purification Conditions:

[0583] Column / dimensions: CHIRALPAK IK (30 x 250) mm, 5p; %CC>2: 60; %Co solvent: 40 (0.1% DEA in MeOH) Flow: 100 mL / min; Back Pressure: 100 bar; Temperature: 300C; UV: 220 nm; Solubility: MeOH + THF.

[0584] Compound 18-PK1:

[0585] LC-MS (ESI): m / z = 556.24 [M+H]+

[0586] 'H NMR (400 MHz, DMSO-< / 6): d 9.67 (s, 1H), 8.44 (s, 1H), 7.99 (d, J= 2.0 Hz, 1H), 7.88 (dd, J= 8.4 & 2.0 Hz, 1H), 7.52-7.47 (m, 3H), 7.32-7.30 (m, 1H), 4.79 (d, J= 2.4 Hz, 1H), 4.60-4.43 (m, 2H), 3.02 (s, 3H), 2.82 (s, 3H), 2.38-2.32 (m, 1H), 1.11 (d, J= 6.8 Hz, 3H), 0.65 (d, = 6.4 Hz, 3H).

[0587] Compound 18-PK2:

[0588] LC-MS (ESI): m / z = 556.24 [M+H]+

[0589] 'H NMR (400 MHz, DMSO-< / 6): 69.67 (s, 1H), 8.44 (s, 1H), 7.99 (d, J= 2.0 Hz, 1H), 7.88 (dd, J= 8.4 & 2.0 Hz, 1H), 7.52-7.47 (m, 3H), 7.32-7.30 (m, 1H), 4.79 (d, J= 2.4 Hz, 1H), 4.60-4.43 (m, 2H), 3.02 (s, 3H), 2.82 (s, 3H), 2.38-2.35 (m, 1H), 1.11 (d, J= 6.8 Hz, 3H), 0.65 (d, = 6.4 Hz, 3H). EXAMPLE 19: SCHEME 19

[0590] Step 1: Synthesis of Compound 67-Racemic

[0591] To a stirred solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)- A,A-dimethylbenzamide hydrochloride (0.35 g, 0.951 mmol, 1.0 equiv.) in DCM (3.5 mL) was added triethyl amine (0.71 mL, 4.755 mmol, 5.0 equiv.) and stirred at rt for 10 min. Isopropyl sulfamoyl chloride (0.373 g, 2.377 mmol, 2.5 equiv.) was added at 0 °C and the reaction was stirred at rt for 16 h. The reaction was concentrated under reduced pressure and crude compound was purified by flash column (davisil silica; 0-70 % EtOAc in Pet. ether) to afford 2-chloro-4-(6-isopropyl-5-(7V-isopropylsulfamoyl)-5,6-dihydropyrrolo[3,4-c]pyrazol- 2(4J7)-yl)-A,A-dimethylbenzamide (0.35 g, 76%) as an off-white solid.

[0592] LC-MS (ESI): m / z = 454.66 [M+H]+

[0593] Spectra:

[0594] Step-2: Synthesis of Compound 67-PK1 and Compound 67-PK2

[0595] The racemate (0.35 g) was separated by chiral SFC purification to give Compound 67-PK1 (97 mg) and Compound 67-PK2 (105 mg) as off-white solids.

[0596] Chiral SFC purification Conditions:

[0597] Column / dimensions: Chiralpak AD-H (30*250) mm, 5 p; % CO2: 73; %Co solvent: 27 (0.1% NH3 in MeOH), Flow: 100 mL / min; Back Pressure: 100 bar; Temperature: 30 °C; UV: 220 nm; Solubility: MeOH.

[0598] Compound 67-PK1:

[0599] LC-MS (ESI): m / z = 454.38 [M+H]+

[0600] 'H NMR (400 MHz, DMSO-d6): 6 8.42 (s, 1H), 7.97 (d, J= 2.0 Hz, 1H), 7.88-7.85 (m, 1H), 7.48 (d, J= 8.4 Hz, 1H), 7.26 (d, J= 7.6 Hz, 1H), 4.69-4.65 (m,lH), 4.47-4.30 (m, 2H), 3.43- 3.38 (m, 1H), 3.02 (s, 3H), 2.81 (s, 3H), 2.29.2.24 (m, 1H), 1.11 (d, J= 6.8 Hz, 3H), 1.07- 1.03 (m, 6H), 0.70 (d, J= 6.8 Hz, 3H).

[0601] Compound 67-PK2:

[0602] LC-MS (ESI): m / z = 454.38 [M+H]+ 'H NMR (400 MHz, DMSO-d6): 6 8.42 (s, 1H), 7.97 (d, J= 2.0 Hz, 1H), 7.88-7.85 (m, 1H), 7.48 (d, J= 8.4 Hz, 1H), 7.27 (d, J= 8.0 Hz, 1H), 4.69-4.65 (m,lH), 4.47-4.30 (m, 2H), 3.43- 3.36 (m, 1H), 3.02 (s, 3H), 2.81 (s, 3H), 2.29.2.26 (m, 1H), 1.11 (d, J= 6.8 Hz, 3H), 1.07- 1.04 (m, 6H), 0.70 (d, J= 6.8 Hz, 3H).

[0603] EXAMPLE 20: SCHEME 20

[0604] Step-1: Synthesis of methyl 4-methoxy-4-(trifluoromethyl)cyclohexane-l-carboxylate To a stirred solution of 4-hydroxy-4-(trifluoromethyl)cyclohexane-l -carboxylic acid (5.0 g, 23.566 mmol, 1.0 equiv.) in DMF:THF (100 mL; 1 : 1) at 0 °C was portion wise added NaH (2.8 g, 70.699 mmol, 3.0 equiv.) and the resulting solution was stirred at same temperature for 5 min. lodomethane (10.4 mL, 164.964 mmol, 7.0 equiv.) was added and the reaction was stirred at RT for 16 h. The reaction was cooled to 0 °C and ice-cold water (100 mL) was added. The resulting mixture was extracted with ethyl acetate (100 mL x 2), combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography using 0-20% EtOAc in petroleum ether to afford methyl 4-methoxy-4-(trifluoromethyl)cyclohexane-l -carboxylate (5.5 g, 97%) as a colorless liquid.

[0605] 'H NMR (400 MHz, CDCh): 8 3.67 (s, 3H), 3.38 (d, J= 1.2 Hz, 3H), 2.29-2.24 (m, 1H), 2.07-2.03 (m, 2H), 1.91-1.87 (m, 2H), 1.70-1.54 (m, 2H), 1.52-1.47 (m, 2H).

[0606] Step-2: Synthesis of (4-methoxy-4-(trifluoromethyl)cyclohexyl)methanol

[0607] To a stirred solution of methyl 4-methoxy-4-(trifluoromethyl)cyclohexane-l -carboxylate (5.5 g, 22.895 mmol, 1.0 equiv.) in THF (110.0 mL) was added lithium aluminium hydride, 2M solution in THF (22.9 mL, 45.791 mmol, 2.0 equiv.) dropwise at 0 °C. The reaction was stirred at 0 °C for 2 h. The Reaction was carefully quenched at 0 °C with ice-cold water (2.4 mL) followed by with 10% aq. NaOH solution (2.4 mL). The mixture was filtered and the filtrate was concentrated under reduced pressure to get (4-methoxy-4- (trifluoromethyl)cyclohexyl)methanol (4 g, crude) as a colorless viscous liquid.

[0608] 'H NMR (400 MHz, CDC13): 6 3.50 (d, J= 6.0 Hz, 2H), 3.39 (d, J= 1.2 Hz, 3H), 2.06-2.02 (m, 2H), 1.72-1.54 (m, 2H), 1.53-1.42 (m, 3H), 1.28-1.22 (m, 3H).

[0609] Step-3: Synthesis of 4-methoxy-4-(trifluoromethyl)cyclohexane-l-carbaldehyde

[0610] To a stirred solution of (4-methoxy-4-(trifluoromethyl)cyclohexyl)methanol (2.0 g, 9.425 mmol, 1.0 equiv.) in DCM (40.0 mL) was added pyridinium chlorochromate (4.1 g, 18.849 mmol, 2.0 equiv.) at 0 °C and the resulting solution was stirred for 2 h at RT. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (100- 200 mesh) column chromatography using 0-15% EtOAc in petroleum ether to afford 4- methoxy-4-(trifluoromethyl)cyclohexane-l-carbaldehyde (0.95 g, 48%) as a colorless viscous liquid.

[0611] Step-4: Synthesis of 2-chloro-4-(6-isopropyl-5-((4-methoxy-4- (trifluoromethyl)cyclohexyl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4Z / )-yl)- V, V- dimethylbenzamide (Compound 48-Racemic)

[0612] To a stirred solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)- A,A-dimethylbenzamide hydrochloride (0.4 g, 1.083 mmol, 1.0 equiv.) and 4-methoxy-4- (trifluoromethyl)cyclohexane-l-carbaldehyde (1.138 g, 5.416 mmol, 5.0 equiv.) in DCM (16 mL) was added sodium cyanoborohydride (0.14 g, 2.166 mmol, 2.0 equiv.) at RT. The reaction was stirred at RT for 16 h. The reaction was diluted with water and extracted with DCM (50 mL x 2) then collected organic part was washed with brine (50 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography using 0-30% EtOAc in petroleum ether to afford 2-chloro-4-(6-isopropyl-5- ((4-methoxy-4-(trifluoromethyl)cyclohexyl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)- yl)-A,A-dimethylbenzamide (0.32 g, 56%) as a white solid.

[0613] LC-MS (ESI): m / z = 527.38 [M+H]+

[0614] Step-4: Synthesis of Compound 48-PK1 and Compound 48-PK2

[0615] The racemate (0.32 g) was separated by chiral prep-SFC into Compound 48-PK1 (0.09080 g) and Compound 48-PK2 (0.09440 g) as white solids. Chiral Purification Method:

[0616] Column / dimensions: CHIRALPAK IF (30 x 250) mm, 5 p % CO2: 70; % Co solvent: 30 (0.1% 7N MeOH ammonia in MeOH); Flow: 100 mL / min; Back Pressure: 100 bar; Temperature: 30 °C; UV: 280 nm; Solubility: MeOH. 527.38 [M+H]+DMSO-d6): 6 8.28 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 8.4 & J = 8.4 Hz, 1H), 4.12 (d, J = 12.4 Hz, 1H), 3.62 (d, J = 3.2 Hz, 1H), 01 (s, 3H), 2.81 (s, 3H), 2.59-2.56 (m, 2H), 1.97-1.91 (m, 4H), 1.60- 12 (m, 4H), 1.09-0.98 (m, 1H), 0.79 (d, J = 4.0 Hz, 3H).

[0617] LC-MS (ESI): m / z = 527.38 [M+H]+

[0618] 'H NMR (400 MHz, DMSO-d6): 8.28 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 8.4 &

[0619] 2.0 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 4.12 (d, J = 12.4 Hz, 1H), 3.63 (d, J = 3.2 Hz, 1H), 3.39-3.32 (m, 4H), 3.01 (s, 3H), 2.81 (s, 3H), 2.57-2.59 (m, 2H), 1.96 (d, J = 12.0 Hz, 4H), 1.60-1.49 (m, 4H), 1.17-1.12 (m, 4H), 1.06-0.98 (m, 1H), 0.79 (d, J = 6.4 Hz, 3H).

[0620] EXAMPLE 21: SCHEME 21

[0621] Step-1: Synthesis of trimethyl((8-(trifluoromethyl)-l,4-dioxaspiro[4.5]decan-8- yl)oxy)silane

[0622] To a stirred solution of l,4-dioxaspiro[4.5]decan-8-one (10.0 g, 64.029 mmol, 1.0 equiv.) in 1,2-dimethoxy ethane (100 mL) was added caesium carbonate (31.3 g, 96.044 mmol, 1.5 equiv.) under N2. After 5 min solution of trimethyl (trifluoromethyl)silane (91.043 g, 640 mmol, 10.0 equiv.) in 1,2-dimethoxy ethane (200 mL) was dropwise added. The resultant mixture was stirred at rt for 16 h. The reaction was quenched by water (250 mL) and extracted with DCM (2 x 250 mL). The combined organic layer washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) flash column using 0-20% ethyl acetate in petroleum ether to afford trimethyl((8-(trifluoromethyl)-l,4-dioxaspiro[4.5]decan-8- yl)oxy)silane (8.0 g, 41% yield) as a light brown liquid.

[0623] Step-2: Synthesis of 8-(trifluoromethyl)-l,4-dioxaspiro[4.5]decan-8-ol

[0624] To a stirred solution of trimethyl((8-(trifluoromethyl)-l,4-dioxaspiro[4.5]decan-8- yl)oxy)silane (8.0 g, 26.812 mmol, 1.0 equiv.) was added tetrabutylammonium fluoride (ca. Imol / L in tetrahydrofuran) (107 mL, 107.247 mmol, 4.0 equiv.) at 0 °C. The resultant mixture was stirred at rt for 3 h. the reaction was quenched by ice cold water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer washed with brine (100 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford 8- (trifluoromethyl)-l,4-dioxaspiro[4.5]decan-8-ol (6.0 g, crude) as a brown viscous liquid.

[0625] Step-3: Synthesis of 8-methoxy-8-(trifluoromethyl)-l,4-dioxaspiro[4.5]decane

[0626] To a stirred solution of 8-(trifluoromethyl)-l,4-dioxaspiro[4.5]decan-8-ol (6.0 g, 26.526 mmol, 1.0 equiv.) in tetrahydrofuran (60 mL) was added sodium hydride (60%, dispersion in Paraffin Liquid) (2.1 g, 53.052 mmol, 2.0 equiv.) at 0 °C, and stirred for 1 h. lodomethane (18.8 g, 132.629 mmol, 5.0 equiv.) was dropwise added and the mixture was stirred at RT for 16 h. the reaction was quenched with ice cold water (50 mL) and extracted with DCM (2 x 100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford 8-methoxy-8-(trifluoromethyl)- l,4-dioxaspiro[4.5]decane (2.5 g, 39% yield) as a pale yellow liquid.

[0627] 'H NMR (400 MHz, CDCI3): 8 4.00-3.93 (m, 1H), 3.41 (s, 3H), 2.00-1.97 (m, 2H), 1.89- 1.81 (m, 4H), 1.78-1.74 (m, 2H).

[0628] Step-4: Synthesis 4-methoxy-4-(trifluoromethyl) cyclohexan-l-one

[0629] To a stirred solution of 8-methoxy-8-(trifluoromethyl)-l,4-dioxaspiro[4.5]decane (1.0 g, 4.163 mmol, 1.0 equiv.) in mixture of acetone (5 mL) and water (2.5 mL) was added p- toluenesulfonic acid monohydrate (0.16 g, 0.833 mmol, 0.16 equiv.). The resultant mixture was refluxed for 16h. the reaction was diluted with water (50 mL) and extracted with diethyl ether (2 x 50 mL). The combined organic dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by silica gel (100-200 mesh) flash column using 0-20% ethyl acetate in petroleum ether to afford 4-methoxy-4- (trifluoromethyl) cyclohexan-l-one (0.5 g, 61% yield) as a brown viscus liquid.

[0630] 'H NMR (400 MHz, CDC13): 6 3.52 (s, 3H), 2.60-2.51 (m, 3H), 2.36-2.30 (m, 4H), 2.02- 1.94 (m, 2H).

[0631] Step-5: Synthesis of 2-chloro-4-(6-isopropyl-5-(4-methoxy-4- (trifluoromethyl)cyclohexyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4Z / )-yl)-7V,7V- dimethylbenzamide (Compound 47-racemic)

[0632] To a stirred solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)- V V-dimethylbenzamide hydrochloride (0.5 g, 1.354 mmol, 1.0 equiv.) in DCM (5 mL) was added 4-methoxy-4-(trifluoromethyl)cyclohexan-l-one (1.3 g, 6.770 mmol, 5.0 equiv.) at rt. After Ih, sodium cyanoborohydride (0.26 g, 4.062 mmol, 3.0 equiv.) was added in portions at 0 °C. The resultant mixture was stirred at rt for 6 h. The reaction was diluted with water (25 mL) and extracted with ethyl acetate (2 x 25 mL). The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography using 0-40% ethyl acetate in petroleum ether followed by achiral SFC to afford 2-chloro-4-(6-isopropyl-5-(4-methoxy-4- (trifluoromethyl)cyclohexyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)-A, N- dimethylbenzamide (0.08 g, 10%) as an off-white solid.

[0633] Compound 47 racemate achiral SFC purification Conditions:

[0634] DCPAK P4VP (30 x 250) mm, 5p; %CCh: 85; %Co solvent: 10 (0.2 % Isopropyl amine in 2- propanol; Flow: 95 mL / min; Back Pressure: 100 bar, Temperature: 30 °C, UV: 280 nm; Solubility: MeOH+THF,

[0635] The racemate (0.08 g) was separated by chiral prep-SFC into Compound 47-PK1 (0.025 g) and Compound 47-PK2 (0.017 g) as off-white solids.

[0636] Preparative SFC Conditions:

[0637] Column / dimensions: Chiralpak IH (30 x 250) mm, 5p; %CC>2: 75; %Co solvent: 25% (0.2% 7N MeOHic ammonia); Flow rate: 100 mL / min; Back Pressure: 100 bar, Temperature: 30 °C, UV: 279 nm.

[0638] Compound 47-PK1:

[0639] LC-MS (ESI): m / z= 513.37 [M+H]+

[0640] 'H NMR (400 MHz, DMSO-d6): 3 8.26 (s, IH), 7.93 (d, J= 2.0 Hz, IH), 7.83 (dd, J= 8.4 & 2.0 Hz, IH), 7.43 (d, J= 8.4 Hz, IH), 3.96-3.91 (m, 2H), 3.80-3.76 (m, IH), 3.35 (s, 3H), 3.01 (s, 3H), 2.81-2.76 (m, 4H), 2.01-1.92 (m, 3H), 1.70-1.57 (m, 2H), 1.55-1.42 (m, 4H), 1.12 (d, J= 6.8 Hz, 3H), 0.75 (d, J= 6.4 Hz, 3H). Compound 47-PK2:

[0641] LC-MS (ESI): m / z= 513.41 [M+H]+

[0642] 'H NMR (400 MHz, DMSO-d6): <5 8.26 (s, 1H), 7.93 (d, J= 2.0 Hz, 1H), 7.83 (dd, J= 8.4 & 2.0 Hz, 1H), 7.43 (d, J= 8.4 Hz, 1H), 3.96-3.91 (m, 2H), 3.80-3.76 (m, 1H), 3.35 (s, 3H), 3.01 (s, 3H), 2.81-2.76 (m, 4H), 2.00-1.92 (m, 3H), 1.70-1.59 (m, 2H), 1.55-1.43 (m, 4H), 1.12 (d, J= 6.8 Hz, 3H), 0.75 (d, J= 6.8 Hz, 3H).

[0643] EXAMPLE 22: SCHEME 22

[0644] Step-1: Synthesis of 4-(5-acetyl-6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)- 2-chloro- V, V-dimethylbenzamide

[0645] To a stirred solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)- 7V,7V-dimethylbenzamide hydrochloride (1.0 g, 2.717 mmol, 1.0 equiv.) and triethyl amine (1.1 mL, 8.124 mmol, 3.0 equiv.) in DCM (10.00 mL) was dropwise added acetic anhydride (0.28 mL, 2.979 mmol, 1.1 equiv.) at 0 °C. The reaction was diluted with water (50 mL) and DCM (2 x 100 mL). The combined organic layer was washed with brine (50 mL), was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) flash column using 0-20% ethyl acetate in petroleum ether to afford 4-(5-acetyl-6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4Z / )- yl)-2-chloro-7V,7V-dimethylbenzamide (0.5 g 49%) as an off white solid.

[0646] LC-MS (ESI): m / z= 375.55 [M+H]+

[0647] Step-2: Synthesis of ethyl 4-(2-(3-chloro-4-(dimethylcarbamoyl)phenyl)-6-isopropyl-2,6- dihydr opyr rolo [3,4-c] pyrazol-5(4EZ)-yl)-2,4-dioxobutanoate

[0648] To a stirred solution of 4-(5-acetyl-6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)- 2-chloro-7V,7V-dimethylbenzamide (0.5 g, 1.334 mmol, 1.0 equiv.) in THF (5.0 mL) was added potassium tert-Butoxide (0.33 g, 2.934 mmol, 2.2 equiv.) and diethyl oxalate (0.36 mL, 2.668 mmol, 2.0 equiv.). The resultant mixture was stirred at 80 °C for 1 h in microwave. The reaction was diluted with water (25 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (230-400 mesh) flash column using 0-30% ethyl acetate in petroleum ether to afforded ethyl 4-(2-(3- chloro-4-(dimefhylcarbamoyl)phenyl)-6-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4J7)- yl)-2,4-dioxobutanoate (0.3 g, 47% ) as a white sticky solid.

[0649] LC-MS (ESI): m / z= 475.68 [M+H]+

[0650] Step-3: Synthesis of ethyl 5-(2-(3-chloro-4-(dimethylcarbamothioyl)phenyl)-6-isopropyl-

[0651] 2.6-dihydropyrrolo|3.4-c|pyrazol- (4 / / )-yl)-l-(2.6-dichlorobenzyl)-l / / -pyrazole-3- carboxylate

[0652] To a stirred solution ethyl 4-(2-(3-chloro-4-(dimethylcarbamoyl)phenyl)-6-isopropyl-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4J7)-yl)-2,4-dioxobutanoate (0.3 g, 0.632 mmol, 1.0 equiv.) and pyridine (0.2 mL, 2.527 mmol, 4.0 equiv.) in THF (15.0 mL) were added (2,6- dichlorobenzyl) hydrazine hydrochloride (0.17 g, 0.758 mmol, 1.2 equiv.) and Lawesson's reagent (0.56 g, 1.390 mmol, 2.2 equiv.). The resultant mixture was stirred at 60 °C for 16 h and concentrated under reduced pressure. The crude product was purified by silica gel (230- 400 mesh) flash column using 0-30% ethyl acetate in petroleum ether to afford ethyl 5-(2-(3- chloro-4-(dimethylcarbamothioyl)phenyl)-6-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazol- 5(4J7)-yl)-l-(2,6-dichlorobenzyl)-lJ / -pyrazole-3-carboxylate (0.26 g, 63%) as a pale yellow solid.

[0653] LC-MS (ESI): m / z= 645.64 [M+H]+

[0654] Step-4: Synthesis of ethyl 5-(2-(3-chloro-4-(dimethylcarbamoyl)phenyl)-6-isopropyl-2,6- dihydropyrrolo|3.4-c|pyrazol-5(4 / / )-yl)-l-(2.6-dichlorobenzyl)-l / / -pyrazole-3- carboxylate

[0655] To a stirred solution of ethyl 5-(2-(3-chloro-4-(dimethylcarbamothioyl)phenyl)-6-isopropyl-

[0656] 2.6-dihydropyrrolo[3,4-c]pyrazol-5(4J7)-yl)-l-(2,6-dichlorobenzyl)-17 / -pyrazole-3- carboxylate (0.25 g, 0.387 mmol, 1.0 equiv.) in DCM (3.8 mL) was dropwise added mCPBA (0.080 g, 0.464 mmol, 1.2 equiv.) at 0 °C. The resultant mixture was stirred at rt for 4 h then diluted with sat. ammonium chloride (25 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by Prep. HPLC.

[0657] (Column / dimensions: X SELECT C18 (19 x 250) 5 um; Mobile phase A: 0.1% FA in water; Mobile phase B: Acetonitrile; Gradient (Time / %B): 0 / 60, 1 / 60, 10 / 85, 13.5 / 85, 13.6 / 100, 15 / 100, 15.1 / 60, 18 / 60; Flow rate: 17 mL / min; Solubility: Acetonitrile + THF) to afford ethyl 5-(2-(3-chloro-4-(dimethylcarbamoyl)phenyl)-6-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazol- 5(4J7)-yl)-l-(2,6-dichlorobenzyl)-U / -pyrazole-3-carboxylate (0.08 g 33% yield) as a white solid.

[0658] LC-MS (ESI): m / z= 629.87 [M+H]+

[0659] Step-5: Synthesis of Compound 21-Racemic

[0660] To a stirred solution of ethyl 5-(2-(3-chloro-4-(dimethylcarbamoyl)phenyl)-6-isopropyl-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4J7)-yl)-l-(2,6-dichlorobenzyl)-U / -pyrazole-3-carboxylate (0.075 g, 0.119 mmol, 1.0 equiv.) in DCM (1.5 mL) was dropwise added methyl magnesium bromide, 3M in diethyl ether (0.16 mL, 0.476 mmol, 4.0 equiv.) at 0 °C under nitrogen. The resulting mixture was stirred at rt for 1 h then quenched with sat. solution of ammonium chloride solution (5 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic layer was washed with brine (30 mL). The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) flash column by using 0-100% ethyl acetate in petroleum ether to afford 2- chloro-4-(5-(l-(2,6-dichlorobenzyl)-3-(2-hydroxypropan-2-yl)-U / -pyrazol-5-yl)-6-isopropyl- 5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)-A,A-dimethylbenzamide (0.05 g, 68% yield) as an off white solid.

[0661] The racemate (0.05 g) was separated by chiral prep-SFC into Compound 21-PK1 (8.9 mg) and Compound 21-PK2 (6.4 mg) as white solids.

[0662] Preparative SEC Conditions: Column / dimensions: CHIRALPAK H4 (30*250) mm; 5p; %CC>2: 65; %Co solvent: 35 (0.2% 7N MeOH ammonia in MeOH); Flow rate: 100 mL / min;

[0663] Back Pressure: 100 bar, Temperature: 30 °C, UV: 280 nm, solubility: MeOH.

[0664] Compound 21-PK1:

[0665] LC-MS (ESI): m / z = 615.42 [M+H]+

[0666] 'H NMR (400 MHz, DMSO-d6): 8 8.42 (s, 1H), 8.00 (d, J= 2.0 Hz, 1H), 7.89 (dd, J= 8.4 & 2.0 Hz, 1H), 7.50-7.47 (m, 3H), 7.40-7.36 (m, 1H), 6.01 (s, 1H), 5.38 (q, J= 11.2 Hz, 2H), 4.77 (d, J= 12.0 Hz, 1H), 4.66-4.62 (m, 2H), 4.05 (d, J= 12.0 Hz, 1H), 3.03 (s, 3H), 2.83 (s, 3H), 2.00-1.93 (m, 1H), 1.26-1.24 (m, 6H), 1.14 (d, J = 6.8 Hz, 3H), 0.80 (d, J = 6.4 Hz, 3H).

[0667] Compound 21-PK2:

[0668] LC-MS (ESI): m / z = 615.05 [M+H]+

[0669] 'H NMR (400 MHz, DMSO-d6): 6 8.41 (s, 1H), 8.00 (d, J= 2.0 Hz, 1H), 7.89 (dd, J= 8.4

[0670] & 2.0 Hz, 1H), 7.50-7.47 (m, 3H), 7.40-7.36 (m, 1H), 6.01 (s, 1H), 5.38 (q, J= 11.2 Hz, 2H), 4.77 (d, J= 11.6 Hz, 1H), 4.66-4.62 (m, 2H), 4.05 (d, J= 12.4 Hz, 1H), 3.02 (s, 3H), 2.83 (s, 3H), 2.00-1.93 (m, 1H), 1.26-1.24 (m, 6H), 1.15 (d, J = 6.8 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H).

[0671] EXAMPLE 23: SCHEME 23 Step 1: Synthesis of tert-butyl 2-(3-chloro-4-(methoxycarbonyl)phenyl)-6-isopropyl-2,6- d ihy dr opyrrolo|3.4-c|pyrazole-5(4 / / )-car boxy late

[0672] To a stirred solution of tert-butyl 6-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4Z / )- carboxylate (4.0 g, 15.915 mmol, 1.0 equiv.) and methyl 4-bromo-2-chlorobenzoate (4.765 g, 19.098 mmol, 1.2 equiv.) in 1,4 dioxane (40 mL) were added potassium carbonate (6.6 g, 47.746 mmol, 3.0 equiv.) and copper(I) iodide (1.5 g, 7.958 mmol, 0.5 equiv.). The mixture was purged with nitrogen for 10 min and (±)-traws-l,2-diaminocyclohexane (0.91 g, 7.958 mmol, 0.5 equiv.) was added. The resulting mixture was heated at 100 °C for 16 h. The mixture was filtered through celite, concentrated under reduced pressure and purified by flash column (davisil silica) using 0-20% EtOAc in petroleum ether to afford tert-butyl 2-(3- chloro-4-(methoxycarbonyl)phenyl)-6-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4Z / )- carboxylate (3.6 g, 54%) as an off white solid. LC-MS (ESI): m / z= 420.68 [M+H]+

[0673] Step 2: Synthesis of methyl 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol- 2(4ET)-yl)benzoate hydrochloride

[0674] To solution of tert-butyl 2-(3-chloro-4-(methoxycarbonyl)phenyl)-6-isopropyl-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4J7)-carboxylate (3.6 g, 8.573 mmol, 1.0 equiv.) in DCM (18 mL) at 0 °C was added 4M HC1 in dioxane (18 mL). The reaction was allowed to stir at rt for 2 h. The reaction was dried under vacuum and the crude compound was triturated with diethyl ether (3 X 50 mL) to afford methyl 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4- c]pyrazol-2(4J7)-yl)benzoate hydrochloride (2.7 g, crude) as an off white solid.

[0675] LC-MS (ESI): m / z= 320.72 [M+H]+

[0676] Step 3: Synthesis of methyl 2-chloro-4-(6-isopropyl-5-(2-(trifluoromethyl)pyrimidin-4- yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4ET)-yl)benzoate

[0677] To a stirred solution of methyl 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol- 2(4J7)-yl)benzoate hydrochloride (3.0 g, 8.421 mmol, 1.0 equiv.) and DIPEA (7.5 mL, 42.106 mmol, 5.0 equiv.) in IPA (30 mL) was added 4-chloro-2-(trifluoromethyl)pyrimidine (1.9 g, 10.105 mmol, 1.2 equiv.) at rt. The reaction was concentrated under reduced pressure and purified by flash column (davisil silica) using 0-80% EtOAc in petroleum ether to afford methyl 2-chloro-4-(6-isopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)benzoate (3.0 g, 76%) as an off white solid.

[0678] LC-MS (ESI): m / z= 466.67 [M+H]+

[0679] Step 4: Synthesis of 2-chloro-4-(6-isopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)-5,6- dihydr opyr rolo [3,4-c] pyrazol-2(4Z7)-yl)benzoic acid

[0680] To a solution of methyl 2-chloro-4-(6-isopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)benzoate (2.5 g, 5.366 mmol, 1.0 equiv.) in THF :MeOH: water (36 mL; 1 : 1 : 1) at 0 °C was added LiOH monohydrate (0.68 g, 16.099 mmol, 3.0 equiv.) and the mixture was stirred at rt for 6 h. The reaction was concentrated under reduced pressure. Crude compound was taken in water (25 mL) and neutralize with 10% aq. citric acid. The solid formed was filtered, washed with fresh cold water and dried under vacuum to afford 2-chloro-4-(6-isopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)- 5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)benzoic acid (2.0 g, 82%) as an off white solid.

[0681] LC-MS (ESI): m / z= 452.63 [M+H]+

[0682] Step 5: Synthesis of azetidin-l-yl(2-chloro-4-(6-isopropyl-5-(2- (trifluoromethyl)pyrimidin-4-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4ZZ)- yl)phenyl)methanone (Compound 87-Racemate) To a stirred solution of 2-chloro-4-(6-isopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)benzoic acid (0.35 g, 0.775 mmol, 1.0 equiv.) and DIPEA (0.690 mL, 3.873 mmol, 5.0 equiv.) in dry DMF (3.5 mL) at 0 °C was added HATU (0.44 g, 1.162 mmol, 1.5 equiv.) followed by azetidine hydrochloride (0.11 g, 1.162 mmol, 1.5 equiv.). The reaction was stirred at rt for 4 h. Ice cold water (30 mL) was added and extracted with ethyl acetate (3 X 50 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude compound was purified by flash column (davisil silica) using 0-10% MeOH in DCM to afford azetidin-l-yl(2-chloro-4-(6-isopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)- 5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)phenyl)methanone (0.3 g, 78%) as an off white solid.

[0683] LC-MS (ESI): m / z= 491.75 [M+H]+

[0684] Step 6: Synthesis of Compound 87-PK1 and Compound 87-PK2

[0685] The racemate (0.3 g) was separated by chiral prep-SFC to give Compound 87-PK1 (80 mg) and Compound 87-PK2 (70 mg) as white solids.

[0686] Compound 87-PK1 and Compound 87-PK2 Chiral SEC purification Conditions: Column / dimensions: Chiral Pak AD-H (30 x 250) mm, 5 p; %CC>2: 75; %Co solvent: 25 (0.1% MeOH ammonia in ACNTPA; 1 : 1); Flow: 100 mL / min; Back Pressure: 100 bar; Temperature: 30 °C; UV: 274 nm Solubility: MeOH + Acetonitrile

[0687] Compound 87-PK1:

[0688] LC-MS (ESI): m / z= 491.35 [M+H]+

[0689] 'H NMR (400 MHz, DMSO-d6): 8 8.57-8.52 (m, 1H), 8.45-8.40 (m, 1H), 8.02 (d, J= 2.0 Hz, 1H), 7.92-7.89 (m,lH), 7.56 (d, J= 8.4 Hz, 1H), 7.62-6.91 (m, 1H), 5.20-5.15 (m, 1H), 4.83-4.62 (m, 2H), 4.06 (t, J= 8.0 Hz, 2H), 3.93 (t, J= 8.0 Hz, 2H), 2.82 (bs, 1H), 2.28-2.22 (m, 2H), 1.20-1.88 (m, 3H), 0.53 (d, J= 6.8 Hz, 3H).

[0690] Compound 87-PK2:

[0691] LC-MS (ESI): m / z= 491.35 [M+H]+.

[0692] 'H NMR (400 MHz, DMSO-d6): 6 8.57-8.52 (m, 1H), 8.45-8.40 (m, 1H), 8.02 (d, J= 2.0 Hz, 1H), 7.92-7.89 (m,lH), 7.56 (d, J= 8.4 Hz, 1H), 7.06-6.91 (m, 1H), 5.20-5.15 (m, 1H), 4.83-4.62 (m, 2H), 4.06 (t, J= 8.0 Hz, 2H), 3.93 (t, J= 8.0 Hz, 2H), 2.81-2.78 (m, 1H), 2.30- 2.23 (m, 2H), 1.25-1.88 (m, 3H), 0.53 (d, J= 6.8 Hz, 3H). EXAMPLE 24: SCHEME 24

[0693] Step 2: Synthesis of 4-(5-(tert-butoxycarbonyl)-6-isopropyl-5,6-dihydropyrrolo[3,4- c] py razol-2(4 / / )-y I )-2-c hlorobenzoic acid

[0694] To a solution of tert-butyl 2-(3-chloro-4-(methoxycarbonyl)phenyl)-6-isopropyl-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4rt)-carboxylate (1.4 g, 3.334 mmol, 1.0 eq) in THF:

[0695] MeOH: water (1 :1 : 1; 21.0 mL) at 0 °C was added LiOH monohydrate (0.42 g, 10.002 mmol, 3.0 eq) and the mixture was stirred at rt for 6 h. The reaction was concentrated under reduced pressure. The residue was taken in water (25 mL) and neutralized with 10% aq. citric acid. The solid formed was collected by filtration washed with fresh ice-cold water (10 mL) and dried under vacuum to afford 4-(5-(tert-butoxycarbonyl)-6-isopropyl-5,6-dihydropyrrolo[3,4- c]pyrazol-2(4rt)-yl)-2-chlorobenzoic acid (1.3 g, 96%) as an off white solid.

[0696] LC-MS (ESI): m / z= 406.70 [M+H]+

[0697] Step 3: Synthesis of tert-butyl 2-(4-(bis (methyl-d3) carbamoyl)-3-chlorophenyl)-6- isopropyl-2, 6-dihydropyrrolo [3, 4-c] pyr:izole-5(4 / / )-c:irboxylate

[0698] To a stirred solution of 4-(5-(tert-butoxycarbonyl) -6-isopropyl-5, 6 -dihydropyrrolo [3,4- c]pyrazol-2(4rt)-yl)-2-chlorobenzoic acid (1.5 g, 3.696 mmol, 1.0 eq) in DMF (15.0 mL) at 0 °C were added DIPEA (3.29 mL, 18.478 mmol, 5.0 eq) and HATU (2.108 g, 5.544 mmol, 1.5 eq). This was followed by an addition of dimethyl-de-amine hydrochloride (0.49 g, 5.544 mmol, 1.5 eq). The resulting mixture was stirred at rt for 4 h. Ice-cold water (50 mL) was added and the mixture was extracted with ethyl acetate (3x100 mL). The combined organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Crude compound was purified by flash column (devisal silica; 10% MeOH in DCM) to afford tert-butyl 2-(4-(bis (methyl-d3) carbarn oyl)-3 -chi orophenyl)-6- isopropyl-2, 6-dihydropyrrolo [3, 4-c] pyrazole-5(4rt)-carboxylate (1.3 g, 80%) as an off white solid.

[0699] LC-MS (ESI): m / z= 439.88 [M+H]+

[0700] Step 4: Synthesis of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4ZZ)-yl)- A,7V-bis(methyl-d3)benzamide hydrochloride

[0701] To solution of tert-butyl 2-(4-(bis(methyl-d3)carbamoyl)-3-chlorophenyl)-6-isopropyl-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4J7)-carboxylate (1.3 g, 2.961 mmol, 1.0 eq) in DCM (6.5 mL) at 0 °C under N2 was added 4M HC1 in dioxane (6.5 mL) and the mixture was allowed to stir at rt for 2 h. The mixture was concentrated under reduced pressure and the crude compound was triturated with diethyl ether (3x50 mL) to afford 2-chloro-4-(6-isopropyl-5,6- dihydropyrrolo[3,4-c]pyrazol-2(47 / )-yl)-A,A-bis(methyl-d3 (benzamide hydrochloride (1.0 g, crude) as an off white solid.

[0702] LC-MS (ESI): m / z= 339.76 [M+H]+

[0703] Step 5: Synthesis of 2-chloro-4-(6-isopropyl-5-(2-(trifluoromethyl) pyrimidin-4-yl)-5, 6- dihydropyrrolo [3, 4-c] pyr:izol-2(4 / / )-yl)-\. \-bis (methyl-d3) benzamide (Compound 101-Racemate)

[0704] To a stirred solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)- AA-bis(methyl-d3)benzamide (0.25 g, 0.670 mmol, 1.0 equiv.) and DIPEA (0.54 mL, 3.351 mmol, 5.0 eq) in IPA (2.5 mL) was added 4-chloro-2-(trifluoromethyl) pyrimidine (0.15 g, 0.804 mmol, 1.2 eq) at rt. Reaction was stirred for 5 h at 110°C. The mixture was concentrated under reduced pressure and crude compound was purified by flash column (devisal silica; 0-5% MeOH in DCM) to afford 2-chloro-4-(6-isopropyl-5-(2- (trifluoromethyl) pyrimidin-4-yl)-5, 6-dihydropyrrolo [3, 4-c] pyrazol-2(47 / (-yl(-A, A-bis (methyl-d3) benzamide (0.16 g, 44%) as an off-white solid

[0705] LC-MS (ESI): m / z= 485.74 [M+H]+

[0706] Step-6: Synthesis of Compound 101-PK1 and Compound 101-PK2

[0707] The racemate (0.15 g) was separated by chiral prep-SFC into Compound 101-PK1 (51 mg) and Compound 101-PK2 (56 mg) as white solids. Compound 101-PK1 and Compound 101-PK2 Chiral SFC purification Conditions: Purification Method: Preparative SFC Conditions

[0708] Column / dimensions: Chirapak IH (30 x 250) mm, 5 p; % CO2: 70; % Co solvent: 30 (MeOH); Flow: 110 mL / min; Back Pressure: 100 bar; Temperature: 30 °C; UV: 270 nm; Solubility: MeOH +THF.

[0709] Compound 101-PK1:

[0710] LC-MS (ESI): m / z= 485.44 [M+H]+

[0711] 'H NMR (400 MHz, DMSO-d6): d 8.56-8.52 (m, IH), 8.45-8.40 (m, IH), 8.03 (d, J= 2.0 Hz, IH), 7.91 (dd, J= 2.0 Hz & J= 8.4 Hz, IH), 7.50 (d, J= 8.4 Hz,lH), 7.06-6.91 (m, IH), 5.21-5.15 (m, IH), 4.84-4.62 (m, 2H), 2.82-2.79 (m, IH), 1.25-1.19 (m, 3H), 0.53 (d, J= 6.8 Hz, 3H).

[0712] Compound 101-PK2:

[0713] LC-MS (ESI): m / z= 485.44 [M+H]+

[0714] 'H NMR (400 MHz, DMSO-d6): d 8.56-8.52 (m, IH), 8.45-8.40 (m, IH), 8.03 (d, J= 2.0 Hz, IH), 7.91 (dd, J= 2.4 Hz & J= 8.4 Hz, IH), 7.49 (d, J= 8.4 Hz,lH), 7.06-6.91 (m, IH), 5.21-5.15 (m, IH), 4.83-4.62 (m, 2H), 2.82-2.79 (m, IH), 1.25-1.19 (m, 3H), 0.53 (d, J= 6.8 Hz, 3H).

[0715] EXAMPLE 25: SCHEME 25

[0716] Step 1: Synthesis of 2-chloro-4-(6-isopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4Z7)-yl)-7V-methylbenzamide

[0717] To a stirred solution of 2-chloro-4-(6-isopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)- 5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)benzoic acid (1.0 g, 2.213 mmol, 1.0 equiv.) and DIPEA (1.97 mL, 11.066 mmol, 5.0 equiv.) in DMF (10.0 mL) at 0 °C was added HATU (1.3 g, 3.320 mmol, 1.5 equiv.) followed by methylamine 2.0 M in THF (5.5 mL, 11.066 mmol, 5.0 equiv.). The reaction was stirred at rt for 4 h. Cold water (50 mL) was added and extracted with ethyl acetate (3 X 50 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by flash column (davisil silica) using 0-10% MeOH in DCM to afford 2-chloro-4-(6-isopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)-A-methylbenzamide (1.0 g, 76%) as a brown gum solid.

[0718] LC-MS (ESI): m / z= 465.65 [M+H]+

[0719] Step 2: Synthesis of 2-chloro-7V-(difluoromethyl)-4-(6-isopropyl-5-(2- (trifluoromethyl)pyrimidin-4-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4ZZ)-yl)-N- methylbenzamide (Compound 94-racemic)

[0720] To a stirred solution of 2-chloro-4-(6-isopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)-A-methylbenzamide (0.5 g, 1.07 mmol, 1.0 equiv.) in DMF (5.0 mL) at 0 °C was added sodium hydride (60%; 0.085 g, 2.14 mmol, 2.0 equiv.) followed by dropwise addition of difluoroiodomethane ca. 45%, ca. 3.0 mol / L in acetonitrile (3.6 mL, 10.75 mmol, 10.0 equiv.). The reaction was stirred at 50 °C for 16 h. Cold water (10 mL) was added and extracted with ethyl acetate (3 X 20 mL). The combined organic layer was washed with brine (30 mL) and dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. Crude compound was purified by flash column (davisil silica) using 0-70% EtOAC in pet ether to afford 2-chloro-A-(difluoromethyl)-4-(6-isopropyl-5-(2- (trifluoromethyl)pyrimidin-4-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)-yl)-N- methylbenzamide (50 mg, 10%) as a pale yellow solid.

[0721] LC-MS (ESI): m / z= 515.69 [M+H]+

[0722] Step 2: Synthesis of Compound 94-PK1 and Compound 94-PK2

[0723] The racemate (50 mg) was separated by chiral prep-SFC in to Compound 94-PK1 (5.25 mg) and Compound 94-PK2 (6.3 mg) as white solids.

[0724] Compound 94-PK1 and Compound 94-PK2 Chiral SEC purification Conditions:

[0725] Column / dimensions: Chiralcel OD-H (30*250) mm, 5 p; %CC>2: 80; %Co solvent: 20 (IP A); Flow: 100 mL / min; Back Pressure: 100 bar; Temperature: 30 °C; UV: 278 nm; Solubility: MeOH + MeCN.

[0726] Compound 94-PK1:

[0727] LC-MS (ESI): m / z= 515.26 [M+H]+ 'H NMR (400 MHz, DMSO-d6): 6 8.60-8.56 (m, 1H), 8.45-8.42 (m, 1H), 8.11 (d, J= 1.6 Hz, 1H), 8.00-7.97 (m, 1H), 7.61-6.81 (m, 3H), 5.21-5.16 (m, 1H), 4.85-4.63 (m, 2H), 3.18- 2.82 (m, 4H), 1.24-1.19 (m, 3H), 0.53 (d, J= 6.8 Hz, 3H).

[0728] Compound 94-PK2: LC-MS (ESI): m / z= 515.03 [M+H]+

[0729] 'H NMR (400 MHz, DMSO-d6): 6 8.60-8.56 (m, 1H), 8.45-8.42 (m, 1H), 8.11 (s, 1H), 8.00- 7.97 (m, 1H), 7.61-6.91 (m, 3H), 5.21-5.16 (m, 1H), 4.85-4.63 (m, 2H), 3.18-2.82 (m, 4H), 1.26-1.19 (m, 3H), 0.53 (d, J= 6.4 Hz, 3H).

[0730] EXAMPLE 26: SCHEME 26 Step-1: Synthesis of tert-butyl (7?)-(l-(2,2-dimethyl-4,6-dioxo-l,3-dioxan-5-ylidene)-l- hydroxy-3-methylbutan-2-yl) carbamate

[0731] To a stirred solution of (tert-butoxycarbonyl)-D-valine (100 g, 460.267 mmol, 1.0 equiv.) in DCM (500 mL) were added 2, 2-dimethyl-l,3-dioxane-4, 6-dione (79.604 g, 552.321 mmol, 1.2 equiv.), A,A'-dicyclohexylcarbodiimide (142.450 g, 690.401 mmol, 1.5 equiv.) and 4- dimethylaminopyridine (73.100 g, 598.348 mmol, 1.3 equiv.) at 0 °C. The resultant mixture was stirred at RT for 16 h. The reaction was filtered through a celite bed. The filtrate was washed with IN HC1 (250 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford tert-butyl ( / )-(! -(2,2- dimethyl-4,6-dioxo-l,3-dioxan-5-ylidene)-l-hydroxy-3-methylbutan-2-yl) carbamate (135 g, 85% yield) as a yellow oil.

[0732] LC-MS (ESI): m / z= 342.54 [M-H]’

[0733] Step-2: Synthesis of tert-butyl ( / ?)-3-hydroxy-2-isopropyl-5-oxo-2.5-dihydro-l / / -pyrrole- 1-carboxylate

[0734] A solution of tert-butyl (A)-(l-(2,2-dimethyl-4,6-dioxo-l,3-dioxan-5-ylidene)-l-hydroxy-3- methylbutan-2-yl)carbamate (67 g, 196.50 mmol, 1.0 equiv.) in ethyl acetate (1350 mL) was refluxed for 2 h. the reaction was cooled to RT and concentrated under reduced pressure to get tert-butyl (A)-3-hydroxy-2-isopropyl-5-oxo-2,5-dihydro-U / -pyrrole-l-carboxylate (60 g, 94% yield) as a colourless viscous liquid.

[0735] LC-MS (ESI): m / z= 242.42 [M+H]+

[0736] Step-3: Synthesis of tert-butyl (21?)-3-hydroxy-2-isopropyl-5-oxopyrrolidine-l- carboxylate

[0737] A solution of tert-butyl (A)-3-hydroxy-2-isopropyl-5-oxo-2,5-dihydro-17 / -pyrrole-l- carboxylate (40 g, 165.78 mmol, 1.0 equiv.) in DCM (400 mL) at -15 °C were added acetic acid (100 mL) and sodium borohydride (18.814 g, 497.333 mmol, 3 equiv.) and the reaction was stirred at RT for 16 h. The reaction was diluted with 10% aq. citric acid solution (1000 mL) and extracted with DCM (2x1000 mL). The combined organic layer was washed with brine (500 mL). The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) flash column by using 0-20% ethyl acetate in petroleum ether to afford Zc / V-butyl (2 / ?)- 3-hydroxy-2-isopropyl-5-oxopyrrolidine-l-carboxylate (10.1 g, 40% yield) as a pale-yellow sticky solid.

[0738] LC-MS (ESI): m / z= 188.36 [M-56+H]+ Step-4: Synthesis of tert-butyl (21?)-3-((tert-butyldimethylsilyl)oxy)-2-isopropyl-5- oxopyrrolidine-l-carboxylate

[0739] To a solution of tert-butyl (2R)-3-hydroxy-2-isopropyl-5-oxopyrrolidine-l-carboxylate (10 g, 41.101 mmol, 1.0 equiv.) in DCM (100 mL) were added imidazole (4.197 g, 61.652 mmol, 1.5 equiv.) and tert-butyldimethylsilyl chloride (7.434 g, 49.321 mmol, 1.2 equiv.) at 0 °C and the reaction was stirred at RT for 16 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (2 x 150 mL) The combined organic layer was washed with brine (100 mL). The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) flash column by using 0-20% ethyl acetate in petroleum ether to afford temperature and concentrated under reduced pressure to get / c / V-butyl (2 / )-3-(( / c77-butyldimethylsilyl)oxy)-2- isopropyl-5-oxopyrrolidine-l-carboxylate (7.5 g 54% yield) as a white solid.

[0740] LC-MS (ESI): m / z= 302.49 [M+H]+

[0741] Step-5: Synthesis of tert-butyl (57?)-4-((tert-bntyldimethylsilyl)oxy)-2-hydroxy-2,5- diisopropylpyrrolidine-l-carboxylate

[0742] To a stirred solution of tert-butyl tert-butyl (2 / ?)-3-((tert-butyldimethylsilyl)oxy)-2-isopropyl- 5-oxopyrrolidine-l -carboxylate (22.5 g, 63.02 mmol, 1.0 equiv.) in dry THF (225 mL) was dropwise added isopropylmagnesium bromide, IM in THF (315 mL, 315.13 mmol, 5.0 equiv.) at -78 °C. and the mixture was stirred at the same temperature for 3 h. The reaction was quenched with sat. solution of NH4Q and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was washed with brine (25 mL), was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (230-400 mesh) flash column using 0-20% ethyl acetate in petroleum ether to afford tert- butyl (5 / )-4-(( / c77-butyldimethylsilyl)oxy)-2-hydroxy-2,5-diisopropylpyrrolidine- l - carboxylate (7.0 g 28% yield) as a colourless viscous liquid.

[0743] LC-MS (ESI): m / z= 302.30 [M-100+H]+

[0744] Step-6: Synthesis of (27?)-3-((terf-butyldimethylsilyl)oxy)-2,5-diisopropylpyrrolidine

[0745] To a stirred solution of tert-butyl (57?)-4-((tert-butyldimethylsilyl)oxy)-2-hydroxy-2,5- diisopropylpyrrolidine-1 -carboxylate (7.0 g, 17.45 mmol, 1.0 equiv.) in DCM (25.0 mL) at - 78 °C was added boron trifluoride diethyl etherate (5.4 mL, 43.63 mmol, 2.5 equiv.) and stirred for 10 min. Triethylsilane (27.7 mL, 174.50 mmol, 10.0 equiv.) was added at same temperature and stirring was continued for additional 2 h. Then, the reaction was allowed to warm to rt and stirred for 16 h. The reaction was diluted with water (25 mL) and extracted with DCM (50 mL x 2). The combined organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afforded (2R)-3- (tert- butyldimethylsilyl)oxy)-2,5-diisopropylpyrrolidine (3.1 g, 62%) as a white solid.

[0746] LC-MS (ESI): m / z= 286.20 [M+H]+

[0747] Step-7: Synthesis of 4-((27?)-3-((tert-butyldimethylsilyl)oxy)-2,5-diisopropylpyrrolidin-l- yl)-2-(trifluoromethyl) pyrimidine

[0748] To a stirred solution of (5A)-4-((te / 7-butyldimethylsilyl)oxy)-2,5-diisopropylpyrrolidin-2-ol (3.0 g, 10.51 mmol, 1.0 equiv.) in isopropyl alcohol (30.0 mL) were added DIPEA (9.15 mL, 52.53 mmol, 5.0 equiv.) and 4-chloro-2-(trifluoromethyl)pyrimidine (2.3 g, 12.61 mmol, 1.2 equiv.). The resulting mixture was stirred at 110 °C for 4 h. The reaction was concentrated under reduced pressure and the crude was purified by flash column (Devisil silica) chromatography using 0-30% ethyl acetate in petroleum ether to afford 4-((2 / )-3-(( / c / 7- butyldimethylsilyl)oxy)-2,5-diisopropylpyrrolidin-l-yl)-2-(trifluoromethyl) pyrimidine (1.1 g, 36 % yield) as a colorless sticky solid.

[0749] LC-MS (ESI): m / z = 432.20 [M+H]+

[0750] Step-8: Synthesis of (27?)-2,5-diisopropyl-l-(2-(trifluoromethyl)pyrimidin-4- yl)pyrrolidin-3-ol

[0751] To a stirred solution of 4-((2A)-3-((te / 7-butyldimethylsilyl)oxy)-2,5-diisopropylpyrrolidin-l- yl)-2-(trifluoromethyl)pyrimidine (1.1 g, 2.549 mmol, 1.0 equiv.) in THF (7.500 mL) was dropwise added tetrabutylammonium fluoride, IM solution in THF (3.82 mL, 3.823 mmol, 1.5 equiv.) at 0 °C. The resultant mixture was stirred at RT for 4 h. The reaction was diluted with water (25 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (230-400 mesh) flash column using 0-30% ethyl acetate in petroleum ether to afford (2A)-2,5-diisopropyl-l-(2-(trifluoromethyl)pyrimidin-4- yl)pyrrolidin-3-ol (0.65 g 80% yield) as an off white solid.

[0752] LC-MS (ESI): m / z= 318.20 [M+H]+

[0753] Step-9: Synthesis of (27?)-2,5-diisopropyl-l-(2-(trifluoromethyl)pyrimidin-4- yl)pyrrolidin-3-one

[0754] To a stirred solution of (2A)-2,5-diisopropyl-l-(2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidin- 3-ol (0.65 g, 1.508 mmol, 1.0 equiv.) in DCM (6.5 mL) was added Dess-Martin periodinane (1.303 g, 3.072 mmol, 1.5 equiv.) at 0 °C. The resultant mixture was stirred at RT for 4 h. The reaction was filtered through a celite bed. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel (230-400 mesh) flash column using 0- 30% ethyl acetate in petroleum ether to afford (2A)-2,5-diisopropyl-l-(2- (trifluoromethyl)pyrimidin-4-yl)pyrrolidin-3-one (0.52 g 80% yield) as a white solid. LC-MS (ESI): m / z= 316.20 [M+H]+

[0755] Step-10: Synthesis of (21?,Z)-4-((dimethylamino)methylene)-2,5-diisopropyl-l-(2- (trifluoromethyl)pyrimidin-4-yl)pyrrolidin-3-one

[0756] A solution of (2A)-2,5-diisopropyl-l-(2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidin-3-one (0.5 g, 1.586 mmol, 1.0 equiv.) in A, A-dimethylformamide dimethyl acetal (2.0 mL) was refluxed for 4 h. The reaction was cooled to RT and concentrated under reduced pressure to get (2A,^)-4-((dimethylamino)methylene)-2,5-diisopropyl-l-(2-(trifluoromethyl)pyrimidin-4- yl)pyrrolidin-3-one (0.5 g 85% yield) as a yellow viscous liquid.

[0757] LC-MS (ESI): m / z= 371.42 [M+H]+

[0758] Step-11: Synthesis of (67?)-4,6-diisopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)-2,4,5,6- tetr ahydropyrr olo [3,4-c] pyrazole

[0759] A solution of (2A,^)-4-((dimethylamino)methylene)-2,5-diisopropyl-l-(2-(trifluoromethyl) pyrimidin-4-yl)pyrrolidin-3-one (0.5 g, 1.350 mmol, 1.0 equiv.), acetic acid (0.75 mL) and hydrazine monohydrate (1.3 mL) was refluxed for 16 h. The reaction was cooled to RT and water (25 mL) was added. The resulting mixture was extracted with ethyl acetate (2 x 50 mL) and the combined organic layer was washed with brine (25 mL). The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (230-400 mesh) flash column using 0-50% ethyl acetate in petroleum ether to afford (6A)-4,6-diisopropyl-5-(2-(trifluoromethyl)pyrimidin-4- yl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (0.23 g 50% yield) as an off white liquid. LC-MS (ESI): m / z= 340.20 [M+H]+

[0760] Step-12: Synthesis of Compound 29 and Compound 30

[0761] To a stirred solution of (6A)-4,6-diisopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)-2, 4,5,6- tetrahydropyrrolo[3,4-c]pyrazole (0.21 g, 0.619 mmol, 1.0 equiv.) in 1,4 dioxane (4.1 mL) were added 4-bromo-2-chloro-A,A-dimethylbenzamide (0.195 g, 0.743 mmol, 1.2 equiv.), potassium carbonate (0.22 g, 1.857 mmol, 3.0 equiv.) and 4-bromo-2-chloro-A,A- dimethylbenzamide (0.195 g, 0.743 mmol, 1.2 equiv.) and the mixture was purged with nitrogen for 10 min. Copper(I) iodide (0.059 g, 0.309 mmol, 0.5 equiv.) and (±) trans- cyclohexane-l,2-diamine (0.035 g, 0.309 mmol, 0.5 equiv.) were added. The resultant mixture was stirred at 110 °C for 16 h. The reaction was cooled to rt, filtered through a celite bed. The filtrate was diluted with water (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (230-400 mesh) flash column using 0-100% ethyl acetate in petroleum ether to afford 2-chloro-4-((67?)-4,6- diisopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4J7)- yl)-7V,7V-dimethylbenzamide (0.13 g 40% yield) as an off white solid.

[0762] The racemate (0.130 g) was separated by chiral prep-SFC into Compound 29 (0.079 g) and

[0763] Compound 30 (0.0068 g) as off-white solids. SEC Conditions: Column / dimensions CHIRALPAK-IH (4.6 x 250) mm, 5 p;

[0764] %CC>2: 70; %Co solvent: 30% (0.2% 7N MeOH ammonia in ACN); Flow rate: 100 mL / min;

[0765] Back Pressure: 100 bar, Temperature: 30 °C, UV: 277 nm.

[0766] Compound 29:

[0767] LC-MS (ESI): m / z= 521.33 [M+H]+

[0768] 'H NMR (400 MHz, DMSO-d6): <5 8.62 (s, 1H), 8.42 (d, J= 6.0 Hz, 1H), 8.05 (d, J= 2.0 Hz, 1H), 7.93 (dd, J= 8.4 Hz & 2.0, 1H), 7.48 (d, J= 8.4 Hz, 1H), 7.12 (d, J= 6.4 Hz, 1H),

[0769] 5.02 (bs, 2H), 3.02 (s, 3H), 2.82 (s, 3H), 2.14-2.10 (m, 2H), 1.17-1.10 (m, 9H), 0.97 (d, J= 6.4 Hz, 3H).

[0770] Compound 130:

[0771] LC-MS (ESI): m / z= 521.36 [M+H]+

[0772] 'H NMR (400 MHz, DMSO-d6): <5 8.62 (s, 1H), 8.42 (d, J= 6.0 Hz, 1H), 8.06 (s, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.48 (d, J= 8.4 Hz, 1H), 7.12 (d, J= 6.4 Hz, 1H), 5.01 (bs, 2H), 3.02 (s, 3H), 2.81 (s, 3H), 2.14-2.10 (m, 2H), 1.17-1.11 (m, 9H), 0.97 (d, J= 6.4 Hz, 3H).

[0773] EXAMPLE 27: SCHEME 27 Step-1: Synthesis of tert-butyl 6-isopropyl-2-(2-(trifluoromethyl) pyrimidin-4-yl)-2,6- dihydr opyr rolo [3,4-c] py razole-5(4ZZ)-carboxylate

[0774] To a stirred solution of tert-butyl 6-isopropyl-2,6-dihydropyrrolo[3,4-c] pyrazole-5(4Z / )- carboxylate (0.5 g, 1.992 mmol, 1.0 equiv.) in DMF (5.0 mL) was added sodium hydride (60%, dispersion in paraffin Liquid) (0.095 g, 3.984 mmol, 2.0 equiv.) at 0 °C and stirred for 5 min. 4-Chloro-2-(trifluoromethyl) pyrimidine (0.436 g, 2.3904 mmol, 1.2 equiv.) was added and stirred at rt for 2 h. Reaction was quenched with ice cold water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column (SiCh 100-200 mesh) using 0-5% ethyl acetate in pet ether to give tert-butyl 6-isopropyl-2-(2-(trifluoromethyl)pyrimidin-4-yl)-2,6-dihydropyrrolo[3,4-c] pyrazole-5(4J7)-carboxylate (0.7 g, 89%) as an off white solid.

[0775] LC-MS (ESI): m / z = 398.73 [M+H]+

[0776] Step-2: Synthesis of 6-isopropyl-2-(2-(trifluoromethyl) pyrimidin-4-yl)-2,4,5,6- tetrahydropyrrolo [3,4-c] pyrazole hydrochloride

[0777] To a stirred solution of tert-butyl 6-isopropyl-2-(2-(trifluoromethyl) pyrimidin-4-yl)-2,6- dihydropyrrolo[3,4-c] pyrazole-5(4J7)-carboxylate (0.5 g, 1.258 mmol, 1.0 equiv.) in DCM (5.0 mL) was added 4 M HC1 in dioxane (5.0 mL) at 0°C and stirred at rt for 2 h. The reaction was concentrated under educed pressure and co-distilled with toluene. The crude was triturated with / / -pentane and dried under vacuum to get 6-isopropyl-2-(2-(trifluoromethyl) pyrimidin-4-yl)-2,4,5,6-tetrahydropyrrolo[3,4-c] pyrazole hydrochloride (0.4 g, 96%) as an off white solid.

[0778] LC-MS (ESI): m / z = 298.60 [M+H]+

[0779] Step-3: Synthesis of Compound 19-Racemic

[0780] To a stirred solution of 6-isopropyl-2-(2-(trifluoromethyl) pyrimidin-4-yl)-2, 4,5,6- tetrahydropyrrolo[3,4-c] pyrazole (0.4 g, 1.2048 mmol, 1.0 equiv.) and 4-bromo-2-chloro- 7V,7V-dimethylbenzamide (0.32 g, 1.3253 mmol, 1.1 equiv.) in tetrahydrofuran (4.0 mL) and added with cesium carbonate (1.17 g, 3.6144 mmol, 3.0 equiv.) and purged with nitrogen for 10 min. Ruphos (0.056 g, 0.1205 mmol, 0.1 equiv.) and Ruphos-Pd-G2 (0.093 g, 0.1205 mmol, 0.1 equiv.). The reaction was stirred at 80 °C for 16 h. The reaction filtered through a celite bed and filtrate was concentrated under reduced pressure. The crude product was purified by flash column (SiCh, 100-200) chromatography using 0-40% ethyl acetate in pet ether to afford 2-chloro-4-(6-isopropyl-2-(2-(trifluoromethyl)pyrimidin-4-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4J7)-yl)-7V,7V-dimethylbenzamide (0.19 g, 33%) as an off- white solid.

[0781] LC-MS (ESI): m / z = 479.79 [M+H]+

[0782] Step-4: Synthesis of Compound 19-PK1 and Compound 19-PK2

[0783] The racemate (0.190 g) was separated by chiral prep. SFC in to Compound 19-PK1 (59 mg) and Compound 19-PK2 (62 mg) as off-white solids.

[0784] Compound 19-PK1 and Compound 19-PK2

[0785] Chiral SFC purification Conditions:

[0786] Dimensions: Chiralpak AD-H (30 x 250) mm, 5 p; CO2: 63%; Co-solvent: 37% (0.1% DEA in MeOH); Flow: 100 mL / min; Back Pressure: 100 bar; Temperature: 30 °C; UV: 285 nm;

[0787] Solubility: MeOH+ MeCN.

[0788] Compound 19-PK1:

[0789] LC-MS (ESI): m / z = 479.29 [M+H]+

[0790] 'H NMR (400 MHz, DMSO-< / 6): d 9.06 (d, J= 5.6 Hz, 1H), 8.58 (s, 1H), 8.15 (d, J= 6.0 Hz, 1H), 7.19 (d, J= 8.4 Hz, 1H), 6.80-6.77 (m, 2H), 5.06 (d, J= 2.4 Hz, 1H), 4.63 (d, J = 13.6 Hz, 1H), 4.38 (d, J= 14.0 Hz, 1H), 2.98 (s, 3H), 2.82 (s, 3H), 2.45-2.41 (m, 1H), 1.24 (d, J = 6.8 Hz, 3H), 0.50 (d, J = 6.4 Hz, 3H).

[0791] Compound 19-PK2:

[0792] LC-MS (ESI): m / z = 479.29 [M+H]+

[0793] Hl NMR (400 MHz, DMSO-< / 6): d 9.06 (d, J= 5.6 Hz, 1H), 8.58 (s, 1H), 8.15 (d, J= 6.0 Hz, 1H), 7.19 (d, J= 8.4 Hz, 1H), 6.80-6.77 (m, 2H), 5.06 (d, J= 2.4 Hz, 1H), 4.63 (d, J = 13.6 Hz, 1H), 4.38 (d, J= 14.0 Hz, 1H), 2.98 (s, 3H), 2.82 (s, 3H), 2.47-2.41 (m, 1H), 1.24 (d, J = 6.8 Hz, 3H), 0.50 (d, J = 6.4 Hz, 3H).

[0794] EXAMPLE 28: SCHEME 28

[0795] Step-1: Synthesis of l-benzyl-3-isopropylpiperidin-4-one

[0796] To a stirred suspension of potassium / c / 7-butoxide (32.6 g, 290.621 mmol, 1.1 equiv.) in tetrahydrofuran (300 mL) at -10 °C was added l-benzylpiperidin-4-one (50.0 g, 264.201 mmol, 1.0 equiv.). The mixture was stirred at the same temperature for 30 min and 2- iodopropane (49.403 g, 290.621 mmol, 1.1 equiv.) was dropwise added. The mixture was stirred at rt for 16 h and refluxed for 5 h. The reaction was concentrated under reduced pressure and ice-cold water (300 mL) was added. The mixture was extracted with ethyl acetate (3 x 200 mL), the combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrate under reduced pressure. The crude was purified by silica gel (100- 200) flash column using 2-15% ethyl acetate in petroleum ether to afford l-benzyl-3- isopropylpiperidin-4-one (0.67 g, 16% yield) as a pale-yellow viscous liquid.

[0797] LC-MS (ESI): m / z = [M+H]+ Step-2: Synthesis of 5-benzyl-7-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c] pyridine

[0798] To a stirred solution of l-benzyl-3-isopropylpiperidin-4-one (6.0 g, 25.936 mmol, 1.0 equiv.) in A, A-dimethylformamide (60 mL) was added -di methyl form am ide dimethyl acetal (3.4 g, 28.530 mmol, 1.1 equiv.) and the resulting mixture was refluxed for 16 h. The reaction was concentrated under reduced pressure. The viscous liquid was taken up in glacial acetic acid (9 mL) and hydrazine monohydrate (15 mL) was added. The mixture was stirred at rt for 0.5 h and refluxed for 16 h. The reaction was concentrated under reduced pressure and the crude was purified by silica gel (100-200) flash column using 2-10% MeOH in DCM to afford 5-benzyl-7-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c] pyridine (1.1 g, 20% yield).

[0799] LC-MS (ESI): m / z = 256.46 [M+H]+

[0800] Step-3: Synthesis of 5-benzyl-7-isopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7- tetrahydr o-2H-pyrazolo [4 ,3-c] pyridine

[0801] To a stirred solution of 5-benzyl-7-isopropyl-4,5,6,7-tetrahydro-2A-pyrazolo[4,3-c]pyridine (0.7 g, 2.741 mmol, 1.0 equiv.) in tetrahydrofuran (7.0 mL) at 0 °C was added sodium hydride (60%, dispersion in paraffin liquid) (0.22 g, 5.482 mmol, 2.0 equiv.) and stirred for 30 min. Then 2- (trimethyl silyl)ethoxymethyl chloride (0.73 mL, 4.112 mmol, 1.5 equiv.) was added at the same temperature and stirred at rt for 16 h. The reaction was quenched with water (50 mL) and the mixture was extracted with ethyl acetate (3 x 60 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by silica gel (100-200) flash column using 0-50% ethyl acetate in petroleum ether to afford 5-benzyl-7-isopropyl-2-((2- (trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (0.9 g, 85% yield) as a pale-yellow viscous liquid.

[0802] LC-MS (ESI): m / z = 386.63 [M+H]+

[0803] Step-4: Synthesis of 7-isopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro- 2 / / -pyrazolo [4, 3-c] pyridine

[0804] A solution of 5-benzyl-7-isopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro- 2A-pyrazolo[4,3-c]pyridine (0.85 g, 2.204 mmol, 1.0 equiv.) in THF (8.5 mL) and MeOH (8.5 mL) purged under nitrogen and palladium on activated carbon, 10% Pd, (50% wet with water, unreduced; 0.87 g) was added and the mixture was stirred under H2 (70 psi) in parr shaker at RT for 16 h. The reaction was diluted with THF (40 mL) and filtered through a celite bed. The filtrate was concentrated under reduced pressure to afford 7-isopropyl-2-((2- (trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-2J / -pyrazolo[4,3-c]pyridine (0.65 g, crude) as a brown viscous liquid.

[0805] LC-MS (ESI): m / z = 296.20 [M+H]+

[0806] Step-5: Synthesis of 7-isopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)-2-((2- (triinetliylsilyl)etli()xy)inetliyl)-4.5.6.7-tetr:iliydro-2 / / -pyr:iz()lo|4.3-c|pyridine

[0807] To a stirred solution of 7-isopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro- 2J / -pyrazolo[4,3-c]pyridine (0.62 g, 2.098 mmol, 1.0 equiv.) and 4-chloro-2-(trifluoromethyl) pyrimidine (0.467 g, 2.558 mmol, 1.2 equiv.) in isopropyl alcohol (6.2 mL) was added DIPEA (1.857 mL, 10.660 mmol, 5.0 equiv.) and stirred at 125 °C for 3 h. The reaction was concentrated under reduced pressure. The crude was purified by flash column (Devis silica) using 0-60% ethyl acetate in petroleum ether to afford 7-isopropyl-5-(2- (trifluoromethyl)pyrimidin-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-2J / - pyrazolo[4,3-c]pyridine (0.58 g, 62% yield) as a brown viscous liquid.

[0808] LC-MS (ESI): m / z = 442.30 [M+H]+

[0809] Step-6: Synthesis of 7-isopropyl-5-(2-(trifluoromethyl) pyrimidin-4-yl)-4,5,6,7- tetr a hy d ro-2 / / -py razolo [4 ,3-c] pyridine

[0810] To a stirred solution of 7-isopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)-2-((2- (trimethylsilyl)ethoxy) methyl)-4,5,6,7-tetrahydro-2J / -pyrazolo[4,3-c]pyridine (0.58 g, 1.313 mmol, 1.0 equiv.) in DCM (1.75 mL) was added TFA (1.75 mL) at 0 °C and stirred at rt for 3 h. The reaction was concentrated under reduced pressure and triturated with / / -pentane to afford 7-isopropyl-5-(2-(trifluoromethyl) pyrimidin-4-yl)-4,5,6,7-tetrahydro-2JT- pyrazolo[4,3-c] pyridine (0.65 g, crude) as brown viscous liquid.

[0811] LC-MS (ESI): m / z = 312.17 [M+H]+

[0812] Step-7: Synthesis of Compound 32-Racemic

[0813] To a stirred solution of 7-isopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)-4,5,6,7-tetrahydro- 2J / -pyrazolo[4,3-c]pyridine (0.55 g, 1.767 mmol, 1.0 equiv.) and 4-bromo-2-chloro-A,A- dimethylbenzamide (0.46 g, 1.767 mmol, 1.0 equiv.) in 1,4 dioxane (4 mL) and was added potassium carbonate (1.22 g, 8.834 mmol, 5.0 equiv.) and purged with nitrogen for 10 min. Copper (I) iodide (0.336 g, 1.767 mmol, 1.0 equiv.) and (±)- trans -1,2- diaminocyclohexane (0.20 g, 1.767 mmol, 1.0 equiv.) were added and the reaction was heated at 120 °C for 20 h. The recti on mixture was filtered through a celite bed and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel (230-400) flash column using 0-5% MeOH in DCM to afford 2-chloro-4-(7-isopropyl-5- (2-(trifluoromethyl)pyrimidin-4-yl)-4,5,6,7-tetrahydro-2Z / -pyrazolo[4,3-c]pyridin-2-yl)-7V,7V- dimethylbenzamide (0.16 g, 18% yield) as an off-white solid.

[0814] LC-MS (ESI): m / z = 493.33 [M+H]+

[0815] The racemate (0.16 g) was separated by chiral prep-SFC into Compound 32-PK1 (45.6 mg) and Compound 32-PK2 (49.1 mg) as off-white solids.

[0816] Preparative SEC Conditions: Column / dimensions: CHIRALPAK-AD-H (30 x 250) mm, 5 p; %CC>2: 70; %Co solvent: 30 (0.1% MeOH ammonia in MeCN: MeOH; 1 : 1); Flow rate: 100 mL / min; Back Pressure: 100 bar; Temperature: 30 °C; UV: 272 nm.

[0817] Compound 32-PK1:

[0818] LC-MS (ESI): m / z = 493.33 [M+H]+

[0819] 'H NMR (400 MHz, DMSO-d6: 8 8.51 (s, 1H), 8.40 (d, J= 6.4 Hz, 1H), 7.96 (s, 1H), 7.86 (d, J= 8.0 Hz, 1H), 7.48 (d, J= 8.0 Hz, 1H), 7.17 (bs, 1H), 4.76-3.78 (m, 4H), 3.02 (s, 3H), 2.81 (s, 4H), 1.97 (bs, 1H), 1.04-1.01 (m, 6H).

[0820] Compound 32-PK2:

[0821] LC-MS (ESI): m / z = 493.33 [M+H]+

[0822] 'H NMR (400 MHz, DMSO-d6): 6 8.51 (s, 1H), 8.40 (d, J= 6.4 Hz, 1H), 7.97 (s, 1H), 7.86 (d, J= 8.4 Hz, 1H), 7.48 (d, J= 8.4 Hz, 1H), 7.17 (bs, 1H), 4.76-3.78 (m, 4H), 3.02 (s, 3H), 2.81 (s, 4H), 1.95 (bs, 1H), 1.04-1.01 (m, 6H).

[0823] EXAMPLE 29: SCHEME 29: Compound 143-PK-l, PK-2 and Compound 129-PK-l,

[0824] PK-2

[0825] Step 1: Synthesis of tert-butyl 2-(5-(dimethylcarbamoyl)-6-methoxypyridin-2-yl)-6- isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate

[0826] To a solution of tert-butyl 6-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (500 mg, 1.989 mmol, 1 eq.) in 1,4-Dioxane (5.000 mL) was added 6-chloro-2-methoxy- N,N-dimethylnicotinamide (427.026 mg, 1.989 mmol, 1 eq.), followed added by the addition of Palladium(II) acetate (223.322 mg, 0.995 mmol, 0.5 eq.), BINAP (123.742 mg, 0.199 mmol, 0.1 eq.), CsCOs (1944.575 mg, 5.968 mmol, 3 eq.) at RT and the resulting mixture was stirred (Microwave) at 130°C for 4 h. The mixture was diluted with water (20 mL) and extracted with DCM (2x30 mL), combined organic layers were washed with brine solution (30 mL), dried over Na2SO4 (200 mg), filtered and the filtrate was concentrated under reduced pressure then purified by silica gel (100-200 mesh) column chromatography, eluted with 28% of ethyl acetate in pet ether to afford tert-butyl 2-(5-(dimethylcarbamoyl)-6- methoxypyridin-2-yl)-6-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (170 mg, Yield 19.9%) as an off-white solid.

[0827] LC-MS (ESI): m / z = 430.42 [M+H]+

[0828] Step-2: Synthesis of Compound 143-PK-l and PK-2

[0829] The Racemate (0.070 g) separated by chiral prep-SFC into PK-1 (17.5 mg) as an off-white solid and PK-2 (17.6 mg) as an off-white solid.

[0830] Chiral SEC purification Conditions:

[0831] Preparative SFC Conditions: Column / Dimensions: Chiralpak IG (150X21X5p) Packed, %CO2: 75%, % Co solvent: 25% (100% MeOH), Total Flow: 80 g / min, Back Pressure: 100.0 bar, Temperature: 30.0° C.

[0832] PK-1:

[0833] LC-MS (ESI): m / z = 430.33 [M+H]+

[0834] 'H NMR (400 MHz, DMSO-d6): 6 8.46 (d, J= 18.01 Hz, 1H), 7.80 (d, J= 8.00 Hz, 1H), 7.42-7.49 (m, 1H), 4.73 (d, J= 7.25 Hz, 1H), 4.50 (d, J= 14.26 Hz, 1H), 4.28-4.40 (m, 1H), 3.99 (s, 3H), 2.98 (s, 3H), 2.83 (s, 3H), 2.41 (dd, J= 10.13, 6.38 Hz, 1H), 1.46 (s, 9H), 1.12 (d, J= 6.75 Hz, 3H), 0.58 (dd, 7=12.13, 6.63 Hz, 3H).

[0835] PK-2:

[0836] LC-MS (ESI): m / z = 430.33 [M+H]+

[0837] 'H NMR (400 MHz, DMSO-d6): 6 8.47 (d, J= 18.26 Hz, 1H), 7.80 (d, J= 7.75 Hz, 1H), 7.46 (dd, J= 7.88, 2.63 Hz, 1H), 4.73 (dd, J= 10.13, 3.38 Hz, 1H), 4.50 (d, J= 14.51 Hz, 1H), 4.28-4.40 (m, 1H), 3.99 (s, 3H), 2.98 (s, 3H), 2.83 (s, 3H), 2.37-2.45 (m, 1H), 1.46 (s, 9H), 1.12 (d, J= 7.00 Hz, 3H), 0.58 (dd, J= 12.26, 6.75 Hz, 3H).

[0838] Step-3: Synthesis of 6-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-2- methoxy-N,N-dimethylnicotinamide hydrochloride

[0839] To a solution of tert-butyl 2-(5-(dimethylcarbamoyl)-6-methoxypyridin-2-yl)-6-isopropyl- 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (240 mg, 0.559 mmol, 1 eq.) in 1,4- di oxane (1.5 mL) was added 4M HC1 in 1,4-dioxane (5 mL) at 0 °C and the resulting mixture was stirred at 50 °C for 3 h. The reaction was concentrated under reduced pressure to afford 6-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-2-methoxy-N,N- dimethylnicotinamide hydrochloride (180 mg, Yield 88%) as an off-white solid.

[0840] LC-MS (ESI): m / z = 330.49 [M+H]+

[0841] Step 4: Synthesis of Compound 129-Racemate

[0842] To a solution of 6-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-2-methoxy-N,N- dimethylnicotinamide hydrochloride (200 mg, 0.547 mmol, 1 eq.) in acetonitrile (5 mL) were added potassium carbonate (377.765 mg, 2.733 mmol, 5 eq.), 4-chloro-2-(trifluoromethyl) pyrimidine (99.781 mg, 0.547 mmol, 1 eq.) at RT and the mixture was stirred at 110° C for 16 h. The mixture was diluted with water (20 mL) and extracted with DCM (2 x 30 mL), combined organic layers were washed with brine solution (30 mL), dried over anhydrous Na2SC>4 (200 mg), filtered and the filtrate was concentrated under reduced pressure and, purified by silica gel (100-200 mesh) column chromatography, eluted with 50% of ethyl acetate in pet ether to afford 4-(6-isopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,N,2-trimethylbenzamide (110 mg, Yield 43.89%) as an off-white solid.

[0843] LC-MS (ESI): m / z = 476.37 [M+H]+

[0844] Step-5: Synthesis

[0845] The Racemate (0.110 g) separated by chiral prep-SFC into PK-1 (49.8 mg) as a white solid and PK-2 (41.5 mg) as a white solid.

[0846] Chiral SEC purification Conditions: Column / Dimensions: AMYLOSE C-NEO (250X30X5p), % CO2: 70%, % Co solvent: 30% (100% Methanol), Total Flow: 100 g / min, Back Pressure: 100.0 bar, Temperature: 300C, Wavelength: 307 nm, Stack time: 5.0 Min / injections, Load ability: 13mg / inj ection

[0847] PK-1:

[0848] LC-MS (ESI): m / z = 476.33 [M+H]+

[0849] 'H NMR (400 MHz, DMSO-d6): 6 8.53-8.64 (m, 1H), 8.37-8.48 (m, 1H), 7.83 (d, J= 7.75 Hz, 1H), 7.51 (d, J= 8.00 Hz, 1H), 6.88-7.11 (m, 1H), 5.13-5.25 (m, 1H), 4.57-4.85 (m, 2H), 4.02 (s, 3H), 2.99 (s, 3H), 2.76-2.88 (m, 3H), 2.38-2.47 (m, 1H), 1.15-1.29 (m, 3H), 0.54 (d, J = 6.75 Hz, 3H).

[0850] PK-2:

[0851] LC-MS (ESI): m / z = 476.33 [M+H]+

[0852] 'H NMR (400 MHz, DMSO-d6): 6 8.52-8.64 (m, 1H), 8.37-8.48 (m, 1H), 7.83 (d, J= 8.00 Hz, 1H), 7.51 (d, J= 8.00 Hz, 1H), 6.88-7.09 (m, 1H), 5.12-5.26 (m, 1H), 4.55-4.86 (m, 2H), 4.02 (s, 3H), 2.99 (s, 2H), 2.75-2.89 (m, 3H), 2.35-2.47 (m, 1H), 1.14-1.29 (m, 3H), 0.54 (d, J = 6.75 Hz, 3H).

[0853] EXAMPLE 30: SCHEME 30: Compound 135-PK-l, PK-2:

[0854] Step-1: Synthesis of (2-(trifluoromethyl)pyrimidin-4-yl)methanol

[0855] To a stirred solution of 4-chloro-2-(trifluoromethyl)pyrimidine (1.5 g, 8.218 mmol, 1 eq.) in Toluene (15 mL) was added (Tributyltin)m ethanol (3.957 g, 12.327 mmol, 1.5 eq.) at 25 °C and the mixture was degassed with N2 for 10 min. Pd(PPh3)4 (949.644 mg, 0.822 mmol, 0.1 eq.) was added at same temperature and the rx mixture was irradiated with microwave at 100 °C for 2 h. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (2 x 70 ml), combined organic layers were washed with brine solution (80 ml), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. Crude residue was purified by column chromatography using silica gel (230-400 mesh), eluted with 15% ethyl acetate in pet ether to afford (2-(trifluoromethyl)pyrimidin-4-yl)methanol (320 mg. Yield 22%) as a light yellow liquid.

[0856] LC-MS (ESI): m / z = 177.06 [M-H]+

[0857] Step-2: Synthesis of 2-chloro-4-(6-isopropyl-5-((2-(trifluoromethyl)pyrimidin-4- yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,N-dimethylbenzamide

[0858] To a solution of (2-(trifluoromethyl)pyrimidin-4-yl)methanol (300 mg, 1.684 mmol, 1 eq.) in DCM (10 mL). The mixture was cooled to 0 °C, and DMP (928.394 mg, 2.190 mmol, 1.3 eq.) was added in one portion and the reaction was stirred at RT for 2 h. 2-Chloro-4-(6- isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,N-dimethylbenzamide HC1 (435.400 mg, 1.179 mmol, 0.7 eq.) and STAB (892.434 mg, 4.211 mmol, 2.5 eq.) was added at 0 °C and the mixture was stirred at RT for 2 h. The mixture was quenched with sat. NaHCCh solution and extracted with ethyl acetate (2x70 ml). The combined organic layers were washed with brine solution (50 ml), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. Crude residue was purified by column chromatography using silica gel (100-200 mesh), eluted with 45% of ethyl acetate in pet ether to afford 2- chloro-4-(6-isopropyl-5-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)-5,6-dihydropyrrolo[3,4- c]pyrazol-2(4H)-yl)-N,N-dimethylbenzamide (160 mg, Yield 19%) as a yellow solid.

[0859] LC-MS (ESI): m / z = 493.10 [M+H]+

[0860] Step-3: Synthesis of Compound 130-PK-l and PK-2

[0861] The Racemate (0.160 g) separated by chiral prep-SFC into PK-1 (0.0468 g) as a pale-yellow solid and PK-2 (0.0452 g) as a pale-yellow solid.

[0862] Chiral SEC purification Conditions:

[0863] Preparative SFC Conditions Column / dimensions: Column / Dimensions: Chiralpak AS-H (30*250) mm, 5mic, % CO2: 70%, % Co solvent: 30% (100% MeOH), Total Flow: 100 g / min, Back Pressure: 100.0 bar, Temperature: 30.0° C, Wavelength: 279nm, Stack time: 7.00 Min / injections, Load ability: 32 mg / injection.

[0864] PK-1:

[0865] LC-MS (ESI): m / z = 493.30 [M+H]+

[0866] 'H NMR (400 MHz, DMSO-d6): 6 9.04 (d, J= 5.00 Hz, 1H), 8.31 (s, 1H), 7.91-7.97 (m, 2H), 7.85 (dd, J= 8.38, 2.13 Hz, 1H), 7.46 (d, J= 8.25 Hz, 1H), 4.39 (d, J= 16.76 Hz, 1H), 4.08-4.18 (m, 2H), 3.98-4.03 (m, 1H), 3.59 (d, J= 12.51 Hz, 1H),3.O2 (s, 3H), 2.82 (s, 3H), 1.96-2.07 (m, 1H), 1.16 (d, J= 7.00 Hz, 3H), 0.86 (d, J= 6.75 Hz, 3H).

[0867] PK-2:

[0868] LC-MS (ESI): m / z = 493.30 [M+H]+

[0869] 'H NMR (400 MHz, DMSO-d6): 6 9.04 (d, J= 5.25 Hz, 1H), 8.31 (s, 1H), 7.91-7.97 (m, 2H), 7.85 (dd, J= 8.38, 2.13 Hz, 1H), 7.46 (d, J= 8.50 Hz, 1H), 4.39 (d, J= 17.01 Hz, 1H),

[0870] 4.08-4.18 (m, 2H), 4.01 (d, J= 4.00 Hz, 1H), 3.71-3.76 (m, 1H), 3.59 (d, J= 12.51 Hz, 1H), 3.02 (s, 3H), 2.82 (s, 3H), 1.96-2.07 (m, 1H), 1.16 (d, J= 6.75 Hz, 3H), 0.86 (d, J= 6.75 Hz, 3H).

[0871] EXAMPLE 31 SCHEME 31 Compound 137-PK-l, PK-2 Experimental Procedure

[0872] Step-1: Synthesis of 2,6-dichlorophenyl carbonochloridate

[0873] To a stirred solution of 2,6-dichlorophenol (500 mg, 3.067 mmol, 1 eq.) and phosgene 20% in Toluene (0.482 mL, 4.601 mmol, 1.5 eq.) in toluene (20 mL, 61.350 mmol, 20 eq.) was added N,N-Dimethylaniline (0.391 mL, 3.067 mmol, 1 eq.) at 0 °C and mixture was stirred at RT for 5 h. The mixture was quenched with IN HC1 solution (50 mL), extracted with ethyl acetate (2x75mL). The combined organic layer was washed with brine (45 mL), dried over Na2SC>4, filtered and filtrate was concentrated under reduced pressure to afford crude compound (400 mg, Yield 58%). Crude compound was used for the next without any further purification.

[0874] Step 2: Synthesis of 2,6-dichlorophenyl 2-(3-chloro-4-(dimethylcarbamoyl)phenyl)-6- isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate

[0875] To a stirred solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)- N,N-dimethylbenzamidehydrochloride (300 mg, 0.812 mmol, 1 eq.) in dichloromethane (1.038 mL, 16.247 mmol, 20 eq.) was added dropwise, Triethylamine (0.340 mL, 2.437 mmol, 3 eq.) at 0 °C and mixture was stirred at same temperature for 20 min. 2,6- dichlorophenyl carbonyochlorinate (219.778 mg, 0.975 mmol, 1.2 eq.) was added at 0 °C and mixture was stirred at RT for 16 h. The mixture was quenched with ice water solution (50 mL), extracted with ethyl acetate (2x100 mL), The combined organic layer was separated, washed with brine (50 mL), dried over Na2SC>4, filtered and filtrate was concentrated. Crude compound was purified by column chromatography using silica gel (100-200 mesh), eluted with 35% ethyl acetate in pet ether to afford 2,6-dichlorophenyl 2-(3-chloro-4- (dimethylcarbamoyl)phenyl)-6-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)- carboxylate (240 mg, Yield 56.6%) as a white solid.

[0876] LC-MS (ESI): m / z = 523.39 [M+H]+

[0877] Step-3: Synthesis of PK-1 and PK-2

[0878] The Racemate (0.110 g) separated by chiral prep-SFC into PK-1 (0.0681 g) as a white solid and PK-2 (0.0600 mg) as a white solid.

[0879] Chiral SEC purification Conditions: Column / Dimensions: Chiral pak IG (150X25X5p), % CO: 65%, % Co solvent: 35% (100% Methanol), Total Flow: 80 g / min, Back pressure: 85 BAR, Temperature: 30.0° C.

[0880] PK-1:

[0881] LC-MS (ESI): m / z = 521.35 [M+H] 'H NMR (400 MHz, DMSO-d6): 6 8.51 (s, 1H), 8.02 (d, J= 1.75 Hz, 1H), 7.91 (dd, J = 8.38, 1.88 Hz, 1H), 7.61 (d, J= 8.25 Hz, 2H), 7.50 (dd, J= 8.25, 1.25 Hz, 1H), 7.36 (td, J = 8.13, 1.25 Hz, 1H), 5.11 (d, 3.00 Hz, 1H), 4.52-4.96 (m, 3H), 3.03 (s, 3H), 2.73-2.85 (m,

[0882] 4H), 1.11-1.26 (m, 3H), 0.69 (dd, J= 6.63, 5.13 Hz, 3H).

[0883] PK-2:

[0884] LC-MS (ESI): m / z = 521.35 [M+H]+

[0885] 'H NMR (400 MHz, DMSO-d6): 6 8.51 (s, 1H), 8.02 (d, J= 2.00 Hz, 1H), 7.91 (dd, J = 8.38, 2.13 Hz, 1H), 7.61 (d, J= 8.25 Hz, 2H), 7.50 (dd, J= 8.38, 1.38 Hz, 1H), 7.36 (td, J = 8.13, 1.25 Hz, 1H), 5.11 (d, 3.00 Hz, 1H), 4.55-4.95 (m, 2H), 3.03 (s, 3H), 2.72-2.85 (m,

[0886] 4H), 1.11-1.25 (m, 3H), 0.69 (dd, J = 6.63, 5.13 Hz, 3H).

[0887] EXAMPLE 32: SCHEME 32: Compound 157-PK-l, PK-2

[0888] Experimental Procedure

[0889] Step-1: Synthesis of 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-l,3,5-triazine

[0890] To a solution of 2,2,2-trifluoroacetimidamide (10 g, 89.242 mmol, 1 eq.) in dichloromethane (50 mL) was added 2,2,2-trichloroacetonitrile (17.90 mL, 178.48 mmol, 2 eq.) at 0 °C followed added by addition of trifluoroacetic anhydride (15.10 mL, 107.09 mmol, 1.2 eq.) at 0 °C and the rx mixture was stirred at same temperature for 16 h. The mixture was concentrated under reduced pressure. The crude was purified by fractional distillation to afford 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-l,3,5-triazine (1.8 g, Yield 6.03%) as an off-white gum.

[0891] LC-MS (ESI): m / z = 336.16 [M-H]+

[0892] Step-2: Synthesis of Racemate

[0893] To a solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-7V,7V- dimethylbenzamide (700 mg, 2.103 mmol,l eq.) in acetonitrile (5 mL) were added 2- (trichloromethyl)-4,6-bis(trifhioromethyl)-l,3,5-triazine (703.355 mg, 2.103 mmol, 1 eq.) followed added by addition of potassium carbonate (871.971 mg, 6.309 mmol, 3 eq.), 4- dimethylaminopyridine (256.943 mg, 2.103 mmol, 1 eq.) at RT and the resulting mixture was stirred at 85 °C for 16 h. The mixture was diluted with water (20 mL) and extracted with DCM twice. The combined organic layer was washed with brine solution (30 mL) and dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel (100-200 mesh) column chromatography, eluted with 50% of ethyl acetate in pet ether to afford 4-(5-(4,6-bis(trifluoromethyl)-l,3,5-triazin-2- yl)-6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-2-chloro-7V,7V- dimethylbenzamide (220 mg, Yield 19.1% ) as an off-white solid.

[0894] LC-MS (ESI): m / z = 548.59 [M-H]+

[0895] Step-4: Synthesis of PK-1 and PK-2

[0896] The Racemate (0.220 g) separated by chiral prep-SFC into PK-1 (0.0914 g) as a white solid and PK-2 (0.0421 g) as an off-white solid.

[0897] Chiral SEC purification Conditions:

[0898] Preparative SFC Conditions: Column / Dimensions: CELLULOSE-4 (250X30X5p), % CO2: 85%, % Co solvent: 15% (100%MeOH), Total Flow: 100 mL / min, Back Pressure: 100 Bar, Temperature: 30.0 ° C.

[0899] PK-1:

[0900] LC-MS (ESI): m / z = 548.36 [M+H]+

[0901] 'H NMR (400 MHz, DMSO-d6): 8 8.55 (s, 1H), 8.04 (d, J= 2.0 Hz, 1H), 7.93 (dd, J= 2.1, 8.4 Hz, 1H), 7.50 (d, J= 8.5 Hz, 1H), 5.22 (d, J= 3.5 Hz, 1H), 4.93 - 4.87 (m, 1H), 4.81 - 4.73 (m, 1H), 3.02 (s, 3H), 2.82 (s, 3H), 2.78 - 2.70 (m, 1H), 1.22 (d, J= 7.0 Hz, 3H), 0.60 (d, J = 6.8 Hz, 3H).

[0902] PK-2:

[0903] LC-MS (ESI): m / z = 548.36 [M+H]+

[0904] Hl NMR (400 MHz, DMSO): 6 8.55 (s, 1H), 8.04 (d, J= 2.0 Hz, 1H), 7.93 (dd, J= 2.1, 8.4

[0905] Hz, 1H), 7.50 (d, J= 8.5 Hz, 1H), 5.22 (d, J= 3.5 Hz, 1H), 4.93 - 4.87 (m, 1H), 4.80 - 4.73

[0906] (m, 1H), 3.03 (s, 3H), 2.82 (s, 3H), 2.78 - 2.69 (m, 1H), 1.22 (d, J= 7.0 Hz, 3H), 0.60 (d, J = 6.8 Hz, 3H).

[0907] EXAMPLE 33: SCHEME 33: Compound 159-PK-l and PK-2

[0908] Step-1: Synthesis of Racemate

[0909] To a solution of 2-methoxybenzoic acid (300 mg, 1.972 mmol, 1 eq.) in dichloromethane (30 mL) were added Pyridine (0.637 mL, 7.887 mmol, 4 eq.) T3P (1.162 mL, 3.944 mmol, 2 eq.) and 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,N- dimethylbenzamide (71.887 mg, 1.972 mmol, 1 eq.) at 0 °C and the reaction was stirred at RT for 16 h. The mixture was diluted with water (50 mL) and extracted with dichloromethane (2 x 40 mL). The combined organic layers were washed with brine solution (30 mL), dried over Na2SO4 (200 mg), filtered and filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 2-chloro-4-(6-isopropyl- 5(2-methoxybenzoyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,N- dimethylbenzamide(280 mg, Yield 30%) as an off white solid.

[0910] LC-MS (ESI): m / z = 467.35 [M+H]+

[0911] Step-2: Synthesis of PK-1 and PK-2

[0912] The Racemate (0.080 g) separated by chiral prep-SFC into PK-1 (0.0886 g) as an off-white solid and PK-2 (0.0922 g) as a white solid.

[0913] Chiral SEC purification Conditions:

[0914] Column / Dimensions: (R,R)Whelk -01 (250X30X5p), % CO2: 60%,% Co solvent: 40% (0.5% Methanolic Ammonia In Methanol), Total Flow: 100 mL / min, Back Pressure: 100 Bar, Temperature: 30.0 °C.

[0915] PK-1:

[0916] LC-MS (ESI): m / z = 467.41 [M+H]+

[0917] 'H NMR (400 MHz, DMSO-d6): 6 8.52 - 8.30 (m, 1H), 7.98 (d, J= 1.5 Hz, 1H), 7.91 - 7.82 (m, 1H), 7.56 - 7.41 (m, 2H), 7.34 - 7.24 (m, 1H), 7.15 (d, J= 8.3 Hz, 1H), 7.09 - 6.99 (m, 1H), 5.16 - 5.08 (m, 1H), 4.85 - 4.13 (m, 2H), 3.91 - 3.73 (m, 3H), 3.07 - 2.92 (m, 3H), 2.81 (s, 3H), 2.75 - 2.63 (m, 1H), 1.33 - 1.11 (m, 3H), 0.75 - 0.43 (m, 3H).

[0918] PK-2:

[0919] LC-MS (ESI): m / z = 467.41 [M+H]+

[0920] 'H NMR (400 MHz, DMSO-d6): 6 8.50 - 8.31 (m, 1H), 7.98 (d, J= 2.0 Hz, 1H), 7.91 - 7.83 (m, 1H), 7.55 - 7.39 (m, 2H), 7.34 - 7.24 (m, 1H), 7.15 (d, J= 8.0 Hz, 1H), 7.04 (dt, J= 0.8, 7.5 Hz, 1H), 5.12 (d, J= 3.8 Hz, 1H), 4.86 - 4.09 (m, 2H), 3.88 - 3.76 (m, 3H), 3.07 - 2.94 (m, 3H), 2.81 (s, 3H), 2.74 - 2.63 (m, 1H), 1.29 - 1.10 (m, 3H), 0.73 - 0.46 (m, 3H).

[0921] EXAMPLE 34: SCHEME 34: Synthesis of Compound 162-PK-l, PK-2 Step-1: Synthesis of Racemate

[0922] To a solution of 2-chloro-4-(6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,N- dimethylbenzamide (300 mg, 0.901 mmol, 1 eq.) in THF (3 mL) was added sodium hydride (68.675 mg, 1.803 mmol, 2 eq.) at 0 °C and stirred for 20 min. 2,4-Difluoropyrimidine (83.695 mg, 0.721 mmol, 0.8 eq.) was added at RT and the mixture was stirred at same temperature for 16 h. The reaction was quenched with ice-cold water (40 mL) and extracted with ethyl acetate twice. The combined organic layer was washed with brine solution (30 mL), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to crude compound. The crude compound both peaks was purified by silica gel (100- 200 mesh) column chromatography, eluted with 60% of ethyl acetate in pet ether to afford 2- chloro-4-(5-(2-fluoropyrimidin-4-yl)-6-isopropyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)- yl)-N,Ndimethylbenzamide (Peak 1, 100 mg, Yield 25.87%) and (Peak 2, 140 mg) and as an off-white solid.

[0923] LC-MS (ESI): m / z = 429.34 [M+H]+

[0924] Step-2: Synthesis of PK-1 and PK-2

[0925] The Racemate (0.241 g) separated by chiral prep-SFC into PK-1 (0.0217 g) as a white solid and PK-2 (0.0131 g) as a white solid.

[0926] Chiral SEC purification Conditions:

[0927] Preparative SFC Conditions: Column / Dimensions: Chiralpak IG (250X30X5p), % CO2: 60%, % Co solvent: 40% (Methanol), Total Flow: 100 mL / min, Back Pressure: 100 Bar, Temperature: 30.0 °C.

[0928] PK-1:

[0929] LC-MS (ESI): m / z = 429.30 [M+H]+

[0930] 'H NMR (400 MHz, DMSO-d6): 6 8.58 - 8.50 (m, 2H), 8.02 (d, J= 2.0 Hz, 1H), 7.90 (dd, J = 2.0, 8.5 Hz, 1H), 7.65 - 7.45 (m, 2H), 6.52 (dd, J= 1.9, 5.4 Hz, 1H), 5.19 - 4.97 (m, 1H), 4.86 - 4.51 (m, 2H), 3.02 (s, 3H), 2.87 - 2.62 (m, 4H), 1.21 (d, J = 7.0 Hz, 3H), 0.53 (d, J = 6.8 Hz, 3H).

[0931] PK-2:

[0932] LC-MS (ESI): m / z = 429.30 [M+H]+

[0933] 'H NMR (400 MHz, DMSO-d6): 6 8.57 - 8.50 (m, 2H), 8.02 (d, J= 2.0 Hz, 1H), 7.90 (dd, J = 2.1, 8.4 Hz, 1H), 7.49 (d, J= 8.5 Hz, 1H), 6.52 (dd, J= 2.0, 5.5 Hz, 1H), 5.17 - 5.00 (m, 1H), 4.85 - 4.52 (m, 2H), 3.02 (s, 3H), 2.87 - 2.68 (m, 4H), 1.21 (d, J= 6.8 Hz, 3H), 0.53 (d, J= 6.8 Hz, 3H). EXAMPLE 35: Synthesis of Compounds 314-S, 265-S, 315-S, 316-S, 317-S, and 318-S

[0934] Step-1: Synthesis of 4-bromo-2-chloro-l-(prop-l-yn-l-yl)benzene

[0935] To a solution of 4-bromo-2-chl oro-1 -iodobenzene (10 g, 31.511 mmol, 1 equiv.) in THF (100 mL) was added Copper(I) iodide (180 mg, 0.945 mmol, 0.03 equiv.), Triethylamine (22.1 mL, 157.6 mmol, 5 equiv.) and Bis(triphenylphosphine)palladium(II) dichloride (884.7 mg, 1.26 mmol, 0.04 equiv.) at 25 °C and the reaction was degassed with N2 for 15 min. Prop-l-yne (4% in DMF) (41.031 mL, 40.964 mmol, 1.3 equiv.) was added at 25 °C and the reaction was stirred at 25 °C for 6 h. The reaction was diluted with water (200 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layer was washed with brine solution (150 mL), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure . The was purified by silica gel (230-400 mesh) column chromatography, eluted with 100% pet ether to afford 4-bromo-2-chloro-l-(prop-l-yn-l- yl)benzene (5.5 g, Yield 76%) as a pale yellow liquid.

[0936] 'H NMR (400 MHz, CDCh) 8 = 7.54 (d, J= 1.6 Hz, 1H), 7.32 - 7.26 (m, 2H), 2.10 (s, 3H).

[0937] Step-2: Synthesis of 4-(4-bromo-2-chlorophenyl)-5-methyl-lH-l,2,3-triazole

[0938] To a solution of 4-bromo-2-chloro-l-(prop-l-yn-l-yl)benzene (5.5 g, 23.965 mmol, 1 equiv.) in DMF (50 mL) was added sodium azide (9.348 g, 143.790 mmol, 6 equiv.) at 25 °C and the reaction was stirred at 120 °C for 72 h. The reaction was diluted with water

[0939] (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine solution (80 mL), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel (100- 200 mesh) column chromatography, eluted with 40% of ethyl acetate in pet ether to afford 4- (4-bromo-2-chlorophenyl)-5-methyl-lH-l,2,3-triazole (2 g, Yield 30.6%) as an off white solid.

[0940] LC-MS (ESI): m / z = 272.05 [M+H]+

[0941] Step-3: Synthesis of 4-(4-bromo-2-chlorophenyl)-l,5-dimethyl-lH-l,2,3-triazole, 4-(4- bromo-2-chlorophenyl)-2,5-dimethyl-2H-l,2,3-triazole, 5-(4-bromo-2-chlorophenyl)-l,4- dimethyl- 1H- 1 ,2,3-tr iazole

[0942] To a stirred solution of 4-(4-bromo-2-chlorophenyl)-5-methyl-lH-l,2,3-triazole (2 g, 7.339 mmol, 1 equiv.) in DMF (20 mL) was added sodium hydride (60%, dispersion in Paraffin Liquid) (0.352 mg, 8.806 mmol, 1.2 equiv.) at 0 °C and the reaction was stirred at same temperature for 10 min. lodomethane (0.503 mL, 8.073 mmol, 1.1 equiv.) was added at 0 °C and the reaction was stirred at 25 °C for 3 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine solution (100 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel (100-200 mesh) column chromatography, eluted with 20% to 35% of ethyl acetate in pet ether to afford 4-(4-bromo-2-chlorophenyl)-l,5-dimethyl-lH-l,2,3-triazole (400 mg, Yield 19.0%) as a yellow solid, 4-(4-bromo-2-chlorophenyl)-2,5-dimethyl-2H- 1,2, 3 -triazole (800 mg, Yield 38.0%) as a pale yellow solid and 5-(4-bromo-2-chlorophenyl)-l,4-dimethyl-lH-l,2,3- triazole (280 mg, Yield 13.3%) as a brown gum liquid.

[0943] 4-(4-bromo-2-chlorophenyl)-l,5-dimethyl-lH-l,2,3-triazole

[0944] LC-MS (ESI): m / z = 285.94 [M+H]+

[0945] 'H NMR (400 MHz, CDC13) 8 = 7.65 (d, J= 2.0 Hz, 1H), 7.50 - 7.47 (m, 1H), 7.37 - 7.35 (d, J= 8.0 Hz, 1H), 4.02 (s, 3H), 2.27 (s, 3H).

[0946] 4-(4-bromo-2-chlorophenyl)-2,5-dimethyl-2H-l,2,3-triazole

[0947] LC-MS (ESI): m / z = 285.94 [M+H]+

[0948] 'H NMR (400 MHz, CDCI3) 6 = 7.66 (d, J= 2.0 Hz, 1H), 7.46 (dd, J= 2.0, 8.0 Hz, 1H), 7.26 (d, J= 1.2 Hz, 1H), 4.18 (s, 3H), 2.24 (s, 3H).

[0949] 5-(4-bromo-2-chlorophenyl)-l,4-dimethyl-lH-l,2,3-triazole

[0950] LC-MS (ESI): m / z = 285.94 [M+H]+

[0951] 'H NMR (400 MHz, CDCI3) 6 = 7.74 (d, J= 2.0 Hz, 1H), 7.55 (dd, J= 2.0, 8.4 Hz, 1H), 7.12 (d, J= 8.4 Hz, 1H), 3.84 (s, 3H), 2.22 (s, 3H).

[0952] Step-4: Synthesis of Compound 316-S

[0953] To a solution of 4-(4-bromo-2-chlorophenyl)-l,5-dimethyl-lH-l,2,3-triazole (400 mg, 1.396 mmol, 1 equiv.) in 1,4-Dioxane (8 mL) was added tert-butyl (S)-6-isopropyl-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (280.662 mg, 1.117 mmol, 0.8 equiv.), Cui (132.609 mg, 0.698 mmol, 0.5 equiv.) and K2CO3 (577.9 mg, 4.188 mmol, 3 equiv.) at 25 °C and the reaction was degassed with nitrogen for 15 min. Then, (lR,2R)-cyclohexane-l,2- diamine (79.697 mg, 0.698 mmol, 0.5 equiv.) was added at 25 °C and the reaction was stirred at 120 °C for 16 h. The reaction was filtered through a pad of celite and washed with ethyl acetate (2 x 50 mL), filtrate was diluted with water (40 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layer was washed with brine solution (30 mL), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The was purified by silica gel (100-200 mesh) column chromatography, eluted with 50% of ethyl acetate in pet ether to afford tert-butyl (S)-2-(3-chloro-4-(l,5-dimethyl-lH-l,2,3-triazol-4- yl)phenyl)-6-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (250 mg, Yield 39.1%) as a white solid. LC-MS (ESI): m / z = 457.44 [M+H]+

[0954] 'H NMR (400 MHz, DMSO-d6) 6 = 8.44 (d, J= 8.0 Hz, 1H), 8.05 (s, 1H), 7.90 (d, J= 8.4 Hz, 1H), 7.54 (d, J= 8.8 Hz, 1H), 4.73 (d, J= 8.0 Hz, 1H), 4.51 (d, J= 13.6 Hz, 1H), 4.39 - 4.31 (m, 1H), 4.00 (s, 3H), 2.50 - 2.42 (m, 1H), 2.26 (s, 3H), 1.46 (s, 9H), 1.12 (d, J= 6.8 Hz, 3H), 0.59 (dd, J= 6.8, 10.0 Hz, 3H).

[0955] Step-5: Synthesis of (S)-2-(3-chloro-4-(l,5-dimethyl-lH-l,2,3-triazol-4-yl)phenyl)-6- isopropyl-2,4,5,6-tetr ahydropyrr olo [3,4-c] pyrazole hydrochloride

[0956] To a stirred solution of tert-butyl (S)-2-(3-chloro-4-(l,5-dimethyl-lH-l,2,3-triazol-4- yl)phenyl)-6-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (200 mg, 0.438 mmol) in DCM (5 mL) was added 4M HC1 in 1,4-Dioxane (1 mL) at 0 °C and the reaction was stirred at 25 °C for 8 h. The reaction was concentrated under reduced pressure. The crude residue was washed with pentane and dried under reduced pressure to afford (S)-2-(3-chloro- 4-(l,5-dimethyl-lH-l,2,3-triazol-4-yl)phenyl)-6-isopropyl-2,4,5,6-tetrahydropyrrolo[3,4- c]pyrazole hydrochloride (170 mg, Yield 98.7%) as a brown solid.

[0957] LC-MS (ESI): m / z = 357.21 [M+H]+

[0958] Step-6: Synthesis of Compound 265-S

[0959] To a stirred solution of (S)-2-(3-chloro-4-(l,5-dimethyl-lH-l,2,3-triazol-4-yl)phenyl)-6- isopropyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole hydrochloride (150 mg, 0.381 mmol, 1 equiv.) in Isopropyl Alcohol (5 mL) were added N,N-Diisopropylethylamine (0.333 mL, 1.907 mmol, 5 equiv.) and 4-chloro-2-(trifhioromethyl)pyrimidine (69.612 mg, 0.381 mmol, 1 equiv.) at 25 °C and the reaction was stirred at 100 °C for 16 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine solution (30 mL), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel (100-200 mesh) column chromatography, eluted with 100% ethyl acetate to afford the product, which was further purified by chiral SFC and collected the major peak to afford (S)- 2-(3-chloro-4-(l,5-dimethyl-lH-l,2,3-triazol-4-yl)phenyl)-6-isopropyl-5-(2- (trifluoromethyl)pyrimidin-4-yl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (82 mg, Yield 42.7%) as a white solid.

[0960] Chiral SFC purification Conditions:

[0961] Preparative SFC Conditions

[0962] Column / Dimensions: Chiral ART Cellulose - SC (250x30)mm, 5pm, % CO2: 65%, % Co solvent: 35% (100% Methanol), Total Flow: 100 mL / min, Back Pressure: 100 Bar, Temperature: 30.0 °C. LC-MS (ESI): m / z = 503.41 [M+H]+

[0963] 'H NMR (400 MHz, DMSO-d6) 6 = 8.59 - 8.54 (m, 1H), 8.45 - 8.42 (m, 1H), 8.10 (d, J= 2.0 Hz, 1H), 7.95 (dd, J= 2.4, 8.4 Hz, 1H), 7.57 (d, J= 8.4 Hz, 1H), 7.07 - 6.92 (m, 1H), 5.21 - 5.16 (m, 1H), 4.84 - 4.63 (m, 2H), 4.01 (s, 3H), 2.82 - 2.49 (m, 1H), 2.27 (s, 3H), 1.26 - 1.20 (m, 3H), 0.54 (d, J= 6.8 Hz, 3H).

[0964] Step-4a: Synthesis of Compound 315-S

[0965] To a solution of 4-(4-bromo-2-chlorophenyl)-2,5-dimethyl-2H-l,2,3-triazole (500 mg, 1.745 mmol, 1 equiv.) in 1,4-Dioxane (8 mL) were added tert-butyl (S)-6-isopropyl-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (350.827 mg, 1.396 mmol, 0.8 equiv.), Cui (165.761 mg, 0.872 mmol, 0.5 equiv.) and K2CO3 (722.369 mg, 5.235 mmol, 3 equiv.) at 25 °C and the reaction was degassed with nitrogen for 15 min. Then, (lR,2R)-cyclohexane-l,2- diamine (99.621 mg, 0.872 mmol, 0.5 equiv.) was added at 25 °C and the reaction was stirred at 120 °C for 16 h. The reaction was filtered through a pad of celite and washed with ethyl acetate (2 x 50 mL), filtrate was diluted with water (50 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layer was washed with brine solution (30 mL), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel (100-200 mesh) column chromatography, eluted with 35% of ethyl acetate in pet ether to afford tert-butyl (S)-2-(3-chloro-4-(2,5-dimethyl-2H- l,2,3-triazol-4-yl)phenyl)-6-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (290 mg, Yield 36.3%) as a white solid.

[0966] LC-MS (ESI): m / z = 457.37 [M+H]+

[0967] 'H NMR (400 MHz, DMSO-d6) 6 = 8.44 (d, J= 8.4 Hz, 1H), 8.06 (s, 1H), 7.89 (d, J= 8.4 Hz, 1H), 7.55 (d, J= 8.4 Hz, 1H), 4.73 (d, J= 10.0 Hz, 1H), 4.51 (d, J= 13.6 Hz, 1H), 4.39 - 4.31 (m, 1H), 4.14 (s, 3H), 2.50 - 2.41 (m, 1H), 2.19 (s, 3H), 1.46 (s, 9H), 1.12 (d, J= 6.8 Hz, 3H), 0.59 (d, J = 6.8 Hz, 3H).

[0968] Step-5a: Synthesis of (S)-2-(3-chloro-4-(2,5-dimethyl-2H-l,2,3-triazol-4-yl)phenyl)-6- isopropyl-2,4,5,6-tetr ahydropyrr olo [3,4-c] pyrazole hydrochloride

[0969] To a stirred solution of tert-butyl (S)-2-(3-chloro-4-(2,5-dimethyl-2H-l,2,3-triazol-4- yl)phenyl)-6-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (250 mg, 0.547 mmol, 1 equiv.) in DCM (5 mL) was added 4M HC1 in 1,4-Dioxane (1 mL) at 0 °C and the reaction was stirred at 25 °C for 8 h. The reaction was directly concentrated under reduced pressure to get . The crude residue was washed with pentane and dried under reduced pressure to afford (S)-2-(3-chloro-4-(2,5-dimethyl-2H-l,2,3-triazol-4-yl)phenyl)-6-isopropyl- 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole hydrochloride (200 mg, Yield 92.9%) as an off white solid.

[0970] LC-MS (ESI): m / z = 357.17 [M+H]+

[0971] Step-6a: Synthesis of Compound 316-S

[0972] To a stirred solution of (S)-2-(3-chloro-4-(2,5-dimethyl-2H-l,2,3-triazol-4-yl)phenyl)-6- isopropyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole hydrochloride (180 mg, 0.458 mmol, 1 equiv.) in isopropyl alcohol (5 mL) were added N,N-Diisopropylethylamine (0.400 mL, 2.288 mmol, 5 equiv.) and 4-chloro-2-(trifhioromethyl)pyrimidine (83.534 mg, 0.458 mmol, 1 equiv.) at 25 °C and the reaction was stirred at 110 °C for 16 h. The reaction was diluted with water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel (100- 200 mesh) column chromatography, eluted with 40% of ethyl acetate in pet ether to afford the product (S)-2-(3-chloro-4-(2,5-dimethyl-2H-l,2,3-triazol-4-yl)phenyl)-6-isopropyl-5-(2- (trifluoromethyl)pyrimidin-4-yl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (118 mg, Yield 51.2%) as an off white solid.

[0973] LC-MS (ESI): m / z = 503.41 [M+H]+

[0974] 'H NMR (400 MHz, DMSO-d6) 6 = 8.59- 8.55 (m, 1H), 8.45 - 8.40 (m, 1H), 8.11 (d, J= 2.4 Hz, 1H), 7.94 (dd, J= 2.4, 8.4 Hz, 1H), 7.57 (d, J= 8.4 Hz, 1H), 7.05 - 6.91 (m, 1H), 5.21 - 5.16 (m, 1H), 4.84 - 4.63 (m, 2H), 4.15 (s, 3H), 2.82 - 2.45 (m, 1H), 2.20 (s, 3H), 1.26 - 1.20 (m, 3H), 0.54 (d, J = 6.8 Hz, 3H).

[0975] Step-4b: Synthesis of Compound 317-S

[0976] To a solution of 5-(4-bromo-2-chlorophenyl)-l,4-dimethyl-lH-l,2,3-triazole (320 mg, 1.117 mmol, 1 equiv.) in 1,4-Dioxane (5 mL) were added tert-butyl (S)-6-isopropyl-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (224.529 mg, 0.893 mmol, 0.8 equiv.), Cui (106.087 mg, 0.558 mmol, 0.5 equiv.) and K2CO3 (462.316 mg, 3.350 mmol, 3 equiv.) at 25 °C and the reaction was degassed with nitrogen for 15 min. Then, (lR,2R)-cyclohexane-l,2- diamine (63.758 mg, 0.558 mmol, 0.5 equiv.) was added at 25 °C and the reaction was stirred at 120 °C for 16 h. The reaction was filtered through a pad of celite and washed with ethyl acetate (2 x 50 mL), filtrate was diluted with water (50 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layer was washed with brine solution (30 mL), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The crude was purified by silica gel (100-200 mesh) column chromatography, eluted with 40% of ethyl acetate in pet ether to afford tert-butyl (S)-2-(3-chloro-4-(l,4-dimethyl-lH-l,2,3-triazol- 5-yl)phenyl)-6-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (250 mg, Yield 48.9%) as a white solid.

[0977] LC-MS (ESI): m / z = 457.48 [M+H]+

[0978] 'H NMR (400 MHz, DMSO-d6) 6 = 8.48 (d, J= 9.2 Hz, 1H), 8.15 (s, 1H), 7.97 (d, J= 8.4 Hz, 1H), 7.62 (d, J= 8.4 Hz, 1H), 4.73 (d, J= 8.0 Hz, 1H), 4.52 (d, J= 14.0 Hz, 1H), 4.39 - 4.32 (m, 1H), 3.82 (s, 3H), 2.50 - 2.40 (m, 1H), 2.13 (s, 3H), 1.46 (s, 9H), 1.12 (d, J = 7.2 Hz, 3H), 0.58 (dd, J= 6.8, 10.0 Hz, 3H).

[0979] Step-5b: Synthesis of (S)-2-(3-chloro-4-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)phenyl)-6- isopropyl-2,4,5,6-tetr ahydropyrr olo [3,4-c] pyrazole hydrochloride

[0980] To a stirred solution of tert-butyl (S)-2-(3-chloro-4-(l,4-dimethyl-lH-l,2,3-triazol-5- yl)phenyl)-6-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (200 mg, 0.438 mmol, 1 equiv.) in DCM (5 mL) was added 4M HC1 in 1,4-Dioxane (1 mL) at 0 °C and the reaction was stirred at 25 °C for 8 h. The reaction was directly concentrated under reduced pressure. The crude residue was washed with pentane and dried under reduced pressure to afford (S)-2-(3-chloro-4-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)phenyl)-6-isopropyl-2,4,5,6- tetrahydropyrrolo[3,4-c]pyrazole hydrochloride (170 mg, Yield 98.3%) as a brown solid. LC-MS (ESI): m / z = 357.21 [M+H]+

[0981] Step-6b: Synthesis of Compound 318-S

[0982] To a stirred solution of (S)-2-(3-chloro-4-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)phenyl)-6- isopropyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole hydrochloride (150 mg, 0.381 mmol, 1 equiv.) in Isopropyl Alcohol (5 mL) were added N,N-Diisopropylethylamine (0.333 mL, 1.907 mmol, 5 equiv.) and 4-chloro-2-(trifhioromethyl)pyrimidine (69.612 mg, 0.381 mmol, 1 equiv.) at 25 °C and reaction was stirred at 110 °C for 16 h. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel (100- 200 mesh) column chromatography, eluted with 100% of ethyl acetate to afford the product (S)-2-(3-chloro-4-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)phenyl)-6-isopropyl-5-(2- (trifluoromethyl)pyrimidin-4-yl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (103 mg, Yield 53.7%) as an off white solid.

[0983] LC-MS (ESI): m / z = 503.41 [M+H]+

[0984] 'H NMR (400 MHz, DMSO-d6) 6 = 8.63- 8.59 (m, 1H), 8.45 - 8.41 (m, 1H), 8.20 (d, J= 1.6 Hz, 1H), 8.02 (dd, J= 2.4, 8.8 Hz, 1H), 7.65 (d, J= 8.4 Hz, 1H), 7.07 - 6.92 (m, 1H), 5.22 - 5.17 (m, 1H), 4.85 - 4.63 (m, 2H), 3.83 (s, 3H), 2.82 - 2.49 (m, 1H), 2.14 (s, 3H), 1.26 - 1.15

[0985] (m, 3H), 0.53 (d, J = 6.8 Hz, 3H).

[0986] EXAMPLE 36: Synthesis of Compounds 340-S and 327-S

[0987] Step-1: Synthesis of 4-bromo-2-chlorobenzohydrazide

[0988] To a stirred solution of methyl 4-bromo-2-chlorobenzoate (3 g, 12.025 mmol, 1 equiv.), in methanol (30 mL) was added hydrazine monohydrate (5.845 mL, 120.245 mmol, 10 equiv.) at 25°C and the reaction was stirred at 90 °C for 16 h. and the reaction was stirred at 70 °C for 16 h. The reaction was directly concentrated under reduced pressure to get white solid, the solid was triturated with diethyl ether and filtered, dried under vacuum to afford 4- bromo-2-chlorobenzohydrazide (2 g, Yield 66.67%) as a white solid.

[0989] LC-MS ESI: (m / z) = 249.11 [M+H]+ion present.

[0990] Step-2: Synthesis of 3-(4-bromo-2-chlorophenyl)-4-methyl-4H-l,2,4-triazole

[0991] To a stirred solution of 4-bromo-2-chlorobenzohydrazide (2 g, 8.016 mmol, 1 equiv.) in (DMF) (5 mL) was added N, N-Dimethylformamide dimethyl acetal (1.278 mL, 9.620 mmol, 1.2 equiv.) at 25 °C and the reaction was stirred at 130 °C for 30 min. The reaction was cooled to 0 °C, then methylene amine (40%) in methanol (3.1 mL, 40.1 mmol, 5 equiv.) and acetic acid (2.64 mL, 45.693 mmol, 5.7 equiv.) at 0 °C and the reaction was stirred at 130 °C for 1 h. The reaction was quenched with ice cold water (100 mL), extracted with ethyl acetate twice (80 mL). The combined organic layer was washed with brine (80 mL), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel (100-200 mesh) column chromatography, eluted with 10% of methanol in DCM to afford 3-(4-bromo-2-chlorophenyl)-4-methyl-4H-l,2,4-triazole (600 mg, Yield 27.46%) as a brown gum.

[0992] LC-MS ESI: (m / z) = 272.07 [M+H]+ion present.

[0993] Step-3: Synthesis of 340-S

[0994] To a stirred solution of 3 -(4-bromo-2-chlorophenyl)-4-methyl-4H- 1,2, 4-triazole (500 mg, 1.835 mmol, 1 equiv.), in 1,4-Dioxane (10 mL) was added tert-butyl (S)-6-isopropyl-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (368 mg, 1.468 mmol, 0.8 equiv.), Cui (174 mg, 0.917 mmol, 0.5 equiv.) and K2CO3 (759 mg, 5.504 mmol, 3 equiv.) at 25 °C and the reaction was degassed with nitrogen for 15 min. (lR,2R)-cyclohexane-l,2-diamine (104 mg, 0.917 mmol, 0.5 equiv.), was added at 25 °C and the reaction was stirred at 120 °C for 16 h. The reaction was quenched with ice cold water (50 mL), extracted with ethyl acetate twice (40 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The compound (200 mg) was purified by prep HPLC Mobile Phase: A-lOmM ammonium bicarbonate in Water: B-Acetonitrile Column: X-Terra C8 19X50mm, 5pm Gradient: Time / %B 0 / 40; 11 / 90; 11.1 / 98; 15 / 98; 15.1 / 40; 18 / 40 Flow Rate: 12 ml / min to afford tert-butyl(S)-2-(3-chloro-4-(4-methyl- 4H-l,2,4-triazol-3-yl)phenyl)-6-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)- carboxylate (79 mg, Yield 0.097%) as a white solid.

[0995] LC-MS ESI: (m / z) = 443.44 [M+H]+ion present.

[0996] 'HNMR (400 MHz, DMSO-de): 6 = 8.66 (s, 1H), 8.49 (d, J= 8.8 Hz, 1H), 8.15 (s, 1H), 7.99 - 7.97 (m, 1H), 7.67 (d, J= 8.4 Hz, 1H), 4.76 - 4.72 (m, 1H), 4.54 - 4.51 (m, 1H), 4.43 - 4.30 (m, 1H), 3.54 (s, 3H), 2.45 - 2.33 (m, 1H), 1.47 (s, 9H), 1.13 (d, J= 7.2 Hz, 3H), 0.62 - 0.57 (m, 3H).

[0997] Step-4: Synthesis of (S)-2-(3-chloro-4-(4-methyl-4H-l,2,4-triazol-3-yl) phenyl)-6- isopropyl-2,4,5,6- tetrahydropyrrole [3,4-c] pyrazole hydrochloride

[0998] To a stirred solution of tert-butyl (S)-2-(3-chloro-4-(4-methyl-4H-l,2,4-triazol-3-yl) phenyl)- 6-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (350 mg, 0.790 mmol, 1 equiv.) in DCM (5 mL) was added 4M Hydrochloric acid in 1,4-di oxane (2 mL) at 0 °C and the reaction was stirred at 25 °C for 8 h. The reaction was directly concentrated under reduced pressure. The residue was washed with pentane and dried under reduced pressure to afford (S)- 2-(3-chloro-4-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-6-isopropyl-2,4,5,6- tetrahydropyrrole[3,4-c]pyrazole HC1 (280 mg).

[0999] LC-MS ESI: (m / z) = 343.36 [M+H]+ion present.

[1000] Step-5: Synthesis of 327-S

[1001] To a stirred solution of (S)-2-(3-chloro-4-(4-methyl-4H-l,2,4-triazol-3-yl) phenyl)-6- isopropyl-2,4,5,6-tetrahydropyrrolo[3,4-c] pyrazole hydrochloride (250 mg, 0.659 mmol, 1 equiv.) in Isopropyl alcohol (5 mL) were added N, N-Diisopropylethylamine (0.576 mL, 3.296 mmol, 5 equiv.) and 4-chloro-2-(trifluoromethyl) pyrimidine (120 mg, 0.659 mmol, 1 equiv.) at 25 °C and reaction was stirred at 110 °C for 16 h. The reaction was diluted with water ice water (60 mL) and extracted with ethyl acetate (2x40 mL), combined organic layers were washed with brine solution (30 mL), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure and purified by prep HPLC Mobile Phase: A- lOmM ammonium bicarbonate in Water : B-Acetonitrile Column: YMC Actus EXRS (250*20)mm 5pm Gradient: Time / %B 0 / 45 ;11 / 90; 11.1 / 100; 15 / 100; 15.1 / 45; 18 / 45 Flow Rate: 12 ml / min. to afford (S)-2-(3-chloro-4-(4-methyl-4H-l,2,4-triazol-3-yl)phenyl)-6-isopropyl-5-(2- (trifluoromethyl)pyrimidin-4-yl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (92 mg, Yield

[1002] 27.98%) as an white solid.

[1003] LC-MS ESI: (m / z) = 443.44 [M+H]+ion present.

[1004] 'H NMR (400 MHz, DMSO-de): 6 = 8.67 - 8.60 (m, 2H), 8.50 - 8.39 (m, 1H), 8.19 (d, J= 2.0 Hz, 1H), 8.03 (dd, J = 2.0, 8.4 Hz, 1H), 7.70 (d, J= 8.4 Hz, 1H), 7.10 - 6.91 (m, 1H), 5.27 -

[1005] 5.13 (m, 1H), 4.89 - 4.63 (m, 2H), 3.55 (s, 3H), 2.91 - 2.73 (m, 1H), 1.32 - 1.14 (m, 3H), 0.55 (d, J = 6.8 Hz, 3H).

[1006] EXAMPLE 37: Synthesis of Compounds 341-S and 328-S

[1007] Step-1: Synthesis of 4-bromo-2-chlorobenzamide

[1008] To a stirred solution of 4-bromo-2-chlorobenzoic acid (5 g, 21.235 mmol, 1 equiv.) in DMF (50 mL) were added HATU (12.11g, 31.85 mmol, 1.5 equiv.), DIPEA (11.11 mL, 63.71 mmol, 3 equiv.) and ammonium chloride (2.272 g, 42.470 mmol, 2 equiv.) at 25 °C and the reaction was stirred at 25 °C for 16 h. The reaction was diluted with ice cold water, solid was formed and filtered by vacuum, the solid was washed with water (2x30 mL) and dried under vacuum to afford 4-bromo-2-chlorobenzamide (4.5 g, Yield 90.38 %) as an off-white solid.

[1009] LC-MS (ESI): m / z = 233.99 [M+H]+ion present.

[1010] Step-2: Synthesis of (E)-4-bromo-2-chloro-N-((dimethylamine)methylene) benzamide

[1011] To a stirred solution of 4-bromo-2-chlorobenzamide (4 g, 17.059 mmol, 1 equiv.) in N,N- Dimethylformamide dimethyl acetal (4.532 mL, 34.118 mmol, 2 equiv.) at 25 °C and the reaction was stirred at 120 °C for 2 h. The reaction was allowed to warn to RT and the solid was observed, the solid was filtered through vacuum and washed with diethyl ether, dried under vacuum afford (E)-4-bromo-2-chloro-N-((dimethylamine)methylene) benzamide (3.5 g, Yield 70.86 %) as an pale yellow solid.

[1012] LC-MS (m / z): 289.06 [M+H]+ion present.

[1013] Step-3: Synthesis of 3-(4-bromo-2-chlorophenyl)-4H-l,2,4-triazole

[1014] To a stirred solution of hydrazine monohydrate (0.646 mL, 13.296 mmol, 1.1 equiv.) in Acetic Acid (3.490 mL, 60.437 mmol, 5 equiv.) was added (E)-4-bromo-2-chloro-N- ((dimethylamino) methylene) benzamide (3.5 g, 12.087 mmol, 1 equiv.) at 0 °C and the reaction was stirred at 90 °C for 2 h. The reaction was directly concentrated under reduced pressure to get white solid, the white solid was filtered through vacuum, the solid was washed with ether and dried under vacuum to 3-(4-bromo-2-chlorophenyl)-4H-l,2,4-triazole (2 g, Yield 64.01%) as a white solid.

[1015] LC-MS (ESI): m / z = 258.01 [M+H]+ion present. Step-4: Synthesis of 5-(4-bromo-2-chlorophenyl)-l-methyl-lH-l,2,4-triazole and 3-(4- bromo-2-chlorophenyl)-l-methyl-lH-l,2,4-triazole

[1016] To a stirred solution of 3-(4-bromo-2-chlorophenyl)-4H-l, 2, 4-triazole (1 g, 3.868 mmol, 1 equiv.) in DMF (10 mL) were added sodium hydride (60%, dispersion in Paraffin Liquid) (0.309 mg, 7.737 mmol, 2 equiv.) at 0 °C and the reaction was stirred at same temperature for 20 min. lodomethane, 98% (0.361 mL, 5.803 mmol, 1.5 equiv.) was added at 0 °C and the resulting mixture was stirred at 25 °C for 3 h. The reaction was quenched with ice cold water (60 mL), extracted with ethyl acetate twice (40 mL). The combined organic layer was washed with brine (40 mL), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to afford crude compound. Crude compound was purified by silica gel (100-200 mesh) column chromatography, eluted with 40% of ethyl acetate in pet ether to afford 5-(4-bromo-2- chlorophenyl)-l-methyl-lH-l, 2, 4-triazole (Peak-1, 380 mg, Yield 36.0 %) as an off-white solid, and 3-(4-bromo-2-chlorophenyl)-l-methyl-lH-l, 2, 4-triazole (Peak-2, 550 mg, Yield 48.0 %).

[1017] LC-MS (ESI): m / z = 271.92 [M+H]+ion present.

[1018] Step-5: Synthesis of 341-S

[1019] To a stirred solution of 5-(4-bromo-2-chlorophenyl)-l -methyl- 1H- 1,2, 4-triazole (Peak-1, 350 mg, 1.284 mmol, 1 equiv.), in 1,4-dioxane (5 mL) were added tert-butyl (S)-6-isopropyl-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (258 mg, 1.027 mmol, 0.8 equiv.), Cui (122 mg, 0.642 mmol, 0.5 equiv.) and K2CO3 (531 mg, 3.853 mmol, 3 equiv.) at 25 °C and the reaction was degassed with nitrogen for 15 min. (lR,2R)-cyclohexane-l,2-diamine (73 mg, 0.642 mmol, 0.5 equiv.) was added at 25 °C and the reaction was stirred at 120 °C for 16 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate twice. The combined organic layer was washed with brine solution (100 mL), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography, eluted with 70% of ethyl acetate in pet ether to afford tert-butyl (S)-2-(3-chloro-4-(l-methyl-lH-l,2,4-triazol-5- yl)phenyl)-6-isopropyl-2,6-dihydropyrrolo[3,4-c] pyrazole-5(4H)-carboxylate (270 mg, Yield 47.46%) as a white solid.

[1020] LC-MS (ESI): m / z = 443.31 [M+H]+ion present.

[1021] 'HNMR (400 MHz, DMSO-de): 8 = 8.50 (d, J = 8.8 Hz, 1H), 8.15 - 8.14 (m, 1H), 8.09 (s, 1H), 7.99 - 7.97 (m, 1H), 7.69 (d, J = 8.4 Hz, 1H), 4.76 - 4.72 (m, 1H), 4.54 - 4.51 (m, 1H), 4.44 - 4.29 (m, 1H), 3.75 (s, 3H), 2.43 - 2.39 (m, 1H), 1.47 (s, 9H), 1.13 (d, J = 6.8 Hz, 3H), 0.62 - 0.57 (m, 3H). Step-6: Synthesis of (S)-2-(3-chloro-4-(l-methyl-lH-l,2,4-triazol-5-yl) phenyl)-6- isopropyl-2,4,5,6-tetr ahydropyrr olo [3,4-c] pyr azole hydrochloride

[1022] To a stirred solution of tert-butyl (S)-2-(3-chloro-4-(l-methyl-lH-l,2,4-triazol-5-yl) phenyl)- 6-isopropyl-2,6-dihydropyrrolo[3,4-c] pyrazole-5(4H)-carboxylate (200 mg, 0.452 mmol, 1 equiv.) in DCM (5 mL) was added 4M Hydrochloric acid in 1,4-Dioxane (1.5 mL) at 0 °C and the reaction was stirred at 25 °C for 6 h. The reaction was concentrated under reduced pressure to afford (170 mg) crude compound.

[1023] LC-MS (ESI): m / z = 343.39 [M+H]+ion present.

[1024] Step-7: Synthesis of AM-AR-474S

[1025] To a stirred solution of (S)-2-(3-chloro-4-(l-methyl-lH-l,2,4-triazol-5-yl)phenyl)-6- isopropyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole hydrochloride (150 mg, 0.395 mmol, 1 equiv.) in isopropyl alcohol (5 mL) were added N,N-Diisopropylethylamine (0.345 mL, 1.977 mmol, 5 equiv.) and 4-chloro-2-(trifluoromethyl)pyrimidine (72.186 mg, 0.395 mmol, 1 equiv.) at 25 °C and reaction was stirred at 110 °C for 16 h. The reaction was quenched with ice cold water (50 mL), extracted with ethyl acetate twice (30 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. Crude product was purified by silica gel (100-200 mesh) column chromatography, eluted with 95% of ethyl acetate in pet ether to afford (S)-2-(3-chloro-4-(l- methyl-lH-l,2,4-triazol-5-yl)phenyl)-6-isopropyl-5-(2-(trifluoromethyl)pyrimidin-4-yl)- 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (85 mg, Yield 43.96 %) as an white solid.

[1026] LC-MS (ESI): m / z = 489.27 [M+H]+ion present.

[1027] 'H NMR (400 MHz, DMSO-de): 6 = 8.67 - 8.56 (m, 1H), 8.49 - 8.38 (m, 1H), 8.19 (d, J = 2.0

[1028] Hz, 1H), 8.10 (s, 1H), 8.03 (dd, J = 2.0, 8.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.11 - 6.88 (m, 1H), 5.28 - 5.13 (m, 1H), 4.91 - 4.61 (m, 2H), 3.76 (s, 3H), 2.82-2.84 (m, 1H), 1.31 - 1.16 (m, 3H), 0.55 (d, J = 6.4 Hz, 3H).

[1029] EXAMPLE 38: Synthesis of Compound 334-S

[1030] Step-1: Synthesis of (4-bromo-2-chlorophenyl) ethynyl) trimethyl silane

[1031] To a solution of 4-bromo-2-chl oro-1 -iodobenzene (5 g, 15.755 mmol, 1 equiv.) in THF (50 mL) were added Copper(I) iodide (90 mg, 0.473 mmol, 0.03 equiv.) Triethylamine (11 mL, 78.8 mmol, 5 equiv.) and Bis(triphenylphosphine) palladium (II) dichloride (442 mg, 0.630 mmol, 0.04 equiv.) at 25 °C and the reaction was degassed with nitrogen for 15 min, after ethynyl trimethyl silane (2.84 mL, 20.48 mmol, 1.3 equiv.) was added at 25 °C and the reaction was stirred at 25 °C for 3 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (2 x 150 mL), combined organic layers were washed with brine solution (100 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford product (3.8 g, Yield 83.85 %) as a black liquid.

[1032] Step-2: Synthesis of 4-bromo-2-chloro-l-ethynylbenzene

[1033] To a stirred solution of (4-bromo-2-chlorophenyl) ethynyl) trimethyl silane (4 g, 13.905 mmol, 1 equiv.) in methanol (40 mL) was added potassium carbonate (3.843 g, 27.811 mmol, 2 equiv.) at 25 °C and the reaction was stirred at 25 °C for 3 h. The reaction was diluted with water (200 mL) and extracted with Diethyl ether (2 x 100 mL), combined organic layers were washed with brine solution (80 mL), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel (100-200 mesh) column chromatography, eluted with 100% Pet ether to afford the product (2 g, Yield 53.40 %) as an off white solid.

[1034] Step-3: Synthesis of 4-(4-bromo-2-chlorophenyl)-l-methyl-lH-l,2,3-triazole

[1035] To a solution of 4-bromo-2-chl oro-1 -ethynylbenzene (2.8 g, 12.995 mmol, 1 equiv.) in DMF (20 mL) were added sodium azide (6.758 g, 103.957 mmol, 8 equiv.) at 25 °C and the reaction was stirred at 120 °C for 16 h. The reaction was concentrated under reduced pressure and purified by silica gel (100-200 mesh) column chromatography, eluted with 25% of ethyl acetate in Pet ether to afford the product as a light yellow solid (600 mg, Yield 17.86%).

[1036] LC-MS (ESI): m / z = 258.04 [M+H]+ion present.

[1037] Step-4: Synthesis of 4-(4-bromo-2-chlorophenyl)-l-(4-methoxybenzyl)-lH-l,2,3-triazole

[1038] To a solution of 4-(4-bromo-2-chlorophenyl)-lH-l,2,3-triazole (600 mg, 2.321 mmol, 1 equiv.) in DMF (10 mL) were added cesium carbonate (1.512 g, 4.642 mmol, 2 equiv.) and 1- (chloromethyl)-4-methoxybenzene (0.363 mL, 2.553 mmol, 1.1 equiv.) at RT and the reaction was stirred at 25 °C for 16 h. The reaction was diluted with water (30 ml) and extracted with EtOAc (2 x 50 ml), combined organic layers were washed with brine solution (80 ml), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The crude was purified by silica gel (100-200 mesh) column chromatography, eluted with 20% of EtOAc in Pet ether to afford the product as two factions. (450 mg, Yield 67.27%) as a yellow gum.

[1039] LC-MS (ESI): m / z = 378.10 [M+H]+ion present.

[1040] Step-5: Synthesis of tert-butyl (S)-2-(3-chloro-4-(lH-l,2,4-triazol-5-yl) phenyl)-6- isopropyl-2,6-dihydr opyr rolo [3,4-c] py razole-5(4H)-carboxylate

[1041] To a solution of 3-(4-bromo-2-chlorophenyl)-4H-l,2,4-triazole (250 mg, 0.967 mmol, 1 equiv.) in 1,4 Dioxane (10 mL) were added potassium carbonate (400.962 mg, 2.901 mmol, 3 equiv.) , Copper(I) iodide (92.093 mg, 0.484 mmol, 0.5 equiv.) and tert-butyl (S)-6-isopropyl- 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (243.063 mg, 0.967 mmol, 1 equiv.) at RT under nitrogen purging for 10 min. Then (lR,2R)-(-)-l,2-Diaminocyclohexane (55.125 mg, 0.484 mmol, 0.5 equiv.) added to the reaction and the reaction was stirred at 120 °C for 16 h. The reaction was diluted with water (80 ml) and extracted with EtOAc (2 x 50 ml), combined organic layers were washed with brine solution (80 ml), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The crude was purified by silica gel (100-200 mesh) column chromatography, eluted with 35% of EtOAc in Pet ether to afford the product (150 mg, Yield 36.2%) as a yellow solid LC-MS (ESI): m / z = 549.58 [M+H]+ion present.

[1042] Step-6: Synthesis of (S)-2-(3-chloro-4-(l-(4-methoxybenzyl)-lH-l,2,3-triazol-4-yl) phenyl)-6-isopropyl-2,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole hydrochloride

[1043] To a stirred solution of tert-butyl (S)-2-(3-chloro-4-(l-(4-methoxybenzyl)-lH-l,2,3-triazol-4- yl)phenyl)-6-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (350 mg, 0.637 mmol, 1 equiv.) in DCM (8 mL) was added 4M Hydrochloric acid in 1,4-Dioxane (3 mL, 3.187 mmol, 5 equiv.) at 0 °C and the reaction was stirred at 25 °C for 3h. The reaction was directly concentrated under reduced pressure. The residue was washed with pentane and dried under reduced pressure to afford product (220 mg, Yield 71.1%) as an off-white solid.

[1044] LC-MS (ESI): m / z = 324.71 [M+H]+ion present.

[1045] Step-7: Synthesis of (S)-2-(3-chloro-4-(l-(4-methoxybenzyl)-lH-l,2,3-triazol-4-yl) phenyl)-6-isopropyl-5-(2-(trifluoromethyl) pyrimidin-4-yl)-2, 4,5,6- tetrahydropyrrolo [3,4-c] pyrazole

[1046] To a solution of (S)-2-(3-chloro-4-(l-(4-methoxybenzyl)-lH-l,2,3-triazol-4-yl)phenyl)-6- isopropyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole hydrochloride (220 mg, 0.453 mmol, 1 equiv.) in IPA (10 mL) was added DIPEA (0.237 mL, 1.360 mmol, 3 equiv.), 4-chloro-2- (trifluoromethyl)pyrimidine (66.181 mg, 0.363 mmol, 0.8 equiv.) at 25 °C and the reaction stirred at 80 °C for 16 h. The reaction was directly distilled under reduced pressure and purified by silica gel (100-200 mesh) column chromatography, eluted with 45% of EtOAc in Pet ether to afford the product (200 mg, Yield 74.16%) as a white solid.

[1047] LC-MS (ESI): m / z = 595.28 [M+H]+ion present.

[1048] Step-8: Synthesis of 334-S

[1049] To a solution of (S)-2-(3-chloro-4-(l-(4-methoxybenzyl)-lH-l,2,3-triazol-4-yl) phenyl)-6- isopropyl-5-(2-(trifluoromethyl) pyrimidin-4-yl)-2,4,5,6-tetrahydropyrrolo[3,4-c] pyrazole (200 mg, 0.336 mmol, 1 equiv.) in TFA (5 mL) at 25 °C and the reaction was stirred at 80 °C for 16 h. The reaction was concentrated under reduced pressure, basified pH~8 with NaHCCh and extracted with ethyl acetate, combined organic layers were washed with brine solution (50 ml), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The crude was purified by silica gel (100-200 mesh) column chromatography, eluted with 100% of EtOAc to afford the product (60 mg) as a crude compound, and purified by Prep HPLC. Mobile Phase: A-lOmM Ammonium bicarbonate in Water: B-Acetonitrile Column: YMC Actus TRAIT C18(150x20) mm 5pm Gradient: Time / %B 0 / 30; 11 / 90; 11.1 / 100; 14 / 100; 14.1 / 30; 17 / 30 Flow Rate: 15ml / min (29 mg, Yield 16.9%) as a white Solid.

[1050] LC-MS (ESI): m / z = 475.42 [M+H]+ion present.XHNMR (400 MHz, DMSO-de) 6 = 15.61 - 14.98 (m, 1H), 8.62 - 8.50 (m, 1H), 8.47 - 8.35 (m, 2H), 8.12 - 8.05 (m, 2H), 7.96 (dd, J = 2.0, 8.8 Hz, 1H), 7.13 - 6.85 (m, 1H), 5.27 - 5.11 (m, 1H), 4.87 - 4.60 (m, 2H), 2.92 - 2.75 (m, 1H), 1.30 - 1.17 (m, 3H), 0.54 (d, J= 6.8 Hz, 3H). The following compounds were prepared using procedures similar to those described above (data shown) or can be prepared using procedures similar to those described above:

[1051] TABLE B

[1052]

[1053]

[1054]

[1055]

[1056]

[1057]

[1058]

[1059]

[1060]

[1061]

[1062]

[1063]

[1064]

[1065] EXAMPLE : BIOLOGICAL ACTIVITY ASSAY

[1066] Time-Resolved Fluorescence Energy Transfer (TR-FRET) Assays for LXR In Vitro Compound Binding The TR-FRET assay measures the binding of a test compound to full length 6X-His tagged LXRa or LXRp through its ability to displace FITC-labeled GW3965, a dual agonist reference LXR agonist. The extent of displacement was determined in a 10 pl reaction containing assay buffer (50mM K3PO4, 150mM KC1, ImM DTT, 0.5mM EDTA, 0.001% CHAPS, pH-7.4), test compound, 1 nM MAb Anti-6His Tb cryptate Gold (a monoclonal antibody raised against a polyhistidine-tagged fusion protein labeled with Terbium, Fisher Scientific), 15 nM 6X-His + SUMO-tagged LXRa or 15 nM 6X-His + MBP-tagged LXRP, and 40 nM FITC-GW3965. The reaction was incubated with shaking in a 384 well plate for 1 hr at RT and read on a PerkinElmer Envision 2105 plate reader, with excitation at 340 nm and Time-Resolved emissions measured at 520 nm and 485 nm. With the displacement of LXR bound FITC-GW3965 by a test compound, the donor-acceptor pair is no longer in close proximity and, thus, decreases the acceptor FITC fluorescence at 520 nm resulting from excitation from the donor Tb. A series of 10 3-fold dilutions of each test compound, from 0.5 to 10,000 nM, was tested and a non-linear 4 parameter variable slope curve was fitted to the data using GraphPad Prism, allowing the calculation of ECso and percent FITC-GW3965 displacement relative to unlabeled GW3965.

[1067] Cellular LXR Transactivation Assays

[1068] To measure the ability of compounds to activate or inhibit LXR transcriptional activity in whole cells, cellular reporter assays for LXRa and LXRp were used. Compound activities were measured in cultured HEK293 cells transfected with plasmids expressing full length LXRa (pCDNA3 4-HuLXRa) or LXRP (pCDNA3.4-HuLXRP), a luciferase reporter plasmid (pGL4.19[luc2CPNeo]-3xLXRE-mTK) containing 3 LXR response elements (LXRE) upstream of a minimal TK promoter, followed by a luciferase gene, and a Renilla luciferase expressing plasmid to control for transfection efficiency (pRL-CMV, Promega Corp.). HEK293 cells were placed in DMEM high glucose (phenol-free media) containing 10% FBS and transfected in suspension with a mixture of pCDNA3.4-HuLXRa or pCDNA3.4-HuLXRp, pGL4.19[luc2CPNeo]-3xLXRE-mTK, pRL-CMV and Fugene (Promega Corp), and incubated at RT for 5 minutes. Cells were plated at 50,000 cells per well of a 96 well plate and incubated for 24 hours at 37°C in 5% CO2. A series of 10 3-fold dilutionsof each test compound was added to each well, resulting in a final assay concentration ranging from 0.5 to 10,000 nM. The same was also done for the full dual agonist reference compound T0901317. Following an 18-hour incubation, media was removed and Passive Lysis buffer (Dual-Glo® Luciferase Assay System (Promega)) was added to each well, then firefly and renilla luminescence were measured in an Envision 2105 plate reader. A non-linear 4 parameter variable slope curve was fitted to the data using GraphPad Prism, and EC50 and % of maximal efficacy compared to the T0901317 reference compound was determined.

[1069] Biological data is summarized in Table C below.

[1070] In certain embodiments, the compound is a LXRP-selective agonist. As used herein, an “LXRP-selective agonist” is a compound that binds and activates LXRp with at least about 2-fold greater potency than it binds and activates LXRa in the Cellular LXR Transactivation Assay described herein. TABLE C References

[1071] 1. Yin F. Lipid metabolism and Alzheimer’s disease: clinical evidence, mechanistic link and therapeutic promise. The FEBS Journal. 2023;290(6):1420-1453. doi: 10.1111 / febs.16344

[1072] 2. Hampel H, Hardy J, Blennow K, et al. The Amyloid-P Pathway in Alzheimer’s Disease. Mol Psychiatry. 2021 ;26( 10) : 5481 -5503. doi : 10.1038 / s41380-021 -01249-0

[1073] 3. Janowski BA, Grogan MJ, Jones SA, et al. Structural requirements of ligands for the oxy sterol liver X receptors LXRa and LXRb.

[1074] 4. Venkateswaran A, Laffitte BA, Joseph SB, et al. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXRa. CELL BIOLOGY.

[1075] 5. Tontonoz P, Mangel sdorfD J. Liver X Receptor Signaling Pathways in Cardiovascular Disease. Molecular Endocrinology . 2003;17(6):985-993. doi: 10.1210 / me.2003-0061

[1076] 6. Kirchgessner TG, Sleph P, Ostrowski J, et al. Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils. Cell Metabolism. 2016;24(2):223-233. doi:10.1016 / j.cmet.2016.07.016

[1077] 7. Zelcer N. Liver X receptors as integrators of metabolic and inflammatory signaling. Journal of Clinical Investigation. 2006; 116(3):607-614. doi: 10.1172 / JCI27883

[1078] 8. Zelcer N, Khanlou N, Clare R, et al. Attenuation of neuroinflammation and Alzheimer’s disease pathology by liver x receptors. Proc Natl Acad Sci USA.

[1079] 2007; 104(25): 10601-10606. doi : 10.1073 / pnas.0701096104

[1080] 9. Lefterov I, Bookout A, Wang Z, Staufenbiel M, Mangelsdorf D, Koldamova R.

[1081] Expression profiling in APP23 mouse brain: inhibition of Ap amyloidosis and inflammation in response to LXR agonist treatment. Mol Neurodegeneration. 2007;2(l):20. doi: 10.1186 / 1750-1326-2-20

[1082] 10. Skerrett R, Malm T, Landreth G. Nuclear receptors in neurodegenerative diseases. Neurobiology of Disease. 2014;72: 104-116. doi:10.1016 / j.nbd.2014.05.019

[1083] 11. Fitz NF, Cronican A, Pham T, et al. Liver X Receptor Agonist Treatment Ameliorates Amyloid Pathology and Memory Deficits Caused by High-Fat Diet in APP23 Mice. J Neurosci. 2010;30(20):6862-6872. doi: 10.1523 / JNEUROSCI.1051-10.2010

[1084] 12. Wheeler S, Sillence DJ. Niemann-Pick type C disease: cellular pathology and pharmacotherapy. Journal of Neurochemistry . 2020;153(6):674-692. doi: 10.1111 / jnc.14895

[1085] 13. Alnaaim SA, Al-Kuraishy HM, Alexiou A, Papadakis M, Saad HM, Batiha GES. Role of Brain Liver X Receptor in Parkinson’s Disease: Hidden Treasure and Emerging Opportunities. Mol Neurobiol. 2024;61(l):341-357. doi: 10.1007 / sl2035-023-03561-y 14. Mouzat K, Raoul C, Polge A, Kantar J, Camu W, Lumbroso S. Liver X receptors: from cholesterol regulation to neuroprotection — a new barrier against neurodegeneration in amyotrophic lateral sclerosis? Cell Mol Life Sci . 2016;73(20):3801-3808. doi : 10.1007 / s00018-016-2330-y

[1086] 15. Morales JR, Ballesteros I, Deniz JM, et al. Activation of Liver X Receptors Promotes Neuroprotection and Reduces Brain Inflammation in Experimental Stroke. Circulation. 2008;118(14): 1450-1459. doi: 10.1161 / CIRCULATIONAHA.108.782300

[1087] 16. Choudhary M, Ismail EN, Yao PL, et al. LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target. JCI Insight.

[1088] 2020;5(l):el31928. doi : 10.1172 / j ci.insight.131928

[1089] 17. Song X, Gustafsson jA. Therapeutic potential of liver X receptor beta in depression and anxiety. Brain Medicine . Published online October 4, 2024: 1-4. doi: 10.61373 / bm024b.0085

[1090] 18. Tontonoz P, Mangel sdorfD J. Liver X Receptor Signaling Pathways in Cardiovascular Disease. Molecular Endocrinology . 2003;17(6):985-993. doi: 10.1210 / me.2003-0061

[1091] 19. Lee SD, Tontonoz P. Liver X receptors at the intersection of lipid metabolism and atherogenesis. Atherosclerosis. 2015;242(l):29-36. doi : 10.1016 / j . atherosclerosis.2015.06.042

[1092] 20. Cao G, Liang Y, Broderick CL, et al. Antidiabetic Action of a Liver X Receptor Agonist Mediated By Inhibition of Hepatic Gluconeogenesis. Journal of Biological Chemistry. 2003;278(2): 1131-1136. doi: 10.1074 / jbc.M210208200

[1093] 21. Ramalingam PS, Elangovan S, Mekala JR, Arumugam S. Liver X Receptors (LXRs) in cancer-an Eagle’s view on molecular insights and therapeutic opportunities. Front Cell Dev Biol. 2024; 12: 1386102. doi: 10.3389 / fcell.2024.1386102

[1094] 22. Lin CY, Gustafsson jA. Targeting liver X receptors in cancer therapeutics. Nat Rev Cancer. 2015;15(4):216-224. doi: 10.1038 / nrc3912

[1095] While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

[1096] The patent and scientific literature referred to herein establishes the knowledge that is available to those with skill in the art. All United States patents and published or unpublished United States patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference. All other published references, documents, manuscripts and scientific literature cited herein are hereby incorporated by reference. The relevant teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

Claims

We Claim:

1. A compound having the Formula (I):and pharmaceutically acceptable salts thereof, wherein:X is a bond or a linker, such as a substituted or unsubstituted alkylene (e.g., C1-7 alkylene or -C(R)2), substituted or unsubstituted cycloalkylene (e.g., C3-7 cycloalkylene), substituted or unsubstituted heterocycle (e.g., 3 to 7 membered ring with one, two or three heteroatoms (O, S, or N)), substituted or unsubstituted aryl, -SO2-, -NRSO2-, -CO-, -NRCO-, or -OCO-; each R is independently selected from H, D, halogen (e.g., F, Cl, Br, I), OH, substituted or unsubstituted alkyl (preferably C1-7 alkyl substituted by one or more halogen, deuterium, OH, alkoxy), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two Rs together with the carbon to which they are attached form a 3 to 7 membered ring, preferably cycloalkyl;Ri is selected from substituted or unsubstituted alkyl (preferably C1-7 alkyl substituted by one or more halogen, deuterium, CF3, OH, alkoxy, or substituted or unsubstituted aryl), substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2 is selected from F, substituted or unsubstituted alkyl (such as a C1-7 alkyl or C1-7 alkyl substituted with one or more R), or substituted or unsubstituted cycloalkyl;R3 is selected from H, D, F, substituted or unsubstituted alkyl (such as unsubstituted C1-7 alkyl, C1-7 alkyl substituted by one or more halogen (e.g., F, Cl, Br, I), deuterium, OH, alkoxy), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl); or R2 and R3 together with the carbon to which they are attached form a substituted or unsubstituted spiro 3 to 7-membered substituted or unsubstituted ring, preferably a substituted or unsubstituted cycloalkyl;R4 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rs is independently selected from H, D, F, substituted or unsubstituted alkyl (such as unsubstituted C1-7 alkyl or C1-7 alkyl substituted by one or more halogen, deuterium, OH, alkoxy), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or wherein the two Rs are taken together with the carbon to which they are attached form a substituted or unsubstituted spiro 3 to 6 membered ring; and n is 0 or 1, preferably 0.

2. The compound of claim 1, wherein R2 is an unsubstituted C1-7 alkyl, preferably a branched C3-5 alkyl, more preferably isopropyl or t-butyl.

3. The compound of claim 1 or 2, wherein R4 is a substituted aryl or a substituted heteroaryl.

4. The compound of claim 3, wherein R4 is an aryl or heteroaryl substituted by a CON(R)2, SO2R, CN, or SO2N(R)2. (preferably, an aryl or heteroaryl substituted by CON(R)2, such as CON(CH3)2), and optionally further substituted.

5. The compound of claim 4 having the Formula (la)wherein:R6is CON(R)2, SO2R, CN, or SO2N(R)2, (preferably CON(R)2, such as CON(CH3)2); and R7 is H, halogen, alkyl or haloalkyl, preferably Cl.

6. The compound of claim 4 having the Formula (la-1) :wherein:R6is CON(R)2, SO2R, CN, or SO2N(R)2, (preferably CON(R)2, such as CON(CH3)2); and R7 is H, halogen, alkyl or haloalkyl, preferably Cl.

7. The compound of any one of the preceding claims, wherein n is 0.

8. The compound of claim 1 having the Formula (lb):wherein:X is a bond or a linker, such as a substituted or unsubstituted alkylene (e.g., C1-7 alkylene or -C(R)2), substituted or unsubstituted cycloalkylene (e.g., C3-7 cycloalkylene), substituted or unsubstituted heterocycle (e.g., 3 to 7 membered ring with one, two or three heteroatoms (O, S, or N)), aryl, -SO2-, -NRSO2-, -CO-, -NRCO-, or -OCO-; each R is independently selected from H, D, halogen (e.g., F, Cl, Br, I), OH, substituted or unsubstituted alkyl (preferably C1-7 alkyl substituted by one or more halogen, deuterium, OH, alkoxy), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;or two Rs together with the carbon to which they are attached form a substituted or unsubstituted 3 to 7-membered ring, preferably substituted or unsubstituted cycloalkyl;Ri is selected from substituted or unsubstituted alkyl (preferably C1-7 alkyl substituted by one or more halogen, deuterium, CF3, OH, alkoxy, or substituted or unsubstituted aryl), substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2 is selected from F or substituted or unsubstituted alkyl (such as an unsubstituted C1-7 alkyl or C1-7 alkyl substituted with one or more R);R3 is independently selected from H, D, F, substituted or unsubstituted alkyl (such as unsubstituted C1-7 alkyl or C1-7 alkyl substituted by one or more halogen, deuterium, OH, or alkoxy), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl); or R2 and R3 together with the carbon to which they are attached form a spiro 3 to 7- membered substituted or unsubstituted ring; each Rs is independently selected from H, D, F, substituted or unsubstituted alkyl (such as unsubstituted C1-7 alkyl or C1-7 alkyl substituted by one or more halogen, deuterium, OH, or alkoxy), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two Rs are taken together with the carbon to which they are attached form a substituted or unsubstituted 3 to 7-membered ring;R6is CON(R)2, SO2R, CN, or SO2N(R)2, (preferably CON(R)2, such as CON(CH3)2); and R7 is H, halogen, alkyl or haloalkyl, preferably Cl.

9. The compound of claim 8, wherein each R> is H, R3 is H and R2 is a C1-7 alkyl, preferably a branched C3-5 alkyl, more preferably isopropyl or t-butyl.

10. The compound of any one of the preceding claims, wherein X is a bond, -CO-, -O- CO-, -SO2-, -C(R)2-, or -NHSO2-.

11. The compound of any one of the preceding claims, wherein Ri is a substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

12. The compound of claim 1 having the Formula (Ic):wherein: each R is a substituted or unsubstituted alkyl (e.g., methyl);R? is H or halogen; R2 is alkyl (preferably isopropyl);Ri is a substituted or unsubstituted phenyl, pyridine, pyrimidine, pyridazine or pyrazine; andX is a bond or -CO-.

13. The compound of claim 1 having the Formula (Ic-1):(ic-i); wherein: each R is a substituted or unsubstituted alkyl (e.g., methyl);R7 is H or halogen;R2 is alkyl (preferably isopropyl); each Rs is independently selected from halogen (e.g., F, Cl, Br or I, preferably F), substituted or unsubstituted alkyl (e.g., methyl, CF3, CHF2); and m is 0, 1 or 2.

14. The compound of claim 1 having the Formula (Ic-2):(Ic-2) wherein: each R is a substituted or unsubstituted alkyl (e.g., methyl);R7 is H or halogen;R2 is alkyl (preferably isopropyl); each Rs is independently selected from halogen (e.g., F, Cl, Br or I, preferably F), substituted or unsubstituted alkyl (e.g., methyl, CF3, CHF2); and m is 0, 1 or 2.

15. The compound of claim 1 having the Formula (Ic-3):(Ic-3) wherein: each R is a substituted or unsubstituted alkyl (e.g., methyl);R7 is H or halogen;R2 is alkyl (preferably isopropyl); and each Rs is independently selected from H, halogen (e.g., F, Cl, Br or I, preferably F), substituted or unsubstituted alkyl (e.g., methyl, CF3, CHF2); and m is 0, 1 or 2.

16. The compound of claim 1 having the Formula (Ic-4):(Ic-4) wherein: each R is a substituted or unsubstituted alkyl (e.g., methyl);R? is H or halogen;R2 is alkyl (preferably isopropyl); each Rs is independently selected from H, halogen (e.g., F, Cl, Br or I, preferably F), substituted or unsubstituted alkyl (e.g., methyl, CF3, CHF2); and m is 0, 1 or 2.

17. The compound of claim 1 having the Formula (Ic-5):(Ic-5) wherein: each R is a substituted or unsubstituted alkyl (e.g., methyl);R7 is H or halogen;R2 is alkyl (preferably isopropyl); each Rs is independently selected from H, halogen (e.g., F, Cl, Br or I, preferably F), substituted or unsubstituted alkyl (e.g., methyl, CF3, CHF2); and m is 0, 1 or 2.The compound of claim 1 having the Formula (Ic-6):(Ic-6) wherein: each R is a substituted or unsubstituted alkyl (e.g., methyl);R7 is H or halogen;R2 is alkyl (preferably isopropyl); each Rs is selected from H, halogen (e.g., F, Cl, Br or I, preferably F), substituted or unsubstituted alkyl (e.g., methyl, CF3, CHF2); and m is 0, 1 or 2.wherein: each R is a substituted or unsubstituted alkyl (e.g., methyl);R7 is H or halogen;R2 is alkyl (preferably isopropyl); each Rs is independently selected from halogen (e.g., F, Cl, Br or I, preferably F), substituted or unsubstituted alkyl (e.g., methyl, CF3, CHF2); and m is 0, 1 or 2.wherein: each R is a substituted or unsubstituted alkyl (e.g., methyl);R7 is H or halogen;R2 is alkyl (preferably isopropyl); each Rs is independently selected from halogen (e.g., F, Cl, Br or I, preferably F), substituted or unsubstituted alkyl (e.g., methyl, CF3, CHF2); and m is 0, 1 or 2.

21. The compound of claim 1 having the Formula (Ic-9):wherein: each R is a substituted or unsubstituted alkyl (e.g., methyl);R? is H or halogen;R2 is alkyl (preferably isopropyl); each Rs is independently selected from halogen (e.g., F, Cl, Br or I, preferably F), substituted or unsubstituted alkyl (e.g., methyl, CF3, CHF2); and m is 0, 1 or 2.

22. The compound of claim 1 having the Formula (Ic-10):wherein: each R is a substituted or unsubstituted alkyl (e.g., methyl);R7 is H or halogen;R2 is alkyl (preferably isopropyl); each Rs is independently selected from halogen (e.g., F, Cl, Br or I, preferably F), substituted or unsubstituted alkyl (e.g., methyl, CF3, CHF2); and m is 0, 1 or 2.

23. The compound of claim 1 having the Formula (Ic-11):wherein: each R is a substituted or unsubstituted alkyl (e.g., methyl);R? is H or halogen;R2 is alkyl (preferably isopropyl); each Rs is independently selected from halogen (e.g., F, Cl, Br or I, preferably F), substituted or unsubstituted alkyl (e.g., methyl, CF3, CHF2); and m is 0, 1 or 2.

24. The compound of claim 1 having the Formula (Ic-12):wherein: each R is a substituted or unsubstituted alkyl (e.g., methyl);R7 is H or halogen;R2 is alkyl (preferably isopropyl); each Rs is independently selected from halogen (e.g., F, Cl, Br or I, preferably F), substituted or unsubstituted alkyl (e.g., methyl, CF3, CHF2); and m is 0, 1 or 2.

25. The compound of claim 1 having the Formula (Ic-13):wherein: each R is a substituted or unsubstituted alkyl (e.g., methyl);R? is H or halogen;R2 is alkyl (preferably isopropyl); each Rs is independently selected from halogen (e.g., F, Cl, Br or I, preferably F), substituted or unsubstituted alkyl (e.g., methyl, CF3, CHF2); and m is 0, 1 or 2.

26. The compound of claim 1 having the Formula (Ic-14):(Ic-14); wherein: each R is a substituted or unsubstituted alkyl (e.g., methyl);R? is H or halogen;R2 is alkyl (preferably isopropyl); each Rs is independently selected from halogen (e.g., F, Cl, Br or I, preferably F), substituted or unsubstituted alkyl (e.g., methyl, CF3, CHF2); and m is 0, 1 or 2.

27. The compounds of any one of claims 13 to 26, wherein at least one Rs is CF3.

28. The compound of claim 1 wherein the compound is selected from Compound 2, 37, 45, 56 or 57, or a pharmaceutically acceptable salt thereof:

29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

30. A method of treating a subject with a disease or disorder that is treatable by upregulating LXR activity comprising administering an effective amount of the compound of any one of claims 1 to 28 to the subject.

31. A method for the treatment of Alzheimer's Disease, Neimann-Pick disease type Cl, Parkinson's Disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis, age-related macular degeneration, schizophrenia, depression, Stargardt's disease, cardiovascular disease, obesity or diabetes in a patient in need thereof, said method comprising administering aneffective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28 to the patient.

32. A compound according to any one of claims 1 to 28, or pharmaceutically acceptable salt thereof, for use as a medicament.

33. Use of a compound according to any one of claims 1 to 28, or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of Alzheimer's Disease, Neimann-Pick disease type Cl, Parkinson's Disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis, age-related macular degeneration, schizophrenia, depression, Stargardt's disease, cardiovascular disease, obesity or diabetes.

34. A compound having the Formula (I):and pharmaceutically acceptable salts thereof, wherein:X is a bond or a linker, such as a substituted or unsubstituted alkylene (e.g., C1-7 alkylene or -C(R)2), substituted or unsubstituted cycloalkylene (e.g., C3-7 cycloalkylene), substituted or unsubstituted heterocycle (e.g., 3 to 7 membered ring with one, two or three heteroatoms (O, S, or N)), substituted or unsubstituted aryl, -SO2-, -NRSO2-, -CO-, -C(=NH)-, -NRCO-, or -OCO-; each R is independently selected from H, D, halogen (e.g., F, Cl, Br, I), OH, substituted or unsubstituted alkyl (preferably C1-7 alkyl substituted by one or more halogen, deuterium, OH, alkoxy), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two Rs together with the carbon to which they are attached form a 3 to 7 membered ring, preferably cycloalkyl;Ri is selected from substituted or unsubstituted alkyl (preferably C1-7 alkyl substituted by one or more halogen, deuterium, CF3, OH, alkoxy, or substituted or unsubstituted aryl),substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2 is selected from F, substituted or unsubstituted alkyl (such as a C1-7 alkyl or C1-7 alkyl substituted with one or more R), substituted or unsubstituted cycloalkyl or Si(R)s wherein each R can independently be a substituted or unsubstituted alkyl, preferably methyl or ethyl.;R3 is selected from H, D, F, substituted or unsubstituted alkyl (such as unsubstituted C1-7 alkyl, C1-7 alkyl substituted by one or more halogen (e.g., F, Cl, Br, I), deuterium, OH, alkoxy), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl); or R2 and R3 together with the carbon to which they are attached form a substituted or unsubstituted spiro 3 to 7-membered substituted or unsubstituted ring, preferably a substituted or unsubstituted cycloalkyl;R4 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted -COaryl or CH2aryl; each Rs is independently selected from H, D, F, substituted or unsubstituted alkyl (such as unsubstituted C1-7 alkyl or C1-7 alkyl substituted by one or more halogen, deuterium, OH, alkoxy), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or wherein the two Rs are taken together with the carbon to which they are attached form a substituted or unsubstituted spiro 3 to 6 membered ring; and n is 0 or 1, preferably 0.

35. A compound having the Formula (Ic-14):or a pharmaceutically acceptable salt thereof, wherein: each R is independently a H or substituted or unsubstituted alkyl;R7 is halogen;R2 is alkyl or substituted alkyl, preferably isopropyl or t-Butyl;each Rs is independently H or halogen; m is 0, 1, 2, or 3.

36. A compound having the Formula:or a pharmaceutically acceptable salt thereof, wherein: each R is independently a H or substituted or unsubstituted alkyl;R? is halogen;R2 is alkyl or substituted alkyl, preferably isopropyl or t-Butyl.

Images