CYP51 inhibitors and method of using same

Abstract

Disclosed herein are compounds, compositions, and methods for inhibiting CYP51. Also disclosed herein are methods of promoting myelination and treating myelin-related disorders (e.g., multiple sclerosis).

Description

CTQ-01425 CYP51 INHIBITORS AND METHOD OF USING SAME RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent ApplicationNo.: 63 / 668,541, filed July 8, 2024. The entire teachings of the above application are incorporated herein by reference. BACKGROUND

[0002] Myelin-related disorders are disorders that result in abnormalities of the myelin sheath(e.g., dysmyelination, demyelination and hypomyelination) in a subject’s neural cells, e.g., CNS neurons including their axons. Loss or degradation of the myelin sheath in such disorders produces a slowing or cessation of nerve cell conduction. The resulting myelin related disorders are characterized by deficits in sensation, motor function, cognition, or other physiological functions. Myelin related disorders include, but are not limited to, multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophies, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander's disease, Pelizaeus Merzbacher disease (PMD), Vanishing White Matter Disease, Wallerian Degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillian-Barre syndrome, Charcot-Marie-Tooth disease, Bell's palsy and radiation-induced demyelination.

[0003] MS is the most common myelin-related disorder affecting several million peopleglobally and is estimated to result in about 18,000 deaths per year. MS is a complex neurological disease characterized by deterioration of central nervous system (CNS) myelin. Myelin, composed in its majority by lipids (70% lipids, 30% protein), protects axons and makes saltatory conduction possible, which speeds axonal electric impulse. Demyelination of axons in chronic MS can result in axon degeneration and neuronal cell death. Additionally, MS destroys oligodendrocytes, the highly specialized CNS cells that generate and maintain - 1 -CTQ-01425 myelin. A repair process, called remyelination, takes place in early phases of the disease, but over time, the oligodendrocytes are unable to completely rebuild and restore the myelin sheath. Repeated attacks lead to successively less effective remyelination, until a scar-like plaque is built up around the damaged axons.

[0004] At present, there is no cure for myelin-related disorders, and no current therapyprevents progression in MS. Accordingly, there is a need for new therapeutic approaches to the treatment of myelin-related disorders, including the promotion of remyelination. The subject matter described herein addresses this unmet need. SUMMARY OF THE INVENTION

[0005] In one aspect, the present invention relates to compounds, or a pharmaceuticallyacceptable salts thereof, having the structure of formula (I):wherein: Ar1is optionally substituted heteroaryl; R1is –H or –OH; L2is (–CH2–)p or (–CH2–)p–O–, wherein p is an integer from 1-4; Ar2is optionally substituted aryl, heteroaryl, or bicycloalkyl; Ring B is a 4-10-membered heterocycloalkyl ring, optionally substituted by 1-4 occurrences of Rb; and Rb, independently for each occurrence is alkyl, alkenyl, cycloalkyl, or heterocycloalkyl; or two geminal occurrences of Rb, taken together with the intervening atoms, form a spirocycloalkyl ring on Ring B; or two vicinal occurrences of Rb, taken together with the intervening atoms, form a fused cycloalkyl ring on Ring B.

[0006] In another aspect, the present invention relates to compounds, or a pharmaceuticallyacceptable salts thereof, having the structure of formula (II):- 2 -CTQ-01425 wherein: W, X, Y, and Z are each independently CH, CR1a, or N; wherein at least one of W, X, Y, and Z is N; each R1ais independently alkyl, cycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy, halo, haloalkoxy, haloalkyl, -NH2, -NH(alkyl), or cyano; R3is alkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl; R4is alkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, haloalkyl, or alkoxyalkyl; Rcis H or OH; L2is (–CH2–)p or (–CH2–)p–O–, wherein p is an integer from 1-4; and Ar2is optionally substituted aryl, heteroaryl, or bicycloalkyl.

[0007] In another aspect, the present disclosure relates to pharmaceutical compositionscomprising a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient.

[0008] In another aspect, the present disclosure relates to methods of promoting myelinationin a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0009] In another aspect, the present disclosure relates to using the compounds,pharmaceutically acceptable salts thereof, and compositions disclosed herein for use in treating a disorder in a subject in need thereof.

[0010] In another aspect, the present disclosure relates to using the compounds,pharmaceutically acceptable salts thereof, and compositions disclosed herein for use in promoting myelination in a subject in need thereof.

[0011] In another aspect, the present disclosure relates to using the compounds,pharmaceutically acceptable salts thereof, and compositions disclosed herein for use in the manufacture of a medicament for treating a disorder in a subject in need thereof.

[0012] In another aspect, the present disclosure relates to using the compounds,pharmaceutically acceptable salts thereof, and compositions disclosed herein for use in the manufacture of a medicament for promoting myelination in a subject in need thereof.

[0013] In another aspect, the present invention provides methods of inhibiting CYP51(lanosterol demethylase) comprising contacting CYP51 with a compound of the invention, or - 3 -CTQ-01425 a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIGs. 1A-1C show the in vitro activity and pharmacokinetic properties of Example 5,first compound.

[0015] FIGs. 2A-2D show the in vitro activity and pharmacokinetic properties of Example 9,first compound. DETAILED DESCRIPTION OF THE INVENTION

[0016] Described herein are myelin-promoting compounds of Formula I and Formula II,methods of making the compounds, their pharmaceutical compositions, and their use in the treatment of myelin-related disorders.

[0017] The enhancement and / or inducement of the accumulation of Δ8,9-unsaturated sterolintermediates of the cholesterol biosynthesis pathway in oligodendrocyte progenitor cells (OPCs) can induce oligodendrocyte generation. Enhancement and / or inducement of the accumulation of Δ8,9-unsaturated sterol intermediates can be provided by modulating and / or inhibiting enzymes within the cholesterol biosynthesis pathway in OPCs that enhance and / or induce Δ8,9-unsaturated sterol intermediate accumulation and / or for which the Δ8,9- unsaturated sterol intermediates are substrates as well as directly and / or indirectly administering Δ8,9-unsaturated sterol intermediates to the OPCs. Enhancement and / or inducement of the accumulation of Δ8,9-unsaturated sterol intermediates can promote OPC differentiation, survival, proliferation and / or maturation and treat disease and / or disorders in subjects where myelination is beneficial to the subject.

[0018] As such, in some embodiments an agent, such as a compound of Formula I orFormula II, or a pharmaceutically acceptable salt or solvate thereof, that can enhance and / or induce accumulation of Δ8,9-unsaturated sterol intermediates of the cholesterol biosynthesis pathway in the OPCs can be administered to a subject and / or the OPCs at an amount effective to promote and / or induce OPC differentiation, proliferation and / or maturation as well as oligodendrocyte generation. In certain embodiments, the agent, for example a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or solvate thereof, is a compound that inhibits enzyme mediated synthesis of one or more sterol intermediates in the - 4 -CTQ-01425 cholesterol biosynthesis pathway of the OPCs and / or promotes accumulation of Δ8,9- unsaturated sterol intermediates.

[0019] In certain embodiments, the compound of Formula I or Formula II, or apharmaceutically acceptable salt or solvate thereof, can modulate and / or inhibit one or more enzyme-mediated conversion steps of the cholesterol biosynthesis pathway, such as in the pathway from lanosterol to cholesterol, for example, between lanosterol and / or lathosterol; modulating and / or inhibiting one or more of these steps in OPCs may promote and / or induce oligodendrocyte generation. For example, the compound of Formula I or Formula II can inhibit CYP51, sterol 14-reductase (TM7SF2 and / or LBR), SC4MOL, NSDHL, and / or EBP enzyme mediated synthesis of sterol intermediates in the cholesterol biosynthesis pathway. In certain embodiments, the compound of Formula I or Formula II can inhibit CYP51, sterol 14-reductase and / or EBP. In certain embodiments, the compound of Formula I or Formula II can inhibit CYP51.

[0020] For example, in certain embodiments, the compound of Formula I or Formula II usedin the methods described herein can inhibit CYP51 enzyme activity in the cholesterol biosynthetic pathway. Alternatively, in certain embodiments, the compound of Formula I or Formula II used in the methods described herein can inhibit sterol C14 reductase enzyme activity in the cholesterol biosynthesis pathway or can inhibit enzyme mediated conversion of zymostenol to lathosterol through the inhibition of emopamil binding protein (EBP) isomerase enzyme activity.

[0021] CYP51 belongs to the cytochrome P450 (CYP) monooxygenase superfamily andmediates an essential step in the sterol biosynthesis pathway. CYP51 proteins are the most conserved protein in the CYP superfamily. Unlike other CYP enzymes, CYP51 has a strong substrate specificity. It catalyzes the demethylation of a narrow range of substrates, including lanosterol, and 24,25-dihydrolanosterol. CYP51 proteins are also referred to as sterol 14α- demethylases and are the only invariant P450 present in all sterol biosynthetic pathways.

[0022] Without being bound by a particular theory, it is believed that compounds of FormulaI or Formula II, or a pharmaceutically acceptable salt or solvate thereof, can inhibit CYP51 mediated conversion of lanosterol to 14-demethyl-14-dehydrolanosterol (FF-MAS) and 24,25-dihydrolanosterol to MAS-412 in the cholesterol biosynthesis pathway of OPCs resulting in enhancement and / or inducement of the accumulation of Δ8,9-unsaturated sterol intermediates. In some embodiments, enhancement and / or inducement of the accumulation of Δ8,9-unsaturated sterol intermediates can promote OPC differentiation, survival, proliferation - 5 -CTQ-01425 and / or maturation and treat disease and / or disorders in subjects where myelination or myelinization is beneficial to the subject. This mechanism of promoting myelination is distinct from the primary action of immunomodulatory agents that are often used to treat myelin-related disorders.

[0023] In one aspect, the present invention relates to compounds, or a pharmaceuticallyacceptable salts thereof, having the structure of formula (I):wherein: Ar1is optionally substituted heteroaryl; R1is –H or –OH; L2is (–CH2–)p or (–CH2–)p–O–, wherein p is an integer from 1-4; Ar2is optionally substituted aryl, heteroaryl, or bicycloalkyl; Ring B is a 4-10-membered heterocycloalkyl ring, optionally substituted by 1-4 occurrences of Rb; and Rb, independently for each occurrence is alkyl, alkenyl, cycloalkyl, or heterocycloalkyl; or two geminal occurrences of Rb, taken together with the intervening atoms, form a spirocycloalkyl ring on Ring B; or two vicinal occurrences of Rb, taken together with the intervening atoms, form a fused cycloalkyl ring on Ring B.

[0024] In another aspect, the present invention relates to compounds, or a pharmaceuticallyacceptable salts thereof, having the structure of formula (I):wherein: Ar1is optionally substituted 5-12-membered heteroaryl; R1is –H or –OH; L2is (–CH2–)por (–CH2–)p–O–, wherein p is an integer from 1-4; Ar2is optionally substituted (C6-C12)aryl, 5-12-membered heteroaryl, or (C5- C12)bicycloalkyl; - 6 -CTQ-01425 Ring B is a 4-10-membered heterocycloalkyl ring, optionally substituted by 1-4 occurrences of Rb; and Rb, independently for each occurrence is (C1-C10)alkyl, (C2-C10)alkenyl, (C3- C10)cycloalkyl, or 5-to-12-membered heterocycloalkyl; or two geminal occurrences of Rb, taken together with the intervening atoms, form a (C3- C6)spirocycloalkyl ring on Ring B; or two vicinal occurrences of Rb, taken together with the intervening atoms, form a fused cycloalkyl ring on Ring B.

[0025] In certain embodiments, Ring B is a 4-7-membered heterocycloalkyl ring, optionallysubstituted by 1-4 occurrences of Rb. In certain embodiments, Ring B is a 4-6-membered heterocycloalkyl ring, optionally substituted by 1-4 occurrences of Rb. In certain embodiments, Ring B is a 5-6-membered heterocycloalkyl ring, optionally substituted by 1-4 occurrences of Rb. In some embodiments, Ring B is a 6-membered heterocycloalkyl ring, optionally substituted by 1-4 occurrences of Rb.

[0026] In certain embodiments, the compound having the structure of formula (I) has astructure of formula (Ia):In certain embodiments, R1is –OH.

[0027] In certain embodiments, the compound having the structure of formula (I) has astructure of formula (Ib):

[0028] In further embodiments, the compound having the structure of formula (I) has astructure of formula (Ib-1):

[0029] In some embodiments, the compound having the structure of formula (I) has thestructure of formula (Ib-a), (1b-b), (Ib-c), or (1b-d): - 7 -CTQ-01425

[0030] In certain embodiments, the compound having the structure of formula (I) has thestructure of formula (Ib-a). In certain embodiments, the compound having the structure of formula (I) has the structure of formula (Ib-b). In certain embodiments, the compound having the structure of formula (I) has the structure of formula (Ib-c). In certain embodiments, the compound having the structure of formula (I) has the structure of formula (Ib-d).

[0031] In certain embodiments, L2 is –CH2–, –CH2CH2–, or –CH2O–. In certainembodiments, L2is –CH2–. In certain embodiments, L2is –CH2O–. In certain embodiments, Ar1is optionally substituted pyridinyl.

[0032] In certain embodiments,R1ais H, alkyl, cycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy, halo, haloalkoxy, haloalkyl, -NH2, -NH(alkyl), or cyano; and n is an integer from 1-3. - 8 -CTQ-01425

[0033] In certain embodiments,certain embodiments, R1a is alkoxy,cycloalkoxy, heterocycloalkoxy, or cycloalkyl. In certain embodiments,,

[0034] In certain embodiments, Ar2 is aryl or heteroaryl, optionally substituted with one ormore substituents selected from halo, haloalkyl, alkoxy, alkyl, haloalkoxy, cyano, and – SO2(alkyl). In certain embodiments, Ar2is aryl or heteroaryl, substituted with at least one substituent selected from halo, haloalkyl, alkoxy, alkyl, haloalkoxy, cyano, and –SO2(alkyl). In certain embodiments, Ar2is aryl or heteroaryl, substituted with two occurrences of halo. In certain embodiments, Ar2is aryl or heteroaryl, substituted with one occurrence of haloalkyl. In certain embodiments, Ar2is phenyl, substituted with 1-2 occurrences of R2a, wherein each occurrence of R2ais independently halo, haloalkyl, alkoxy, alkyl, haloalkoxy, cyano, or – SO2(alkyl).

[0035] In certain embodiments,wherein m is an integer from 0-1. Incertain embodiments,. In certain embodiments, Ar2is. In certain embodiments, Ar2is. In certain embodiments,.

[0036] In some embodiments, the compound having the structure of formula (I) has thestructure of formula (Ib-1a), (1b-1b), (Ib-1c), or (1b-1d): - 9 -CTQ-01425R1ais alkoxy or cycloalkoxy, and v is 0 or 1.

[0037] In some embodiments v is 1. In some embodiments v is 0.

[0038] In certain embodiments, the compound having the structure of formula (I) has thestructure of formula (Ib-1a). In certain embodiments, the compound having the structure of formula (I) has the structure of formula (Ib-1b). In certain embodiments, the compound having the structure of formula (I) has the structure of formula (Ib-1c). In certain embodiments, the compound having the structure of formula (I) has the structure of formula (Ib-1d).

[0039] In certain embodiments, Ar2 is pyridinyl, substituted with 1-2 occurrences of R2a,wherein each occurrence of R2ais independently halo, haloalkyl, alkoxy, alkyl, haloalkoxy, cyano, or –SO2(alkyl). - 10 -CTQ-01425

[0041] In certain embodiments, Ar2 is optionally substituted bicycloalkyl. In someembodiments, Ar2is optionally substituted bridged bicycloalkyl, such as bicyclo[1.1.1]pentane.

[0042] In certain embodiments, the compound is selected from the group consisting of:- 11 -CTQ-01425- 12 -CTQ-01425- 13 -CTQ-01425- 14 -CTQ-01425or a pharmaceutically acceptable salt thereof.

[0043] In certain embodiments, the compound is selected from the group consisting of:- 15 -CTQ-01425- 16 -CTQ-01425- 17 -CTQ-01425- 18 -CTQ-01425; or a pharmaceutically acceptable salt thereof.

[0044] In another aspect, the present invention relates to compounds, or a pharmaceuticallyacceptable salts thereof, having the structure of formula (II): - 19 -CTQ-01425wherein: W, X, Y, and Z are each independently CH, CR1a, or N; wherein at least one of W, X, Y, and Z is N; each R1ais independently alkyl, cycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy, halo, haloalkoxy, haloalkyl, -NH2, -NH(alkyl), or cyano; R3is alkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl; R4is alkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, haloalkyl, or alkoxyalkyl; Rcis H or OH; L2is (–CH2–)por (–CH2–)p–O–, wherein p is an integer from 1-4; and Ar2is optionally substituted aryl, heteroaryl, or bicycloalkyl.

[0045] In another aspect, the present invention relates to compounds, or a pharmaceuticallyacceptable salts thereof, having the structure of formula (II)wherein: W, X, Y, and Z are each independently CH, CR1a, or N; wherein at least one of W, X, Y, and Z is N; each R1ais independently (C1-C10)alkyl, (C3-C10)cycloalkyl, (C1-C10)alkoxy, (C3- C10)cycloalkoxy, 5-to-12-membered heterocycloalkoxy, halo, halo(C1-C10)alkoxy, halo(C1-C10)alkyl, -NH2, -NH((C1-C10)alkyl), or cyano; Rcis H or OH; R3is (C1-C10)alkyl, (C3-C10)cycloalkyl(C1-C10)alkyl, 5-to-12-membered heterocycloalkyl(C1-C10)alkyl, (C6-C12)aryl(C1-C10)alkyl, 5-to-12-membered heteroaryl(C1-C10)alkyl, halo(C1-C10)alkyl, (C1-C10)hydroxyalkyl, or (C1- C10)alkoxy(C1-C10)alkyl; - 20 -CTQ-01425 R4is (C1-C10)alkyl, (C3-C10)cycloalkyl(C1-C10)alkyl, 5-to-12-membered heterocycloalkyl(C1-C10)alkyl, (C6-C12)aryl(C1-C10)alkyl, 5-to-12-membered heteroaryl(C1-C10)alkyl, halo(C1-C10)alkyl, or (C1-C10)alkoxy(C1-C10)alkyl; L2is (–CH2–)p or (–CH2–)p–O–, wherein p is an integer from 1-4; and Ar2is optionally substituted (C6-C12)aryl, 5-12-membered heteroaryl, or (C5- C12)bicycloalkyl.

[0046] In certain embodiments, one or two of W, X, Y, and Z is N. In certain emboidments,one of W, X, Y, and Z is N. In certain embodiments, Y is N.

[0047] In certain embodiments, the compound having the structure of formula (II) has astructure of formula (IIa):

[0048] In certain embodiments, the compound having the structure of formula (II) has astructure of formula (IIa-a), (IIa-b), (IIa-c), or (IIa-d):

[0049] In certain embodiments, the compound having the structure of formula (II) has astructure of formula (IIa-a). In certain embodiments, the compound having the structure of formula (II) has a structure of formula (IIa-b). In certain embodiments, the compound having - 21 -CTQ-01425 the structure of formula (II) has a structure of formula (IIa-c). In certain embodiments, the compound having the structure of formula (II) has a structure of formula (IIa-d).

[0050] In certain embodiments, L2 is –CH2–, –CH2CH2–, or –CH2O–. In certainembodiments, L2is –CH2–. In certain embodiments, L2is –CH2O–.

[0051] In certain embodiments, R1a is alkoxy. In certain embodiments, R1a is methoxy orisopropyloxy. In certain embodiments, R1ais methoxy. In certain embodiments, R1ais isopropyloxy.

[0052] In certain embodiments, the compound having the structure of formula (II) has astructure of formula (IIb-a), (IIb-b), (IIb-c), or (IIb-d):wherein R1ais alkoxy. In some embodiments, R1ais methoxy.

[0053] In certain embodiments, the compound having the structure of formula (II) has astructure of formula (IIb-a). In certain embodiments, the compound having the structure of formula (II) has a structure of formula (IIb-b). In certain embodiments, the compound having the structure of formula (II) has a structure of formula (IIb-c). In certain embodiments, the compound having the structure of formula (II) has a structure of formula (IIb-d).

[0054] In certain embodiments, R3 is methyl.In certain embodiments, the compound having the structure of formula (II) has a structure of formula (IIb) or (IIc): - 22 -CTQ-01425c).

[0055] In certain embodiments, R4 is n-propyl.

[0056] In certain embodiments, Ar2 is aryl or heteroaryl, optionally substituted with one ormore substituents selected from halo, haloalkyl, alkoxy, alkyl, haloalkoxy, cyano, and – SO2(alkyl). In certain embodiments, Ar2is aryl or heteroaryl, substituted with at least one substituent selected from halo, haloalkyl, alkoxy, alkyl, haloalkoxy, cyano, and –SO2(alkyl). In certain embodiments, Ar2is aryl or heteroaryl, substituted with two occurrences of halo. In certain embodiments, Ar2is aryl or heteroaryl, substituted with one occurrence of haloalkyl. In certain embodiments, Ar2is phenyl, substituted with 1-2 occurrences of R2a, wherein each occurrence of R2ais independently halo, haloalkyl, alkoxy, alkyl, haloalkoxy, cyano, or – SO2(alkyl).

[0057] In certain embodiments, Ar2 is; wherein m is an integer from 0-1. Incertain embodiments,. In certain embodiments, Ar2is. In certain embodiments, Ar2is. In certain embodiments,.

[0058] In certain embodiments, the compound having the structure of formula (II) has astructure of formula (IIb-1a), (IIb-1b), (IIb-1c), or (IIb-1d): - 23 -CTQ-01425wherein R1ais alkoxy, and some embo 1adiments, R ismethoxy. In certain embodiments, Ar2is. In certain embodiments, Ar2is. , .

[0060] In certain embodiments, the compound having the structure of formula (II) has astructure of formula (IIb-1a). In certain embodiments, the compound having the structure of formula (II) has a structure of formula (IIb-1b). In certain embodiments, the compound having the structure of formula (II) has a structure of formula (IIb-1c). In certain embodiments, the compound having the structure of formula (II) has a structure of formula (IIb-1d).

[0061] In certain embodiments, Ar2 is pyridinyl, substituted with 1-2 occurrences of R2a,wherein each occurrence of R2ais independently halo, haloalkyl, alkoxy, alkyl, haloalkoxy, cyano, or –SO2(alkyl). - 24 -CTQ-01425

[0062] In certain embodiments, Ar2 is. In certainembodiments,.

[0063] In certain embodiments, Rc is -OH.

[0064] In certain embodiments, the compound is selected from the group consisting of:- 25 -CTQ-01425or a pharmaceutically acceptable salt thereof.

[0065] In certain embodiments, the compound is selected from the group consisting of:- 26 -CTQ-01425; or a pharmaceutically aceptable salt thereof. Definitions

[0066] Definitions of specific functional groups and chemical terms are described in moredetail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general - 27 -CTQ-01425 principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0067] Compounds described herein can comprise one or more asymmetric centers, and thuscan exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York, 1981; Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds, McGraw-Hill, NY, 1962; and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268, E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972. The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0068] Unless otherwise stated, structures depicted herein are also meant to include allisomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each stereocenter. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0069] Unless otherwise stated, structures depicted herein are also meant to includecompounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of12C with13C or14C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays. - 28 -CTQ-01425

[0070] When a range of values is listed, it is intended to encompass each value and sub-rangewithin the range. For example, "C1-6alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0071] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.Likewise, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0072] The term "alkyl" refers to a radical of a straight-chain or branched saturatedhydrocarbon group having from 1 to 10 carbon atoms ("C1-10alkyl"). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C1-9alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-8 alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C1-7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-6alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-5alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-2alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-6 alkyl"). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n­butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3- methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10 alkyl (such as unsubstituted C1-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-10alkyl (such as substituted C1-6alkyl, e.g., -CF3, Bn).

[0073] The term "haloalkyl" refers to a substituted alkyl group, wherein one or more of thehydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C1-8haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C1-6 haloalkyl"). In some - 29 -CTQ-01425 embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C1-4 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C1-3haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C1-2 haloalkyl"). Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, - CFCl2, -CF2Cl, and the like.

[0074] The term "deuteroalkyl" refers to an alkyl group, wherein one or more of thehydrogen atoms are independently replaced by deuterium. In some embodiments, the deuteroalkyl moiety has 1 to 8 carbon atoms ("C1-8deuteroalkyl"). In some embodiments, the deuteroalkyl moiety has 1 to 6 carbon atoms ("C1-6deuteroalkyl”). In some embodiments, the deuteroalkyl moiety has 1 to 4 carbon atoms ("C1-4 deuteroalkyl "). In some embodiments, the deuteroalkyl moiety has 1 to 3 carbon atoms ("C1-3 deuteroalkyl "). In some embodiments, the deuteroalkyl moiety has 1 to 2 carbon atoms ("C1-2deuteroalkyl"). In some embodiments, the deuteroalkyl moiety is C1, C2, C3, C4, C5, or C6 deuteroalkyl. A deuteroalkyl moiety having n carbon atoms can have from 1 to 2n+1 deuterium atoms. Examples of deuteroalkyl groups include -CHD2, -CH2D, -CD3, -CH2CD3, -CD2CD3, -CD2CD2CD3, -CH(CD3)2, -CD(CD3)2, - C(CD3)3, and the like.

[0075] The term "hydroxyalkyl" is a substituted alkyl group, wherein one or more of thehydrogen atoms are independently replaced by a hydroxyl. In some embodiments, the hydroxyalkyl moiety has 1 to 8 carbon atoms ("C1-8hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 6 carbon atoms ("C1-6 hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 4 carbon atoms ("C1-4hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 3 carbon atoms ("C1-3 hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 2 carbon atoms ("C1-2 hydroxyalkyl").

[0076] The term "alkoxy" refers to an alkyl group, as defined herein, appended to the parentmolecular moiety through an oxygen atom. In some embodiments, the alkoxy moiety has 1 to 8 carbon atoms ("C1-8 alkoxy"). In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms ("C1-6alkoxy"). In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms ("C1-4alkoxy"). In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms ("C1-3alkoxy"). In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms ("C1-2 alkoxy"). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy. - 30 -CTQ-01425

[0077] The term "haloalkoxy" refers to a haloalkyl group, as defined herein, appended to theparent molecular moiety through an oxygen atom. In some embodiments, the alkoxy moiety has 1 to 8 carbon atoms ("C1-8 haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms ("C1-6 haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms ("C1-4haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms ("C1-3 haloalkoxy"). In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms ("C1-2 haloalkoxy"). Representative examples of haloalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0078] The term "alkoxyalkyl" is a substituted alkyl group, wherein one or more of thehydrogen atoms are independently replaced by an alkoxy group, as defined herein. In some embodiments, the alkoxyalkyl moiety has 1 to 8 carbon atoms ("C1-8 alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 6 carbon atoms ("C1-6alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 4 carbon atoms ("C1-4 alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 3 carbon atoms ("C1-3 alkoxyalkyl"). In some embodiments, the alkoxyalkyl moiety has 1 to 2 carbon atoms ("C1-2alkoxyalkyl").

[0079] The term "heteroalkyl" refers to an alkyl group, which further includes at least oneheteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected, for example, from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroC1-20 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1or more heteroatoms within the parent chain ("heteroC1-18 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroC1-16 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroC1-14 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroC1-12alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroC1-10 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroC1-8alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent - 31 -CTQ-01425 chain ("heteroC1-6 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroC1-4alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain ("heteroC1-3 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain ("heteroC1-2 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10 alkyl.

[0080] The term "alkenyl" refers to a radical of a straight-chain or branched hydrocarbongroup having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C2-9 alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-8 alkenyl"). In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C2-7alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-4alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon- carbon double bonds can be internal (such as in 2- butenyl) or terminal (such as in 1-butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl - 32 -CTQ-01425 group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH3 or) may be an (E)- or (Z)- double bond.

[0081] The term "heteroalkenyl" refers to an alkenyl group, which further includes at leastone heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected, for example, from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-10alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-9 alkenyl").

[0082] In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least onedouble bond, and 1 or more heteroatoms within the parent chain ("heteroC2-8alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-7 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-6alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-5alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-4 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain ("heteroC2-3alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-6 alkenyl"). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10alkenyl. - 33 -CTQ-01425

[0083] The term "alkynyl" refers to a radical of a straight-chain or branched hydrocarbongroup having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C2-10 alkynyl"). In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C2-9 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2-8alkynyl"). In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C2-7 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2-6 alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2-5alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2-4alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2-3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkynyl groups include the aforementioned C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-10alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10 alkynyl.

[0084] The term "heteroalkynyl" refers to an alkynyl group, which further includes at leastone heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected, for example, from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-10 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-9alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-8 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-7alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more - 34 -CTQ-01425 heteroatoms within the parent chain ("heteroC2-6 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-5 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and l or 2 heteroatoms within the parent chain ("heteroC2-4alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain ("heteroC2-3 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-6alkynyl"). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-10alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10 alkynyl.

[0085] The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclichydrocarbon group having from 3 to 14 ring carbon atoms ("C3-14carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C3-10 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C3-8carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C3-7carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C4-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("C5-6carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C5-10 carbocyclyl"). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like.

[0086] Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementionedC3-8carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing - 35 -CTQ-01425 examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic carbocyclyl") or tricyclic system ("tricyclic carbocyclyl")) and can be saturated or can contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14carbocyclyl.

[0087] In some embodiments, "cycloalkyl" is a monocyclic, saturated carbocyclyl grouphaving from 3 to 14 ring carbon atoms ("C3-14 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C3-10cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C4-6cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-6cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-10 cycloalkyl"). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C6). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14cycloalkyl.

[0088] In some embodiments, "bicycloalkyl" is a bicyclic, saturated carbocyclyl grouphaving from 4 to 14 ring carbon atoms ("C3-14 bicycloalkyl"). Examples of bicycloalkyls are cycloalkyl groups that comprise a bridged (e.g., bicyclo[2.2.1]heptane), spiro (e.g., spiro[2.5]octane), or fused bicyclic system (e.g., decahydronaphthalene).In some embodiments, a bicycloalkyl group has 4 to 10 ring carbon atoms ("C4-10 bicycloalkyl"). In - 36 -CTQ-01425 some embodiments, a bicycloalkyl group has 4 to 8 ring carbon atoms ("C4-8 bicycloalkyl"). In some embodiments, a bicycloalkyl group has 4 to 6 ring carbon atoms ("C4-6bicycloalkyl"). In some embodiments, a bicycloalkyl group has 5 to 6 ring carbon atoms ("C5- 6 bicycloalkyl"). In some embodiments, a bicycloalkyl group has 5 to 10 ring carbon atoms ("C5-10bicycloalkyl"). Examples of C5-6bicycloalkyl groups include bicyclopentane (C5) and bicyclohexane (C6). Examples of C4-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as bicyclobutane (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as bicycloheptane (C7) and bicyclooctane (C8). Unless otherwise specified, each instance of a bicycloalkyl group is independently unsubstituted (an "unsubstituted bicycloalkyl") or substituted (a "substituted bicycloalkyl") with one or more substituents. In certain embodiments, the bicycloalkyl group is an unsubstituted C4-14bicycloalkyl. In certain embodiments, the bicycloalkyl group is a substituted C4-14 bicycloalkyl.

[0089] The term "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 14-memberednon-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl") or tricyclic system ("tricyclic heterocyclyl")), and can be saturated or can contain one or more carbon- carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl. - 37 -CTQ-01425

[0090] In some embodiments, a heterocyclyl group is a 4-10 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("4-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 4-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1- 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0091] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, withoutlimitation, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofurany1, tetrahydrothiopheny1, dihydrothiopheny1, pyrrolidiny1, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, - 38 -CTQ-01425 octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H­ furo[3,2-b]pyranyl, 5,7-dihydro-4H- thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3- b]pyridinyl, 4,5,6,7 -tetrahydro-1H-pyrrolo[2,3-b ]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2- c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4- tetrahydro-1,6-naphthyridinyl, and the like.

[0092] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic ortricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-14aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C6aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C10 aryl"; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C14aryl"; e.g., anthracyl). "Aryl" also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6-14 aryl. In certain embodiments, the aryl group is a substituted C6-14aryl.

[0093] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an arylgroup, wherein the point of attachment is on the alkyl moiety.

[0094] The term "heteroaryl" refers to a radical of a 5-14 membered monocyclic orpolycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein - 39 -CTQ-01425 the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0095] In some embodiments, a heteroaryl group is a 5-12 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-12 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5- 14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0096] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, withoutlimitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups - 40 -CTQ-01425 containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6- membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7- membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0097] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by aheteroaryl group, wherein the point of attachment is on the alkyl moiety.

[0098] The term "unsaturated bond" refers to a double or triple bond.

[0099] The term "unsaturated" or "partially unsaturated" refers to a moiety that includes atleast one double or triple bond.

[0100] The term "saturated" refers to a moiety that does not contain a double or triplebond, i.e., the moiety only contains single bonds.

[0101] Affixing the suffix "-ene" to a group indicates the group is a divalent moiety,e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl. - 41 -CTQ-01425

[0102] A group is optionally substituted unless expressly provided otherwise. Theterm "optionally substituted" refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. "Optionally substituted" refers to a group which may be substituted or unsubstituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term "substituted" is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The invention is not intended to be limited in any manner by the exemplary substituents described herein.

[0103] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X-, -N(ORcc)Rbb, --C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, - SC(=O)Raa, -P(=O)(Raa)2, -P(=O)(ORcc)2, -OP(=O)(Raa)2, -OP(=O)(ORcc)2, - - 42 -CTQ-01425 P(=O)(N(Rbb)2)2,-OP(=O)(N(Rbb)2)2, -NRbbP(=O)(Raa)2, -NRbbP(=O)(ORcc)2, - NRbbP(=O)(N(Rbb)2)2, -P(Rcc)2, -P(ORcc)2, -P(Rcc)3+X–, -P(ORcc)3+X–, -P(Rcc)4, -P(ORcc)2, - OP(Rcc)2, -OP(Rcc)3+X–, -OP(ORcc)2, -OP(ORcc)3+X–, -OP(Rcc)4, -OP(ORcc)4, -B(Raa)2, - B(ORcc)2, -BRaa(ORcc), C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2- 10 alkynyl, heteroC1-10 alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X–is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbbor =NORcc; each instance of Raais, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, -OH, -ORaa, -N(Rcc)2, -CN, -C(=O)Raa, -C(=O)N(Rcc)2, -CO2Raa, -SO2Raa, -C(=NRcc)ORaa, - C(=NRcc)N(Rcc)2, -SO2N(Rcc)2, -SO2Rcc, -SO2ORcc, -SORaa, -C(=S)N(Rcc)2, -C(=O)SRcc, - C(=S)SRcc, -P(=O)(Raa)2, -P(=O)(ORcc)2, -P(=O)(N(Rcc)2)2, C1-10 alkyl, C1-10 perhaloalkyl, C2- 10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X–is a counterion; each instance of Rccis, independently, selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, - - 43 -CTQ-01425 ON(Rff)2, -N(Rff)2, -N(Rff)3+X–, -N(ORee)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, - CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, - NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, - C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, - SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, - C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =O or =S; wherein X–is a counterion; each instance of Reeis, independently, selected from C1-6alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl and 5- 10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; and each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -ON(C1-6 alkyl)2, -N(Cl-6 alkyl)2, -N(Cl-6alkyl)3+X–, -NH(Cl-6alkyl)2+X–, -NH2(C1-6alkyl)+X–, -NH3+X–, -N(OC1-6alkyl)(Cl-6alkyl), -N(OH)(Cl-6 alkyl), -NH(OH), -SH, -SC1-6 alkyl, -SS(Cl-6 alkyl), -C(=O)(Cl-6 alkyl), - CO2H, -CO2(C1-6 alkyl), -OC(=O)(Cl-6 alkyl), -OCO2(C1-6 alkyl), -C(=O)NH2, -C(=O)N(C1-6 alkyl)2, -OC(=O)NH(C1-6alkyl), -NHC(=O)(Cl-6alkyl), -N(Cl-6alkyl)C(=O)( C1-6alkyl), - NHCO2(C1-6alkyl), -NHC(=O)N(Cl-6alkyl)2, -NHC(=O)NH(Cl-6alkyl), -NHC(=O)NH2, - C(=NH)O(Cl-6 alkyl), -OC(=NH)(Cl-6 alkyl), -OC(=NH)OCl-6 alkyl, -C(=NH)N(Cl-6 alkyl)2, - C(=NH)NH(Cl-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C1-6 alkyl)2, -OC(=NH)NH(C1-6 alkyl), - OC(=NH)NH2, -NHC(=NH)N(C1-6alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-6alkyl), -SO2N(C1-6 alkyl)2, -SO2NH(C1-6 alkyl), -SO2NH2, -SO2(C1-6 alkyl), -SO2O(C1-6 alkyl), -OSO2(C1-6 - 44 -CTQ-01425 alkyl), -SO(C1-6 alkyl), -Si(Cl-6 alkyl)3, -OSi(Cl-6 alkyl)3, -C(=S)N(Cl-6 alkyl)2, -C(=S)NH(Cl-6alkyl), -C(=S)NH2, -C(=O)S(Cl-6alkyl), -C(=S)SC1-6alkyl, -SC(=S)SC1-6alkyl, - P(=O)(OC1-6 alkyl)2, -P(=O)(C1-6 alkyl)2, -OP(=O)(Cl-6 alkyl)2, -OP(=O)(OCl-6 alkyl)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X–is a counterion.

[0104] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0105] The term "hydroxyl" or "hydroxy" refers to the group -OH. The term"substituted hydroxyl" or "substituted hydroxyl," by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -ORaa, -ON(Rbb)2, -OC(=O)SRaa, - OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, - OC(=NRbb)N(Rbb)2, -OS(=O)Raa, -OSO2Raa, -OSi(Raa)3, -OP(Rcc)2, -OP(Rcc)3+X–, - OP(ORcc)2, -OP(ORcc)3+X–, -OP(=O)(Raa)2, -OP(=O)(ORcc)2, and -OP(=O)(N(Rbb)2)2, wherein X–, Raa, Rbband Rccare as defined herein.

[0106] The term "amino" refers to the group -NH2. The term "substituted amino," byextension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the "substituted amino" is a monosubstituted amino or a disubstituted amino group.

[0107] The term "monosubstituted amino" refers to an amino group wherein thenitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from -NH(Rbb), -NHC(=O)Raa, - NHCO2Raa, -NHC(=O)N(Rbb)2, -NHC(=NRbb)N(Rbb)2, -NHSO2Raa, -NHP(=O)(ORcc)2, and -NHP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, and wherein Rbbof the group -NH(Rbb) is not hydrogen.

[0108] The term "disubstituted amino" refers to an amino group wherein the nitrogenatom directly attached to the parent molecule is substituted with two groups other than hydrogen, and

[0109] includes groups selected from -N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -NRbbSO2Raa, -NRbbP(=O)(ORcc)2, and - - 45 -CTQ-01425 NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0110] The term "trisubstituted amino" refers to an amino group wherein the nitrogenatom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N(Rbb)2and -N(Rbb)3+X–, wherein Rbband X–are as defined herein.

[0111] The term "sulfonyl" refers to a group selected from -SO2N(Rbb)2, -SO2Raa,and­ SO2ORaa, wherein Raaand Rbbare as defined herein.

[0112] The term "sulfinyl" refers to the group -S(=O)Raa, wherein Raa is as definedherein.

[0113] The term "acyl" refers to a group having the general formula -C(=O)RX1, -C(=O)ORX1, -C(=O)-O-C(=O)RX1, -C(=O)SRX1, -C(=O)N(RX1)2, -C(=S)RX1, -C(=S)N(RX1)2, -C(=S)O(RX1), -C(=S)S(RX1), -C(=NRX1)RX1, -C(=NRX1)ORX1, -C(=NRX1)SRX1, and - C(=NRX1)N(RX1)2, wherein RX1is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di­alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- or di­heteroarylamino; or two RX1groups taken together form a 5- to 6-membered heterocyclic ring.

[0114] Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H),ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, - 46 -CTQ-01425 heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0115] The term "carbonyl" refers a group wherein the carbon directly attached to theparent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (e.g., -C(=O)Raa), carboxylic acids (e.g., -CO2H), aldehydes(­ CHO), esters (e.g., -CO2Raa, -C(=O)SRaa, -C(=S)SRaa), amides (e.g., - C(=O)N(Rbb)2,­C(=O)NRbbSO2Raa, -C(=S)N(Rbb)2, and imines (e.g., -C(=NRbb)Raa, - C(=NRbb)ORaa), ­C(=NRbb)N(Rbb)2, wherein Raaand Rbbare as defined herein.

[0116] The term "oxo" refers to the group =O, and the term "thiooxo" refers to thegroup =S.

[0117] Nitrogen atoms can be substituted or unsubstituted as valency permits, andinclude primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -ORaa, -N(Rcc)2, -CN, -C(=NRcc)N(Rcc)2, -SO2N(Rcc)2, -SO2Rcc, -SO2ORcc, -SORaa, -C(=S)N(Rcc)2, -C(=O)SRcc, - C(=S)SRcc, -P(=O)(ORcc)2, -P(=O)(Raa)2, -P(=O)(N(Rcc)2)2, C1-10 alkyl, C1-10 perhaloalkyl, C2- 10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rcc,and Rddare as defined herein. In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include, but are not limited to, -OH, -ORaa, -N(Rcch, -C(=O)Raa, -C(=O)N(Rcc)2, -CO2Raa, - SO2Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRcc)N(Rcc)2, -SO2N(Rcc)2, -SO2Rcc, -SO2ORcc, - SORaa, -C(=S)N(Rcc)2, -C(=O)SRcc, -C(=S)SRcc, C1-10 alkyl (e.g., aralkyl, heteroaralkyl), C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in - 47 -CTQ-01425 Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0118] For example, nitrogen protecting groups such as amide groups (e.g., -C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p- phenylbenzamide, o­ nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'- dithiobenzyloxyacylamina)acetamide, 3-(p-hydroxypheny1)propanamide, 3-(o-nitrophen y1)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methy1-2-(o- phenylazophenoxy )propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o­nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o­(benzoyloxymethyl)benzamide.

[0119] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)ORaa)include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfa)fluorenylmethy1 carbamate, 9-(2,7-dibromo)fluoroenylmethy1 carbamate, 2,7-di-t-buty1- [9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4- methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1- (1-adamantyl)-1- methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1- dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1- methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t- butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N­ dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1- isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N­ hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p- bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4- methylsulfinylbenzyl carbamate (Msz), 9- anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2- methylsulfonylethyl carbamate, 2-(p- toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4- methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2- phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1- - 48 -CTQ-01425 dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p­ (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)- 6- chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o- nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p­ decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido )benzy1 carbamate, 1,1-dimethy1-3-(N,N- dimethylcarboxamido )propy1 carbamate, 1,1-dimethylpropynyl carbamate, di(2- pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p' -methoxyphenylazo )benzyl carbamate, 1-methylcyclobutyl carbamate, 1- methylcyclohexyl carbamate, 1-methyl-1- cyclopropylmethyl carbamate, 1-methyl-1-(3,5- dimethoxyphenyl)ethyl carbamate, 1-methyl- 1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1- phenylethyl carbamate, 1-methyl-1-(4- pyridyl)ethyl carbamate, phenyl carbamate, p­ (phenylazo)benzyl carbamate, 2,4,6-tri-t- butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0120] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)2Raa)include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6- trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4- methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6- dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), - trimethylsilylethanesulfonamide (SES), 9- anthracenesulfonamide, 4-(4',8'- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS ), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0121] Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)­ acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'- phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2- one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3- diphenylmaleimide, N-2,5- dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethy1-1,3,5-triazacyclohexan- 2-one, 5-substituted - 49 -CTQ-01425 1,3-dibenzyl-1 ,3,5-triazacyclohexan- 2-one, 1-substituted 3,5-dinitro-4-pyridone, N- methylamine, N-allylamine, N-[2- (trimethylsilyl)ethoxy ]methylamine (SEM), N-3- acetoxypropylamine, N-(1-isopropyl-4-nitro-2- oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4- methoxyphenyl)methylamine, N-5- dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4- methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7- dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fern), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methox ybenzy lideneamine, N-diphenylmethyleneamine, N-[(2-pyrid y1)mesity1]methyleneamine, N-(N' ,N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N- p­nitrobenzylideneamine, N-salicylideneamine, N- 5-chlorosalicylideneamine, N-(5-chloro- 2- hydrox yphen y1)phenylmethyleneamine, N -cyclohex ylideneamine, N-(5,5-dimethy1-3- oxo-1- cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N­ [phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N­ nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o­ nitrobenzenesulfenamide (Nps ), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In certain embodiments, a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2- trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0122] In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to herein as an "hydroxyl protecting group"). Oxygen protecting groups include, but are not limited to, -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, - CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, - SO2Raa, -Si(Raa)3, -P(Rcc)2, -P(Rcc)3+X–, -P(ORcc)2, -P(ORcc)3+X–, -P(=O)(Raa)2, - P(=O)(ORcc)2, and -P(=O)(N(Rbb)2)2, wherein X–, Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic - 50 -CTQ-01425 Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0123] Exemplary oxygen protecting groups include, but are not limited to, methyl,methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethy1, bis(2-chloroethoxy)methy1, 2- (trimethylsilyl)ethoxymeth yl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexy1, 4- methoxytetrahydropyrany1 (MTHP), 4-methoxytetrahydrothiopyrany1, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-meth y1)pheny1]-4-methox ypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a­octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1- (2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1- benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t- butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p- methoxybenzyl, 3,4-dimethoxybenzyl, o­nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6- dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- picolyl, 4-picolyl, 3-methyl-2-picolyl N- oxido, diphenylmethyl, p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a- naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacy loxyphen y1)diphen ylmethy1, 4,4',4"-tris(4,5-dichlorophthalimidopheny1)methy1, 4,4',4"- tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1- yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9- anthryl, 9- (9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S­ dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t­ butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TEMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3- phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio )pentanoate - 51 -CTQ-01425 (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p­ phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2- (trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p- methoxybenzyl carbonate, 3,4- dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p- nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl)benzoate, 2- formylbenzenesulfonate, 2-(methylthiomethoxy)ethy1, 4-(meth ylthiomethoxy)butyrate, 2-(methylthiomethoxymethy1)benzoate, 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4- ( 1,1,3,3-tetramethylbuty1)phenoxyacetate, 2,4-bis( 1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o­(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N,N,N',N'- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, an oxygen protecting group is silyl. In certain embodiments, an oxygen protecting group is t­ butyldiphenylsilyl (TBDPS), t- butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2- trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2- trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2- trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p- methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0124] In certain embodiments, the substituent present on a sulfur atom is a sulfurprotecting group (also referred to as a "thiol protecting group"). Sulfur protecting groups include, but are not limited to, -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, - C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, - Si(Raa)3, -P(Rcc)2, -P(Rcc)3+X–, -P(ORcc)2, -P(ORcc)3+X–, -P(=O)(Raa)2, -P(=O)(ORcc)2, and - P(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic - 52 -CTQ-01425 Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

[0125] A "counterion" as used herein can be an anionic counterion or a cationiccounterion.

[0126] An “anionic counterion" is a negatively charged group associated with apositively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (i.e., including one formal negative charge). An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary anionic counterions include halide ions (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HCO3–, HSO4–, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p­ toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2- sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4–, PF4–, PF6–, AsF6–, SbF6–, B[3,5- (CF3)2C6H3] 4–, B(C6F5) 4–, BPh4–, Al(OC(CF3)3) 4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). Exemplary anionic counterions which may be multivalent include CO32–, HPO42–, PO43–, B4O72–, SO42–, S2O32–, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0127] A “cationic counterion" is a positively charged group associated with anegatively charged group in order to maintain electronic neutrality. A cationic counterion may be monovalent (i.e., including one formal positive charge). A cationic counterion may also be multivalent (i.e., including more than one formal positive charge), such as divalent or trivalent. Exemplary cationic counterions include, for example, cations of metals, such as alkali metals and alkaline earth metals, as well as NH4+, NH3(C1-6alkyl)+, NH2(C1-6alkyl)2+, NH (C1-6alkyl)3+, and N+(C1–6alkyl)4 cations, where the C1-6alkyl can be optionally substituted as discussed above. Representative cations of alkali and alkaline earth metals include Li+, Na+, K+, Mg2+, and Ca2+, and the like. Pharmaceutical Compositions and Modes of Administration

[0128] In another aspect, the present invention relates to pharmaceutical compositionscomprising a compound a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. - 53 -CTQ-01425

[0129] Compounds provided herein are usually administered in the form ofpharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that comprise one or more of the compounds described herein or a pharmaceutically acceptable salt, a stereoisomer, or a mixture of stereoisomers thereof and one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients may include, for example, inert solid diluents and fillers, liquid diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa.17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc.3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0130] In some embodiments, the pharmaceutical composition comprises a compoundof Formula I or Formula II, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula Ib, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula IIa, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0131] In some embodiments, the pharmaceutical composition comprises a compoundof Formula Ib-a, Ib-b, Ib-c, Ib-d, Ib-1a, Ib-1b, Ib-1c, Ib-1d, IIa-a, IIa-b, IIa-c, IIa-d, IIb-a, IIb- b, IIb-c, IIb-d, IIb-1a, IIb-1b, IIb-1c, or IIb-1d, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula IIb, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula IIIc, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. - 54 -CTQ-01425

[0132] The pharmaceutical compositions may be administered in either single ormultiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0133] One mode for administration is parenteral, for example, by injection. Theforms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0134] Oral administration may be another route for administration of the compoundsdescribed herein. Administration may be via, for example, capsule or tablet, such as enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, a stereoisomer, or a mixture of stereoisomers thereof, the active ingredient is usually diluted by an excipient and / or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi- solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0135] Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.

[0136] The compositions that include at least one compound described herein or apharmaceutically acceptable salt, a stereoisomer, or a mixture of stereoisomers thereof can be formulated so as to provide quick, sustained, or delayed release of the active ingredient after - 55 -CTQ-01425 administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0137] For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, a stereoisomer, or a mixture of stereoisomers thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0138] The tablets or pills of the compounds described herein may be coated orotherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0139] Compositions for inhalation or insufflation may include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use - 56 -CTQ-01425 of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

[0140] The specific dose level of a compound of the present application for anyparticular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg / kg). Dosages of between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg / kg may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject. A dose may be administered once a day (QID), twice per day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound. In addition, toxicity factors may influence the dosage and administration regimen. When administered orally, the pill, capsule, or tablet may be ingested daily or less frequently for a specified period of time. The regimen may be repeated for a number of cycles of therapy. Methods of Treatment

[0141] In another aspect, the present invention relates to methods of promotingmyelination in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein, a pharmaceutically accept salt thereof, or a composition disclosed herein.

[0142] In another aspect, the present disclosure relates to using the compounds,pharmaceutically acceptable salts thereof, and compositions disclosed herein for use in treating a disorder in a subject in need thereof. - 57 -CTQ-01425

[0143] In another aspect, the present disclosure relates to using the compounds,pharmaceutically acceptable salts thereof, and compositions disclosed herein for use in promoting myelination in a subject in need thereof.

[0144] In another aspect, the present disclosure relates to using the compounds,pharmaceutically acceptable salts thereof, and compositions disclosed herein for use in the manufacture of a medicament for treating a disorder in a subject in need thereof.

[0145] In another aspect, the present disclosure relates to using the compounds,pharmaceutically acceptable salts thereof, and compositions disclosed herein for use in the manufacture of a medicament for promoting myelination in a subject in need thereof.

[0146] In certain embodiments, the subject has a myelin-related disorder. In certainembodiments, the myelin-related disorder is multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophy, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander's disease, Pelizaeus Merzbacher disease (PMD), Vanishing White Matter Disease, Wallerian Degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Komzweig syndrome, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barre syndrome, Charcot-Marie-Tooth disease, Bell's palsy, or radiation-induced demyelination. In certain embodiments, the disorder is multiple sclerosis.

[0147] In another aspect, the present invention relates to method of inhibiting CYP51(lanosterol demethylase) comprising contacting CYP51 with a compound disclosed herein, a pharmaceutically accept salt thereof, or a composition disclosed herein.

[0148] Described herein are methods for promoting myelination of central nervoussystem neurons in a subject suffering from a myelin-related disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of Formulae I, II, Ia, Ib, IIa, IIb, and IIc, or a pharmaceutical composition comprising the same. In certain embodiments, the subject matter disclosed herein is directed to a compound of Formulae I, II, Ia, Ib, IIa, IIb, and IIc, or a pharmaceutically acceptable salt or solvate thereof, for promoting myelination of central nervous system neurons in a subject suffering from a myelin-related - 58 -CTQ-01425 disorder. In another embodiment, the subject matter described herein is directed to the use of a compound of Formulae I, II, Ia, Ib, IIa, IIb, and IIc, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for promoting myelination of central nervous system neurons in a subject suffering from a myelin-related disorder.

[0149] In certain embodiments, in the methods for promoting myelination of centralnervous system neurons in a subject suffering from a myelin-related disorder, the compound of Formulae I, II, Ia, Ib, IIa, IIb, and IIc, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, inhibits enzyme mediated synthesis of one or more sterol intermediates in the cholesterol biosynthesis pathway.

[0150] In certain embodiments, in the methods for promoting myelination of centralnervous system neurons in a subject suffering from a myelin-related disorder, the compound of Formulae I, II, Ia, Ib, IIa, IIb, and IIc, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, promotes accumulation of Δ8,9-unsaturated sterol intermediates in the cholesterol biosynthesis pathway.

[0151] In certain embodiments, in the methods for promoting myelination of centralnervous system neurons in a subject suffering from a myelin-related disorder, the compound of Formulae I, II, Ia, Ib, IIa, IIb, and IIc, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, inhibits one or more of CYP51, sterol-14-reductase, or EBP enzyme mediated synthesis of sterol intermediates in the cholesterol biosynthesis pathway. In certain embodiments, the compound of Formulae I, II, Ia, Ib, IIa, IIb, and IIc, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, inhibits CYP51.

[0152] In certain embodiments, in the methods for promoting myelination of centralnervous system neurons in a subject suffering from a myelin-related disorder, the compound of Formulae I, II, Ia, Ib, IIa, IIb, and IIc, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, induces, promotes, and / or modulates oligodendrocyte precursor cell (OPC) differentiation, proliferation and / or maturation. In certain embodiments, the induction of OPC differentiation is characterized by an increase in myelin basic protein (MBP) expression.

[0153] In certain embodiments, the subject matter described herein is directed to amethod of treating a disorder in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formulae I, II, Ia, Ib, IIa, IIb, and IIc, or a pharmaceutically acceptable salt or solvate - 59 -CTQ-01425 thereof. In certain embodiments, the subject has a myelin-related disorder. In some embodiments, the compound of Formula I is a compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIc, or a pharmaceutically acceptable salt or solvate thereof.

[0154] In certain embodiments, the subject matter disclosed herein is directed to acompound of Formulae I, II, Ia, Ib, IIa, IIb, and IIc, or a pharmaceutically acceptable salt or solvate thereof, for use in treating a disorder in a subject in need thereof. In certain embodiments, the subject has a myelin-related disorder. In some embodiments, the compound of Formula I is a compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIc, or a pharmaceutically acceptable salt or solvate thereof.

[0155] In certain embodiments, the subject matter disclosed herein is directed to theuse of a compound of Formulae I, II, Ia, Ib, IIa, IIb, and IIc, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof. In certain embodiments, the subject has a myelin-related disorder. In some embodiments, the compound of Formula I is a compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIc, or a pharmaceutically acceptable salt or solvate thereof. - 60 -CTQ-01425

[0156] In certain embodiments, the subject matter disclosed herein is directed to amethod of promoting myelination in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formulae I, II, Ia, Ib, IIa, IIb, and IIc, or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the subject has a myelin-related disorder. In some embodiments, the compound of Formula I is a compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIc, or a pharmaceutically acceptable salt or solvate thereof.

[0157] In certain embodiments, the subject matter disclosed herein is directed to acompound of Formulae I, II, Ia, Ib, IIa, IIb, and IIc, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the compound, for use in promoting myelination in a subject in need thereof. In certain embodiments, the subject has a myelin-related disorder. In some embodiments, the compound of Formula I is a compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIc, or a pharmaceutically acceptable salt or solvate thereof.

[0158] In certain embodiments, the subject matter disclosed herein is directed to useof a compound of Formulae I, II, Ia, Ib, IIa, IIb, and IIc, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the compound, in the manufacture of a medicament for promoting myelination in a subject in need thereof. In certain embodiments, the subject has a myelin-related disorder. In some embodiments, the compound of Formula I is a compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, - 61 -CTQ-01425 the compound of Formula II is a compound of Formula IIa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIc, or a pharmaceutically acceptable salt or solvate thereof.

[0159] In certain embodiments, the subject matter disclosed herein is directed to amethod of inducing endogenous oligodendrocyte precursor cell (OPC) differentiation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formulae I, II, Ia, Ib, IIa, IIb, and IIc, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same. In certain embodiments, the subject is suffering from a myelin-related disorder. In certain embodiments, the myelin-related disorder is multiple sclerosis.

[0160] Such myelin-related disorders include, but are not limited to, multiple sclerosis(MS), neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophies, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander's disease, Pelizaeus Merzbacher disease (PMD), Vanishing White Matter Disease, Wallerian Degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillian-Barre syndrome, Charcot-Marie-Tooth disease, Bell's palsy, and radiation-induced demyelination.

[0161] The compound of Formulae I, II, Ia, Ib, IIa, IIb, and IIc, or a pharmaceuticallyacceptable salt or solvate thereof can be administered alone or in combination with another agent to a subject suffering from a myelin-related disorder to promote myelination of neurons (e.g., neuronal axons). A myelin-related disorder can include any disease, condition (e.g., those occurring from traumatic spinal cord injury and cerebral infarction), or disorder resulting in abnormalities of the myelin sheath. Abnormalities can be caused by loss of myelin referred to as demyelination, dysfunctional myelin referred to as dysmyelination, or failure to form enough myelin referred to as hypomyelination. A myelin related disorder as - 62 -CTQ-01425 described herein can arise from a genetic disorder or from one or more of a variety of neurotoxic insults. In some embodiments, the compound of Formula I is a compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula II is a compound of Formula IIc, or a pharmaceutically acceptable salt or solvate thereof.

[0162] Additionally, described herein are methods for promoting myelination ofcentral nervous system neurons in a subject suffering from a myelin-related disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula Ib-a, Ib-b, Ib-c, Ib-d, Ib-1a, Ib-1b, Ib-1c, Ib-1d, IIa-a, IIa-b, IIa-c, IIa- d, IIb-a, IIb-b, IIb-c, IIb-d, IIb-1a, IIb-1b, IIb-1c, or IIb-1d, or a pharmaceutical composition comprising the same. In certain embodiments, the subject matter disclosed herein is directed to a compound of Formula Ib-a, Ib-b, Ib-c, Ib-d, Ib-1a, Ib-1b, Ib-1c, Ib-1d, IIa-a, IIa-b, IIa-c, IIa-d, IIb-a, IIb-b, IIb-c, IIb-d, IIb-1a, IIb-1b, IIb-1c, or IIb-1d, or a pharmaceutically acceptable salt or solvate thereof, for promoting myelination of central nervous system neurons in a subject suffering from a myelin-related disorder. In another embodiment, the subject matter described herein is directed to the use of a compound of Formula Ib-a, Ib-b, Ib- c, Ib-d, Ib-1a, Ib-1b, Ib-1c, Ib-1d, IIa-a, IIa-b, IIa-c, IIa-d, IIb-a, IIb-b, IIb-c, IIb-d, IIb-1a, IIb-1b, IIb-1c, or IIb-1d, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for promoting myelination of central nervous system neurons in a subject suffering from a myelin-related disorder.

[0163] In certain embodiments, in the methods for promoting myelination of centralnervous system neurons in a subject suffering from a myelin-related disorder, the compound of Formula Ib-a, Ib-b, Ib-c, Ib-d, Ib-1a, Ib-1b, Ib-1c, Ib-1d, IIa-a, IIa-b, IIa-c, IIa-d, IIb-a, IIb- b, IIb-c, IIb-d, IIb-1a, IIb-1b, IIb-1c, or IIb-1d, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, inhibits enzyme mediated synthesis of one or more sterol intermediates in the cholesterol biosynthesis pathway.

[0164] In certain embodiments, in the methods for promoting myelination of centralnervous system neurons in a subject suffering from a myelin-related disorder, the compound - 63 -CTQ-01425 of Formula Ib-a, Ib-b, Ib-c, Ib-d, Ib-1a, Ib-1b, Ib-1c, Ib-1d, IIa-a, IIa-b, IIa-c, IIa-d, IIb-a, IIb- b, IIb-c, IIb-d, IIb-1a, IIb-1b, IIb-1c, or IIb-1d, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, promotes accumulation of Δ8,9-unsaturated sterol intermediates in the cholesterol biosynthesis pathway.

[0165] In certain embodiments, in the methods for promoting myelination of centralnervous system neurons in a subject suffering from a myelin-related disorder, the compound of Formula Ib-a, Ib-b, Ib-c, Ib-d, Ib-1a, Ib-1b, Ib-1c, Ib-1d, IIa-a, IIa-b, IIa-c, IIa-d, IIb-a, IIb- b, IIb-c, IIb-d, IIb-1a, IIb-1b, IIb-1c, or IIb-1d, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, inhibits one or more of CYP51, sterol-14-reductase, or EBP enzyme mediated synthesis of sterol intermediates in the cholesterol biosynthesis pathway. In certain embodiments, the compound of Formula Ib- a, Ib-b, Ib-c, Ib-d, Ib-1a, Ib-1b, Ib-1c, Ib-1d, IIa-a, IIa-b, IIa-c, IIa-d, IIb-a, IIb-b, IIb-c, IIb-d, IIb-1a, IIb-1b, IIb-1c, or IIb-1d, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, inhibits CYP51.

[0166] In certain embodiments, in the methods for promoting myelination of centralnervous system neurons in a subject suffering from a myelin-related disorder, the compound of Formula Ib-a, Ib-b, Ib-c, Ib-d, Ib-1a, Ib-1b, Ib-1c, Ib-1d, IIa-a, IIa-b, IIa-c, IIa-d, IIb-a, IIb- b, IIb-c, IIb-d, IIb-1a, IIb-1b, IIb-1c, or IIb-1d, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, induces, promotes, and / or modulates oligodendrocyte precursor cell (OPC) differentiation, proliferation and / or maturation. In certain embodiments, the induction of OPC differentiation is characterized by an increase in myelin basic protein (MBP) expression.

[0167] In certain embodiments, the subject matter described herein is directed to amethod of treating a disorder in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula Ib-a, Ib-b, Ib-c, Ib-d, Ib-1a, Ib-1b, Ib-1c, Ib-1d, IIa-a, IIa-b, IIa-c, IIa-d, IIb-a, IIb- b, IIb-c, IIb-d, IIb-1a, IIb-1b, IIb-1c, or IIb-1d, or a pharmaceutically acceptable salt or solvate thereof.

[0168] In certain embodiments, the subject matter disclosed herein is directed to acompound of Formula Ib-a, Ib-b, Ib-c, Ib-d, Ib-1a, Ib-1b, Ib-1c, Ib-1d, IIa-a, IIa-b, IIa-c, IIa- d, IIb-a, IIb-b, IIb-c, IIb-d, IIb-1a, IIb-1b, IIb-1c, or IIb-1d, or a pharmaceutically acceptable - 64 -CTQ-01425 salt or solvate thereof, for use in treating a disorder in a subject in need thereof. In certain embodiments, the subject has a myelin-related disorder.

[0169] In certain embodiments, the subject matter disclosed herein is directed to theuse of a compound of Formula Ib-a, Ib-b, Ib-c, Ib-d, Ib-1a, Ib-1b, Ib-1c, Ib-1d, IIa-a, IIa-b, IIa-c, IIa-d, IIb-a, IIb-b, IIb-c, IIb-d, IIb-1a, IIb-1b, IIb-1c, or IIb-1d, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof. In certain embodiments, the subject has a myelin-related disorder.

[0170] In certain embodiments, the subject matter disclosed herein is directed to amethod of promoting myelination in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula Ib-a, Ib-b, Ib-c, Ib- d, Ib-1a, Ib-1b, Ib-1c, Ib-1d, IIa-a, IIa-b, IIa-c, IIa-d, IIb-a, IIb-b, IIb-c, IIb-d, IIb-1a, IIb-1b, IIb-1c, or IIb-1d, or a pharmaceutically acceptable salt or solvate thereof.

[0171] In certain embodiments, the subject matter disclosed herein is directed to acompound of Formula Ib-a, Ib-b, Ib-c, Ib-d, Ib-1a, Ib-1b, Ib-1c, Ib-1d, IIa-a, IIa-b, IIa-c, IIa- d, IIb-a, IIb-b, IIb-c, IIb-d, IIb-1a, IIb-1b, IIb-1c, or IIb-1d, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the compound, for use in promoting myelination in a subject in need thereof.

[0172] In certain embodiments, the subject matter disclosed herein is directed to useof a compound of Formula Ib-a, Ib-b, Ib-c, Ib-d, Ib-1a, Ib-1b, Ib-1c, Ib-1d, IIa-a, IIa-b, IIa-c, IIa-d, IIb-a, IIb-b, IIb-c, IIb-d, IIb-1a, IIb-1b, IIb-1c, or IIb-1d, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the compound, in the manufacture of a medicament for promoting myelination in a subject in need thereof. In certain embodiments, the subject has a myelin-related disorder.

[0173] In certain embodiments, the subject matter disclosed herein is directed to amethod of inducing endogenous oligodendrocyte precursor cell (OPC) differentiation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula Ib-a, Ib-b, Ib-c, Ib-d, Ib-1a, Ib-1b, Ib-1c, Ib-1d, IIa-a, IIa-b, IIa-c, IIa-d, IIb-a, IIb-b, IIb-c, IIb-d, IIb-1a, IIb-1b, IIb-1c, or IIb-1d, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same. In certain embodiments, the subject is suffering from a myelin-related disorder. In certain embodiments, the myelin-related disorder is multiple sclerosis. - 65 -CTQ-01425

[0174] Such myelin-related disorders include, but are not limited to, multiple sclerosis(MS), neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophies, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander's disease, Pelizaeus Merzbacher disease (PMD), Vanishing White Matter Disease, Wallerian Degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillian-Barre syndrome, Charcot-Marie-Tooth disease, Bell's palsy, and radiation-induced demyelination.

[0175] The compound of Formula Ib-a, Ib-b, Ib-c, Ib-d, Ib-1a, Ib-1b, Ib-1c, Ib-1d, IIa-a, IIa-b, IIa-c, IIa-d, IIb-a, IIb-b, IIb-c, IIb-d, IIb-1a, IIb-1b, IIb-1c, or IIb-1d, or a pharmaceutically acceptable salt or solvate thereof can be administered alone or in combination with another agent to a subject suffering from a myelin-related disorder to promote myelination of neurons (e.g., neuronal axons). A myelin-related disorder can include any disease, condition (e.g., those occurring from traumatic spinal cord injury and cerebral infarction), or disorder resulting in abnormalities of the myelin sheath. Abnormalities can be caused by loss of myelin referred to as demyelination, dysfunctional myelin referred to as dysmyelination, or failure to form enough myelin referred to as hypomyelination. A myelin related disorder as described herein can arise from a genetic disorder or from one or more of a variety of neurotoxic insults.

[0176] “Demyelination” as used herein, refers to the act of demyelinating, or thedamage or loss of part or all of the myelin sheath insulating the nerves, and is the hallmark of myelin-related disorders. In certain embodiments, demyelination refers to the damage or loss of part or all of the myelin sheath insulating a subset of nerves in an individual, such as, for example, one or more nerves localized in a particular area of the body (e.g., neurons in the brain or spinal cord, or both brain and spinal cord; or the optic nerve).

[0177] Myelination of neurons requires oligodendrocytes. The term “myelination”,as used herein, refers to the generation of the nerve’s myelin sheath by replacing myelin producing cells or restoring their function. The neurons that undergo remyelination may be - 66 -CTQ-01425 in the brain, spinal cord, or both the brain and spinal cord. Restoring the function of a myelin producing cell may include, for example, increasing the rate of myelin production in a cell (or cells) with a less-than-average production level. Such increase may encompass raising the rate of myelin production up to or exceeding average production level; but also may encompass raising the rate of myelin production to a level that is still less than average, but higher than the previous level.

[0178] “Promoting Myelination” as used herein refers to increasing the rate ofmyelin production rather than a mere net increase in the amount of myelin as compared to a baseline level of myelin production rate in a subject. An increase in the rate of myelin production can be determined using imaging techniques or functional measurements. In some embodiments, myelination is promoted by increasing the differentiation of OPCs, increasing the accumulation of 8,9-unsaturated sterol intermediates in the biosynthetic pathway, increasing the formation of OPCs, or any combinations thereof. Such activities may be evaluated, for example, using one or more in vitro assays, such as those described herein or known to one of skill in the art.

[0179] A “baseline level of myelin production rate” as used herein, refers to the rateof myelin production in subject being treated before the onset of treatment. - 67 -CTQ-01425 PREPARATION OF INTERMEDIATES Intermediate A tert-butyl (R)-2-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate

[0180] To a mixture of (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (10.0g, 43.62 mmol, 1 eq) and N,O-dimethylhydroxylamine hydrochloride (10.64 g, 109.04 mmol, 2.5 eq) in DCM (150 mL) was added DIEA (28.19 g, 218.08 mmol, 37.99 mL, 5 eq) and HATU (41.46 g, 109.04 mmol, 2.5 eq) in one portion at 0 °C. The mixture was stirred at 25 °C for 16 hours. TLC (petroleum ether / ethyl acetate = 5 / 1, Rf = 0.54) showed the starting material consumed and a new spot appeared. The mixture was diluted with H2O (50 mL), and extracted with DCM (100 mL × 2 ), the combined organic phase was washed with saturated NaHCO3 (40 mL × 2) and brine (50 mL × 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (0 - 10% ethyl acetate in petroleum ether) to afford the title compound (11.43 g, 96%) as a colorless oil.1H NMR (400 MHz, CDCl3): δ 5.10 - 4.81 (m, 1H), 4.03 - 3.88 (m, 1H), 3.78 (s, 3H), 3.52 - 3.36 (m, 1H), 3.19 (s, 3H), 2.03 - 1.93 (m, 1H), 1.76 - 1.56 (m, 3H), 1.48 - 1.35 (m, 11H). Intermediate B tert-butyl (R)-2-(4-methoxynicotinoyl)piperidine-1-carboxylate

[0181] To a mixture of 3-bromo-4-methoxypyridine (4.14 g, 22.03 mmol, 2 eq) inTHF (30 mL) was added n-BuLi (2.5 M in hexane, 8.81 mL, 2 eq) at -75 °C under N2atmosphere. The mixture was stirred at -75 °C for 0.5 hour, then tert-butyl (R)-2- - 68 -CTQ-01425 (methoxy(methyl)carbamoyl)piperidine-1-carboxylate (3.0 g, 11.02 mmol, 1 eq) was added into it at -75 °C. The mixture was stirred at -75 °C for 1 hour. LCMS (5- 95AB_220&254_Agilent.M): RT = 0.733 min, [M+H]+= 321.2 showed 58% of desired product. The reaction was quenched with saturated NH4Cl (20 mL), the mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (100 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (0 - 40% ethyl acetate in petroleum ether) to afford the title compound (2.21 g, 63%) as a yellow solid.1H NMR (400 MHz, CDCl3): δ 8.70 - 8.56 (m, 1H), 8.46 - 8.40 (m, 1H), 6.84 - 6.79 (m, 1H), 5.66 - 5.45 (m, 1H), 3.96 - 3.85 (m, 4H), 3.07 - 2.98 (m, 1H), 2.01 - 1.53 (m, 4H), 1.47 - 1.40 (m, 10H), 1.20 - 1.11 (m, 1H); LCMS (ESI): m / z 321.2 (M+H)+. Intermediate C (R)-(4-methoxypyridin-3-yl)(piperidin-2-yl)methanone hydrochloride

[0182] A mixture of tert-butyl (R)-2-(4-methoxynicotinoyl)piperidine-1-carboxylate(1.50 g, 4.68 mmol, 1 eq) in HCl / dioxane (4 M / mol, 20 mL) was stirred at 25 °C for 1 hour. TLC (petroleum ether / ethyl acetate / ethanol = 4 / 3 / 1, Rf= 0.05) showed the starting material consumed and a new spot appeared. The reaction mixture was concentrated in vacuum to afford the title compound (1.5 g, crude) as a yellow solid.. The crude product would be directly used in the next step without purification. Intermediate D (4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochlorideStep 1: tert-butyl (2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidine-1- carboxylate - 69 -CTQ-01425

[0183] To a solution of tert-butyl (R)-2-(4-methoxynicotinoyl)piperidine-1-carboxylate (3.57 g, 11.14 mmol, 1 eq) in THF (21 mL) and MeOH (7 mL) was added NaBH4(843.13 mg, 22.29 mmol, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. LCMS (5 - 95AB_1.5 min): RT = 0.632 min, [M+H]+= 323.1, showed 70% of desired product. The mixture was quenched with water (20 mL), extracted with ethyl acetate (100 mL × 3). The organic layers were combined, washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to provide a residue. The residue was purified by flash chromatography on silica gel (0 - 50% ethyl acetate in petroleum ether) to afford the title compound (3.06 g, 85%) as a yellow oil. LCMS (ESI): m / z 323.1 (M+H)+. Step 2: (4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride

[0184] To a solution of tert-butyl (2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidine-1-carboxylate (3.06 g, 9.49 mmol, 1 eq) in dioxane (10 mL) was added HCl / dioxane (4 M / L, 10 mL). The mixture was stirred at 25 °C for 1 h. TLC (petroleum ether : ethyl acetate = 1:1, Rf= 0.15) showed the starting material consumed and a new spot appeared. The mixture was concentrated to afford the title compound (2.46 g, crude) as a white solid. LCMS (ESI): m / z 223.1 (M+H)+. Intermediate E (S)-(4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride & (R)-(4- methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride- 70 -CTQ-01425Step 1: tert-butyl (R)-2-((S)-hydroxy(4-methoxypyridin-3-yl)methyl)piperidine-1-carboxylate & tert-butyl (R)-2-((R)-hydroxy(4-methoxypyridin-3-yl)methyl)piperidine- 1-carboxylate

[0185] To a solution of tert-butyl (R)-2-(4-methoxynicotinoyl)piperidine-1-carboxylate (5.0 g, 15.61 mmol, 1 eq) in THF (36 mL) and MeOH (12 mL) was added NaBH4 (1.50 g, 39.65 mmol, 2.54 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hr. LCMS (10-80CD_4min_220&254_Agilent): RT =2.020 min & 2.190 min, [M+H]+=323.2, showed 22% and 69% of the desired product. The reaction solution was diluted with saturated NH4Cl (30 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Xtimate C18150×40mm×10um, water(NH3H2O+NH4HCO3)-ACN, 36%-66% B over 7 min) to afford tert-butyl (R)-2-((S)-hydroxy(4-methoxypyridin-3- yl)methyl)piperidine-1-carboxylate ( the first peak, 0.7 g, 14%, SFC showed 13:87) and tert- butyl (R)-2-((R)-hydroxy(4-methoxypyridin-3-yl)methyl)piperidine-1-carboxylate (the second peak, 1.6 g, 32%, SFC showed 86:14) as a white solid. LCMS (ESI): m / z 323.2 (M+H)+. Step 2: (S)-(4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride

[0186] To a solution of tert-butyl (R)-2-((S)-hydroxy(4-methoxypyridin-3-yl)methyl)piperidine-1-carboxylate (0.7 g, 2.17 mmol, 1 eq) was added HCl / dioxane (10 mL, 4M / L). The mixture was stirred at 25°C for 1 hr. TLC (Ethyl acetate:Petroleum ether=1:1) showed a new spot. The reaction was filtered and concentrated under reduced pressure to afford the title compound (562 mg, crude) as a yellow oil. - 71 -CTQ-01425Step 3: (R)-(4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochlorideTo a solution of tert-butyl (R)-2-((R)-hydroxy(4-methoxypyridin-3-yl)methyl)piperidine-1- carboxylate (1.6 g, 4.96 mmol, 1 eq) was added HCl / dioxane (20 mL, 4M / L). The mixture was stirred at 25°C for 1 hr. TLC (Ethyl acetate:Petroleum ether=1:1) showed a new spot. The reaction was filtered and concentrated under reduced pressure to afford the title compound (1.28 g, crude) as a yellow oil. Structural confirmationStep 1: (1S,8aR)-1-(4-methoxypyridin-3-yl)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one

[0187] To a solution of tert-butyl (2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidine-1-carboxylate (50 mg, 155.09 μmol, 1 eq) in THF (1.5 mL) and H2O (0.5 mL) was added LiOH.H2O (26.03 mg, 620.35 μmol, 4 eq). The mixture was stirred at 25 °C for 1 hr. LCMS (5-95AB_220&254_Agilent.M): RT = 0.10 min, [M+1]+=249.3 showed desired product and no starting material remained. The residue was diluted with H2O(20 mL) and the solution was extracted with ethyl acetate (30 mL × 3). The combined organiclayers were washed with brine (10 mL × 3), filtered and concentrated under reduced pressure- 72 -CTQ-01425 to give a residue. The residue was purified by flash silica gel chromatography (0 - 50% (ethanol: ethyl acetate =3:1) in petroleum ether) to afford the title compound (5 mg, 13%) as a yellow oil.2D-NMR (NOE) revealed a cis configuration.1H NMR (400 MHz, CDCl3): δ 8.58 - 8.50 (m, 2H), 6.85 - 6.82 (m, 1H), 5.78 (d, J = 8.0 Hz, 1H), 4.03 - 3.85 (m, 5H), 2.98 - 2.86 (m, 1H), 2.39 - 2.16 (m, 1H), 1.88 - 1.74 (m, 1H), 1.62 - 1.60 (m, 1H), 1.46 - 1.35 (m, 2H), 1.16 - 1.05 (m, 1H); LCMS (ESI): m / z 249.3 (M+H)+.Step 2: (1R,8aR)-1-(4-methoxypyridin-3-yl)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one

[0188] To a solution of tert-butyl (2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidine-1-carboxylate (50.00 mg, 155.09 μmol, 1 eq) in THF (1.5 mL) and H2O (0.5 mL) was added LiOH.H2O (26.03 mg, 620.35 μmol, 4 eq). The mixture was stirred at 25 °C for 16 hr. LCMS (5-95AB _1.5min ):RT= 0.406 min, [M+1]+=249.1 showed 50% ofdesired product. The residue was diluted with water 10 mL and extracted with ethyl acetate(20 mL × 3). The combined organic layers were washed with brine (20mL × 3), filtered andconcentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether: EE(Ethyl acetate / EtOH=3:1)=1:1) to afford the title compound (6 mg, 16%) as a white solid.2D-NMR (NOE) revealed a trans configuration.1H NMR (400 MHz, CDCl3): δ 8.61 - 8.41 (m, 2H), 6.92 - 6.80 (m, 1H), 5.35 - 5.32 (m, 1H), 3.97 - 3.88 (m, 4H), 3.51 - 3.42 (m, 1H), 2.90 - 2.78 (m, 1H), 2.06 - 1.92 (m, 2H), 1.75 - 1.66 (m, 1H), 1.56 - 1.44 (m, 2H), 1.44 - 1.36 (m, 1H); LCMS (ESI): m / z 249.1 (M+H)+. Intermediate F (4-methoxypyridin-3-yl)((S)-piperidin-2-yl)methanol hydrochloride- 73 -CTQ-01425Step 1: tert-butyl (2S)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidine-1-carboxylate

[0189] To the solution of 3-bromo-4-methoxy-pyridine (1.32 g, 7.03 mmol, 1.5 eq)in THF (20 mL) was added n-BuLi (2.5 M in hexane, 2.81 mL, 1.5 eq) at -78 °C, the mixture was stirred at -78 °C for 20 mins, then tert-butyl (2S)-2-formylpiperidine-1-carboxylate (1.0 g, 4.69 mmol, 1 eq) in THF (2 mL) was added into the reaction solution at -78 °C. The mixture was stirred at -78 °C for 1 h. LCMS (5-95AB_1.5min): RT = 1.571 min & 1.698 min, [M+1]+= 323.3 showed 43% &41% of desired product. The residue was quenched with saturated NH4Cl (20 mL) and extracted with dichloromethane (30 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 25% ethyl acetate in petroleum ether) to afford the title compound (800 mg, 53%) as yellow solid. LCMS (ESI): m / z 323.3 (M+H)+.Step 2: (4-methoxypyridin-3-yl)((S)-piperidin-2-yl)methanol hydrochloride

[0190] To a solution of tert-butyl (2S)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidine-1-carboxylate (800 mg, 2.48 mmol, 1 eq) in dioxane (5 mL) was added HCl / dioxane (4 M / L, 5 mL). The mixture was stirred at 25 °C for 1 h. TLC (petroleum ether : ethyl acetate =1:1, Rf = 0.51) showed the starting material consumed and a new spot appeared. The reaction mixture was concentrated to afford the title compound (642 mg, crude) as a yellow solid. Intermediate G tert-butyl (S)-2-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate- 74 -CTQ-01425

[0191] To a solution of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (9.6g, 41.87 mmol, 1 eq) and N,O-dimethylhydroxylamine hydrochloride (10.21 g, 104.68 mmol, 2.5 eq) in DCM (150 mL) was added DIEA (27.06 g, 209.36 mmol, 5 eq) and HATU (39.80 g, 104.68 mmol, 2.5 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h. TLC (Petroleum ether: Ethyl acetate =3:1, Rf=0.52) showed the starting material consumed and a new spot appeared. The residue was diluted with water (40 mL) and extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 20% ethyl acetate in petroleum ether) to afford the title compound (10.57 g, 93%) as a white oil.1H NMR (400 MHz, CDCl3): δ 5.11 - 4.89 (m, 1H), 4.00 - 3.82 (m, 1H), 3.76 (s, 3H), 3.46 - 3.32 (m, 1H), 3.17 (s, 3H), 1.99 - 1.96 (m, 1H), 1.85 - 1.51 (m, 4H), 1.44 (s, 9H), 1.42 - 1.32 (m, 1H). Intermediate H (4-methoxypyridin-3-yl)((S)-piperidin-2-yl)methanol hydrochlorideStep 1: tert-butyl (S)-2-(4-methoxynicotinoyl)piperidine-1-carboxylate

[0192] To a solution of 3-bromo-4-methoxypyridine (8.28 g, 44.06 mmol, 2 eq) inTHF (60 mL) was added n-BuLi (2.5 M in hexane, 17.63 mL, 2 eq) at -78 °C for 20 min, then tert-butyl (S)-2-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (6.0 g, 22.03 mmol, 1 eq) in THF (5 mL) was added into the mixture at -78 °C. The mixture was stirred at -78 °C for 1 h. LCMS (5-95AB_1.5min): RT = 0.669 min, [M+1]+= 321.1 showed 50% of desired product. The residue was diluted with saturated NH4Cl (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3), filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 20% ethyl acetate in petroleum ether) to afford the title compound (1.9 g, 27%) as a light yellow solid. LCMS (ESI): m / z 321.2 (M+H)+. - 75 -CTQ-01425 Step 2: tert-butyl (2S)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidine-1- carboxylate

[0193] To a solution of tert-butyl (S)-2-(4-methoxynicotinoyl)piperidine-1-carboxylate (1.90 g, 5.93 mmol, 1 eq) in MeOH (5 mL) and THF (15 mL) was added NaBH4 (0.5 g, 13.22 mmol, 2.23 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS(5- 95AB_1.5min): RT = 0.624 min, [M+1]+= 323.1 showed 92% of desired product. The residue was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (20 mL × 3), filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 50% ethyl acetate in petroleum ether) to provide the title compound (1.9 g, crude) as a white oil. LCMS (ESI): m / z 323.1 (M+H)+. Step 4: (4-methoxypyridin-3-yl)((S)-piperidin-2-yl)methanol hydrochloride

[0194] To a solution of tert-butyl (2S)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidine-1-carboxylate (1.90 g, 5.89 mmol, 1 eq) in dioxane (5 mL) was added HCl / dioxane (4 M / L, 1.47 mL). The mixture was stirred at 25 °C for 1 hour. TLC (Petroleum ether: EE (Ethyl acetate / EtOH = 3: 1) = 1 : 1, Rf = 0.14 ) showed the starting material consumed and a new spot appeared. The reaction mixture was concentrated to afford the title compound (1.52 g, crude) as a white solid. Intermediate I (R)-4-methoxy-3-(piperidin-2-ylmethyl)pyridineStep 1: (8aR)-1-(4-methoxypyridin-3-yl)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one - 76 -CTQ-01425

[0195] To a solution of tert-butyl (2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidine-1-carboxylate (400 mg, 1.24 mmol, 1 eq) in propan-2-ol (10 mL) was added t-BuOK (1 M in THF, 124.07 μL, 0.1 eq) at 25 °C. The mixture was stirred at 90 °C for 3 hour. LCMS (5_95AB _1.5min): RT = 0.412 min, [M+1]+= 249.1 showed 60% of desired product. The reaction mixture was concentrated. The residue was purified by flash chromatography on silica gel (0 - 50% (Ethyl acetate / EtOH = 3: 1) in petroleum ether) to afford the title compound (240 mg, 78%) as a white solid.1H NMR (400 MHz, CDCl3): δ 8.60 - 8.50 (m, 2H), 6.85 - 6.76 (m, 1H), 5.79 - 5.77, 5.29 - 5.28 (m, 1H total), 4.01 - 3.89 (m, 4H), 3.48 - 3.43 (m, 1H), 2.98 - 2.80 (m, 1H), 2.05 - 1.78 (m, 2H), 1.72 - 1.59 (m, 1H), 1.55 - 1.21 (m, 3H); LCMS (ESI): m / z 249.1 (M+H)+. Step 2: (R)-4-methoxy-3-(piperidin-2-ylmethyl)pyridine

[0196] To a solution of (8aR)-1-(4-methoxypyridin-3-yl)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (240 mg, 966.66 μmol, 1 eq) in MeOH (10 mL) was added 10% Pd / C (240 mg). The mixture was stirred at 50 °C for 16 hour under H2 (45 psi). LCMS (0-60CD_4min): RT = 2.389 min, [M+1]+= 207.2 showed 61% of desired product, RT = 2.174 min, [M+1]+= 249.1 showed 20% of the starting material. The reaction mixture was filtered and concentrated to afford the title compound (200 mg crude) as a light yellow oil. LCMS (ESI): m / z 207.2 (M+H)+. Intermediate J (2R)-1-(4-methoxypyridin-3-yl)-2-(propylamino)propan-1-ol - 77 -CTQ-01425Step 1: tert-butyl (R)-(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate

[0197] To a mixture of (tert-butoxycarbonyl)-D-alanine (10.0 g, 52.85 mmol, 1 eq),N,O-dimethylhydroxylamine hydrochloride (5.67 g, 58.14 mmol, 1.1 eq) in DMF (100 mL) was added DIEA (15.03 g, 116.27 mmol, 20.25 mL, 2.2 eq) at 0 °C and then HATU (24.11 g, 63.42 mmol, 1.2 eq) was added into it at 0 °C. The reaction was stirred at 0 °C for 1 h. LCMS (5-95AB_1.5min): RT = 0.661 min, [M+H-56]+= 177.1, showed 44% desired product. The reaction solution was diluted into water (500 mL) and then the solution was stirred for 30 min, then filtered to provide the title compound as a white solid, which was further stirred in 0.5M NaOH (150 mL) and then the solution was filtered to afford the title compound (8.9 g, 73%) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 7.03 (br d, J = 7.6 Hz, 1H), 4.42 - 4.35 (m, 1H), 3.72 (s, 3H), 3.10 (s, 3H), 1.36 (s, 9H), 1.14 (d, J = 7.2 Hz, 3H); LCMS (ESI): m / z 177.1 (M+H-56)+.Step 2: tert-butyl (R)-(1-(4-methoxypyridin-3-yl)-1-oxopropan-2-yl)carbamate

[0198] To a mixture of 3-bromo-4-methoxypyridine (5.18 g, 27.55 mmol, 4 eq) inTHF (80 mL) was added n-BuLi (2.5 M / n-hexane, 9.64 mL, 3.5 eq) at -78 °C, and then the solution was stirred at -78 °C for 15 min. A solution of tert-butyl (R)-(1- - 78 -CTQ-01425 (methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (1.6 g, 6.89 mmol, 1 eq) in THF (2 mL) was added into the reaction solution at -78 °C. The mixture was stirred at -78 °C for 0.5 h. LCMS (5-95AB_1.5min): RT = 0.591 min, [M+H]+= 281.2, showed 56% of desired product. The mixture was quenched with saturated NH4Cl (10 mL), extracted with ethyl acetate (100 mL × 2). The organic layers were combined, washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to provide a residue. The residue was purified by flash chromatography on silica gel (0 - 50% (ethyl acetate / EtOH = 3:1) in petroleum ether) to provide the title compound (1.3 g, 66%) as a yellow solid.1H NMR (400 MHz, CDCl3): δ 8.85 (s, 1H), 8.63 (d, J = 5.6 Hz, 1H), 6.96 (d, J = 5.6 Hz, 1H), 5.47 (d, J = 6.4 Hz, 1H), 5.24 - 5.20 (m, 1H), 4.03 (s, 3H), 1.45 (s, 9H), 1.34 (d, J = 7.2 Hz, 3H); LCMS (ESI): m / z 281.1 (M+H)+. Step 3: (R)-2-amino-1-(4-methoxypyridin-3-yl)propan-1-one hydrochloride

[0199] To a mixture of tert-butyl (R)-(1-(4-methoxypyridin-3-yl)-1-oxopropan-2-yl)carbamate (0.5 g, 1.78 mmol, 1 eq) in dioxane (2 mL) was added HCl / dioxane (4 M, 1.34 mL) at 25 °C. The mixture was stirred at 25 °C for 1 h. TLC showed starting material was consumed, and new spots appeared. The mixture was concentrated to provide the title compound (386 mg, crude) as a yellow solid.1H NMR (400 MHz, CD3OD): δ 9.10 (d, J = 1.2 Hz, 1H), 8.91 (dd, J = 7.2, 1.2 Hz, 1H), 7.88 (d, J = 7.2 Hz, 1H), 5.01 (q, J = 7.2 Hz, 1H), 3.66 (s, 3H), 1.55 (d, J = 7.2 Hz, 3H). Step 4: (R)-N-(1-(4-methoxypyridin-3-yl)-1-oxopropan-2-yl)propionamide

[0200] To a mixture of (R)-2-amino-1-(4-methoxypyridin-3-yl)propan-1-onehydrochloride (386 mg, 1.78 mmol, 1 eq) in DCM (13 mL) was added TEA (721.10 mg, 7.13 mmol, 991.88 μL, 4 eq) and propionyl chloride (329.67 mg, 3.56 mmol, 329.67 μL, 2 eq) at 0 °C. The mixture was stirred at 25 °C for 15 h. LCMS (5-95AB_1min): RT = 0.164 min, [M+H]+= 237.1, showed 77% of desired product. The mixture was diluted with methanol (5 mL) and the solution was stirred at 25 °C for 1 h. The mixture was concentrated. The residue - 79 -CTQ-01425 was purified by flash chromatography on silica gel (0 - 50% (ethyl acetate / EtOH = 3:1) in petroleum ether) to provide the title compound (270 mg, 64%) as a yellow oil.1H NMR (400 MHz, CDCl3): δ 8.86 (s, 1H), 8.64 (d, J = 6.0 Hz, 1H), 6.98 (d, J = 6.0 Hz, 1H), 6.53 (d, J = 5.2 Hz, 1H), 5.55 - 5.50 (m, 1H), 4.05 (s, 3H), 2.29 (q, J = 7.6 Hz, 2H), 1.35 (d, J = 7.2 Hz, 3H), 1.18 (t, J = 7.6 Hz, 3H); LCMS (ESI): m / z 237.1 (M+H)+. Step 5: (2R)-1-(4-methoxypyridin-3-yl)-2-(propylamino)propan-1-ol

[0201] To a mixture of (R)-N-(1-(4-methoxypyridin-3-yl)-1-oxopropan-2-yl)propionamide (270 mg, 1.14 mmol, 1 eq) in THF (3 mL) was added BH3.THF (1 M in THF, 11.43 mL, 10 eq) at 0 °C. Then the solution was stirred at 80 °C for 2 h. LCMS(5- 95AB_1min): RT = 0.238 min, [M+H]+= 225.1, showed 99% of desired product. The suspension was cooled to 0 °C. The solution was quenched with methanol (15 mL) and the quenched solution was stirred at 80 °C for 1 h again. The reaction mixture was concentrated to afford the title compound (256 mg, crude) as a yellow oil. LCMS (ESI): m / z 225.1 (M+H)+. Intermediate K (2S)-1-(4-methoxypyridin-3-yl)-2-(propylamino)propan-1-olStep 1: tert-butyl (S)-(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate- 80 -CTQ-01425

[0202] To a mixture of (tert-butoxycarbonyl)-L-alanine (10.0 g, 52.85 mmol, 1 eq),N,O-dimethylhydroxylamine hydrochloride (5.67 g, 58.14 mmol, 1.1 eq) in DMF (100 mL) was added DIEA (15.03 g, 116.27 mmol, 20.25 mL, 2.2 eq) at 0 °C and then HATU (24.11 g, 63.42 mmol, 1.2 eq) was added into it at 0 °C. The reaction was stirred at 0 °C for 1 h. TLC showed starting material was consumed, and a new spot appeared. The reaction solution was diluted with water (500 mL) and then the solution was stirred for 30 min, then filtered to provide the title compound a white solid, which was further stirred in 0.5 M NaOH (150 mL) and then the solution was filtered to provide the title compound (9.5 g, 77%) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 7.02 (d, J = 7.6 Hz, 1H), 4.41 - 4.37 (m, 1H), 3.72 (s, 3H), 3.10 (s, 3H), 1.36 (s, 9H), 1.14 (d, J = 7.2 Hz, 3H). Step 2: tert-butyl (S)-(1-(4-methoxypyridin-3-yl)-1-oxopropan-2-yl)carbamate

[0203] To a mixture of 3-bromo-4-methoxypyridine (5.18 g, 27.55 mmol, 4 eq) inTHF (80 mL) was added n - BuLi (2.5 M in n-hexane, 9.64 mL, 3.5 eq) at -78 °C, and then the solution was stirred for 15 min at -78 °C. tert-butyl (S)-(1-(methoxy(methyl)amino)-1- oxopropan-2-yl)carbamate (1.6 g, 6.89 mmol, 1 eq) in THF (2 mL) was added into the reaction solution at -78 °C. The mixture was stirred at -78 °C for 0.5 h. LCMS (5- 95AB_1.5min): RT = 0.591 min, [M+H]+ = 281.2, showed 56% of desired product. The mixture was quenched with saturated NH4Cl (20 mL), extracted with ethyl acetate (100 mL × 2). The organic layers were combined, washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0 - 50% (Ethyl acetate / EtOH = 3:1) in petroleum ether) to provide the title compound (1.2 g, 60%) as a yellow solid.1H NMR (400MHz, CDCl3): δ 8.85 (s, 1H), 8.62 (d, J = 6.0 Hz, 1H), 6.96 (d, J = 5.6 Hz, 1H), 5.47 (d, J = 6.0 Hz, 1H), 5.24 - 5.20 (m, 1H) , 4.03 (s, 3H), 1.45 (s, 9H), 1.34 (d, J = 7.2 Hz, 3H); LCMS (ESI): m / z 281.1 (M+H)+.Step 3: (S)-2-amino-1-(4-methoxypyridin-3-yl)propan-1-one hydrochloride

[0204] To a mixture of tert-butyl (S)-(1-(4-methoxypyridin-3-yl)-1-oxopropan-2-yl)carbamate (300 mg, 1.07 mmol, 1 eq) in dioxane (1 mL) was added HCl / dioxane (4 M, - 81 -CTQ-01425 1.78 mL) at 25 °C. The mixture was stirred at 25 °C for 1 h. TLC showed starting material was consumed, and new spots appeared. The mixture was concentrated to afford the title compound (231 mg, crude) as a yellow solid.1H NMR (400 MHz, CD3OD): δ 9.11 (d, J = 1.2 Hz, 1H), 8.91 (dd, J = 7.2, 1.2 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 5.03 - 4.98 (m, 1H), 3.66 (s, 3H), 1.55 (d, J = 7.2 Hz, 3H). Step 4: (S)-N-(1-(4-methoxypyridin-3-yl)-1-oxopropan-2-yl)propionamide

[0205] To a mixture of (S)-2-amino-1-(4-methoxypyridin-3-yl)propan-1-onehydrochloride (231 mg, 1.07 mmol, 1 eq) in DCM (9 mL) was added TEA (431.54 mg, 4.26 mmol, 4 eq) and propionyl chloride (197.29 mg, 2.13 mmol, 2 eq) at 0 °C. The mixture was stirred at 20 °C for 1 h. LCMS (5-95AB_1min): RT = 0.158 min & 0.166 min, [M+H]+= 237.1, showed about 16% & 18% of desired product. The mixture was diluted with saturated NaHCO3(10 mL), extracted with ethyl acetate (50 mL × 3). The organic layers were combined, washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to giver a residue. The residue was purified by flash chromatography on silica gel (0 - 50% (ethyl acetate / EtOH=3:1) in petroleum ether) to provide the title compound (44 mg, 17%) as a yellow oil.1H NMR (400 MHz, CDCl3): δ 8.87 (s, 1H), 8.65 (d, J = 6.0 Hz, 1H), 7.00 (d, J = 6.0 Hz, 1H), 6.55 (d, J = 6.4 Hz, 1H), 5.54 - 5.47 (m, 1H), 4.05 (s, 3H), 2.28 (q, J = 7.6 Hz, 2H), 1.36 (d, J = 6.8 Hz, 3H), 1.17 (t, J = 7.6 Hz, 3H); LCMS (ESI): m / z 237.1 (M+H)+. Step 5: (2S)-1-(4-methoxypyridin-3-yl)-2-(propylamino)propan-1-ol

[0206] To a mixture of (S)-N-(1-(4-methoxypyridin-3-yl)-1-oxopropan-2-yl)propionamide (180 mg, 761.85 μmol, 1 eq) in THF (2 mL) was added BH3.THF (1 M in THF, 7.62 mL, 10 eq) at 0 °C. Then the reaction solution was stirred at 80 °C for 2 h. LCMS (5-95AB_1min): RT = 0.235 min, [M+H]+= 225.1, showed 95% of desired product. The suspension was quenched with methanol (15 mL) at 0 °C and the solution was stirred at - 82 -CTQ-01425 80 °C for 1 h. The reaction mixture was concentrated to afford the title compound (170 mg, crude) as a yellow oil. LCMS (ESI): m / z 225.1 (M+H)+. Intermediate L tert-butyl (S)-2-(4-chloronicotinoyl)piperidine-1-carboxylate

[0207] To a solution of 4-chloro-3-iodopyridine (2.64 g, 11.02 mmol, 3 eq) in THF(10 mL) was added isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 8.47 mL, 3 eq) at 0 °C in dropwise for 15 min under N2. The resulting mixture was stirred at 0 °C for 30 mins and then the solution was stirred at 50 °C for 1 h. Then the mixture was cooled to 0 °C. The solution of tert-butyl (S)-2-(methoxy(methyl)carbamoyl)piperidine-1- carboxylate (1.0 g, 3.67 mmol, 1 eq) in THF (3mL) was added into it dropwise. The mixture was stirred at 0 °C for 30 mins and then the reaction was stirred at 20 °C for 16 h. LCMS (5- 95AB_1.5min, 254nm): RT = 0.845 min, [M+H]+= 325.2, showed 12% of desired product. The mixture was quenched with saturated NH4Cl (10 mL), extracted with ethyl acetate (100 mL × 2). The organic layers were combined, washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0 - 20% ethyl acetate in petroleum ether gradient ) to afford the title (0.4 g, 75% purity) as a yellow oil and (1.2 g, 36% purity) as a pray oil. LCMS (ESI): m / z 325.2 (M+H)+. Intermediate M (R)-(4-cyclopropoxypyridin-3-yl)(piperidin-2-yl)methanoneStep 1: tert-butyl (R)-2-(4-cyclopropoxynicotinoyl)piperidine-1-carboxylate - 83 -CTQ-01425

[0208] To solution of 3-bromo-4-cyclopropoxypyridine (1.10 g, 5.14 mmol, 2 eq) inTHF (12 mL) was added n-BuLi (2.5 M in Hexane, 2.06 mL, 2 eq) at -75 °C under N2atmosphere for 10 min. A solution of tert-butyl (R)-2-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (700 mg, 2.57 mmol, 1 eq) in THF (5mL) was added into the solution at -75 °C. The solution was stirred at -75 °C for 40 min. LCMS (5-95AB_220&254_Agilent): RT = 0.728 min, [M+H]+= 347.2, showed 47% of the desired product. The reaction mixture was quenched with saturated NH4Cl (50 mL). The resulting mixture was extracted with ethyl acetate (200 mL × 3) and the combined organic layer was washed with brine (150 mL × 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 40% ethyl acetate in petroleum ether) to afford the title compound (243 mg, 27%) as a yellow oil. LCMS (ESI): m / z 347.2 (M+H)+.Step 2: (R)-(4-cyclopropoxypyridin-3-yl)(piperidin-2-yl)methanone 2,2,2-trifluoroacetate

[0209] A solution of tert-butyl (R)-2-(4-cyclopropoxynicotinoyl)piperidine-1-carboxylate (243 mg, 701.46 μmol, 1 eq) in 5%TFA / HFIP (5 mL) was stirred at 25 °C for 1 hr. TLC (Ethyl acetate / Petroleum ether=1:1) showed a new spot. The reaction was filtered and concentrated under reduced pressure to afford the title compound (173 mg, crude) as a white solid. Intermediate N (4-cyclopropoxypyridin-3-yl)((R)-piperidin-2-yl)methanol- 84 -CTQ-01425 Step 1: tert-butyl (2R)-2-((4-cyclopropoxypyridin-3-yl)(hydroxy)methyl)piperidine-1- carboxylate

[0210] To a solution of tert-butyl (R)-2-(4-cyclopropoxynicotinoyl)piperidine-1-carboxylate (205 mg, 447.43 μmol, 3.10 eq) in THF (4.5 mL) and MeOH (1.5 mL) was added NaBH4 (12.19 mg, 322.35 μmol, 2.23 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hr. LCMS (5-95AB_1.5min_220&254_Shimadzu.lcm), RT = 0.689 min, [M+1]+= 349.3 showed 74% of desired product. The reaction mixture was quenched with NH4Cl (30 mL) and extracted with (100 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (201 mg, crude) as a yellow oil. LCMS (ESI): m / z 349.3 (M+H)+. Step 2: (4-cyclopropoxypyridin-3-yl)((R)-piperidin-2-yl)methanol 2,2,2-trifluoroacetate

[0211] A solution of tert-butyl (2R)-2-((4-cyclopropoxypyridin-3-yl)(hydroxy)methyl)piperidine-1-carboxylate (201 mg, 576.86 μmol, 1 eq) in HFIP (3.8 mL) and TFA (0.2 mL) was stirred at 25 °C for 1 hr. TLC (Petroleum ether : Ethyl acetate=1:1, Rf=0.01) showed a new spot. The reaction mixture was concentrated under reduced pressure to afford the title compound (209 mg, crude) as a yellow oil. Intermediate O (S)-(4-cyclopropoxypyridin-3-yl)(piperidin-2-yl)methanone - 85 -CTQ-01425

[0212] To a solution of 4-chloro-3-nitropyridine (14.5 g, 91.46 mmol, 1 eq) andcyclopropanol (7.97 g, 137.19 mmol, 1.5 eq) in DMF (130 mL) was added Cs2CO3 (44.70 g, 137.19 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 16 hr. LCMS (5- 95AB_1.5min_220&254_Shimadzu.lcm) RT = 0.592 min, [M+1]+= 181.1 showed 93% desired product. The reaction mixture was quenched with saturated H2O (50 mL) and the solution was stirred for 30 mins. The resulting mixture was extracted with ethyl acetate (200 mL × 3) and the combined organic layer was washed with brine (150 mL × 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 20% ethyl acetate in petroleum ether) to afford the title compound (13.0 g, 79%) as a yellow oil.1H NMR (400 MHz, CDCl3): δ 8.99 (s, 1H), 8.64 (d, J = 5.6 Hz, 1H), 7.41 (d, J = 5.6 Hz, 1H), 4.00 - 3.93 (m, 1H), 0.96 - 0.94 (m, 4H); LCMS (ESI): m / z 181.1 (M+H)+.Step 2: 4-cyclopropoxypyridin-3-amine- 86 -CTQ-01425

[0213] To a solution of 4-cyclopropoxy-3-nitropyridine (13.0 g, 72.16 mmol, 1 eq) inEtOH (150 mL) was added 10% Pd / C (1.0 g) at 25 °C. The mixture was stirred at 25 °C for 15 hr under H2 atmosphere. TLC (Ethyl acetate : Petroleum ether=1:1, Rf=0.28) showed a new spot. The reaction was filtered and concentrated under reduced pressure to afford the title compound (10.2 g, crude) as a yellow oil. Step 3: 3-bromo-4-cyclopropoxypyridine

[0214] To a solution of 4-cyclopropoxypyridin-3-amine (6.87 g, 45.75 mmol, 1 eq) inCH3CN (200 mL) was added CuBr2 (12.26 g, 54.90 mmol, 1.2 eq), LiBr (11.92 g, 137.24 mmol, 3 eq) and t-BuONO (9.43 g, 91.49 mmol, 10.88 mL, 2 eq) at 25 °C. The mixture was stirred at 65 °C for 4 hr under N2atmosphere. LCMS (5- 95AB_1.5min_220&254_Shimadzu.lcm), RT = 0.562 min, [M+1]+= 214.0 showed 72% desired product. The reaction mixture was adjusted with saturated NH3.H2O (20 mL) and the solution was stirred for 30 mins. The resulting mixture was extracted with ethyl acetate (200 mL × 3) and the combined organic layer was washed with brine (150 mL × 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (0 - 15% ethyl acetate of petroleum ether ) to afford the title compound (6.9g,70%) as a yellow oil.1H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 8.33 (d, J = 5.6 Hz, 1H), 7.11 (d, J = 5.6 Hz, 1H), 3.81 - 3.79 (m, 1H), 0.83 - 0.81 (m, 4H); LCMS (ESI): m / z 214.0 (M+H)+. Step 4: tert-butyl (S)-2-(4-cyclopropoxynicotinoyl)piperidine-1-carboxylate

[0215] To a mixture of a solution of 3-bromo-4-cyclopropoxypyridine (786.00 mg,3.67 mmol, 2 eq) in THF (7 mL) was added n-BuLi (2.5 M in Hexane, 1.19 mL, 2 eq) at -75 °C under N2 ballooon, and then the mixture was stirred at -75 °C for 10 min under N2 atmosphere. A solution of tert-butyl (S)-2-(methoxy(methyl)carbamoyl)piperidine-1- carboxylate (500 mg, 1.84 mmol, 1 eq) in THF (5 mL) was added into the solution at -75 °C. The solution was stirred at -75 °C for 40 min. LCMS (5-95AB_220&254_Agilent): RT = - 87 -CTQ-01425 0.724 min, [M+H]+= 347.2, showed 58% of the desired product. The reaction mixture was quenched with saturated NH4Cl (50 mL). The resulting mixture was extracted with ethyl acetate (200 mL × 3) and the combined organic layer was washed with brine (150 mL × 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 40% ethyl acetate in petroleum ether) to afford the title compound (301 mg, 47%) as a yellow solid.1H NMR (400 MHz, CDCl3): δ 8.71 - 8.65 (m, 1H), 8.61 - 8.56 (m, 1H), 7.26 - 7.23 (m, 1H), 5.53 - 5.42 (m, 1H), 4.05 - 3.84 (m, 2H), 3.08 - 2.95 (m, 1H), 2.05 - 1.64 (m, 2H), 1.47 - 1.40 (m, 9H), 1.20 - 0.87 (m, 4H), 0.99 - 0.79 (m, 4H); LCMS (ESI): m / z 347.2 (M+H)+. Step 5: (S)-(4-cyclopropoxypyridin-3-yl)(piperidin-2-yl)methanone 2,2,2- trifluoroacetate

[0216] A solution of tert-butyl (S)-2-(4-cyclopropoxynicotinoyl)piperidine-1-carboxylate (300 mg, 866.00 μmol, 1 eq) in 5%TFA in HFIP (5 mL) was stirred at 25 °C 1 hr. TLC(Ethyl acetate / Petroleum ether=1:1) showed a new spot. The reaction was concentrated under reduced pressure to afford the title compound (213 mg,crude) as a white solid. Intermediate P (4-cyclopropoxypyridin-3-yl)((S)-piperidin-2-yl)methanolStep 1: tert-butyl (S)-2-(4-cyclopropoxynicotinoyl)piperidine-1-carboxylate- 88 -CTQ-01425

[0217] To a solution of 3-bromo-4-(cyclopropoxy)pyridine (943.20 mg, 4.41 mmol, 2eq) in THF (20 mL) was added n-BuLi (2.5 M in n-hexane, 1.76 mL, 2 eq) dropwise at - 75 °C for 5 min under N2. The resulting mixture was stirred at -75 °C for 30 mins, then a solution of tert-butyl (S)-2-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (0.6 g, 2.20 mmol, 1 eq) in THF (4 mL) was added into it dropwise at -75 °C. Then the mixture was stirred at -75 °C for 1 h. LCMS (5-95AB_1.5min_220&254_Agilent ): RT = 0.795 min, [M+H]+= 347.2, showed 67% of the desired product . The mixtrue was quenched by saturated NH4Cl (20 mL), extracted with ethyl acetate (50 mL × 2). The organic layers were combined, washed with brine (20 mL × 3), dried over sodium sulfate, filtered and concentrated to provide a residue. The residue was purified by flash chromatography on silica gel (0 - 40% EE (ethyl acetate / EtOH=3:1) in petroleum ether gradient) to afford the title compound (0.2 g, 20%) as a yellow oil. LCMS (ESI): m / z 347.2 (M+H)+. Step 2: tert-butyl (2S)-2-((4-cyclopropoxypyridin-3-yl)(hydroxy)methyl)piperidine-1- carboxylate

[0218] To a mixture of tert-butyl (S)-2-(4-cyclopropoxynicotinoyl)piperidine-1-carboxylate (280 mg, 808.27 μmol, 1 eq) in MeOH (1 mL) and THF (3 mL) was added NaBH4(61.16 mg, 1.62 mmol, 2 eq) in one portion at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (5-95AB_220&254_Agilent.M): RT = 0.691 min, [M+H]+= 349.3, showed 65% of desired product. The reaction was quenched with saturated NH4Cl (2 mL), the mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (50 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to afford the title compound (269 mg, crude) as a yellow solid. LCMS (ESI): m / z 349.3 (M+H)+.Step 3: (4-cyclopropoxypyridin-3-yl)((S)-piperidin-2-yl)methanol 2,2,2-trifluoroacetate

[0219] A mixture of tert-butyl (2S)-2-((4-cyclopropoxypyridin-3-yl)(hydroxy)methyl)piperidine-1-carboxylate (269 mg, 771.74 μmol, 1 eq) in 5% TFA / HFIP - 89 -CTQ-01425 (4.5 mL) was stirred at 25 °C for 1 hour. LCMS (0-60AB_4min_220&254_Shimadzu.lcm): RT = 1.552 min, [M+H]+= 248.7 showed 67% of desired product. The mixture was concentrated to afford the title compound (400 mg, crude) as a yellow oil. Intermediate Q tert-butyl (R)-2-formylpiperidine-1-carboxylate

[0220] To a mixture of tert-butyl (R)-2-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (1.0 g, 3.67 mmol,1 eq) in THF (10 mL) was added LAH (2.5 M in THF, 2.20 mL, 1.5 eq) at 0 °C, the mixture was stirred at 0 °C for 1 hr under N2 atmosphere. TLC (Petroleum ether : Ethyl acetate = 3:1, Rf= 0.43) showed new spots. The reaction mixture was quenched with H2O (0.2 mL), 15% NaOH (0.2 mL) and H2O (0.6 mL). The solution was dried over Na2SO4, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (0 - 5% ethyl acetate in petroleum ether) to afford the title compound (685 mg, 87%) as a yellow oil. LCMS (ESI): m / z 157.9 (M+H-56)+. Intermediate R 3-iodo-4-isopropoxypyridineStep 1: 4-isopropoxy-3-nitropyridine

[0221] To a solution of propan-2-ol (4.55 g, 75.69 mmol, 5.79 mL, 1.2 eq) in DMF(150 mL) was added NaH (3.28 g, 82.00 mmol, 60% in mineral oil, 1.3 eq) at 0° under N2atmosphere for 10 min. A solution of 4-chloro-3-nitropyridine (10.0 g, 63.07 mmol, 1 eq) in DMF (20 mL) was added into the solution at 0 °C. The solution was stirred at 0 °C for 1 hr. TLC (Ethyl acetate : Petroleum ether = 1:1, Rf= 0.39) showed new spots. The reaction - 90 -CTQ-01425 mixture was quenched with H2O (50 mL). The resulting mixture was extracted with ethyl acetate (200 mL × 3) and the combined organic layer was washed with brine (150 mL × 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (0 -40% ethyl acetate in petroleum ether) to afford the title compound (7.8 g, 43%) as a yellow oil.1H NMR (400 MHz, CDCl3): δ 8.96 (s, 1H), 8.58 (d, J = 6.0 Hz, 1H), 6.99 (d, J = 6.0 Hz, 1H), 4.84 - 4.76 (m, 1H), 1.47 (d, J = 6.0 Hz, 6H).Step 2: 4-isopropoxypyridin-3-amine

[0222] To a mixture of 4-isopropoxy-3-nitropyridine (7.8 g, 42.82 mmol, 1 eq) inEtOH (70 mL) was added 10% Pd / C (2.0 g, 1.88 mmol). The mixture was stirred at 25 °C for 16 hr under H2 atmosphere. TLC (Ethyl acetate : Petroleum ether = 1:1, Rf = 0.17) showed new spots. The reaction was filtered and concentrated under reduced pressure to give a residue to provide the title compound (6.5 g,crude) as a yellow oil.1H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.93 (d, J = 5.6 Hz, 1H), 6.67 (d, J = 5.6 Hz, 1H), 4.66 - 4.60 (m, 1H), 3.73 - 3.70 (m, 2H), 1.39 (d, J = 6.0 Hz, 6H).Step 4: 3-iodo-4-isopropoxypyridine

[0223] A mixture of 4-isopropoxypyridin-3-amine (7.23 g, 47.51 mmol, 1 eq) anddiiodomethane (12.72 g, 47.51 mmol, 3.83 mL, 1 eq) in CH3CN (160 mL) was added t- BuONO (22.04 g, 213.77 mmol, 25.43 mL, 4.5 eq). The mixture was stirred at 80 °C for 3hr. LCMS (0-60CD_4min_220&254_Agilent): RT = 0.506 min, [M+H]+= 264.0 showed 80 % of the desired product. The reaction was concentrated under reduced pressure to give a residue. The residue was diluted with H2O (100 mL). The resulting mixture was extracted with ethyl acetate (200 mL × 3) and the combined organic layer was washed with brine (150 mL × 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel - 91 -CTQ-01425 (0 - 10% ethyl acetate in petroleum ether) to afford the title compound (5.5 g, 44%) as a yellow oil.1H NMR (400 MHz, CDCl3): δ 8.76 (s, 1H), 8.35 (d, J = 6.0 Hz, 1H), 6.73 (d, J = 6.0 Hz, 1H), 4.72 - 4.69 (m, 1H), 1.44 (d, J = 6.4 Hz, 6H); LCMS (ESI): m / z 264.0 (M+H)+. Intermediate S 2-(4-(trifluoromethyl)phenoxy)acetic acidStep 1: tert-butyl 2-(4-(trifluoromethyl)phenoxy)acetate

[0224] To a solution of 4-(trifluoromethyl)phenol (3.0 g, 18.51 mmol, 1 eq), tert-butyl 2-bromoacetate (4.33 g, 22.21 mmol, 3.28 mL, 1.2 eq) in acetonitrile (30 mL) was added K2CO3(7.67 g, 55.52 mmol, 3 eq). The mixture was stirred at 25 °C for 12 h under N2atmosphere. The residue was diluted with water (300 mL), extracted with ethyl acetate (500 mL × 3). The organic layers were combined, washed with brine (50 mL × 5), dried over sodium sulfate, filtered and concentrated to giver a residue. The residue was purified by flash silica gel chromatography (0 - 10% ethyl acetate in petroleum ether) to afford the title compound (4.5 g, 88%) as a yellow oil.1H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 4.60 (s, 2H), 1.49 (s, 9H). Step 2: 2-(4-(trifluoromethyl)phenoxy)acetic acid

[0225] To a solution of tert-butyl 2-(4-(trifluoromethyl)phenoxy)acetate (4.5 g, 16.29mmol, 1 eq) in dioxane (5 mL) was added HCl / dioxane (2 M / L, 8.14 mL, 1 eq). The mixture was stirred at 25 °C for 96 h. The residue was concentrated to afford the title compound (3.5 g, 98%) as a white solid. - 92 -CTQ-01425 Intermediate T 2-((5-(trifluoromethyl)pyridin-2-yl)oxy)acetic acidStep 1: tert-butyl 2-((5-(trifluoromethyl)pyridin-2-yl)oxy)acetate

[0226] To a mixture of tert-butyl 2-hydroxyacetate (4.37 g, 33.05 mmol, 1.2 eq) inDMF (100 mL) was added NaH (1.32 g, 33.05 mmol, 60% purity, 1.2 eq) in one portion at 0 °C and the solution was stirred for 30 mins at 0 °C, then 2-chloro-5- (trifluoromethyl)pyridine (5.0 g, 27.54 mmol, 3.53 mL, 1 eq) was added into it at 0 °C, the mixture was stirred at 25 °C for 16 hours. LCMS (5-95AB / 1.5 min): RT = 0.858 min, [M- 56+H]+= 222.0 showed 69% of desired product. The reaction was quenched with H2O (20 mL), then the mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine (50 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (100% petroleum ether) to afford the title compound (3.95 g, 52%) as a yellow liquid. Step 2: 2-((5-(trifluoromethyl)pyridin-2-yl)oxy)acetic acid 2,2,2-trifluoroacetic acid

[0227] To a mixture of tert-butyl 2-((5-(trifluoromethyl)pyridin-2-yl)oxy)acetate(3.95 g, 14.25 mmol, 1 eq) in DCM (30 mL) was added TFA (30 mL) in one portion at 25 °C. The mixture was stirred at 25 °C for 16 hours. LCMS (5-95AB / 1.5 min): RT = 0.647 min, [M+H]+= 222.1 showed 98% of desired product. The solution was concentrated in vacuum to afford the title compound (4.7 g, crude) as a yellow solid. - 93 -CTQ-01425 Intermediate U 1-(tert-butyl) 2-methyl (R)-piperazine-1,2-dicarboxylate

[0228] To a mixture of (R)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (2.5g, 10.86 mmol, 1 eq) in methanol (50 mL) and DCM (57.5 mL) was added TMSCHN2 (2 M in hexane, 14.00 mL, 2.58 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 16 hours. The solution was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (0 - 50% (ethyl acetate: ethanol=3:1) in petroleum ether) to afford the title compound (2.5 g, 94%) as a white oil.1H NMR (400 MHz, CDCl3): δ 4.78 - 4.46 (m, 1H), 3.91 - 3.81 (m, 1H), 3.80 - 3.73 (m, 3H), 3.52 - 3.45 (m, 1H), 3.34 - 2.94 (m, 2H), 2.92 - 2.87 (m, 1H), 2.78 - 2.63 (m, 1H), 1.52 - 1.40 (m, 9H). Intermediate V 2-((6-(trifluoromethyl)pyridin-3-yl)oxy)acetic acidStep 1: tert-butyl 2-((6-(trifluoromethyl)pyridin-3-yl)oxy)acetate

[0229] To a solution of 6-(trifluoromethyl)pyridin-3-ol (2.0 g, 12.26 mmol, 1 eq) inDMF (50 mL) was added tert-butyl 2-bromoacetate (2.63 g, 13.49 mmol, 1.99 mL, 1.1 eq) and K2CO3(3.39 g, 24.53 mmol, 2 eq) and the solution was stirred at 65 °C for 8 hr. LCMS (5-95AB / 1.5min): RT = 0.837 min, [M+H ]+= 277.9 showed 54% of desired product. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (100 mL). The organic fraction was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0 - 15% ethyl acetate in petroleum ether) to afford the title compound (3.2 g, 94%) as a white solid.1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 4.63 (s, 2H), 1.51 (s, 9H). Step 2: 2-((6-(trifluoromethyl)pyridin-3-yl)oxy)acetic acid - 94 -CTQ-01425

[0230] To a solution of tert-butyl 2-((6-(trifluoromethyl)pyridin-3-yl)oxy)acetate (3.2g, 11.54 mmol, 1 eq) in DCM (30 mL) was added TFA (4.61 g, 40.39 mmol, 3.00 mL, 3.50 eq). The reaction was stirred at 40 °C for 10 hr. LCMS (5-95AB / 1.5min): RT = 0.561 min, [M+H]+= 222.1 showed 92% of desired product. The mixture was concentrated under reduced pressure to afford the title compound (3.2 g, 83%) as a pink solid. Intermediate W tert-butyl ((2R)-1-hydroxy-1-(4-isopropoxypyridin-3-yl)propan-2-yl)carbamateStep 1: tert-butyl (R)-(1-oxopropan-2-yl)carbamate

[0231] To a mixture of methyl (tert-butoxycarbonyl)-D-alaninate (10.0 g, 49.20mmol, 1 eq) in DCM (100 mL) was added DIBAL-H (1 M in toluene, 98.41 mL, 2 eq) in one portion at -78 °C under N2 atmosphere. The mixture was stirred at -78 °C for 1 hour. The reaction was quenched with H2O (4 ml), 15% NaOH (4 mL) and H2O (9.8 mL) at 0 °C, then the mixture was stirred at 25 °C for 15 mins, MgSO4was added into it and the mixture was stirred for 15 mins. Then the mixture was filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (0 - 10% ethyl acetate in petroleum ether) to afford the title compound (1.45 g, 17%) as a yellow oil.1H NMR (400 MHz, CDCl3): δ 9.57 (s, 1H), 5.11 (s, 1H), 4.26 - 4.16 (m, 1H), 1.46 (s, 9H), 1.34 (d, J = 7.2 Hz, 3H). Step 2: tert-butyl ((2R)-1-hydroxy-1-(4-isopropoxypyridin-3-yl)propan-2-yl)carbamate- 95 -CTQ-01425

[0232] To a mixture of tert-butyl (R)-(1-oxopropan-2-yl)carbamate (1.45 g, 8.37mmol, 1 eq) and 3-iodo-4-isopropoxypyridine (2.64 g, 10.05 mmol, 1.2 eq) in THF (50 mL) was added i-PrMgCl·LiCl (1.3 M in THF, 12.88 mL, 2 eq) in one portion at 0 °C under N2 atmosphere. The mixture was stirred at 25 °C for 16 hours. LCMS (5-95AB / 1.5 min): RT = 0.636 min, [M+H]+= 311.2, showed 48% of desired product. The reaction was quenched with NH4Cl (10 mL). The mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (20 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (0 - 80% ethyl acetate in petroleum ether) to afford the title compound (324 mg, 12%) as a yellow oil. Intermediate X (R)-N-(1-(4-methoxypyridin-3-yl)propan-2-yl)propan-1-amineStep 1: tert-butyl ((2R)-1-hydroxy-1-(4-methoxypyridin-3-yl)propan-2-yl)carbamate

[0233] To a mixture of 3-iodo-4-methoxypyridine (2.99 g, 12.70 mmol, 2 eq) in THF(20 mL) was added i-PrMgCl·LiCl (1.3 M in THF, 9.77 mL, 2 eq) in one portion at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 30 mins, then the solution was stirred at 25 °C for 2 hours. Then tert-butyl (R)-(1-oxopropan-2-yl)carbamate (1.1 g, 6.35 mmol, 1 eq) was added into it at 0 °C and the mixture was stirred at 25 °C for 16 hours. LCMS (5-95AB / 1.5 min): RT = 0.559 min, [M+H]+= 283.2, showed 50% of desired product. The reaction was quenched with NH4Cl (20 mL). The mixture was diluted with H2O (30 mL) - 96 -CTQ-01425 and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (20 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (0 - 80% ethyl acetate in petroleum ether) to afford the title compound (390 mg, 22%) as a yellow oil. SFC showed 58:5: 21:16. Step 2: (4R)-5-(4-methoxypyridin-3-yl)-4-methyloxazolidin-2-one

[0234] To a mixture of tert-butyl ((2R)-1-hydroxy-1-(4-methoxypyridin-3-yl)propan-2-yl)carbamate (390 mg, 1.38 mmol, 1 eq) in i-PrOH (6 mL) was added t-BuOK (1 M in THF, 276.27 μL, 0.2 eq) in one portion at 25 °C under N2atmosphere. The mixture was stirred at 90 °C for 16 hours. Then t-BuOK (1 M / THF, 207.20 μL, 0.15 eq) was added into it and the mixture was stirred 90 °C for 5 hours. LCMS (10-80CD / 4min): RT = 0.834 min, [M+H]+= 209.2, showed 73% of desired product. The reaction solution was concentrated in vacuum. The residue was purified by silica gel chromatography (0 - 2% methanol in dichloromethane) to afford the title compound (230 mg, 80%) as a yellow oil. Step 3: (R)-1-(4-methoxypyridin-3-yl)propan-2-amine

[0235] To a mixture of (4R)-5-(4-methoxypyridin-3-yl)-4-methyloxazolidin-2-one(230 mg, 1.10 mmol, 1 eq) in EtOH (5 mL) was added 10% Pd / C (200 mg) in one portion at 25 °C. The mixture was stirred at 50 °C for 16 hours under H2 (45 Psi). LCMS (10- 80CD / 4min): RT = 1.354 min, [M+H]+= 167.2 showed 63% of desired product. The solution was filtered and concentrated in vacuum to afford the title compound (153 mg, crude) as a yellow oil. Step 4: (R)-N-(1-(4-methoxypyridin-3-yl)propan-2-yl)propan-1-amine

[0236] To a mixture of (R)-1-(4-methoxypyridin-3-yl)propan-2-amine (153 mg,920.47 μmol, 1 eq) and propionaldehyde (48.11 mg, 828.42 μmol, 60.29 μL, 0.9 eq) in DCE - 97 -CTQ-01425 (5 mL) was added HOAc (276.38 mg, 4.60 mmol, 263.47 μL, 5 eq). The mixture was stirred at 25 °C for 1 hour, then NaBH(OAc)3(390.17 mg, 1.84 mmol, 2 eq) was added in one portion at 0 °C. The mixture was stirred at 25 °C for 16 hours. LCMS (10-80CD / 4min): RT = 2.148 min, [M+H]+= 209.2, showed 40% of desired product. The mixture was adjusted pH to 7 with saturated NaHCO3(8 mL), then the mixture was diluted with H2O (20 mL) and extracted with dichloromethane (30 mL × 3), then the aqueous phase was adjusted pH to 8~9 with 1 M NaOH, the mixture was extracted with dichloromethane (30 mL × 3), the organic layer was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to afford the title compound (160 mg, crude) as a yellow oil. Intermediate Y tert-butyl ((2R)-1-hydroxy-1-(4-isopropoxypyridin-3-yl)pentan-2-yl)(methyl)carbamateStep 1: (R)-2-((tert-butoxycarbonyl)amino)pentanoic acid

[0237] To a mixture of (R)-2-((tert-butoxycarbonyl)amino)pentanoic acid (10.0 g,46.03 mmol, 1 eq) in DMF (125 mL) was added NaH (3.87 g, 96.66 mmol, 60% purity, 2.1 eq) at 0 °C. The solution was stirred at 0 °C for 30 mins. The MeI (7.19 g, 50.63 mmol, 3.15 mL, 1.1 eq) was added into it at 0 °C. The mixture was stirred at 0 °C for 2 h under N2 atmosphere. LCMS (5-95AB / 1.5min), RT = 0.766 min, [M+Na]+= 254.2, showed 10% of the desired product. The reaction mixture was quenched with saturated NH4Cl (50 mL) and the solution was stirred for 30 mins. The resulting mixture was extracted with ethyl acetate (200 - 98 -CTQ-01425 mL × 3) and the combined organic layer was washed with brine (150 mL × 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Xtimate C18 150*40mm*10um, water (FA)-CAN,40%-70% B over 2 min) to afford the title compound (0.97 g, 9%) as a yellow oil. Step 2: methyl (R)-2-((tert-butoxycarbonyl)(methyl)amino)pentanoate

[0238] To a solution of (R)-2-((tert-butoxycarbonyl)amino)pentanoic acid (0.97 g,4.19 mmol, 1 eq) in toluene (9 mL) and MeOH (3 mL) was added TMSCHN2 (2 M in hexane, 5.24 mL, 2.5 eq) under N2 atmosphere. The mixture was stirred at 0 °C for 1 hr. LCMS (5-95AB / 1.5min): RT = 0.743 min, [M+Na]+= 268.2, showed 46% of the desired product. The reaction mixture was adjusted with saturated NaHCO3 (50 mL). The resulting mixture was extracted with ethyl acetate (200 mL × 3) and the combined organic layer was washed with brine (150 mL × 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0 - 10% ethyl acetate in petroleum ether) to afford the title compound (1.0 g, 97%) as a white solid. SFC showed 5:95. Step 3: tert-butyl (R)-methyl(1-oxopentan-2-yl)carbamate

[0239] To a mixture of methyl (R)-2-((tert-butoxycarbonyl)(methyl)amino)pentanoate(953 mg, 3.88 mmol, 1 eq) in DCM (10 mL) was added DIBAL-H (1 M in toluene, 5.83 mL, 1.5 eq) at -78 °C under N2 atmosphere, and then the mixture was stirred at -78 °C for 1hr under N2atmosphere. The reaction mixture was adjusted with saturated NaHCO3(50 mL). The resulting mixture was extracted with ethyl acetate (200 mL × 3) and the combined organic layer was washed with brine (150 mL × 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0 - 10% ethyl acetate in petroleum ether) to afford the title compound (690 mg, 83%) as a yellow oil.1H NMR (400 MHz, CDCl3): δ 9.53 - 99 -CTQ-01425 (s, 1H), 4.35 - 4.29, 3.93 - 3.82 (m, 1H total), 2.84 - 2.68 (m, 3H), 1.88 - 1.78 (m, 1H), 1.64 - 1.53 (m, 1H), 1.42 - 1.36 (m, 9H), 1.34 - 1.20 (m, 2H), 0.93 - 0.87 (m, 3H). Step 4: tert-butyl ((2R)-1-hydroxy-1-(4-isopropoxypyridin-3-yl)pentan-2- yl)(methyl)carbamate

[0240] To a mixture of tert-butyl (R)-methyl(1-oxopentan-2-yl)carbamate (0.69 g,3.21 mmol, 1 eq) and 3-iodo-4-isopropoxypyridine (1.01 g, 3.85 mmol, 1.2 eq) in THF (10 mL) was added isopropyl magnesium chloride (2 M in THF, 4.81 mL, 3 eq) at 0 °C under N2atmosphere, and then the mixture was stirred at 25 °C for 15 hr. LCMS (5-95AB / 1.5min): RT = 0.744 min, [M+H]+= 353.3, showed 24% of the desired product. The reaction mixture was quenched with saturated NH4Cl (50 mL). The resulting mixture was extracted with ethyl acetate (200 mL × 3) and the combined organic layer was washed with brine (150 mL × 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 80% ethyl acetate in petroleum ether) to afford the title compound (105 mg, 9%) as a yellow oil. EXEMPLIFICATION Example 1 2-(3,4-dichlorophenyl)-1-(2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1- yl)ethan-1-one - 100 -CTQ-01425Step 1: tert-butyl 2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidine-1-carboxylate

[0241] To a solution of 3-bromo-4-methoxypyridine (1.98 g, 10.55 mmol, 1.5 eq) inTHF (30 mL) was added n-BuLi (2.5 M in hexane, 4.22 mL, 1.5 eq) at -80 °C under N2. The resulting green solution was stirred at -80 °C for 30 min, and then tert-butyl 2- formylpiperidine-1-carboxylate (1.50 g, 7.03 mmol, 1 eq) in THF (2.5 mL) was added into the solution at -80 °C. The mixture was stirred at -78 °C for 1hr under N2atmosphere. LCMS (RT = 0.637 min & 0.659min, [M+H]+= 323.2) showed 38% & 48% of desired product. The solution was quenched with brine (50 mL). The mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 33% (ethanol: ethyl acetate =3:1) in petroleum ether) to afford the title compound (0.6 g, 1.86 mmol, 26%) as a white solid. LCMS (ESI): m / z 323.2 (M+H)+. Step 2: (4-methoxypyridin-3-yl)(piperidin-2-yl)methanol hydrochloride- 101 -CTQ-01425

[0242] To a solution of tert-butyl 2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidine-1-carboxylate (600 mg, 1.86 mmol, 1 eq) was added HCl / dioxane (4 M / L, 10 mL). The mixture was stirred at 25 °C for 1 hr. The solution was filtered and concentrated under reduced pressure to afford the title compound (413 mg, crude) as a white solid. Step 3: 2-(3,4-dichlorophenyl)-1-(2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin- 1-yl)ethan-1-one (2 compounds)

[0243] To a solution of (4-methoxypyridin-3-yl)(piperidin-2-yl)methanolhydrochloride (413 mg, 1.86 mmol, 1 eq) in DCM (8 mL) was added DIEA (720.40 mg, 5.57 mmol, 3 eq) and 2-(3,4-dichlorophenyl)acetic acid (457.15 mg, 2.23 mmol, 1.2 eq) and HATU (1.06 g, 2.79 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 1hr. LCMS (RT = 0.703 min & 0.722 min, [M+H]+= 409.2) showed 26% & 22% of desired product. The solution was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 40 mm X 10 µm; acetonitrile (20-50% gradient over 7 min) / water (FA) and Welch Xtimate C18150 mm X 40 mm X 10 µm; acetonitrile (20-50% gradient over 2 min) / water (FA)) to afford the first compound (the first peak, 171.02 mg, 22%) as a white solid and the second compound (the second peak, 96.36 mg, 13%) as a white solid.

[0244] The first compound: 1H NMR (400 MHz, DMSO-d6): δ 8.62 - 8.26 (m, 1H),7.45 - 7.41 (m, 1H), 7.12 - 6.69 (m, 3H), 5.74 - 4.74 (m, 2H), 4.36 - 4.04 (m, 1H), 3.83, 3.80 (s, 3H total), 3.66 - 3.57, 3.20 - 3.08 (m, 1H total), 3.53 - 3.38 (m, 2H), 2.93 - 2.81 (m, 1H), 2.23 - 2.09 (m, 1H), 1.81 - 1.50 (m, 3H), 1.38 - 1.16 (m, 2H); LCMS (ESI): m / z 409.1 (M+H)+. SFC (Chiralcel OD-3; CO2 / ethanol (0.05% DEA)) showed 50:50.

[0245] The second compound: 1H NMR (400 MHz, DMSO-d6): δ 8.52 - 8.36 (m,2H), 7.57 - 7.53 (m, 1H), 7.47 - 7.42 (m, 1H), 7.27 - 7.11 (m, 1H), 7.09 - 6.95 (m, 1H), 5.63 - 5.14 (m, 2H), 4.76 - 4.72, 4.43 - 4.39 (m, 1H total), 4.18 - 4.14, 3.99 - 3.67 (m, 6H total), 3.30 - 3.23, 2.70 - 2.76 (m, 1H total), 1.80 - 1.40 (m, 3H), 1.36 - 1.00 (m, 3H); LCMS (ESI): m / z 409.2 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 51:49. Example 2 - 102 -CTQ-01425 2-(3,4-dichlorophenyl)-1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-Step 1: (R)-2-(3,4-dichlorophenyl)-1-(2-(4-methoxynicotinoyl)piperidin-1-yl)ethan-1-one

[0246] To a mixture of (R)-(4-methoxypyridin-3-yl)(piperidin-2-yl)methanonehydrochloride (343 mg, 1.34 mmol, 1 eq) and 2-(3,4-dichlorophenyl)acetic acid (273.94 mg, 1.34 mmol, 1 eq) in DCM (6 mL) was added DIEA (518.01 mg, 4.01 mmol, 698.13 μL, 3 eq) and HATU (609.61 mg, 1.60 mmol, 1.2 eq) in one portion at 0 °C. The mixture was stirred at 0 °C for 1 hour. TLC (petroleum ether / ethyl acetate / ethanol = 4 / 3 / 1, Rf = 0.46) showed the starting material consumed and a new spot appeared. The mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated NaHCO3 (30 mL × 2). The combined organic phase was washed with brine (30 mL × 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (0 - 40% ethyl acetate in petroleum ether) to afford the title compound (430 mg, 79%) as a yellow oil. LCMS (ESI): m / z 407.1 (M+H)+.Step 2: 2-(3,4-dichlorophenyl)-1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)ethan-1-one (2 compounds)- 103 -CTQ-01425 To a mixture of (R)-2-(3,4-dichlorophenyl)-1-(2-(4-methoxynicotinoyl)piperidin-1-yl)ethan- 1-one (430 mg, 1.06 mmol, 1 eq) in MeOH (1 mL) and THF (3 mL) was added NaBH4(79.88 mg, 2.11 mmol, 2 eq) in one portion at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 0.677 min & 0.701 min, [M+H]+= 409.2) showed 42% & 34% of desired product. The reaction was quenched with H2O (20 mL), extracted with ethyl acetate (50 mL × 3), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (0 - 40% EE(ethyl acetate:ethanol = 3:1) in petroleum ether) & purified by reverse phase chromatography (Welch Xtimate C18150 mm X 25 mm X 5 µm; acetonitrile (40-70% gradient) / water-NH4HCO3) to afford the first compound (the first peak, 118.88 mg, 27%) as a white solid and the second compound (the second peak, 59.39 mg, 13%) as a white solid.

[0247] The first compound: 1H NMR (400 MHz, CDCl3): δ 8.62 - 8.30 (m, 2H), 7.31- 7.28 (m, 1H), 7.04 (s, 1H), 6.84 - 6.77 (m, 1H), 6.70 - 6.62 (m, 1H), 5.42 - 4.54 (m, 2H), 3.94, 3.92 (s, 3H total), 3.62 - 3.07 (m, 4H), 2.31 - 2.23 (m, 1H), 1.93 - 1.73 (m, 3H), 1.67 - 1.26 (m, 3H); LCMS (ESI): m / z 409.0 (M+H)+. SFC (Chiralcel OD-3; CO2 / ethanol (0.05% DEA)) showed 16:84.

[0248] The second compound: 1H NMR (400 MHz, CDCl3): δ 8.52 - 8.38 (m, 2H),7.42 - 7.38 (m, 2H), 7.16 - 7.09 (m, 1H), 6.85 - 6.82 (m, 1H), 5.34 - 5.20 (m, 1H), 5.06 - 4.66 (m, 1H), 3.98 - 3.89 (m, 4H), 3.79 - 3.72 (m, 2H), 3.40 - 3.27 (m, 1H), 1.95 - 1.84 (m, 1H), 1.71 - 1.15 (m, 5H); LCMS (ESI): m / z 409.0 (M+H)+. SFC (Chiralcel OD-3; CO2 / ethanol (0.05% DEA)) showed one peak. Example 3 2-(3,4-dichlorophenyl)-1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1- yl)ethan-1-one (2 compounds)

[0249] The 2-(3,4-dichlorophenyl)-1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)ethan-1-one (110 mg, 0.269 mmol) was purified by reversed-phase SFC (column: DAICEL CHIRALPAK AD (250mm×30mm,10um); mobile phase: [CO2- EtOH(0.1%NH3H2O)];B%:50%, isocratic elution mode) to afford the first compound (the first peak on SFC, 16.38 mg,15%) as a white solid & the second compound (second peak on SFC, 85.64 mg,78%) as a white solid. - 104 -CTQ-01425

[0250] The first compound: 1H NMR (400 MHz, CDCl3) δ 8.62 - 8.27 (m, 2H), 7.32 -7.27 (m, 1H), 7.03 (s, 1H), 6.84 - 6.60 (m, 2H), 5.39 - 4.02 (m, 2H), 3.94, 3.91 (s, 3H total), 3.54 - 2.80 (m, 4H), 2.33 - 2.22 (m, 1H), 1.82 - 1.68 (m, 3H), 1.61 - 1.53 (m, 1H), 1.42 - 1.25 (m, 2H); LCMS (ESI): m / z 409.0 (M+H)+.

[0251] The second compound: 1H NMR (400 MHz, CDCl3) δ 8.62 - 8.27 (m, 2H),7.32 - 7.27 (m, 1H), 7.03 (s, 1H), 6.84 - 6.60 (m, 2H), 5.39 - 4.02 (m, 2H), 3.94, 3.91 (s, 3H total), 3.54 - 2.80 (m, 4H), 2.33 - 2.22 (m, 1H), 1.82 - 1.68 (m, 2H), 1.61 - 1.53 (m, 1H), 1.42 - 1.25 (m, 2H); LCMS (ESI): m / z 409.0 (M+H)+. Example 4 1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2-(6- (trifluoromethyl)pyridin-3-yl)ethan-1-one (2 compounds)Step 1: (R)-1-(2-(4-methoxynicotinoyl)piperidin-1-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethan-1-one

[0252] To a mixture of (R)-(4-methoxypyridin-3-yl)(piperidin-2-yl)methanonehydrochloride (0.3 g, 1.17 mmol, 1 eq) and 2-(6-(trifluoromethyl)pyridin-3-yl)acetic acid (215.74 mg, 1.05 mmol, 1 eq) in DCM (5 mL) was added DIEA (407.76 mg, 3.16 mmol, 549.55 μL, 3 eq) and HATU (479.86 mg, 1.26 mmol, 1.2 eq) in one portion at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 0.650 min, [M+H]+= 408.2) showed 52% of desired product. The mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated NaHCO3(20 - 105 -CTQ-01425 mL) and brine (20 mL × 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (0 - 40% EE(ethylacetate:ethanol = 3:1) in petroleum ether) to afford the title compound (160 mg, 37%) as ayellow oil. LCMS (ESI): m / z 408.2 (M+H)+. Step 2: 1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2-(6- (trifluoromethyl)pyridin-3-yl)ethan-1-one (2 compounds)To a mixture of (R)-1-(2-(4-methoxynicotinoyl)piperidin-1-yl)-2-(6-(trifluoromethyl)pyridin- 3-yl)ethan-1-one (160 mg, 392.75 μmol, 1 eq) in MeOH (1 mL) and THF (3 mL) was added NaBH4 (29.72 mg, 785.50 μmol, 2 eq) in one portion at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. LCMS (RT = 1.445 min & 1.575 min, [M+H]+= 410.2) showed 64% & 15 % of desired product. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (50 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by reverse phase chromatography (Welch Xtimate C1875 mm X 30 mm X 3 µm; acetonitrile (25-55% gradient over 7 min) / water- NH4OH-NH4HCO3) to afford the first compound (the first peak, 27.90 mg, 17%) as a white solid and the second compound (the second peak, 3.64 mg, 2%) as a white solid.

[0253] The first compound: 1H NMR (400 MHz, CDCl3): δ 8.66 - 8.22 (m, 3H), 7.58- 7.51 (m, 1H), 7.35 - 7.27 (m, 1H), 6.84 - 6.76 (m, 1H), 5.48 - 4.87 (m, 2H), 4.67 - 4.03 (m, 1H), 3.95 - 3.90 (m, 3H), 3.79 - 3.37 (m, 3H), 3.24 - 3.08 (m, 1H), 2.41 - 2.21 (m, 2H), 1.90 - 1.75 (m, 2H), 1.63 - 1.40 (m, 2H); LCMS (ESI): m / z 410.0 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 20:80.

[0254] The second compound: 1H NMR (400 MHz, MeOD): δ 8.80 - 8.17 (m, 3H),7.96 - 7.75 (m, 2H), 7.35 - 6.98 (m, 1H), 5.47 - 5.44, 5.00 - 4.95 (m, 1H total), 4.64 - 4.01 (m, 3H), 4.00 - 3.96 (m, 4H), 3.55 - 3.47, 2.94 - 2.91 (m, 1H total), 1.95 - 1.75 (m, 2H), 1.61 - 1.26 (m, 4H); LCMS (ESI): m / z 410.1 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 79:21. - 106 -CTQ-01425 Example 5 1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2-(5- (trifluoromethyl)pyridin-2-yl)ethan-1-one (2 compounds)

[0255] To a mixture of (4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanolhydrochloride (168 mg, 649.29 μmol, 1 eq) and 2-(5-(trifluoromethyl)pyridin-2-yl)acetic acid (119.87 mg, 584.36 μmol, 0.9 eq) in DCM (2 mL) was added DIEA (251.75 mg, 1.95 mmol, 3 eq) and HATU (296.26 mg, 779.15 μmol, 1.2 eq) in one portion at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 1.14 min & 1.21 min, [M+H]+= 410.1) showed 11% & 31% of desired product, the mixture was filtered and concentrated in vacuum. The residue was purified by reverse phase chromatography (Welch Xtimate C1875 mm X 30 mm X 3 µm; acetonitrile (29-59% gradient) / water- NH4OH-NH4HCO3) to afford the first compound (the first peak, 22.35 mg, 8%) as a yellow solid and the second compound (the second peak, 70.97 mg, 27%) as a yellow solid.

[0256] The first compound: 1H NMR (400 MHz, CDCl3): δ 8.76 - 8.73 (m, 1H), 8.58- 8.27 (m, 2H), 7.82 - 7.77 (m, 1H), 6.93 - 6.76 (m, 2H), 5.34 - 4.93 (m, 2H), 4.61 - 4.32 (m, 1H), 3.94 (s, 3H), 3.75 - 3.72 (m, 2H), 3.34 - 3.00 (m, 2H), 1.85 - 1.71 (m, 2H), 1.65 - 1.29 (m, 4H); LCMS (ESI): m / z 410.0 (M+H)+. SFC (Chiralcel OD-3; CO2 / ethanol (0.05% DEA)) showed 13:87.

[0257] The second compound: 1H NMR (400 MHz, CDCl3): δ 8.82, 8.79 (s, 1H total),8.52 - 8.45 (m, 2H), 7.93 - 7.90 (m, 1H), 7.52 - 7.48 (m, 1H), 6.85 - 6.82 (m, 1H), 5.41 - 5.11 (m, 2H), 4.73 - 4.53 (m, 1H), 4.38 - 3.97 (m, 2H), 3.95 - 3.86 (m, 4H), 3.36 - 3.32, 2.87 - 2.84 (m, 1H total), 1.81 - 1.70 (m, 2H), 1.65 - 1.52 (m, 2H), 1.49 - 1.41 (m, 2H); LCMS (ESI): m / z 410.1 (M+H)+. SFC (Chiralcel OD-3; CO2 / ethanol (0.05% DEA)) showed 84:16. Example 6 2-fluoro-4-(2-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2- oxoethyl)benzonitrile (2 compounds) - 107 -CTQ-01425To a mixture of (4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride (300 mg, 1.16 mmol, 1 eq) and 2-(4-cyano-3-fluoro-phenyl)acetic acid (249.25 mg, 1.39 mmol, 1.2 eq) in DCM (5 mL) was added HATU (529.03 mg, 1.39 mmol, 1.2 eq) and DIEA (449.55 mg, 3.48 mmol, 3 eq) in one portion at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 1.913 min & 2.101 min, [M+H]+= 384.2) showed 18% & 68% of desired product. The mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated NaHCO3 (10 mL). The combined organic phase was washed with brine (20 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm; acetonitrile (27-57% gradient) / water-NH4OH-NH4HCO3) to afford the first compound (the first peak, 35.45 mg, 8%) as a white solid and the second compound (the second peak, 137.53 mg, 31%) as a white solid.

[0258] The first compound: 1H NMR (400 MHz, CD3OD): δ 8.62 - 8.28 (m, 2H),7.77 - 7.56 (m, 1H), 7.09 - 6.82 (m, 3H), 5.47 - 5.30 (m, 1H), 5.08 - 5.01, 4.51 - 4.38 (m, 1H total), 3.91, 3.84 (s, 3H total), 4.21 - 4.07, 3.80 - 3.45 (m, 3H total), 3.29 - 3.25, 3.14 - 3.03 (m, 1H total), 2.39 - 2.22 (m, 1H), 1.96 - 1.78 (m, 1H), 1.77 - 1.62 (m, 2H), 1.60 - 1.34 (m, 2H); LCMS (ESI): m / z 384.1 (M+H)+. SFC (Chiralcel OD-3; CO2 / ethanol (0.05% DEA)) showed 14:86.

[0259] The second compound: 1H NMR (400 MHz, CD3OD): δ 8.52, 8.48 (s, 1Htotal), 8.41 - 8.34 (m, 1H), 7.70 - 7.67 (m, 1H), 7.28 - 7.20 (m, 2H), 7.13 - 7.05 (m, 1H), 5.42 - 5.36 (m, 1H), 5.02 - 4.95, 4.59 - 4.51 (m, 1H total), 4.37 - 4.05 (m, 2H), 3.97, 3.95 (m, 3H total), 3.92 - 3.78 (m, 1H), 3.52 - 3.41, 2.97-2.86 (m, 1H total), 1.98 - 1.71 (m, 2H), 1.61 - 1.22 (m, 4H); LCMS (ESI): m / z 426.2 (M+H)+. SFC (Chiralcel OD-3; CO2 / ethanol (0.05% DEA)) showed 84:16. Example 7 1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2-(naphthalen-2- yl)ethan-1-one (2 compounds) - 108 -CTQ-01425To a mixture of (4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride (300 mg, 1.16 mmol, 1 eq) and 2-(2-naphthyl)acetic acid (216 mg, 1.16 mmol, 1 eq) in DCM (5 mL) was added DIEA (449.55 mg, 3.48 mmol, 3 eq) and HATU (529.03 mg, 1.39 mmol, 1.2 eq) in one portion at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 2.297 min & 2.403 min, [M+H]+= 391.2) showed 32% & 50% of desired product. The mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated NaHCO3(20 mL), then the combined organic phase was washed with brine (20 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by reverse phase chromatography (Welch Xtimate C18 80 mm X 30 mm X 5 µm; acetonitrile (34-64% gradient) / water-NH4OH-NH4HCO3) to afford the first compound (the first peak, 55.27 mg, 12%) as a white solid and the second compound (the second peak, 162.68 mg, 35%) as a white solid.

[0260] The first compound: 1H NMR (400 MHz, CD3OD): δ 8.65, 8.45 (s, 1H total),8.43 - 8.16 (m, 1H), 7.82 - 7.66 (m, 3H), 7.50 - 7.42 (m, 3H), 7.19 - 6.63 (m, 2H), 5.45 - 5.30 (m, 1H), 5.10 - 5.04, 4.55 - 4.46 (m, 1H total), 4.25 - 4.16, 3.87 - 3.81 (m, 1H total), 3.95 - 3.92 (m, 1H), 3.79 - 3.74, 3.29 - 3.03 (m, 2H), 3.64 - 3.50 (m, 3H), 2.31 - 2.10 (m, 1H), 1.89 - 1.11 (m, 5H); LCMS (ESI): m / z 391.1 (M+H)+. SFC (Chiralcel OJ-3; CO2 / ethanol (0.05% DEA)) showed 85:15.

[0261] The second compound: 1H NMR (400 MHz, CD3OD): δ 8.55, 8.48 (s, 1Htotal), 8.39 - 8.35 (m, 1H), 7.84 - 7.80 (m, 3H), 7.74 - 7.71 (m, 1H), 7.47 - 7.38 (m, 3H), 7.10 - 7.04 (m, 1H), 5.41 - 5.37 (m, 1H), 5.05 - 5.03, 4.66 - 4.59 (m, 1H total), 4.43 - 3.87 (m, 6H), 3.47 - 3.38, 2.99 - 2.89 (m, 1H total), 1.94 - 1.55 (m, 2H), 1.53 - 1.02 (m, 4H); LCMS (ESI): m / z 391.2 (M+H)+. SFC (Chiralcel OJ-3; CO2 / ethanol (0.05% DEA)) showed 86:14. Example 8 4-(2-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2- oxoethyl)benzonitrile (2 compounds) - 109 -CTQ-01425To a mixture of (4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride (300 mg, 1.16 mmol, 1 eq) and 2-(4-cyanophenyl)acetic acid (186.85 mg, 1.16 mmol, 1 eq) in DCM (5 mL) was added DIEA (449.55 mg, 3.48 mmol, 3 eq) and HATU (529.03 mg, 1.39 mmol, 1.2 eq) in one portion at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 1.806 min & 1.988 min, [M+H]+= 366.2) showed 25% & 69% of desired product. The mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated NaHCO3 (20 mL), then the combined organic phase was washed with brine (20 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by reverse phase chromatography (Phenomenex C1880 mm X 30 mm X 5 µm; acetonitrile (28-48% gradient over 7 min) / water-NH4OH-NH4HCO3) to afford the first compound (the first peak, 45.62 mg, 11%) as a white solid and the second compound (the second peak, 138.97 mg, 33%) as a white solid.

[0262] The first compound: 1H NMR (400 MHz, CD3OD): δ 8.63 – 8.30 (m, 2H),7.63 – 7.56 (m, 2H), 7.14 – 7.09 (m, 1H), 7.00 – 6.94 (m, 2H), 5.46 – 5.31 (m, 1H), 5.10 – 5.04, 4.48 – 4.41 (m, 1H total), 4.16 – 4.09, 3.29 – 3.21 (m, 1H total), 3.92, 3.82 (s, 3H total), 3.71 – 3.63, 3.12 – 3.03 (m, 2H total), 3.60 – 3.50 (m, 1H), 2.35 – 2.23 (m, 1H), 1.92 – 1.80 (m, 1H), 1.77 – 1.61 (m, 2H), 1.59 – 1.32 (m, 2H); LCMS (ESI): m / z 366.1 (M+H)+. SFC (Chiralcel OD-3; CO2 / ethanol (0.05% DEA)) showed 14:86.

[0263] The second compound: 1H NMR (400 MHz, CD3OD): δ 8.51, 8.47 (s, 1Htotal), 8.40 - 8.36 (m, 1H), 7.70 - 7.67 (m, 2H), 7.47 - 7.37 (m, 2H), 7.12 - 7.08 (m, 1H), 5.41 - 5.38 (m, 1H), 5.02 - 4.96, 4.60-4.53 (m, 1H total), 4.35 - 4.01 (m, 2H), 3.97, 3.95 (s, 3H total), 3.89 - 3.78 (m, 1H), 3.49 - 3.41, 2.96 - 2.87 (m, 1H total), 1.96 - 1.67 (m, 2H), 1.58 - 1.17 (m, 4H); LCMS (ESI): m / z 366.1 (M+H)+. SFC (Chiralcel OD-3; CO2 / ethanol (0.05% DEA)) showed 90:10. Example 9 1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2-(4- (trifluoromethyl)phenoxy)ethan-1-one (2 compounds) - 110 -CTQ-01425To a mixture of (4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride (300 mg, 1.16 mmol, 1 eq) and 2-(4-(trifluoromethyl)phenoxy)acetic acid (306.30 mg, 1.39 mmol, 1.2 eq) in DCM (5 mL) was added DIEA (449.55 mg, 3.48 mmol, 3 eq) and HATU (529.03 mg, 1.39 mmol, 1.2 eq) in one portion at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 2.345 min & 2.470 min, [M+H]+= 425.2) showed 17% & 64% of desired product. The mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated NaHCO3 (10 mL), the combined organic phase was washed with brine (20 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm; acetonitrile (35-65% gradient over 7 min) / water-NH4OH- NH4HCO3) to afford the first compound (the first peak, 40.46 mg, 8%) as a white solid and the second compound (the second peak, 127.21 mg, 26%) as a white solid.

[0264] The first compound: 1H NMR (400 MHz, CD3OD): δ 8.63, 8.44 (s, 1H total),8.42 - 8.22 (m, 1H), 7.53 - 7.49 (m, 2H), 7.10 - 6.86 (m, 1H), 6.79 - 6.69 (m, 2H), 5.49 - 5.35 (m, 1H), 5.01 - 4.96, 4.70 - 4.57 (m, 2H total), 4.46 - 4.38, 3.72 - 3.63 (m, 1H total), 4.07 - 3.99 (m, 1H), 3.90 (s, 3H), 3.49 - 3.38, 3.18 - 3.09 (m, 1H total), 2.42 - 2.24 (m, 1H), 1.98 - 1.83 (m, 1H), 1.82 - 1.67 (m, 2H), 1.65-1.36 (m, 2H); LCMS (ESI): m / z 425.1 (M+H)+. SFC (Chiralpak AS-3; CO2 / ethanol (0.05% DEA)) showed 14:86.

[0265] The second compound: 1H NMR (400 MHz, CD3OD): δ 8.53 - 8.33 (m, 2H),7.57 (d, J = 8.8 Hz, 2H), 7.16 - 6.99 (m, 3H), 5.44 - 5.41 (m, 1H), 5.31 - 5.11 (m, 2H), 4.81 - 4.78, 4.53 - 4.18 (m, 2H total), 3.95 (s, 3H), 3.80 - 3.45, 3.01 - 2.89 (m, 1H total), 2.02 - 1.24 (m, 6H); LCMS (ESI): m / z 425.1 (M+H)+. SFC (Chiralpak AS-3; CO2 / ethanol (0.05% DEA)) showed 14:86. Example 10 2-(3-chlorophenyl)-1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1- yl)ethan-1-one (2 compounds) - 111 -CTQ-01425To a solution of (4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride (400 mg, 1.55 mmol, 1 eq) and 2-(3-chlorophenyl)acetic acid (263.72 mg, 1.55 mmol, 1 eq) in DCM (5 mL) was added DIEA (599.40 mg, 4.64 mmol, 3 eq) and then HATU (705.37 mg, 1.86 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS (RT = 2.174 min & 2.316 min, [M+H]+= 375.2) showed 17% & 44% of desired product. The reaction mixture was concentrated to provide a crude. The residue was purified by reverse phase chromatography Welch Xtimate C18150 mm X 30 mm; acetonitrile (38-68% gradient) / water- NH4OH-NH4HCO3) to afford the first compound (the first peak, 44.1 mg, 8%) as a white solid and the second compound (the second peak, 233.4 mg, 40%) as a white solid.

[0266] The first compound: 1H NMR (400 MHz, CDCl3): δ 8.60 - 8.25 (m, 2H), 7.19- 7.13 (m, 2H), 7.00 - 6.90 (m, 1H), 6.84 - 6.67 (m, 2H), 5.35 - 5.13 (m, 1H), 4.94 - 4.08 (m, 1H), 3.94 (s, 3H), 3.57 - 3.48 (m, 1H), 3.46 - 3.33 (m, 2H), 3.27 - 2.85 (m, 2H), 2.25 - 2.22 (m, 1H), 1.69 - 1.61 (m, 4H), 1.34 - 1.20 (m, 1H); LCMS (ESI): m / z 375.0 (M+H)+. SFC (Chiralcel OJ-3; CO2 / ethanol (0.05% DEA)) showed 90:10.

[0267] The second compound: 1H NMR (400 MHz, CDCl3): δ 8.49 - 8.40 (m, 2H),7.30 - 7.17 (m, 4H), 6.86 - 6.81 (m, 1H), 5.38 - 5.22 (m, 1H), 5.09 - 4.21 (m, 1H), 4.01 - 3.86 (m, 4H), 3.84 - 3.72 (m, 2H), 3.37 - 2.77 (m, 1H), 1.72 - 1.54 (m, 3H), 1.53 - 1.32 (m, 2H), 1.32 - 1.25 (m, 1H); LCMS (ESI): m / z 375.0 (M+H)+. SFC (Chiralpak AS-3; CO2 / ethanol (0.05% DEA)) showed 10:90. Example 11 1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2-(4- (trifluoromethyl)phenyl)ethan-1-one (2 compounds)- 112 -CTQ-01425 To a solution of (4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride (500 mg, 1.93 mmol, 1 eq) and 2-(4-(trifluoromethyl)phenyl)acetic acid (394.49 mg, 1.93 mmol, 1 eq) in DCM (5 mL) was added DIEA (749.25 mg, 5.80 mmol, 1.01 mL, 3 eq) and HATU (881.71 mg, 2.32 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS (RT = 2.339 min & 2.466 min, [M+H]+= 409.2) showed 15% & 49% of desired product. The reaction mixture was concentrated to provide a crude. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm; acetonitrile (37 - 67% gradient) / water-NH4OH-NH4HCO3) to afford the first compound (the first peak, 95.2 mg, 12%) as a white solid and the second compound (the second peak, 270.8 mg, 34%) as a white solid.

[0268] The first compound: 1H NMR (400 MHz, CDCl3): δ 8.47 - 8.30 (m, 2H), 7.52- 7.46 (m, 2H), 7.11 - 6.93 (m, 2H), 6.82 - 6.75 (m, 1H), 5.39 - 5.12 (m, 1H), 4.97 - 4.07 (m, 1H), 3.90 (s, 3H), 3.54 - 3.43 (m, 2H), 3.38 - 2.85 (m, 2H), 2.26 - 2.23 (m, 1H), 1.81 - 1.51 (m, 4H), 1.39 - 1.21 (m, 1H); LCMS (ESI): m / z 409.1 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 10:90.

[0269] The second compound: 1H NMR (400 MHz, CDCl3): δ 8.53 - 8.39 (m, 2H),7.61 - 7.56 (m, 2H), 7.41 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 6.0 Hz, 1H), 5.40 - 5.19 (m, 1H), 5.07 - 4.19 (m, 1H), 4.12 - 3.96 (m, 1H), 3.95 - 3.91 (m, 3H), 3.88 - 3.72 (m, 2H), 3.36 - 3.29, 2.85 - 2.76 (m, 1H total), 1.78 - 1.34 (m, 5H), 1.31-1.17 (m, 1H); LCMS (ESI): m / z 409.1 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 91:9. Example 12 1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2-(p-tolyl)ethan-1-one (2 compounds)To a solution of (4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride (500 mg, 1.93 mmol, 1 eq) and 2-(p-tolyl)acetic acid (290.20 mg, 1.93 mmol, 1 eq) in DCM (5 mL) was added DIEA (749.25 mg, 5.80 mmol, 1.01 mL, 3 eq) and then HATU (881.71 mg, 2.32 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS (RT = 2.159 min & 2.280min, [M+H]+= 355.2), showed 16% & 50% of desired product. The mixture was - 113 -CTQ-01425quenched with water (5 mL), extracted with DCM (30 mL × 3). The organic layers werecombined, washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to provide a residue. The residue was purified by reverse phase chromatography (Welch XtimateC18150 mm X 30 mm; acetonitrile (33-63% gradient) / water-NH4OH-NH4HCO3) to affordthe first compound (the first peak, 79.1 mg, 12%) as a white solid and the second compound (the second peak, 335.6 mg, 49%) as a white solid.

[0270] The first compound: 1H NMR (400 MHz, CDCl3): δ 8.58 - 8.30 (m, 2H), 7.10- 6.73 (m, 5H), 5.31 - 4.08 (m, 2H), 3.95 (s, 3H), 3.58 - 2.75 (m, 5H), 2.30 (s, 3H), 2.18 - 2.16 (m, 1H), 1.66 - 1.49 (m, 4H), 1.31 - 1.00 (m, 1H); LCMS (ESI): m / z 355.1 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 79:21.

[0271] The second compound: 1H NMR (400 MHz, CDCl3): δ 8.48 - 8.41 (m, 2H),7.18 - 7.09 (m, 4H), 6.83 (d, J = 5.6 Hz, 1H), 5.37 - 4.19 (m, 2H), 4.03 - 3.75 (m, 6H), 3.68 - 2.70 (m, 2H), 2.33, 2.32 (s, 3H total), 1.64 - 1.32 (m, 4H), 1.30 - 1.03 (m, 2H); LCMS (ESI): m / z 355.1 (M+H)+. SFC (Chiralcel OD-3; CO2 / ethanol (0.05% DEA)) showed 79:21. Example 13 1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2-(4- methoxyphenyl)ethan-1-one (2 compounds)To a solution of (4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride (500 mg, 1.93 mmol, 1 eq) and 2-(4-methoxyphenyl)acetic acid (321.12 mg, 1.93 mmol, 1 eq) in DCM (5 mL) was added DIEA (749.25 mg, 5.80 mmol, 1.01 mL, 3 eq) and then HATU (881.71 mg, 2.32 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS (RT = 1.964 min & 2.092min, [M+H]+= 371.2) showed 56% of desired product. The mixture was quenched with water (5 mL), extracted with DCM (30 mL × 3). The organic layers were combined, washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to provide a residue. The residue was purified by reverse phase chromatography (WelchXtimate C18150 mm X 30 mm; acetonitrile (27-57% gradient) / water-NH4OH-NH4HCO3) toafford the first compound (the first peak, 82.8 mg, 12%) as a white solid and the second compound (the second peak, 251.9 mg, 35%) as a white solid. - 114 -CTQ-01425

[0272] The first compound: 1H NMR (400 MHz, CDCl3): δ 8.57 - 8.29 (m, 2H), 6.97- 6.74 (m, 5H), 5.33 - 4.11 (m, 2H), 3.95 (s, 3H), 3.78 (s, 3H), 3.59 - 3.32 (m, 3H), 3.25 - 2.71 (m, 2H), 2.20 - 2.17 (m, 1H), 1.67 - 1.50 (m, 4H), 1.29 - 1.09 (m, 1H); LCMS (ESI): m / z 371.1 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 19:81.

[0273] The second compound: 1H NMR (400 MHz, CDCl3): δ 8.49 - 8.41 (m, 2H),7.20 (d, J = 8.4 Hz, 2H), 6.69 - 6.82 (m, 3H), 5.38 - 4.21 (m, 2H), 4.00 - 3.92 (m, 3H), 3.85 - 3.77 (m, 5H), 3.75 - 3.49 (m, 1H), 3.34 - 2.73 (m, 1H), 1.69 - 1.06 (m, 6H); LCMS (ESI): m / z 371.1 (M+H)+. SFC (Chiralpak AS-3; CO2 / ethanol (0.05% DEA)) showed 20:80. Example 14 2-(4-chlorophenyl)-1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1- yl)ethan-1-one (2 compounds)To a solution of (4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride (500 mg, 1.93 mmol, 1 eq) and 2-(4-chlorophenyl)acetic acid (329.66 mg, 1.93 mmol, 1 eq) in DCM (5 mL) was added DIEA (749.25 mg, 5.80 mmol, 1.01 mL, 3 eq) and then HATU (881.71 mg, 2.32 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS (RT = 2.192 min & 2.337 min, [M+H]+= 375.2) showed 16% & 51% of desired product. The mixture was quenched with water (5 mL), extracted with DCM (30 mL × 3). The organic layers were combined, washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to provide a residue. The residue was purified by reverse phase chromatography (Phenomenex C1880 mm X 30 mm X 5 µm; acetonitrile (31-61% gradient over 7 min) / water-NH4OH-NH4HCO3) to afford the first compound (the first peak, 88.6 mg, 12%) as a white solid and the second compound (the second peak, 208 mg, 29%) as a white solid.

[0274] The first compound: 1H NMR (400 MHz, CDCl3): δ 8.56 - 8.34 (m, 2H), 7.25- 7.19 (m, 2H), 6.92 - 6.83 (m, 3H), 5.37 - 4.05 (m, 2H), 3.96 - 3.92 (m, 3H), 3.55 - 3.38 (m, 2H), 3.29 - 2.80 (m, 2H), 2.29 - 2.17 (m, 1H), 1.84 - 1.64 (m, 3H), 1.58 - 1.48 (m, 1H), 1.33 - 1.19 (m, 1H); LCMS (ESI): m / z 375.2 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 21:79. - 115 -CTQ-01425

[0275] The second compound: 1H NMR (400 MHz, CDCl3): δ 8.52 - 8.38 (m, 2H),7.33 - 7.27 (m, 2H), 7.24 - 7.20 (m, 2H), 6.84 - 6.80 (m, 1H), 5.40 - 4.16 (m, 2H), 4.01 - 3.73 (m, 6H), 3.34 - 3.27, 2.85 - 2.74 (m, 1H total), 1.66 - 1.09 (m, 6H); LCMS (ESI): m / z 375.2 (M+H)+. SFC (Chiralcel OD-3; CO2 / ethanol (0.05% DEA)) showed (79:21). Example 15 3-(3,4-dichlorophenyl)-1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1- yl)propan-1-one (2 compounds)To a solution of (4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride (400 mg, 1.55 mmol, 1 eq) and 3-(3,4-dichlorophenyl)propanoic acid (338.66 mg, 1.55 mmol, 1 eq) in DCM (5 mL) was added DIEA (599.40 mg, 4.64 mmol, 3 eq) and then HATU (705.37 mg, 1.86 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS (RT = 2.551 min & 2.639 min, [M+H]+= 423.2) showed 16% & 48% of desired product. The mixture was quenched by water (5 mL), extracted with DCM (30 mL × 3). The organic layers were combined, washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to provide a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm; acetonitrile (41-71% gradient) / water-NH4OH-NH4HCO3) to afford the first compound (the first peak, 82.8 mg, 13%) as a white solid and the second compound (the second peak, 235.6 mg, 36%) as a white solid.

[0276] The first compound: 1H NMR (400 MHz, CDCl3): δ 8.50 - 8.26 (m, 2H), 7.31(d, J = 8.0 Hz, 1H), 7.20 - 7.09 (m, 1H), 6.90 (dd, J = 8.0, 2.0 Hz, 1H), 6.72 - 6.66 (m, 1H), 5.31 - 4.02 (m, 2H), 3.97, 3.78 (s, 3H total), 3.53 - 3.32 (m, 1H), 3.15 - 2.78 (m, 1H), 2.69 - 2.36 (m, 3H), 2.35 - 2.15 (m, 2H), 1.74 - 1.58 (m, 4H), 1.54 - 1.29 (m, 2H); LCMS (ESI): m / z 423.0 (M+H)+. SFC (Chiralpak AS-3; CO2 / ethanol (0.05% DEA)) showed 14:86.

[0277] The second compound: 1H NMR (400 MHz, CDCl3): δ 8.49 - 8.42 (m, 2H),7.39 - 7.33 (m, 2H), 7.11 - 7.08 (m, 1H), 6.86 - 6.82 (m, 1H), 5.35 - 5.19 (m, 1H), 5.05 - 4.10 (m, 1H), 3.96, 3.87 (s, 3H total), 3.77 - 3.43 (m, 1H), 3.37 - 3.25 (m, 1H), 3.04 - 2.94 (m, 2H), 2.83 - 2.62 (m, 2H), 1.74 - 1.62 (m, 2H), 1.55 - 1.21 (m, 4H); LCMS (ESI): m / z 423.0 (M+H)+. SFC (Chiralcel OJ-3; CO2 / ethanol (0.05% DEA)) showed 11:89. - 116 -CTQ-01425 Example 16 2-(3,4-dichlorophenoxy)-1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1- yl)ethan-1-one (2 compounds)

[0278] To a solution of (4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanolhydrochloride (500.00 mg, 1.93 mmol, 1 eq) and 2-(3,4-dichlorophenoxy)acetic acid (427.14 mg, 1.93 mmol, 1 eq) in DCM (5 mL) was added DIEA (749.25 mg, 5.80 mmol, 3 eq) and then HATU (881.71 mg, 2.32 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS (RT = 2.427 min & 2.541min, [M+H]+= 425.1) showed 13% & 51% of desired product. The mixture was quenched with water (5 mL), extracted with DCM (30 mL × 3). The organic layers were combined, washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to provide a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm; acetonitrile (60-80% gradient) / water-NH4OH-NH4HCO3) to afford the first compound (the first peak, 93.6 mg, 11%) as a white solid and the second compound (the second peak, 287.7 mg, 35%) as a white solid.

[0279] The first compound: 1H NMR (400 MHz, CDCl3): δ 8.59 - 8.29 (m, 2H), 7.30- 7.25 (m, 1H), 6.85 - 6.67 (m, 2H), 6.53 (dd, J = 8.8, 2.8 Hz, 1H), 5.44 - 4.85 (m, 2H), 4.50 - 4.29 (m, 2H), 4.09 - 3.99, 3.63 - 2.88 (m, 3H total), 3.94, 3.89 (s, 3H total), 2.40 - 2.22 (m, 1H), 1.87 - 1.69 (m, 5H); LCMS (ESI): m / z 425.0 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 89:11.

[0280] The second compound: 1H NMR (400 MHz, CDCl3): δ 8.50 - 8.38 (m, 2H),7.36 - 7.28 (m, 1H), 7.13 - 7.05 (m, 1H), 6.85 - 6.80 (m, 2H), 5.40 - 5.11 (m, 1H), 5.06 - 4.71 (m, 2H), 4.61 - 4.21 (m, 1H), 3.95, 3.89 (s, 3H total), 3.82 - 2.81 (m, 2H), 1.84 - 1.60 (m, 5H), 1.35 - 1.26 (m, 1H); LCMS (ESI): m / z 425.0 (M+H)+. SFC (Chiralpak AS-3; CO2 / ethanol (0.05% DEA)) showed 9:91. Example 17 1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2-(4- (methylsulfonyl)phenyl)ethan-1-one (2 compounds) - 117 -CTQ-01425To a solution of (4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride (500 mg, 1.93 mmol, 1 eq) and 2-(4-(methylsulfonyl)phenyl)acetic acid (414.00 mg, 1.93 mmol, 1 eq) in DCM (5 mL) was added DIEA (749.24 mg, 5.80 mmol, 1.01 mL, 3 eq) and then HATU (881.71 mg, 2.32 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS (RT = 1.565 min & 1759 min, [M+H]+= 419.2) showed 16% & 47% of desired product. The mixture was quenched with water (5 mL), extracted with DCM (30 mL × 3). The organic layers were combined, washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to provide a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm; acetonitrile (18-48% gradient) / water-NH4OH-NH4HCO3) to afford the first compound (the first peak, 106.4 mg, 13%) as a white solid and the second compound (the second peak, 300.8 mg, 37%) as a white solid.

[0281] The first compound: 1H NMR (400 MHz, CDCl3): δ 8.62 - 8.27 (m, 2H), 7.83- 7.78 (m, 2H), 7.18 - 7.00 (m, 2H), 6.82 - 6.78 (m, 1H), 5.41 - 4.06 (m, 2H), 3.92, 3.90 (s, 3H total), 3.59 - 3.49 (m, 2H), 3.48 - 3.37, 2.97 - 2.85 (m, 1H total), 3.18 - 3.08 (m, 1H), 3.07 - 3.00 (m, 3H), 2.34 - 2.20 (m, 1H), 1.80 - 1.77 (m, 1H), 1.68 - 1.25 (m, 4H); LCMS (ESI): m / z 419.1 (M+H)+. SFC (Chiralpak AS-3; CO2 / ethanol (0.05% DEA)) showed 17:83.

[0282] The second compound: 1H NMR (400 MHz, CDCl3): δ 8.53 - 8.39 (m, 2H),7.93 - 7.88 (m, 2H), 7.49 (d, J = 8.4 Hz, 2H), 6.86 - 6.82 (m, 1H), 5.41 - 4.21 (m, 2H), 4.13 - 3.89 (m, 5H), 3.83 - 3.70 (m, 1H), 3.37 - 3.36, 2.85 - 2.79 (m, 1H total), 3.06 (s, 3H), 1.70 - 1.16 (m, 6H); LCMS (ESI): m / z 419.1 (M+H)+. SFC (Chiralpak AS-3; CO2 / ethanol (0.05% DEA)) showed 17:83. Example 18 2-chloro-4-(2-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2- oxoethyl)benzonitrile (2 compounds) - 118 -CTQ-01425

[0283] To the solution of 2-(4-bromo-3-chloro-phenyl)acetic acid (1.0 g, 4.01 mmol,1 eq) in MeOH (10 mL) was added H2SO4 (393.12 mg, 4.01 mmol, 1 eq) at 0 °C, then the mixture was stirred at 70 °C for 2 h. TLC (Petroleum ether: Ethyl acetate = 1:1, Rf= 0.13) showed the starting material consumed and a new spot appeared. The reaction mixture was adjusted with saturated NaHCO3 about pH = 7~8, extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3), filtered and concentrated under reduced pressure to afford the title compound (1.2 g, crude) as a yellow solid.1H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.05 (dd, J = 8.0, 2.0 Hz, 1H), 3.72 (s, 3H), 3.58 (s, 2H).Step 2: methyl 2-(3-chloro-4-cyanophenyl)acetate

[0284] A mixture of methyl 2-(4-bromo-3-chloro-phenyl)acetate (1.15 g, 4.36 mmol,1 eq), Pd2(dba)3(399.63 mg, 436.41 μmol, 0.1 eq), dppf (483.87 mg, 872.81 μmol, 0.2 eq) and Zn(CN)2(1.61 g, 13.71 mmol, 3.14 eq) in DMF (5 mL) was stirred at 100 °C for 1 hour under N2 atmosphere in microwave. LCMS (RT = 0.739 min, [M+1]+= 210.1) showed 19% - 119 -CTQ-01425 of desired product. The residue was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 2% ethyl acetate in petroleum ether) to afford the title compound (300 mg, 33%) as a yellow solid. LCMS (ESI): m / z 210.1 (M+H)+.Step 3: 2-(3-chloro-4-cyanophenyl)acetic acid

[0285] To a solution of methyl 2-(3-chloro-4-cyano-phenyl)acetate (250 mg, 1.19mmol, 1 eq) in THF (3 mL) and H2O (1 mL) was added LiOH.H2O (100.09 mg, 2.39 mmol, 2 eq). The mixture was stirred at 25 °C for 2 hour. LCMS (RT = 0.604 min, [M+1]+= 195.9) showed 93% of desired product. The reaction mixture was adjusted with 1M HCl about pH = 3, the residue was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3), filtered and concentrated under reduced pressure to afford the title compound (200 mg, crude) as a white solid. LCMS (ESI): m / z 195.9 (M+H)+.Step 4: 2-chloro-4-(2-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2-oxoethyl)benzonitrile (2 compounds)To a solution of 2-(3-chloro-4-cyano-phenyl)acetic acid (196.55 mg, 1.00 mmol, 1 eq) and (4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride (260 mg, 1.00 mmol, 1 eq) in DCM (5 mL) was added DIEA (389.61 mg, 3.01 mmol, 0.53 mL, 3 eq) and HATU (458.49 mg, 1.21 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 2.041 min & 2.203 min, [M+1]+= 400.2) showed 14% & 46% of desired product. The residue was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine 60 mL (20 mL × 3), filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm; acetonitrile (30-60% gradient) / water- NH4OH-NH4HCO3) to afford the first compound (the first peak, 58.02 mg, 14%) as a white solid and the second compound (the second peak, 164.09 mg, 41%). - 120 -CTQ-01425

[0286] The first compound: 1H NMR (400 MHz, CD3OD): δ 8.63 - 8.29 (m, 2H),7.66 - 7.60 (m, 1H), 7.18 (s, 1H), 7.09 - 6.91 (m, 2H), 5.45 - 5.29 (m, 1H), 5.04- 5.01, 4.45 - 4.42 (m, 1H total), 4.17 - 4.11, 3.77 - 3.69 (m, 1H total), 3.91, 3.85 (s, 3H total), 3.67 - 3.44 (m, 2H), 3.28 - 3.06 (m, 1H), 2.38 - 2.23 (m, 1H), 1.90 - 1.80 (m, 1H), 1.78 - 1.64 (m, 2H), 1.59 - 1.33 (m, 2H); LCMS (ESI): m / z 400.1 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 15:85.

[0287] The second compound: 1H NMR (400 MHz, CD3OD): δ 8.55, 8.52 (s, 1Htotal), 8.49 - 8.38 (m, 1H), 7.76 - 7.71 (m, 1H), 7.56, 7.51 (s, 1H total), 7.39, 7.35 (d, J = 8.0 Hz, 1H total), 7.11, 7.05 (d, J = 6.0 Hz, 1H total), 5.42 - 5.36 (m, 1H), 5.00 - 4.95, 4.58 - 4.52 (m, 1H total), 4.35 - 4.03 (m, 2H), 3.97, 3.95 (s, 3H total), 3.90 - 3.80 (m, 1H), 3.55 - 3.43, 2.97 - 2.86 (m, 1H total), 2.03 - 1.72 (m, 2H), 1.64 - 1.53 (m, 1H), 1.51 - 1.23 (m, 3H); LCMS (ESI): m / z 400.1 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 82:18. Example 19 1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2-((5- (trifluoromethyl)pyridin-2-yl)oxy)ethan-1-one (2 compounds)Step 1: tert-butyl 2-((5-(trifluoromethyl)pyridin-2-yl)oxy)acetate- 121 -CTQ-01425

[0288] To a mixture of tert-butyl 2-hydroxyacetate (1.0 g, 7.57 mmol, 1.2 eq) in DMF(25 mL) was added NaH (302.64 mg, 7.57 mmol, 60% in mineral oil, 1.2 eq) in one portion at 0 °C and the reaction solution was stirred for 30 mins at 0 °C, then 2-chloro-5- (trifluoromethyl)pyridine (1.14 g, 6.31 mmol, 1 eq) was added into it at 0 °C, the mixture was stirred at 0 °C for 1 hour. LCMS (RT = 0.906 min, [M+H-56]+= 222.1) showed 49% of desired product. The reaction was quenched with H2O (50 mL), extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine (50 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flashchromatography on silica gel (100% petroleum ether) to afford the title compound (600 mg,34%) as a yellow liquid. LCMS (ESI): m / z 222.1 (M+H-56)+.Step 2: 2-((5-(trifluoromethyl)pyridin-2-yl)oxy)acetic acid

[0289] To a mixture of tert-butyl 2-((5-(trifluoromethyl)pyridin-2-yl)oxy)acetate (600mg, 2.16 mmol, 1 eq) in dioxane (5 mL) was added HCl / dioxane (4M, 20 mL) in one portion at 25 °C. The mixture was stirred at 25 °C for 16 hours. TLC (petroleum ether / ethyl acetate = 20 / 1, Rf = 0.07) showed the starting material consumed and a new spot appeared, the mixture was concentrated in vacuum to afford the title compound (478 mg, crude) as a yellow solid. The crude product would be directly used in the next step without purification. Step 3: 1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2-((5- (trifluoromethyl)pyridin-2-yl)oxy)ethan-1-one (2 compounds)To a mixture of 2-((5-(trifluoromethyl)pyridin-2-yl)oxy)acetic acid (256.39 mg, 1.16 mmol, 1 eq) and (4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride (300 mg, 1.16 mmol, 1 eq, HCl) in DCM (5 mL) was added DIEA (449.55 mg, 3.48 mmol, 0.61 mL, 3 eq) and HATU (529.03 mg, 1.39 mmol, 1.2 eq) in one portion at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 2.145 min & 2.253 min, [M+H]+= 426.2) showed 14% &37% of desired product. The mixture was diluted with H2O (10 mL) and extracted with ethyl - 122 -CTQ-01425 acetate (30 mL × 3). The combined organic phase was washed with brine (20 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm; acetonitrile (28-58% gradient) / water-NH4OH-NH4HCO3) to afford the first compound (the first peak, 30 mg, 6%) as a white solid and the second compound (the second peak, 109 mg, 22%) as a white solid.

[0290] The first compound: 1H NMR (400 MHz, CD3OD): δ 8.60 - 8.23 (m, 3H),7.92 - 7.89 (m, 1H), 7.12 - 6.88 (m, 2H), 5.49 - 5.33 (m, 1H), 5.03 - 4.89 (m, 2H), 4.52 - 4.34 (m, 1H), 4.12 - 4.03, 3.69 - 3.58 (m, 1H total), 3.94, 3.93 (s, 3H total), 3.50 - 3.39, 3.17 - 3.07 (m, 1H total), 2.35 - 2.20 (m, 1H), 1.98 - 1.84 (m, 1H), 1.83 - 1.37 (m, 4H); LCMS (ESI): m / z 426.2 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 84:16.

[0291] The second compound: 1H NMR (400 MHz, CD3OD): δ 8.51 - 8.39 (m, 3H),7.98 - 7.92 (m, 1H), 7.12 - 6.98 (m, 2H), 5.51 - 5.27 (m, 3H), 5.06 -5.02, 4.55 - 4.43 (m, 1H total), 4.28 - 4.22, 3.81 - 3.72 (m, 1H total), 3.98, 3.94 (s, 3H total), 3.58 - 3.47, 2.99 - 2.89 (m, 1H total), 1.86 - 1.26 (m, 6H); LCMS (ESI): m / z 426.2 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 84:16. Example 20 2-(4-(difluoromethoxy)phenyl)-1-((R)-2-((S)-hydroxy(4-methoxypyridin-3- yl)methyl)piperidin-1-yl)ethan-1-oneTo a solution of 2-(4-(difluoromethoxy)phenyl)acetic acid (78.13 mg, 1 eq) and (S)-(4- methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride (100 mg, 386.48 μmol, 1 eq) and DIEA (199.80 mg, 1.55 mmol, 4 eq) in DCM (5 mL) was added HATU (176.34 mg, 463.78 μmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hr. LCMS (RT = 2.083 min, [M+H]+= 407.2) showed 62% of the desired product. The reaction mixture was quenched with saturated NaHCO3(50 mL). The resulting mixture was extracted with ethyl acetate (200 mL × 3) and the combined organic layer was washed with brine (150 mL × 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Welch Xtimate - 123 -CTQ-01425 C18150 mm X 40 mm X 10 µm; acetonitrile (33-63% gradient) / water-NH4OH-NH4HCO3) to afford the title compound (97.97 mg, 61%) as a white solid.

[0292] 1H NMR (400 MHz, CD3OD): δ 8.64 - 8.43 (m, 2H), 7.11 - 6.88 (m, 6H), 5.45- 5.34 (m, 1H), 5.13 - 5.02, 4.52 - 4.42 (m, 1H total), 4.20 - 4.10, 3.75 - 3.62 (m, 1H total), 3.95, 3.80 (s, 3H total), 3.46 - 3.35 (m, 1H), 3.30 - 3.15 (m, 1H), 3.10 - 2.95 (m, 1H), 2.32 - 2.22 (m, 1H), 1.93 - 1.79 (m, 1H), 1.76 - 1.30 (m, 4H); LCMS (ESI): m / z 429.1 (M+Na)+. SFC (Chiralcel OD-3; CO2 / ethanol (0.05% DEA)) showed 14:86. Example 21 1-((R)-2-((S)-hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2-(2- isopropylpyrimidin-5-yl)ethan-1-oneStep 1: 5-bromo-2-(prop-1-en-2-yl)pyrimidine

[0293] To a mixture of 5-bromo-2-iodopyrimidine (2.0 g, 7.02 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.18 g, 7.02 mmol, 1 eq) in dioxane (50 - 124 -CTQ-01425 mL) and H2O (10 mL) was added Pd(dppf)Cl2 (513.69 mg, 702.05 μmol, 0.1 eq) and Cs2CO3 (6.86 g, 21.06 mmol, 3 eq). The solution was degassed and purged with N2for 3 times. The mixture was stirred at 90 °C for 3hr under N2 atmosphere. TLC (10% ethyl acetate in petroleum ether) showed new spots. The reaction mixture was quenched with H2O (50 mL). The resulting mixture was extracted with ethyl acetate (200 mL × 3) and the combined organic layer was washed with brine (150 mL × 5). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (100% ethyl acetate in petroleum ether) to afford the title compound (896 mg, 64%) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 2H), 6.38 (s, 1H), 5.60 (s, 1H), 2.15 (s, 3H). Step 2: tert-butyl 2-(2-(prop-1-en-2-yl)pyrimidin-5-yl)acetate

[0294] (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide: To a solution of Zn (2.670 g,40.83 mmol, 3.98 eq) in THF (25 mL) was added chloro(trimethyl)silane (222.79 mg, 2.05 mmol, 0.26 mL, 0.2 eq), then tert-butyl 2-bromoacetate (2.0 g, 10.25 mmol, 1.51 mL, 1 eq) in THF (5 mL) was added into it. The mixture was stirred at 25 °C for 1 hr. Then the mixture was stirred at 45 °C for 1 hr. At last, the mixture was stirred at 25 °C for 0.5 hr.

[0295] To a mixture of 5-bromo-2-(prop-1-en-2-yl)pyrimidine (1.0 g, 5.02 mmol, 1eq), (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (0.32 M in THF, 31.40 mL, 2 eq) in THF (15 mL) was added Pd2(dba)3(230.02 mg, 251.20 μmol, 0.05 eq) and X-phos (239.50 mg, 502.39 μmol, 0.1 eq), and then the mixture was stirred at 70 °C for 16 hr under N2 atmosphere. LCMS (RT= 0.810 min, [M+H]+= 235.2) showed 40% of desired product. The reaction mixture was diluted with saturated NH4Cl (50 mL) and the solution was stirred for 30 mins. The resulting mixture was extracted with ethyl acetate (200 mL × 3) and the combined organic layer was washed with brine (150 mL × 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 1% ethyl acetate in petroleum ether) to afford the title compound (892 mg, 76%) as a yellow oil.1H NMR (400 MHz, DMSO-d6): δ 8.68 (s, 2H), 6.36 (s, 1H), 5.52 (s, 1H), 3.67 (s, 2H), 2.16 (s, 3H), 1.41 (s, 9H); LCMS (ESI): m / z 235.2 (M+H)+. - 125 -CTQ-01425Step 3: tert-butyl 2-(2-isopropylpyrimidin-5-yl)acetate

[0296] To a solution of tert-butyl 2-(2-(prop-1-en-2-yl)pyrimidin-5-yl)acetate (0.89 g,3.80 mmol, 1 eq) in EtOH (10 mL) was added 10% Pd / C (0.2 g). The mixture was stirred at 25 °C for 16 hr under H2atmosphere. LCMS (RT=0.781 min [M+H]+= 237.2) showed 66% of desired product. The reaction mixture was filtered and concentrated under reduced pressure to afford the title compound (898 mg, crude) as a white solid.Step 4: 2-(2-isopropylpyrimidin-5-yl)acetic acid

[0297] To a solution of tert-butyl 2-(2-isopropylpyrimidin-5-yl)acetate (0.897 g, 3.80mmol, 1 eq) was added TFA (5 mL) and DCM (5 mL). The mixture was stirred at 25 °C for 4 hr. (RT=0.476 min [M+H]+= 181.1) showed 86% of desired product. The reaction mixture was filtered and concentrated under reduced pressure to afford the title compound (297 mg, crude) as a yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.65 (s, 2H), 3.66 (s, 2H), 3.15 - 3.04 (m, 1H), 1.26 (d, J = 6.8 Hz, 6H); LCMS (ESI): m / z 181.1 (M+H)+.Step 5: 1-((R)-2-((S)-hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2-(2-isopropylpyrimidin-5-yl)ethan-1-oneTo a solution of 2-(2-isopropylpyrimidin-5-yl)acetic acid (75.36 mg, 347.83 μmol, 0.9 eq), (S)-(4-methoxypyridin-3-yl)((R)-piperidin-2-yl)methanol hydrochloride (100 mg, 386.48 μmol, 1 eq) and DIEA (249.75 mg, 1.93 mmol, 5 eq) in DCM (5 mL) was added HATU (176.34 mg, 463.78 μmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hr. LCMS (RT =1.370 min, [M+H]+=385.2) showed 29% of the desired product. The reaction mixture was adjusted with saturated NaHCO3 (50mL). The resulting mixture was extracted with ethyl acetate (200 mL × 3) and the combined organic layer was washed with brine (150 mL × 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Welch Xtimate - 126 -CTQ-01425 C18150 mm X 30 mm; acetonitrile (18-48% gradient over 7 min) / water-NH4OH-NH4HCO3) to afford the title compound (92.6 mg, 62%) as a white solid.

[0298] 1H NMR (400 MHz, CD3OD): δ 8.69 - 8.18 (m, 4H), 7.10 - 6.90 (m, 1H), 5.50- 5.36 (m, 1H), 5.02 - 4.98, 4.48 - 4.39 (m, 1H total), 4.26 - 4.18, 3.86 - 3.77 (m, 1H total), 3.90 (s, 3H), 3.67 - 3.38, 2.94 - 2.86, (m, 3H total), 3.20 - 3.05 (m, 1H), 2.41 - 2.20 (m, 1H), 1.95 - 1.68 (m, 3H), 1.64 - 1.42 (m, 2H), 1.31 - 1.24 (m, 6H); LCMS (ESI): m / z 385.2 (M+H)+. SFC (Chiralcel OD-3; CO2 / ethanol (0.05% DEA)) showed 17:83. Example 22 2-(3,4-dichlorophenyl)-1-((2S)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1- yl)ethan-1-one (2 compounds)To a solution of (4-methoxypyridin-3-yl)((S)-piperidin-2-yl)methanol hydrochloride (321 mg, 1.24 mmol, 1 eq) and 2-(3,4-dichlorophenyl)acetic acid (254.37 mg, 1.24 mmol, 1 eq) in DCM (5 mL) was added HATU (566.06 mg, 1.49 mmol, 1.2 eq) and DIEA (481.02 mg, 3.72 mmol, 0.65 mL, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. LCMS (RT = 0.637 min &0.652 min, [M+1]+= 409.0) showed 33% & 30% of desired product. The residue was diluted with water (10 mL) and extracted with dichloromethane (30 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 40% EE (Ethyl acetate: Ethanol =3:1) in petroleum ether) to afford the compound (507 mg, crude) as yellow oil. The crude was purified by reverse phase chromatography (Welch Xtimate C1880 mm X 30 mm X 5 µm; acetonitrile (40-60% gradient) / water-NH4OH-NH4HCO3) and separated by chiral SFC (Phenomenex-Cellulose-2 (250mm*30mm,10um);mobile phase: [CO2-EtOH(0.1%NH3H2O)];B%:40%, isocratic elution mode) to afford the first compound (the first peak, 111 mg, 22%) as a white solid and the second compound (the second peak, 66 mg, 13%) as a white solid.

[0299] The first compound: 1H NMR (400 MHz, CDCl3): δ 8.63 - 8.29 (m, 2H), 7.33- 7.29 (m, 1H), 7.05 - 7.03 (m, 1H), 6.81 - 6.63 (m, 2H), 5.38 - 4.60 (m, 2H), 3.93 - 3.88 (m, 3H), 3.51 - 2.98 (m, 4H), 2.28 - 2.20 (m, 1H), 1.81 - 1.56 (m, 4H), 1.35 - 1.12 (m, 2H); - 127 -CTQ-01425 LCMS (ESI): m / z 409.0 (M+H)+. SFC (Cellulose-2; CO2 / ethanol (0.05% DEA)) showed one peak.

[0300] The second compound: 1H NMR (400 MHz, CDCl3): δ 8.62 - 8.41 (m, 2H),7.32 - 7.27 (m, 1H), 7.05 - 7.00 (m, 1H), 6.81 - 6.63 (m, 2H), 5.37 - 4.54 (m, 2H), 3.93 - 3.88 (m, 3H), 3.54 - 2.98 (m, 4H), 2.28 - 2.22 (m, 1H), 1.80 - 1.55 (m, 4H), 1.35 - 1.12 (m, 2H); LCMS (ESI): m / z 409.1 (M+H)+. SFC (Cellulose-2; CO2 / ethanol (0.05% DEA)) showed one peak. Example 23 1-((2S)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2-(6- (trifluoromethyl)pyridin-3-yl)ethan-1-one (2 compounds)To a solution of (4-methoxypyridin-3-yl)((S)-piperidin-2-yl)methanol hydrochloride (200 mg, 772.97 μmol, 1 eq) and 2-(6-(trifluoromethyl)pyridin-3-yl)acetic acid (158.56 mg, 772.97 μmol, 1 eq) in DCM (2 mL) was added HATU (352.69 mg, 927.56 μmol, 1.2 eq) and DIEA (299.70 mg, 2.32 mmol, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. LCMS (RT = 1.455 min & 1.586 min, [M+1]+= 410.2) showed 44% & 43% of desired product. The residue was diluted with water 10 mL and extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with saturated NaHCO3(20mL × 3), filtered and concentrated under reduced pressure to give a residue. The mixture was purified by reverse phase chromatography (Welch Xtimate C1880 mm X 30 mm X 5 µm; acetonitrile (35-55% gradient) / water-NH4OH-NH4HCO3) to afford the first compound (the first peak, 66.23 mg, 21%) and the second compound (the second peak, 45.4 mg, 14%) both as white solids.

[0301] The first compound: 1H NMR (400 MHz, CDCl3): δ 8.69 - 8.22 (m, 3H), 7.59- 7.51 (m, 1H), 7.30 - 7.28 (m, 1H), 6.85 - 6.72 (m, 1H), 5.44 - 5.08 (m, 1H), 5.00 - 4.53 (m, 1H), 3.93, 3.92 (s, 3H total), 3.65 - 3.02 (m, 4H), 2.35 - 2.23 (m, 1H), 1.86 - 1.71 (m, 4H), 1.56 - 1.38 (m, 2H); LCMS (ESI): m / z 410.1 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 59:41.

[0302] The second compound: 1H NMR (400 MHz, CDCl3): δ 8.62 (s, 1H), 8.59 -8.38 (m, 2H), 7.88 - 7.82 (m, 1H), 7.70 - 7.63 (m, 1H), 6.89 - 6.83 (m, 1H), 5.39 - 5.11 (m, 1H), 5.03 - 4.62 (m, 1H), 4.30 - 3.73 (m, 6H), 3.51 - 3.36 (m, 1H), 1.86 - 1.73 (m, 2H), 1.70 - - 128 -CTQ-01425 1.61 (m, 2H), 1.54 - 1.40 (m, 2H), 1.37 - 1.24 (m, 1H); LCMS (ESI): m / z 410.1 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 39:61. Example 24 1-((2S)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2-(4- (trifluoromethyl)phenyl)ethan-1-one (2 compounds)To a solution of (4-methoxypyridin-3-yl)((S)-piperidin-2-yl)methanol hydrochloride (500 mg, 1.93 mmol, 1 eq) and 2-(4-(trifluoromethyl)phenyl)acetic acid (394.49 mg, 1.93 mmol, 1 eq) in DCM (10 mL) was added HATU (881.71 mg, 2.32 mmol, 1.2 eq) and DIEA (749.25 mg, 5.80 mmol, 1.01 mL, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 2.355 min & 2.463 min, [M+1]+= 409.2) showed 13% & 65% of desired product. The residue was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm; acetonitrile (37-67% gradient) / water-NH4OH-NH4HCO3) to afford the first compound (the first peak, 60.01 mg, 19%) as a white solid and the second compound (the second peak, 252.14 mg, 82%) as a white solid.

[0303] The first compound: 1H NMR (400 MHz, CDCl3): δ 8.66, 8.43 (s, 1H), 8.43,8.29 (d, J = 5.2 Hz, 1H), 7.56, 7.50 (d, J = 8.0 Hz, 2H), 7.14 - 7.08 (d, J = 8.0 Hz, 1H), 7.03, 6.88 (d, J = 8.0 Hz, 2H), 5.48 - 5.30 (m, 1H), 5.08 - 5.04, 4.38 - 4.33 (m, 1H total), 4.08 - 4.03, 3.29 - 3.03 (m, 2H total), 3.92, 3.78 (s, 3H), 3.72 - 3.51 (m, 2H), 2.31 - 2.25 (m, 1H), 1.91 - 1.78 (m, 1H), 1.76 - 1.59 (m, 2H), 1.58 - 1.27 (m, 2H); LCMS (ESI): m / z 409.5 (M+H)+. SFC (Chiralpak AD-3; CO2 / isopropanol (0.05% DEA)) showed 85:15.

[0304] The second compound: 1H NMR (400 MHz, CDCl3): δ 8.52, 8.47 (s, 1H),8.39, 8.35 (d, J = 5.2 Hz, 1H), 7.64 - 7.59 (m, 2H), 7.46, 7.41 (d, J = 8.0 Hz, 2H), 7.10, 7.04 (d, J = 5.2 Hz, 1H), 5.48 - 5.45 (m, 1H), 5.04 - 4.94, 4.60 - 4.56 (m, 1H total), 4.31 - 3.77 (m, 6H), 3.45 - 3.40, 2.93 - 2.90 (m, 1H total), 1.91 - 1.68 (m, 2H), 1.56 - 1.27 (m, 4H); LCMS - 129 -CTQ-01425 (ESI): m / z 409.5 (M+H)+. SFC (Chiralpak AD-3; CO2 / isopropanol (0.05% DEA)) showed 99:1. Example 25 1-((2S)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2-(p-tolyl)ethan-1-one (2 compounds)To a solution of (4-methoxypyridin-3-yl)((S)-piperidin-2-yl)methanol hydrochloride (500 mg, 1.93 mmol, 1 eq) and 2-(p-tolyl)acetic acid (290.20 mg, 1.93 mmol, 1 eq) in DCM (10 mL) was added HATU (881.71 mg, 2.32 mmol, 1.2 eq) and DIEA (749.25 mg, 5.80 mmol, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 2.146 min & 2.271 min, [M+1]+= 355.3) showed 15% & 39% of desired product. The residue was diluted with water (10 mL) and extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with saturated NaHCO3 (20 mL × 3), filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm X 5 µm; acetonitrile (33-63% gradient) / water-NH4OH- NH4HCO3) to afford the first compound (the first peak, 28.76 mg, 4%) as a white solid and the second compound (the second peak, 162.3 mg, 23%) as a white solid.

[0305] The first compound: 1H NMR (400 MHz, CDCl3): δ 8.63 - 8.45 (m, 1H), 8.35- 8.21 (m, 1H), 7.13 - 7.01 (m, 2H), 6.98 - 6.70 (m, 3H), 5.36 - 5.15 (m, 1H), 4.98 - 4.56 (m, 1H), 3.98 (s, 3H), 3.59 - 3.41 (m, 2H), 3.32 - 2.71 (m, 2H), 2.32 (s, 3H), 2.25 - 2.10 (m, 1H), 1.84 - 1.67 (m, 1H), 1.66 - 1.31 (m, 3H), 1.29 - 1.08 (m, 1H); LCMS (ESI): m / z 355.1 (M+H)+. SFC ((S,S)Whelk-01; CO2 / ethanol (0.05% DEA)) showed 74:26.

[0306] The second compound: 1H NMR (400 MHz, CDCl3): δ 8.52 - 8.44 (m, 1H),8.40 - 8.35 (m, 1H), 7.17 - 7.03 (m, 5H), 5.39 - 5.34 (m, 1H), 4.61 - 4.09 (m, 2H), 3.96, 3.95 (s, 3H total), 3.85 - 3.66 (m, 2H), 3.43 - 3.40, 2.91 - 2.86 (m, 1H total), 2.23 (s, 3H), 1.88 - 1.56 (m, 2H), 1.49 - 1.00 (m, 4H); LCMS (ESI): m / z 355.1 (M+H)+. SFC ((S,S)Whelk-01; CO2 / ethanol (0.05% DEA)) showed 78:22. Example 26 - 130 -CTQ-01425 2-(4-chlorophenyl)-1-((2S)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1- yl)ethan-1-one (2 compounds)To a solution of (4-methoxypyridin-3-yl)((S)-piperidin-2-yl)methanol hydrochloride (500 mg, 1.93 mmol, 1 eq) and 2-(4-chlorophenyl)acetic acid (329.66 mg, 1.93 mmol, 1 eq) in DCM (10 mL) was added HATU (881.71 mg, 2.32 mmol, 1.2 eq) and DIEA (749.25 mg, 5.80 mmol, 1.01 mL, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 2.191 min & 2.336 min, [M+1]+= 375.2) showed 17% & 41% of desired product. The residue was diluted with water (10 mL) and extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with saturated NaHCO3(20 mL × 3), filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm X 5 µm; acetonitrile (33-63% gradient) / water-NH4OH-NH4HCO3) to afford the first compound (the first peak, 28.76 mg, 4%) as a white solid and the second compound (the second peak, 162.3 mg, 23%) as a white solid.

[0307] The first compound: 1H NMR (400 MHz, CDCl3): δ 8.63 - 8.45 (m, 1H), 8.30,8.20 (s, 1H total), 7.25 - 7.18 (m, 2H), 6.98 - 6.78 (m, 3H), 5.36 - 5.15 (m, 1H), 4.98 - 4.56 (m, 1H), 3.95 - 3.92 (m, 3H), 3.59 - 2.81 (m, 4H), 2.20 - 2.10 (m, 1H), 1.80 - 1.67 (m, 1H), 1.65 - 1.31 (m, 3H), 1.29 - 1.08 (m, 1H); LCMS (ESI): m / z 375.0 (M+H)+. SFC ((S,S)Whelk- 01; CO2 / ethanol (0.05% DEA)) showed 100:0.

[0308] The second compound: 1H NMR (400 MHz, CDCl3): δ 8.51 - 8.44 (m, 1H),8.40 - 8.35 (m, 1H), 7.33 - 7.18 (m, 4H), 7.09 - 7.03 (m, 1H), 5.39 - 5.35 (m, 1H), 4.61 - 4.55, 4.31 - 4.28 (m, 1H total), 3.98 - 3.90 (m, 4H), 3.85 - 3.74 (m, 2H), 3.43 - 3.39, 2.92 - 2.88 (m, 1H total), 1.84 - 1.56 (m, 2H), 1.50 - 1.10 (m, 4H); LCMS (ESI): m / z 375.0 (M+H)+. SFC ((S,S)Whelk-01; CO2 / ethanol (0.05% DEA)) showed 80:20. Example 27 2-(3,4-dichlorophenoxy)-1-((2S)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)piperidin-1- yl)ethan-1-one (2 compounds) - 131 -CTQ-01425To a solution of (4-methoxypyridin-3-yl)((S)-piperidin-2-yl)methanol hydrochloride (500 mg, 1.93 mmol, 1 eq) and 2-(3,4-dichlorophenoxy)acetic acid (427.14 mg, 1.93 mmol, 1 eq) in DCM (10 mL) was added DIEA (749.25 mg, 5.80 mmol, 1.01 mL, 3 eq) and HATU (881.71 mg, 2.32 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 2.425 min & 2.538 min, [M+1]+= 425.2) showed 7% & 39% of desired product. The residue was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 25 mm X 5 µm; acetonitrile (40-70% gradient) / water-NH4HCO3) to afford the first compound (the first peak, 38.35 mg, 12%) as a white solid and the second compound (the second peak, 176.21 mg, 58%) as a white solid.

[0309] The first compound: 1H NMR (400 MHz, CD3OD): δ 8.70 - 8.15 (m, 2H),7.35 - 7.28 (m, 1H), 7.13 - 6.75 (m, 2H), 6.68 - 6.57 (m, 1H), 5.48 - 5.19 (m, 1H), 4.98 - 4.94, 4.44 - 4.38 (m, 1H total), 4.71 - 4.51 (m, 2H), 4.03 - 3.98, 3.68 - 3.64 (m, 1H total), 3.94 - 3.88 (m, 3H), 3.41 - 3.35, 3.16 - 3.09 (m, 1H total), 2.44 - 2.22 (m, 1H), 1.93 - 1.82 (m, 1H), 1.80 - 1.38 (m, 4H); LCMS (ESI): m / z 425.0 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 15:85.

[0310] The second compound: 1H NMR (400 MHz, CD3OD): δ 8.55 - 8.40 (m, 2H),7.40 - 7.34 (m, 1H), 7.21 - 7.03 (m, 2H), 6.98 - 6.82 (m, 1H), 5.43 - 5.40 (m, 1H), 5.22 - 5.18, 4.78 - 4.75 (m, 1H total), 5.12 - 5.03 (m, 1H), 4.48 - 4.40 (m, 1H), 4.20 - 4.17 (m, 1H), 3.96 (s, 3H), 3.36 - 3.31 (m, 1H), 2.97 - 2.90 (m, 1H), 2.00 - 1.74 (m, 2H), 1.63 - 1.21 (m, 4H); LCMS (ESI): m / z 425.0 (M+H)+. SFC (Chiralpak AD-3; CO2 / isopropanol (0.05% DEA)) showed 15:85. Example 28 (R)-2-(3,4-dichlorophenyl)-1-(2-((4-methoxypyridin-3-yl)methyl)piperidin-1-yl)ethan-1- one - 132 -CTQ-01425

[0311] To a solution of (R)-4-methoxy-3-(piperidin-2-ylmethyl)pyridine (90 mg,436.29 μmol, 1 eq) and 2-(3,4-dichlorophenyl)acetic acid (107.35 mg, 523.55 μmol, 1.2 eq) in DCM (2 mL) was added HATU (199.07 mg, 523.55 μmol, 1.2 eq) and DIEA (169.16 mg, 1.31 mmol, 0.23 mL, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 2.677 min, [M+1]+= 393.1) showed 77% of desired product. The residue was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18 150 mm X 30 mm; acetonitrile (45-75% gradient) / water-NH4OH-NH4HCO3) to afford the title compound (97.78 mg, 57%) as a yellow oil.

[0312] 1H NMR (400 MHz, CD3OD): δ 8.36 - 8.27 (m, 1H), 8.19, 8.13 (s, 1H total),7.42 - 7.40 (m, 1H), 7.39, 7.37 (s, 1H total), 7.07 - 6.83 (m, 2H), 5.15 - 5.10, 4.49 - 4.28 (m, 1H total), 4.38 - 4.35, 3.81 - 3.73 (m, 1H total), 3.96, 3.89 (s, 3H total), 3.60 - 3.58 (m, 1H), 3.52 - 3.32 (m, 1H), 3.25 - 3.13 (m, 1H), 3.07 - 2.97 (m, 1H), 2.96 - 2.78 (m, 1H), 1.94 - 1.77 (m, 1H), 1.77 - 1.46 (m, 4H), 1.44 - 1.28 (m, 1H). LCMS (ESI): m / z 393.1 (M+H)+. SFC (Chiralcel OD-3; CO2 / ethanol (0.05% DEA)) showed 13:87. Example 29 (R)-1-(2-((4-methoxypyridin-3-yl)methyl)piperidin-1-yl)-2-(4- (trifluoromethyl)phenoxy)ethan-1-oneTo a solution of (R)-4-methoxy-3-(piperidin-2-ylmethyl)pyridine (90 mg, 436.29 μmol, 1 eq) and 2-(4-(trifluoromethyl)phenoxy)acetic acid (115.26 mg, 523.55 μmol, 1.2 eq) in DCM (2 mL) was added HATU (199.07 mg, 523.55 μmol, 1.2 eq) and DIEA (169.16 mg, 1.31 mmol, - 133 -CTQ-01425 3 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 2.632 min, [M+1]+= 409.2) showed 72% of desired product. The residue was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm; acetonitrile (45-75% gradient) / water-NH4OH-NH4HCO3) to afford the title compound (85.93 mg, 47%) as a white solid.1H NMR (400 MHz, CD3OD): δ 8.33 - 8.20 (m, 2H), 7.56 - 7.50 (m, 2H), 7.12 - 7.05 (m, 1H), 6.89 - 6.77 (m, 2H), 5.10 - 5.05, 4.79 - 4.67 (m, 2H total), 4.47 - 4.42, 3.76 - 3.67 (m, 1H total), 4.36 - 4.21 (m, 1H), 3.98, 3.92 (s, 3H total), 3.51 - 3.41, 3.27 - 3.20 (m, 1H total), 3.15 - 3.06 (m, 1H), 3.05 - 2.83 (m, 1H), 2.03 - 1.86 (m, 1H), 1.84 - 1.78 (m, 1H), 1.77 - 1.71 (m, 2H), 1.70 - 1.58 (m, 1H), 1.55 - 1.28 (m, 1H); LCMS (ESI): m / z 409.1 (M+H)+. SFC (Chiralcel OD-3; CO2 / ethanol (0.05% DEA)) showed 7:93. Example 30 2-(3,4-dichlorophenyl)-N-((2R)-1-hydroxy-1-(4-methoxypyridin-3-yl)propan-2-yl)-N- propylacetamide (2 compounds)

[0313] To a mixture of (2R)-1-(4-methoxypyridin-3-yl)-2-(propylamino)propan-1-ol(250 mg, 1.11 mmol, 1 eq) and 2-(3,4-dichlorophenyl)acetic acid (274.24 mg, 1.34 mmol, 1.2 eq) in DCM (5 mL) was added DIEA (432.15 mg, 3.34 mmol, 0.58 mL, 3 eq) and HATU (508.56 mg, 1.34 mmol, 1.2 eq) at 0 °C. The reaction was stirred at 0 °C for 1 h. LCMS (RT = 0.432 min, [M+H]+= 411.1) showed of 68% desired product. The mixture was quenched with water (20 mL), extracted with ethyl acetate (50 mL × 2). The organic layers were combined, washed with 1N NaOH (20 mL × 2) and brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0 - 50% (ethyl acetate / EtOH = 3:1) in petroleum ether) and the crude was further purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm; acetonitrile (20 -50% gradient over 7 min) / water (FA)) to afford the first compound (the first peak, 69 mg, 24%) as a white solid and the second compound (the second peak, 124 mg, 41%) as a white solid. - 134 -CTQ-01425

[0314] The first compound: 1H NMR (400 MHz, CD3OD): δ 8.57 - 8.45 (m, 2H),7.46 - 7.34 (m, 3H), 7.19 - 6.96 (m, 1H), 5.15 - 4.95 (m, 1H), 4.32 - 4.29, 3.90 - 3.72 (m, 1H total), 4.09 - 4.06 (m, 3H), 3.67 - 3.40 (m, 2H), 3.29 - 3.03 (m, 2H), 1.61 - 1.45 (m, 2H), 1.42 - 0.99 (m, 3H), 0.94 - 0.90 (m, 3H); LCMS (ESI): m / z 411.0 (M+H)+. SFC (Chiralcel OD-3; CO2 / isopropanol (0.05% DEA)) showed 87:13.

[0315] The second compound: 1H NMR (400 MHz, CD3OD): δ 8.55 - 8.36 (m, 2H),7.45 - 7.00 (m, 4H), 5.14 - 5.10 (m, 1H), 4.27 - 4.11 (m, 1H), 3.97, 3.94 (s, 3H total), 3.76 - 3.43 (m, 2H), 3.29 - 3.11 (m, 2H), 1.64 - 1.41 (m, 2H), 1.34 - 1.18 (m, 3H), 0.96 - 0.87 (m, 3H); LCMS (ESI): m / z 411.0 (M+H)+. SFC (Chiralcel OD-3; CO2 / isopropanol (0.05% DEA)) showed 14:86. Example 31 N-((2R)-1-hydroxy-1-(4-methoxypyridin-3-yl)propan-2-yl)-N-propyl-2-(4- (trifluoromethyl)phenyl)acetamide (2 compounds)To a solution of (2R)-1-(4-methoxy-3-pyridyl)-2-(propylamino)propan-1-ol (300 mg, 1.34 mmol, 1 eq) and 2-(4-(trifluoromethyl)phenyl)acetic acid (273.05 mg, 1.34 mmol, 1 eq) in DCM (10 mL) was added DIEA (518.58 mg, 4.01 mmol, 3 eq) and HATU (610.27 mg, 1.61 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS (RT = 3.842 min, [M+H]+= 411.2) showed 66% of desired product. The mixture was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with brine (30 mL × 2), dried over sodium sulfate, filtered and concentrated to provide a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C1880 mm X 30 mm X 5 µm; acetonitrile (45-75% gradient) / water-NH4OH-NH4HCO3) to afford the first compound (the first peak, 55 mg, 10%) as a yellow solid and the second compound (the second peak, 70 mg, 23%) as a white solid.

[0316] The first compound: 1H NMR (400 MHz, CD3OD): δ 8.44 - 8.33 (m, 2H),7.76 - 7.56 (m, 2H), 7.40 - 7.21 (m, 2H), 7.10 - 6.95 (m, 1H), 5.23 - 4.92 (m, 1H), 4.41 - 3.86 (m, 4H), 3.85 - 3.55 (m, 2H), 3.52 - 3.37 (m, 1H), 3.22 - 3.09 (m, 1H), 1.92 - 1.43 (m, 2H), 1.38 - 0.94 (m, 3H), 0.94 - 0.82 (m, 3H); LCMS (ESI): m / z 411.1 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 62:2:32:4. - 135 -CTQ-01425

[0317] The second compound:1H NMR (400 MHz, CD3OD): δ 8.54 - 8.33 (m, 2H)7.59 - 7.50 (m, 2H), 7.37 - 7.20 (m, 2H), 7.14 - 6.95 (m, 1H), 5.18 - 5.10 (m, 1H), 4.40 - 3.86 (m, 4H), 3.82 - 3.44 (m, 2H), 3.25 - 3.11 (m, 2H), 1.81 - 1.40 (m, 2H), 1.38 - 1.09 (m, 3H), 0.95 - 0.87 (m, 3H); LCMS (ESI): m / z 411.1 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 9:39:9:43. Example 32 N-((2R)-1-hydroxy-1-(4-methoxypyridin-3-yl)propan-2-yl)-N-propyl-2-(5- (trifluoromethyl)pyridin-2-yl)acetamideTo a solution of (2R)-1-(4-methoxy-3-pyridyl)-2-(propylamino)propan-1-ol (500 mg, 2.23 mmol, 1 eq) and 2-(5-(trifluoromethyl)pyridin-2-yl)acetic acid (457.28 mg, 2.23 mmol, 1 eq) in DCM (10 mL) was added DIEA (864.31 mg, 6.69 mmol, 1.16 mL, 3 eq) and HATU (1.02 g, 2.68 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS (RT = 3.244 min, [M+H]+= 412.2) showed 51% of desired product. The mixture was quenched with water (30 mL), extracted with DCM (30 mL × 3). The organic layers were combined, washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to provide a residue. The residue was purified by reverse phase chromatography (Phenomenex C1880 mm X 30 mm X 5 µm; acetonitrile (37-57% gradient) / water-NH4OH-NH4HCO3) to afford the title compound (200 mg, 22%) as a yellow oil.

[0318] 1H NMR (400 MHz, CD3OD): δ 8.79 - 8.74 (m, 1H), 8.60 - 8.20 (m, 2H), 8.07- 7.98 (m, 1H), 7.54 - 7.36 (m, 1H), 7.10 - 6.96 (m, 1H), 5.25 - 4.95 (m, 1H), 4.55 - 3.83 (m, 6H), 3.59 - 3.08 (m, 2H), 1.75 - 1.44 (m, 2H), 1.37 - 0.99 (m, 3H), 0.98 - 0.84 (m, 3H); LCMS (ESI): m / z 412.1 (M+H)+. SFC (Chiralpak AS-3; CO2 / ethanol (0.05% DEA)) showed 27:41:13:19. Example 33 N-((2R)-1-hydroxy-1-(4-methoxypyridin-3-yl)propan-2-yl)-N-propyl-2-(6- (trifluoromethyl)pyridin-3-yl)acetamide - 136 -CTQ-01425To a solution of (2R)-1-(4-methoxy-3-pyridyl)-2-(propylamino)propan-1-ol (500 mg, 2.23 mmol, 1 eq) and 2-(6-(trifluoromethyl)pyridin-3-yl)acetic acid (457.28 mg, 2.23 mmol, 1 eq) in DCM (10 mL) was added DIEA (864.31 mg, 6.69 mmol, 1.16 mL, 3 eq) and HATU (1.02 g, 2.68 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS (RT = 3.073 min & 3.164 min, [M+H]+= 412.2) showed 28% and 23% of desired product. The mixture was quenched with water (30 mL), extracted with DCM (30 mL × 3). The organic layers were combined, washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to provide a residue. The residue was purified by reverse phase chromatography (Phenomenex C1880 mm X 30 mm X 5 µm; acetonitrile (37-57% gradient) / water-NH4OH- NH4HCO3) to afford the title compound (180 mg, 20%) as a yellow oil.

[0319] 1H NMR (400 MHz, CD3OD): δ 8.57 - 8.29 (m, 3H), 7.93 - 7.71 (m, 2H), 7.11- 6.95 (m, 1H), 5.16 - 4.99 (m, 1H), 4.52 - 4.18 (m, 1H), 4.09 - 3.64 (m, 5H), 3.60 - 3.34 (m, 1H), 3.27 - 3.24 (m, 1H), 1.81 - 1.42 (m, 2H), 1.37 - 1.06 (m, 3H), 1.01 - 0.82 (m, 3H); LCMS (ESI): m / z 412.1 (M+H)+. SFC (Chiralpak AS-3; CO2 / ethanol (0.05% DEA)) showed 25:62:13. Example 34 N-(1-hydroxy-1-(4-methoxypyridin-3-yl)propan-2-yl)-N-propyl-2-(6- (trifluoromethyl)pyridin-3-yl)acetamide (4 compounds)

[0320] The compound N-(1-hydroxy-1-(4-methoxypyridin-3-yl)propan-2-yl)-N-propyl-2-(6-(trifluoromethyl)pyridin-3-yl)acetamide (160.82 mg, 0.388 mmol) was purified by SFC (DAICEL CHIRALPAK IG (250mm*30mm,10um), mobile phase: CO2- MeOH(0.1%NH3H2O)], B%: 40%) to afford the first compound (the first peak, 40 mg, 25%) as a yellow oil and the second compound (the second peak, 2 mg, 7.4%) as a yellow oil and a mixture of the third and fourth compounds, which was further purified by SFC (column: Phenomenex-Cellulose-2 (250mm*30mm,10um);mobile phase: [CO2- - 137 -CTQ-01425 EtOH(0.1%NH3H2O)];B%:25%, isocratic elution mode) to afford the third compound (the third peak, 4 mg, 3%) and the fourth compound (the fourth peak, 15 mg, 9%) as a yellow oil.

[0321] The first compound: 1H NMR (400 MHz, CD3OD): δ 8.57 - 8.29 (m, 3H),7.78 - 7.72 (m, 2H), 7.13 - 6.96 (m, 1H), 5.18 - 5.12 (m, 1H), 4.30 - 4.21 (m, 1H), 3.98 - 3.62 (m, 5H), 3.48 - 3.36 (m, 1H), 3.28 - 3.18 (m, 1H), 1.75 - 1.42 (m, 2H), 1.36 - 1.24 (m, 3H), 0.99 - 0.88 (m, 3H); LCMS (ESI): m / z 412.1 (M+H)+. SFC (Chiralpak IG-3; CO2 / methanol (0.05% DEA)) showed 99%ee.

[0322] The second compound: 1H NMR (400 MHz, CD3OD): δ 8.54 - 8.31 (m, 3H),7.86 - 7.70 (m, 2H), 7.12 - 6.95 (m, 1H), 5.24 - 4.95, 4.51 - 4.36 (m, 2H total), 4.08 - 3.70 (m, 5H), 3.58 - 3.38 (m, 1H), 3.27 - 3.09 (m, 1H), 1.78 - 1.44 (m, 2H), 1.33 - 1.04 (m, 3H), 0.94 - 0.88 (m, 3H); LCMS (ESI): m / z 412.1 (M+H)+. SFC (Chiralpak IG-3; CO2 / methanol (0.05% DEA)) showed 5:94.

[0323] The third compound: 1H NMR (400 MHz, CD3OD): δ 8.54 - 8.31 (m, 3H),7.95 - 7.69 (m, 2H), 7.12 - 6.93 (m, 1H), 5.35 - 4.97, 4.48 - 4.41 (m, 2H total), 4.11 - 3.89 (m, 4H), 3.87 - 3.71 (m, 1H), 3.52 - 3.44 (m, 1H), 3.23 - 3.15 (m, 1H), 2.24 - 1.50 (m, 2H), 1.34 - 1.29 (m, 3H), 0.97 - 0.89 (m, 3H); LCMS (ESI): m / z 412.1 (M+H)+. SFC (Chiralpak IG-3; CO2 / methanol (0.05% DEA)) showed 3:97.

[0324] The fourth compound: 1H NMR (400 MHz, CD3OD): δ 8.57 - 8.29 (m, 3H),7.76 - 7.70 (m, 2H), 7.12 - 6.95 (m, 1H), 5.17 - 5.14 (m, 1H), 4.33 - 4.25 (m, 1H), 4.00 - 3.57 (m, 5H), 3.55 - 3.33 (m, 1H), 3.29 - 3.16 (m, 1H), 1.75 - 1.39 (m, 2H), 1.34 - 1.25 (m, 3H), 0.99 - 0.88 (m, 3H); LCMS (ESI): m / z 412.1 (M+H)+. SFC (Chiralpak IG-3; CO2 / methanol (0.05% DEA)) showed 99%ee. Example 35 (R)-2-(3,4-dichlorophenyl)-N-(1-(4-methoxypyridin-3-yl)propan-2-yl)-N- propylacetamide - 138 -CTQ-01425Step 1: (4R)-5-(4-methoxypyridin-3-yl)-4-methyl-3-propyloxazolidin-2-one

[0325] To a mixture of (2R)-1-(4-methoxypyridin-3-yl)-2-(propylamino)propan-1-ol(445 mg, 1.98 mmol, 1 eq) and CDI (386.04 mg, 2.38 mmol, 1.2 eq) in dioxane (20 mL) was added DIEA (4.36 g, 33.72 mmol, 5.87 mL, 17 eq) in one portion at 25 °C. The mixture was stirred at 80 °C for 16 hours under N2. LCMS (RT = 1.878 min, [M+H]+= 251.2) showed 28% of desired product. The mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (20 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to afford the title compound (450 mg, crude) as a yellow oil. The crude product would be directly used in the next step without purification. LCMS (ESI): m / z 251.2 (M+H)+.Step 2: (R)-N-(1-(4-methoxypyridin-3-yl)propan-2-yl)propan-1-amine

[0326] To a mixture of (4R)-5-(4-methoxypyridin-3-yl)-4-methyl-3-propyloxazolidin-2-one (490 mg, 1.96 mmol, 1 eq) in EtOH (15 mL) was added 10% Pd / C (300 mg) in one portion at 25 °C. The mixture was stirred at 50 °C for 16 hours under H2(45 Psi). LCMS (RT = 2.636 min, [M+H]+= 209.2) showed 69% of desired product. The mixture was filtered and - 139 -CTQ-01425 concentrated in vacuum to afford the title compound (400 mg, crude) as a yellow oil. The crude product would be directly used in the next step without purification. Step 3: (R)-2-(3,4-dichlorophenyl)-N-(1-(4-methoxypyridin-3-yl)propan-2-yl)-N- propylacetamideTo a mixture of (R)-N-(1-(4-methoxypyridin-3-yl)propan-2-yl)propan-1-amine (400 mg, 1.33 mmol, 1 eq) and 2-(3,4-dichlorophenyl)acetic acid (326.01 mg, 1.59 mmol, 1.2 eq) in DCM (5 mL) was added DIEA (513.75 mg, 3.98 mmol, 3 eq) and HATU (604.57 mg, 1.59 mmol, 1.2 eq) in one portion at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 2.953 min, [M+H]+= 396.2) showed 37% of desired product. The mixture was diluted with H2O (15 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (20 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by reverse phase chromatography (Welch Xtimate C18 150 mm X 30 mm X 5 µm; acetonitrile (33-63% gradient) / water-NH4HCO3) to afford the title compound (113.26 mg, 21%) as a colorless oil.

[0327] 1H NMR (400 MHz, CDCl3): δ 8.44 - 8.33 (m, 1H), 8.18 (d, J = 7.2 Hz, 1H),7.35 (t, J = 7.6 Hz, 1H), 7.24 - 7.19 (m, 1H), 6.94 (dd, J = 8.4, 1.6 Hz, 1H), 6.83 - 6.76 (m, 1H), 4.54 - 4.39, 4.21 - 4.06 (m, 1H total), 3.90, 3.88 (s, 3H total), 3.56 - 3.43 (m, 2H), 3.42 - 3.36, 3.12 - 2.95 (m, 2H total), 2.94 - 2.63 (m, 2H), 1.82 - 1.47 (m, 2H), 1.22 - 1.12 (m, 3H), 0.95 - 0.89 (m, 3H); LCMS (ESI): m / z 395.1 (M+H)+. SFC (Chiralcel OJ-H; CO2 / ethanol (0.05% DEA)) showed 68:32. Example 36 2-(3,4-dichlorophenyl)-N-((2S)-1-hydroxy-1-(4-methoxypyridin-3-yl)propan-2-yl)-N- propylacetamide (2 compounds)To a mixture of (2S)-1-(4-methoxypyridin-3-yl)-2-(propylamino)propan-1-ol (170 mg, 757.92 μmol, 1 eq) and 2-(3,4-dichlorophenyl)acetic acid (186.48 mg, 909.50 μmol, 1.2 eq) - 140 -CTQ-01425 in DCM (5 mL) was added DIEA (293.86 mg, 2.27 mmol, 0.40 mL, 3 eq) and HATU (345.82 mg, 909.50 μmol, 1.2 eq) at 0 °C. The reaction was stirred at 0 °C for 1 h. LCMS (RT = 0.458 min, [M+H]+= 411.1) showed 47% desired product. The mixture was quenched with water (20 mL), extracted with ethyl acetate (50 mL × 2). The organic layers were combined, washed with 1N NaOH (20 mL × 2), brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0 - 50%(ethyl acetate / EtOH=3:1) in petroleum ether) and the residue was further purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm; acetonitrile (22-52% gradient over 6 min) / water (FA)) to afford the first compound (the first peak, 51.39 mg, 22%) as a white solid and the second compound (the second peak, 81.72 mg, 35%) as a white solid.

[0328] The first compound: 1H NMR (400 MHz, CD3OD): δ 8.59 - 8.47 (m, 2H),7.49 - 7.22 (m, 3H), 7.17 - 6.97 (m, 1H), 5.28 - 4.97, 4.34 - 4.31 (m, 2H), 4.13, 4.10 (s, 3H total), 3.92 - 3.45 (m, 3H), 3.28 - 3.13 (m, 1H), 1.65 - 1.46 (m, 2H), 1.41 - 1.36 (m, 3H), 0.97 - 0.92 (m, 3H); LCMS (ESI): m / z 411.0 (M+H)+. SFC (Chiralcel OD-3; CO2 / isopropanol (0.05% DEA)) showed 10:90.

[0329] The second compound: 1H NMR (400 MHz, CD3OD): δ 8.58 - 8.39 (m, 2H),7.46 - 7.43 (m, 1H), 7.30 - 7.04 (m, 3H), 5.17 - 5.12 (m, 1H), 4.37 - 4.12 (m, 1H), 3.98, 3.96 (s, 3H total), 3.85 - 3.42, 3.31 - 3.14 (m, 4H), 1.66 - 1.42 (m, 2H), 1.37 - 1.21 (m, 3H), 0.98 - 0.91 (m, 3H); LCMS (ESI): m / z 411.0 (M+H)+. SFC (Chiralcel OD-3; CO2 / isopropanol (0.05% DEA)) showed 89:11. Example 37 N-((2S)-1-hydroxy-1-(4-methoxypyridin-3-yl)propan-2-yl)-N-propyl-2-(4- (trifluoromethyl)phenyl)acetamide (2 compounds)- 141 -CTQ-01425 Step 1: 2-(4-(trifluoromethyl)phenyl)acetyl chloride

[0330] To a solution of 2-(4-(trifluoromethyl)phenyl)acetic acid (500 mg, 2.45 mmol,1 eq) was added SOCl2 (291.39 mg, 2.45 mmol, 0.18 mL, 1 eq). The mixture was stirred at 80 °C for 2 hour. The reaction mixture was concentrated to afford the title compound (545 mg, crude) as a white solid. Step 2: N-((2S)-1-hydroxy-1-(4-methoxypyridin-3-yl)propan-2-yl)-N-propyl-2-(4- (trifluoromethyl)phenyl)acetamide (2 compounds)To a solution of (2S)-1-(4-methoxypyridin-3-yl)-2-(propylamino)propan-1-ol hydrochloride (200 mg, 891.67 μmol, 1 eq) and 2-(4-(trifluoromethyl)phenyl)acetyl chloride (238.17 mg, 1.07 mmol, 1.2 eq) in DCM (3 mL) was added TEA (270.68 mg, 2.68 mmol, 0.37 mL, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 2.604 min, [M+1]+= 411.2) showed 32% of desired product. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with saturated NaHCO3 (20 mL × 3), filtered, dried over Na2SO4 and concentrated. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm; acetonitrile (45-65% gradient) / water-NH4OH-NH4HCO3) to afford the first compound (the first peak, 14.63 mg, 4%) as a white solid and the second compound (the second peak, 7.78 mg, 2%) as a white solid.

[0331] The first compound: 1H NMR (400 MHz, CD3OD): δ 8.57 - 8.28 (m, 2H),7.67 - 7.56 (m, 2H), 7.51 - 7.22 (m, 2H), 7.09 - 6.97 (m, 1H), 5.22 - 4.93 (m, 1H), 4.38 - 4.05 (m, 1H), 4.04 - 3.87 (m, 3H), 3.84 - 3.69 (m, 1H), 3.68 - 3.43 (m, 1H), 3.35 - 3.28 (m, 1H), 3.25 - 3.13 (m, 1H), 1.85 - 1.56 (m, 1H), 1.56 - 1.43 (m, 1H), 1.39 - 1.13 (m, 2H), 1.10 - 0.83 (m, 4H). LCMS (ESI): m / z 411.1 (M+H)+. SFC (Chiralpak AD-3; CO2 / ethanol (0.05% DEA)) showed 33:15:39:13.

[0332] The second compound: 1H NMR (400 MHz, CD3OD): δ 8.54 - 8.29 (m, 2H),7.65 - 7.51 (m, 2H), 7.42 - 7.19 (m, 2H), 7.12 - 6.94 (m, 1H), 5.22 - 5.07 (m, 1H), 4.30 - 3.99 - 142 -CTQ-01425 (m, 1H), 3.98 - 3.86 (m, 3H), 3.84 - 3.42 (m, 2H), 3.28 - 3.14 (m, 2H), 1.76 - 1.41 (m, 2H), 1.37 - 1.14 (m, 3H), 0.95 - 0.86 (m, 3H); LCMS (ESI): m / z 411.1 (M+H)+. SFC (Chiralpak AS-3; CO2 / ethanol (0.05% DEA)) showed 4:41:5:50. Example 38 N-((2S)-1-hydroxy-1-(4-methoxypyridin-3-yl)propan-2-yl)-N-propyl-2-(5- (trifluoromethyl)pyridin-2-yl)acetamideTo a solution of (2S)-1-(4-methoxypyridin-3-yl)-2-(propylamino)propan-1-ol (300 mg, 1.34 mmol, 1 eq) and 2-(5-(trifluoromethyl)pyridin-2-yl)acetic acid (329.24 mg, 1.61 mmol, 1.2 eq) in DCM (5 mL) was added DIEA (518.59 mg, 4.01 mmol, 698.91 μL, 3 eq) and HATU (610.27 mg, 1.61 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 2.582 min, [M+1]+= 412.2) showed 42% of desired product. The residue was diluted with water (10 mL) and extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with saturated NaHCO3 (20 mL × 3), filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm; acetonitrile (31-61% gradient) / water-NH4OH-NH4HCO3) to afford the title compound (174.22 mg, 31%) as a white solid.

[0333] 1H NMR (400 MHz, CD3OD): δ 8.82 - 8.74 (m, 1H), 8.55 - 8.25 (m, 2H), 8.11- 8.00 (m, 1H), 7.55 - 7.36 (m, 1H), 7.12 - 6.96 (m, 1H), 5.24 - 4.94 (m, 1H), 4.68 - 4.00 (m, 2H), 3.98 - 3.86 (m, 4H), 3.48 - 3.33 (m, 1H), 3.29 - 3.08 (m, 1H), 1.78 - 1.44 (m, 2H), 1.37 - 0.99 (m, 3H), 0.98 - 0.86 (m, 3H); LCMS (ESI): m / z 412.2 (M+H)+. SFC (Chiralpak AS-3; CO2 / ethanol (0.05% DEA)) showed 12:33:15:40. Example 39 N-((2S)-1-hydroxy-1-(4-methoxypyridin-3-yl)propan-2-yl)-N-propyl-2-(6- (trifluoromethyl)pyridin-3-yl)acetamide - 143 -CTQ-01425To a solution of (2S)-1-(4-methoxypyridin-3-yl)-2-(propylamino)propan-1-ol (300 mg, 1.34 mmol, 1 eq) and 2-(6-(trifluoromethyl)pyridin-3-yl)acetic acid (329.24 mg, 1.61 mmol, 1.2 eq) in DCM (5 mL) was added DIEA (518.58 mg, 4.01 mmol, 3 eq) and HATU (610.27 mg, 1.61 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 2.251 min, [M+1]+= 412.2) showed 26% of desired product. The residue was diluted with water (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (20 mL × 3), filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm; acetonitrile (30-60% gradient) / water-NH4OH-NH4HCO3) to afford the title compound (165.72 mg, 30%) as a yellow oil.

[0334] 1H NMR (400 MHz, CD3OD): δ 8.61 - 8.29 (m, 3H), 7.90 - 7.68 (m, 2H), 7.12- 6.94 (m, 1H), 5.26 - 4.96 (m, 1H), 4.61 - 4.26 (m, 1H), 4.07 - 3.84 (m, 4H), 3.82 - 3.71 (m, 1H), 3.68 - 3.45 (m, 1H), 3.30 - 3.01 (m, 1H), 1.85 - 1.43 (m, 2H), 1.39 - 1.24 (m, 2H), 1.08 - 0.88 (m, 4H); LCMS (ESI): m / z 412.5 (M+H)+. SFC (Chiralpak AS-3; CO2 / ethanol (0.05% DEA)) showed 22:50:28 Example 40 N-(1-hydroxy-1-(4-methoxypyridin-3-yl)propan-2-yl)-N-propyl-2-(4- (trifluoromethyl)phenoxy)acetamide (4 compounds) - 144 -CTQ-01425Step 1: tert-butyl (1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate

[0335] To a solution of (tert-butoxycarbonyl)alanine (20.0 g, 105.70 mmol, 1 eq),DIEA (40.98 g, 317.11 mmol, 55.23 mL, 3 eq) and N,O-dimethylhydroxylamine hydrochloride (12.37 g, 126.84 mmol, 1.2 eq) in DCM (300 mL) was added HATU (48.23 g, 126.84 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hr. The mixture was quenched with saturated NH4Cl (100 mL), extracted with ethyl acetate (300 mL × 2). The organic layers were combined, washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash chromatography on silica gel (0 - 20% ethyl acetate in petroleum ether) to afford the title compound (24.0 g, 98%) as a white solid.1H NMR (400 MHz, CDCl3): δ 5.26 (d, J = 7.2 Hz, 1H), 4.74 - 4.60 (m, 1H), 3.77 (s, 3H), 3.20 (s, 3H), 1.43 (s, 9H), 1.31 (d, J = 6.8 Hz, 3H). Step 2: tert-butyl (1-(4-methoxypyridin-3-yl)-1-oxopropan-2-yl)carbamate- 145 -CTQ-01425

[0336] To a stirred solution of 3-bromo-4-methoxypyridine (8.09 g, 43.05 mmol, 2eq) in THF (10 mL) was added n-BuLi (2.5 M in hexane, 17.22 mL, 2 eq) at -75 °C for 15 min, and the reaction mixture was stirred at -75 °C for 0.5 hr. Then a solution of tert-butyl (1- (methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (5.0 g, 21.53 mmol, 1 eq) in THF (10 mL) was added into it at -75 °C, the reaction mixture was stirred at -75 °C for 2 hr. TLC (Petroleum ether : Ethyl acetate =1:1, Rf =0.55 ) showed the starting material consumed and a new spot appeared. The mixture was quenched with NH4Cl (100 mL) and the aqueous layer was extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with brine solution (100 mL), dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0 - 20% ethyl acetate in petroleum ether) to afford the title compound (3.2 g, 53% ) as a yellow oil.1H NMR (400 MHz, CDCl3): δ 8.85 (s, 1H), 8.62 (d, J = 5.6 Hz, 1H), 6.94 (d, J = 5.6 Hz, 1H), 5.50 - 5.48 (m, 1H), 5.29 - 5.20 (m, 1H), 4.02 (s, 3H), 1.45 (s, 9H), 1.33 (d, J = 7.2 Hz, 3H); LCMS (ESI): m / z 281.0 (M+H)+. Step 3: 2-amino-1-(4-methoxypyridin-3-yl)propan-1-one hydrochloride

[0337] To a solution of tert-butyl (1-(4-methoxypyridin-3-yl)-1-oxopropan-2-yl)carbamate (3.2 g, 11.42 mmol, 1 eq) in MeOH (5 mL) was added HCl / dioxane (2 M, 48.00 mL, 8.41 eq). The mixture was stirred at 25 °C for 30 min. LCMS (RT=0.694 min, [M+1]+= 181.1) showed 92% of desired product. The reaction mixture was concentrated under reduced pressure to afford the title compound (2.4 g, crude) as a yellow solid. LCMS (ESI): m / z 181.1 (M+H)+. Step 4: N-(1-(4-methoxypyridin-3-yl)-1-oxopropan-2-yl)propionamide

[0338] To a solution of 2-amino-1-(4-methoxypyridin-3-yl)propan-1-onehydrochloride (2.4 g, 11.08 mmol, 1 eq) in DCM (30 mL) was added TEA (3.36 g, 33.23 mmol, 4.63 mL, 3 eq), propanoyl chloride (1.54 g, 16.62 mmol, 1.54 mL, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hr. LCMS (RT = 1.748 min, [M+1]+= 237.2) showed 100% of desired product. The mixture was quenched with H2O (100 mL) and the aqueous layer was - 146 -CTQ-01425 extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0 - 50% (ethyl acetate in EtOH=3:1) in petroleum ether) to afford the title compound (2.1 g, 80%) as a yellow oil. LCMS (ESI): m / z 237.2 (M+H)+. Step 5: 1-(4-methoxypyridin-3-yl)-2-(propylamino)propan-1-ol

[0339] To a solution of N-(1-(4-methoxypyridin-3-yl)-1-oxopropan-2-yl)propionamide (2.1 g, 8.89 mmol, 1 eq) in THF (10 mL) was added BH3.THF (1 M in THF, 17.78 mL, 2 eq) at 0 °C for 5 min, then the mixture was stirred at 80 °C for 2 hour. LCMS (RT = 0.435 min, [M+1]+= 225.2) showed 90% of desired product. The solution was quenched with MeOH under ice bath until bubble disappearance, then the mixture was stirred for at 80 °C 1 hour, at last the solution was concentrated to afford the title compound (2.32 g, crude) as a light yellow oil. LCMS (ESI): m / z 225.2 (M+H)+. Step 6: N-(1-hydroxy-1-(4-methoxypyridin-3-yl)propan-2-yl)-N-propyl-2-(4- (trifluoromethyl)phenoxy)acetamide

[0340] To a solution of 1-(4-methoxypyridin-3-yl)-2-(propylamino)propan-1-ol (1.16g, 4.45 mmol, 1 eq) and 2-(4-(trifluoromethyl)phenoxy)acetic acid (1.08 g, 4.89 mmol, 1.1 eq) in DCM (15 mL) was added DIEA (1.72 g, 13.35 mmol, 2.32 mL, 3 eq) and HATU (2.03 g, 5.34 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1hr. LCMS (RT = 0.684min, [M+1]+ = 427.1) showed 32% of desired product, RT = 0.798 min, [M+1]+ = 629.0showed 39% di-amide coupling by-product (1-(4-methoxypyridin-3-yl)-2-(N-propyl-2-(4- (trifluoromethyl)phenoxy)acetamido)propyl 2-(4-(trifluoromethyl)phenoxy)acetate). The mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), filtered and concentrated to afford a mixture of desired product and by-product (2.8 g, crude) as a yellow oil. - 147 -CTQ-01425

[0341] To a solution of mixture of N-(1-hydroxy-1-(4-methoxypyridin-3-yl)propan-2-yl)-N-propyl-2-(4-(trifluoromethyl)phenoxy)acetamide and 1-(4-methoxypyridin-3-yl)-2-(N- propyl-2-(4-(trifluoromethyl)phenoxy)acetamido)propyl 2-(4- (trifluoromethyl)phenoxy)acetate (2.80 g) in THF (9 mL) and H2O (3 mL) was added lithium hydroxide monohydrate (373.87 mg, 8.91 mmol, 2 eq). The mixture was stirred at 25 °C for 1 hr. LCMS (RT=2.516 min, [M+1]+= 427.2) showed 40% of desired product. The residue was diluted with water (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 40 mm X 10 µm; acetonitrile (35-65% gradient over 8 min) / water-NH4OH- NH4HCO3) to afford the title compound (0.4 g, 21%) as a yellow solid. LCMS (ESI): m / z 427.2 (M+H)+. Step 7: N-(1-hydroxy-1-(4-methoxypyridin-3-yl)propan-2-yl)-N-propyl-2-(4- (trifluoromethyl)phenoxy)acetamide (4 compounds)

[0342] The compound N-(1-hydroxy-1-(4-methoxypyridin-3-yl)propan-2-yl)-N-propyl-2-(4-(trifluoromethyl)phenoxy)acetamide (400 mg) was separated by Chiral SFC (DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [CO2-EtOH(0.1% NH3H2O)]; 30%, isocratic elution mode) to afford the first compound (the first peak on SFC, 96.32 mg, 24%) as a white solid and the second compound (the second peak on SFC, 20.44 mg, 5%) as a light yellow solid. Which (the first compound and the second compound) were further separated by chiral SFC (column: Phenomenex-Cellulose-2 (250mm*30mm,10um);mobile phase: [CO2-EtOH(0.1%NH3H2O)];B%:25%, isocratic elution mode) to yield the third compound (the third peak on SFC, 6.9 mg, 2%) as a white solid and the fourth compound (the fourth peak on SFC, 133.57 mg, 33%) as a white solid.

[0343] The first compound: 1H NMR (400 MHz, CD3OD): δ 8.47 - 8.33 (m, 2H),7.60 - 7.53 (m, 2H), 7.13 - 7.06 (m, 2H), 7.05 - 6.92 (m, 1H), 5.28 - 5.24, 4.34 - 4.21 (m, 1H total), 5.13 - 4.93 (m, 2H), 4.86 - 4.71 (m, 1H), 3.94 (s, 3H), 3.55 - 3.43 (m, 1H), 3.25 - 3.13 - 148 -CTQ-01425 (m, 1H), 1.84 - 1.70 (m, 1H), 1.67 - 1.53 (m, 1H), 1.35 - 1.08 (m, 3H), 0.96 - 0.90 (m, 3H). LCMS (ESI): m / z 427.1 (M+H)+.

[0344] The second compound: 1H NMR (400 MHz, CD3OD): δ 8.58 - 8.31 (m, 2H),7.60 - 7.51 (m, 2H), 7.13 - 7.03 (m, 1H), 7.00 - 6.93 (m, 2H), 5.28 - 5.13 (m, 1H), 4.94 - 4.90, 4.69 - 4.65 (m, 1H total), 4.82 - 4.71 (m, 1H), 4.19 - 4.06 (m, 1H), 3.93, 3.91 (s, 3H total), 3.54 - 3.44 (m, 1H), 3.28 - 3.10 (m, 1H), 1.76 - 1.45 (m, 2H), 1.38 - 1.30 (m, 3H), 0.98 - 0.86 (m, 3H); LCMS (ESI): m / z 427.1 (M+H)+.

[0345] The third compound: 1H NMR (400 MHz, CD3OD): δ 8.57 - 8.33 (m, 2H),7.59 - 7.56 (m, 2H), 7.09 -7.04 (m, 1H), 6.97 (d, J = 8.8 Hz, 2H), 5.28 - 5.12 (m, 1H), 4.94 - 4.89 (m, 1H), 4.81 - 4.74 (m, 1H), 4.72 - 4.64, 3.53 - 3.43 (m, 1H total), 4.19 - 4.06 (m, 1H), 3.92, 3.91 (s, 3H total), 3.29 - 3.11 (m, 1H), 1.76 - 1.45 (m, 2H), 1.38 - 1.28 (m, 3H), 0.97 - 0.86 (m, 3H); LCMS (ESI): m / z 427.2 (M+H)+. The fourth compound:1H NMR (400 MHz, CD3OD): δ 8.47 - 8.32 (m, 2H), 7.60 - 7.53 (m, 2H), 7.15 - 6.92 (m, 3H), 5.30 - 5.24, 4.83 - 4.73 (m, 1H total), 5.12 - 4.93 (m, 2H), 4.61 - 4.21 (m, 1H), 3.94, 3.93 (s, 3H total), 3.55 - 3.43 (m, 1H), 3.25 - 3.09 (m, 1H), 1.84 - 1.49 (m, 2H), 1.36 - 1.06 (m, 3H), 1.03 - 0.89 (m, 3H). LCMS (ESI): m / z 427.1 (M+H)+. Example 41 2-(3,4-dichlorophenyl)-1-((2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)pyrrolidin-1- yl)ethan-1-one- 149 -CTQ-01425 Step 1: tert-butyl (2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)pyrrolidine-1-

[0346] To a mixture of 3-bromo-4-methoxypyridine (2.12 g, 11.29 mmol, 1.5 eq) inTHF (20 mL) was added n-BuLi (2.5 M in hexane, 4.52 mL, 1.5 eq) at -75 °C under N2. The mixture was stirred at -75 °C for 0.5 hour, then tert-butyl (R)-2-formylpyrrolidine-1- carboxylate (1.5 g, 7.53 mmol, 1 eq) in THF (5 mL) was added into it at -75 °C, the mixture was stirred at -78 °C for 1 hour. LCMS (RT = 0.709 min & 0.724 min, [M+H]+= 309.2) showed 47% & 22% of desired product. The reaction was quenched with saturated NH4Cl (15 mL), the mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (100 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (0 - 40% EE (ethyl acetate:ethanol = 3:1) inpetroleum ether) to afford the title compound (1.07 g, 46%) as a yellow oil. LCMS (ESI): m / z309.2 (M+H)+.Step 2: (4-methoxypyridin-3-yl)((R)-pyrrolidin-2-yl)methanol hydrochloride

[0347] A mixture of tert-butyl (2R)-2-(hydroxy(4-methoxypyridin-3-yl)methyl)pyrrolidine-1-carboxylate (500 mg, 1.62 mmol, 1 eq) in HCl / dioxane (4 mol / L, 15 mL) was stirred at 25 °C for 2 hours. TLC (dichloromethane / methanol = 10 / 1, Rf = 0.33) showed the starting material consumed and a new spot appeared. The mixture was concentrated in vacuum to afford the title compound (396 mg, crude) as a yellow solid. The crude product would be directly used in the next step without purification. Step 3: 2-(3,4-dichlorophenyl)-1-((2R)-2-(hydroxy(4-methoxypyridin-3- yl)methyl)pyrrolidin-1-yl)ethan-1-oneTo a mixture of (4-methoxypyridin-3-yl)((R)-pyrrolidin-2-yl)methanol hydrochloride (396.00 mg, 1.62 mmol, 1 eq) and 2-(3,4-dichlorophenyl)acetic acid (331.79 mg, 1.62 mmol, 1 eq) in - 150 -CTQ-01425 DCM (5 mL) was added DIEA (627.42 mg, 4.85 mmol, 0.85 mL, 3 eq) and HATU (738.34 mg, 1.94 mmol, 1.2 eq) in one portion at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (RT = 0.744 min, [M+H]+= 395.1) showed 53% of desired product. The solution was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (0 - 50 % EE (ethyl acetate:ethanol = 3:1) in petroleum ether) and purified by reverse phase chromatography (Welch Xtimate C18150 mm X 40 mm X 10 µm; acetonitrile (25-55% gradient) / water (FA)) to afford the title compound (217 mg, 34%) as a gray solid.

[0348] 1H NMR (400 MHz, MeOD): δ 8.68 - 8.42 (m, 2H), 7.49 - 6.95 (m, 4H), 5.46- 5.10 (m, 1H), 4.73 - 4.39 (m, 1H), 4.19 - 4.09 (m, 3H), 3.75 - 3.54 (m, 4H), 2.26 - 1.63 (m, 4H); LCMS (ESI): m / z 395.0 (M+H)+. SFC ((S,S)Whelk-01; CO2 / methanol (0.05% DEA)) showed 22:29:22:27. Example 42 1-((2R)-2-((4-cyclopropylpyridin-3-yl)(hydroxy)methyl)piperidin-1-yl)-2-(3,4- dichlorophenyl)ethan-1-one (2 compounds)Step 1: tert-butyl (R)-2-(4-chloronicotinoyl)piperidine-1-carboxylate

[0349] To a solution of 3-bromo-4-chloro-pyridine (4.66 g, 24.23 mmol, 3 eq) in THF(15 mL) was added i-PrMgCl-LiCl (1.3 M in THF, 18.64 mL, 3 eq) at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 hr, then the mixture was stirred at 50 °C for 1 hr. At last tert-butyl (R)-2-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (2.2 g, 8.08 mmol, 1 eq) in THF (5 mL) was added into it at 0 °C, the reaction mixture was stirred at 0 °C for 3hr. LCMS (RT = 0.929 min, [M+H]+= 325.1) showed 21% of desired product. The resulting - 151 -CTQ-01425 mixture was quenched with saturated NH4Cl (40 mL) and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with brine solution (100 mL × 3), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash silica gel chromatography (0 - 10% ethyl acetate in petroleum ether gradient) to afford the title compound (600 mg, 23%) as a brown oil. LCMS (ESI): m / z 325.1 (M+H)+. Step 2: tert-butyl (R)-2-(4-cyclopropylnicotinoyl)piperidine-1-carboxylate

[0350] A mixture of tert-butyl (R)-2-(4-chloronicotinoyl)piperidine-1-carboxylate(270 mg, 831.28 μmol, 1 eq), cyclopropylboronic acid (214.21 mg, 2.49 mmol, 3 eq), Cs2CO3 (812.54 mg, 2.49 mmol, 3 eq), Pd(OAc)2(18.66 mg, 83.13 μmol, 0.1 eq) and n-BuPAd2(59.61 mg, 166.26 μmol, 0.2 eq) in H2O (0.2 mL) and toluene (3 mL) was stirred at 120 °C for 1 hr under microwave. LCMS (RT = 0.819 min, [M+1]+= 331.2) showed 69% of desired product. The reaction mixture was concentrated to give a residue. The residue was purified by flash chromatography on silica gel (0 - 30% ethyl acetate in petroleum ether gradient) to afford the title compound (140 mg, 51%) as a yellow oil. LCMS (ESI): m / z 331.2 (M+H)+. Step 3: (R)-(4-cyclopropylpyridin-3-yl)(piperidin-2-yl)methanone hydrochloride

[0351] To a solution of tert-butyl (R)-2-(4-cyclopropylnicotinoyl)piperidine-1-carboxylate (140 mg, 423.70 μmol, 1 eq) in dioxane (5 mL) was added HCl / dioxane (4 M / L, 5 mL). The mixture was stirred at 25 °C for 1 hr. TLC (petroleum ether : ethyl acetate = 1:1, Rf = 0.15) showed the starting material consumed and a new spot appeared. The mixture was concentrated to afford the title compound (113 mg, crude) as a yellow solid. Step 4: (R)-1-(2-(4-cyclopropylnicotinoyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)ethan-1- one - 152 -CTQ-01425

[0352] To a solution of (R)-(4-cyclopropylpyridin-3-yl)(piperidin-2-yl)methanonehydrochloride (113 mg, 423.59 μmol, 1 eq), 2-(3,4-dichlorophenyl)acetic acid (86.85 mg, 423.59 μmol, 1 eq) in DCM (5 mL) was added DIEA (164.24 mg, 1.27 mmol, 3 eq) and HATU (193.28 mg, 508.31 μmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hr. LCMS (RT = 0.789 min, [M+1]+= 417.1) showed 83% of desired product. The reaction mixture was filtered and concentrated. The residue was purified by flash chromatography on silica gel (0 - 40% petroleum ether in ethyl acetate) to afford the title compound (160 mg, 91%) as a yellow oil. LCMS (ESI): m / z 417.2 (M+H)+.Step 5: 1-((2R)-2-((4-cyclopropylpyridin-3-yl)(hydroxy)methyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)ethan-1-one (2 compounds)To a solution of (R)-1-(2-(4-cyclopropylnicotinoyl)piperidin-1-yl)-2-(3,4- dichlorophenyl)ethan-1-one (160 mg, 383.39 μmol, 1 eq) in THF (3 mL) and MeOH (1 mL) was added NaBH4 (40 mg, 1.06 mmol, 2.76 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. LCMS (RT = 1.916 min & 1.993 min, [M+H]+= 419.2) showed 37% & 46% of desired product. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm; acetonitrile (47-77% gradient over 7 min) / water-NH4OH-NH4HCO3) to afford the first compound (the first peak, 8.3 mg, 5%) as a white solid and the second compound (the second peak, 26 mg, 16%) as a white solid.

[0353] The first compound: 1H NMR (400 MHz, CDCl3): δ 8.95 - 7.99 (m, 2H), 7.37- 7.31 (m, 2H), 6.96 (d, J = 8.0 Hz, 1H), 6.78 - 6.60 (m, 1H), 5.72 - 5.48 (m, 1H), 4.84 - 4.51 (m, 1H), 3.67 - 3.41 (m, 4H), 2.40 - 2.32 (m, 1H), 2.00 - 1.62 (m, 4H), 1.55 - 1.31 (m, 2H), 1.16 - 1.14 (m, 2H), 0.78 - 0.75 (m, 2H); LCMS (ESI): m / z 419.0 (M+H)+. SFC (Chiralpak AS-3; CO2 / ethanol (0.05% DEA)) showed 50:50. - 153 -CTQ-01425

[0354] The second compound: 1H NMR (400 MHz, CDCl3): δ 8.61 - 8.35 (m, 2H),7.45 - 7.34 (m, 2H), 7.14 - 7.12 (m, 1H), 6.82 - 6.77 (m, 1H), 5.57 - 5.24 (m, 2H), 4.01 - 3.71 (m, 3H), 3.54 - 3.34 (m, 1H), 2.88 - 2.18 (m, 1H), 1.80 - 1.71 (m, 3H), 1.68 - 1.58 (m, 3H), 1.21 - 1.10 (m, 2H), 0.93 - 0.76 (m, 2H); LCMS (ESI): m / z 419.0 (M+H)+. SFC (Chiralcel OJ-3; CO2 / ethanol (0.05% DEA)) showed 50:50. Example 43 2-(3,4-dichlorophenyl)-1-((2S)-2-(hydroxy(4-methylpyridin-3-yl)methyl)piperidin-1- yl)ethan-1-one (2 compounds)Step 1: tert-butyl (S)-2-(4-methylnicotinoyl)piperidine-1-carboxylate

[0355] A solution of tert-butyl (S)-2-(4-chloronicotinoyl)piperidine-1-carboxylate(0.6 g, 665.02 μmol, 1 eq), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (333.93 mg, 1.33 mmol, 371.86 μL, 2 eq), Cs2CO3(650.03 mg, 2.00 mmol, 3 eq) and Pd(dppf)Cl2(48.66 mg, 66.50 μmol, 0.1 eq) in dioxane (9 mL) was stirred at 120 °C for 60 min under microwave. LCMS (RT = 0.735 min, [M+H]+= 305.2) showed 16% of desired product. The solution was concentrated. The residue was purified by flash chromatography on silica gel (0 - 15% ethyl acetate in petroleum ether) to afford the title compound (120 mg, 59%) as a yellow oil. LCMS (ESI): m / z 305.2 (M+H)+. Step 2: tert-butyl (2S)-2-(hydroxy(4-methylpyridin-3-yl)methyl)piperidine-1-carboxylate- 154 -CTQ-01425

[0356] To a solution of tert-butyl (S)-2-(4-methylnicotinoyl)piperidine-1-carboxylate(217 mg, 712.92 μmol, 1 eq) in THF (3 mL) and MeOH (1 mL) was added NaBH4(0.08 g, 2.11 mmol, 2.97 eq) at 0 °C. Then the mixture was stirred at 0 °C for 1 h. LCMS (RT = 0.640 min, [M+H]+= 307.2) showed 79% of desired product. The mixture was quenched with saturated NH4Cl (5 mL), extracted with ethyl acetate (30 mL × 2). The organic layers were combined, washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (218 mg, curde) as a yellow oil. LCMS (ESI): m / z 307.2 (M+H)+. Step 3: (4-methylpyridin-3-yl)((S)-piperidin-2-yl)methanol hydrochloride

[0357] To a solution of tert-butyl (2S)-2-(hydroxy(4-methylpyridin-3-yl)methyl)piperidine-1-carboxylate (218 mg, 711.49 μmol, 1 eq) in dioxane (2 mL) was added HCl / dioxane (4 M / L, 1.78 mL, 10 eq) at 20 °C. Then the mixture was stirred at 20 °C for 1 h. The mixture was concentrated to afford the title compound (172 mg, crude) as a white solid. Step 4: 2-(3,4-dichlorophenyl)-1-((2S)-2-(hydroxy(4-methylpyridin-3- yl)methyl)piperidin-1-yl)ethan-1-one (2 compounds)To a solution of (4-methylpyridin-3-yl)((S)-piperidin-2-yl)methanol hydrochloride (172 mg, 708.56 μmol, 1 eq), 2-(3,4-dichlorophenyl)acetic acid (152.55 mg, 743.99 μmol, 1.05 eq) and DIEA (274.73 mg, 2.13 mmol, 370.26 μL, 3 eq) in DCM (4 mL) was added HATU (323.30 mg, 850.28 μmol, 1.2 eq) at 0 °C. Then the mixture was stirred at 0 °C for 1 h. LCMS (RT = 0.651 min & 0.702 min, [M+H]+= 393.2) showed 12% & 49% of desired product. The mixture was quenched with saturated NH4Cl (10 mL), extracted with ethyl acetate (50 mL × 2). The organic layers were combined, washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm; acetonitrile (43-73% gradient over 7 min) / water-NH4OH- NH4HCO3) to afford the first compound (the first peak, 23.47 mg, 7%) as a white solid and the second compound (the second peak, 106.85 mg, 34%) as a white solid. - 155 -CTQ-01425

[0358] The first compound : 1H NMR (400MHz, CD3OD): δ 8.72 - 8.17 (m, 2H),7.51 - 6.94 (m, 3H), 6.78-6.76 (m, 1H), 5.36 - 5.16 (m, 1H), 5.00 - 4.99, 4.53 - 4.49, 4.23 - 4.20 (m, 1H total), 3.77 - 3.74 (m, 1H), 3.67 - 3.44 (m, 2H), 3.29 - 2.76 (m, 1H), 2.49, 2.44 (s, 3H total), 2.27 - 1.55 (m, 4H), 1.55 - 1.29 (m, 2H); LCMS (ESI): m / z 393.0 (M+H)+. SFC (Chiralpak AD-3; CO2 / methanol (0.05% DEA)) showed 50:50.

[0359] The second compound : 1H NMR (400MHz, CD3OD): δ 8.56 (d, J = 3.6 Hz,1H), 8.33 - 8.28 (m, 1H), 7.49 - 7.40 (m, 2H), 7.30 - 7.11 (m, 2H), 5.36 - 5.23 (m, 1H), 5.09 - 5.05, 4.61 - 4.57 (m, 1H total), 4.38 - 4.30, 3.87 - 3.82 (m, 1H total), 4.08 - 3.92 (m, 1H), 3.79 - 3.76 (m, 1H), 3.52 - 3.42, 3.02 - 2.91 (m, 1H total), 2.53, 2.50 (s, 3H total), 1.92 - 1.64 (m, 2H), 1.64 - 1.57 (m, 1H), 1.55 - 1.14 (m, 3H); LCMS (ESI): m / z 393.0 (M+H)+. SFC (Chiralpak AD-3; CO2 / methanol (0.05% DEA)) showed 50:50. Example 44 1-((2S)-2-((4-cyclopropylpyridin-3-yl)(hydroxy)methyl)piperidin-1-yl)-2-(3,4- dichlorophenyl)ethan-1-one (2 compounds)Step 1: tert-butyl (S)-2-(4-cyclopropylnicotinoyl)piperidine-1-carboxylate

[0360] A mixture of tert-butyl (S)-2-(4-chloronicotinoyl)piperidine-1-carboxylate (0.6g, 665.02 μmol, 1 eq), cyclopropylboronic acid (171.37 mg, 2.00 mmol, 3 eq), Pd(OAc)2(14.93 mg, 66.50 μmol, 0.1 eq) and n-BuPAd2(47.69 mg, 133.00 μmol, 0.2 eq) and Cs2CO3(650.03 mg, 2.00 mmol, 3 eq) in toluene (9 mL) and H2O (0.9 mL) was stirred at 120 °C for 1 h under microwave. LCMS (RT = 0.749 min, [M+H]+= 331.2) showed 42% of desired - 156 -CTQ-01425 product. The reaction mixture was concentrated to give a residue and then the residue was purified by flash chromatography on silica gel (0 - 15% ethyl acetate in petroleum ether gradient) to afford the title compound (230 mg, 98%) as a yellow oil. LCMS (ESI): m / z 331.2 (M+H)+. Step 2: tert-butyl (2S)-2-((4-cyclopropylpyridin-3-yl)(hydroxy)methyl)piperidine-1- carboxylate

[0361] To a solution of tert-butyl (S)-2-(4-cyclopropylnicotinoyl)piperidine-1-carboxylate (230 mg, 696.08 μmol, 1 eq) in THF (3 mL) and MeOH (1 mL) was added NaBH4 (0.43 g, 11.37 mmol, 16.33 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS (RT = 0.670 min, [M+H]+= 333.3) showed 70% of desired product. The mixture was quenched with saturated NH4Cl (5 mL), extracted with ethyl acetate (30 mL × 2). The organic layers were combined, washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (231 mg, crude) as a yellow oil. LCMS (ESI): m / z 333.3 (M+H)+. Step 3: (4-cyclopropylpyridin-3-yl)((S)-piperidin-2-yl)methanol hydrochloride

[0362] To a solution of tert-butyl (2S)-2-((4-cyclopropylpyridin-3-yl)(hydroxy)methyl)piperidine-1-carboxylate (231 mg, 694.87 μmol, 1 eq) in dioxane (2 mL) was added HCl / dioxane (4 M / L, 1.74 mL, 10 eq) at 20 °C. Then the mixture was stirred at 20 °C for 1.5 h. The mixture was concentrated to afford the title compound (186 mg, crude) as a white solid. Step 4: 1-((2S)-2-((4-cyclopropylpyridin-3-yl)(hydroxy)methyl)piperidin-1-yl)-2-(3,4- dichlorophenyl)ethan-1-one (2 compounds)- 157 -CTQ-01425 To a solution of (4-cyclopropylpyridin-3-yl)((S)-piperidin-2-yl)methanol hydrochloride (186 mg, 692.01 μmol, 1 eq), 2-(3,4-dichlorophenyl)acetic acid (148.98 mg, 726.61 μmol, 1.05 eq) and DIEA (268.31 mg, 2.08 mmol, 3 eq) in DCM (8 mL) was added HATU (315.75 mg, 830.41 μmol, 1.2 eq) at 0 °C. Then the mixture was stirred at 0 °C for 1 h. LCMS (RT = 1.901 min & 1.978 min, [M+H]+= 419.1) showed 17% & 41% of desired product. The mixture was quenched with saturated NH4Cl (10 mL), extracted with ethyl acetate (50 mL × 2). The organic layers were combined, washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm; acetonitrile (45-75% gradient over 7 min) / water-NH4OH- NH4HCO3) to afford the first compound (the first peak, 38.73 mg, 13%) as a white solid and the second compound (the second peak, 79.03 mg, 26%) as a white solid.

[0363] The first compound: 1H NMR (400MHz, CD3OD): δ 8.57 - 8.52 (m, 1H), 8.32- 8.21 (m, 1H), 7.43 - 7.35 (m, 1H), 7.22 - 6.95 (m, 1H), 6.93 - 6.74 (m, 2H), 5.52 - 5.50 (m, 1H), 5.02 - 4.97, 4.53 - 4.49 (m, 1 H total), 4.37 - 4.30, 3.81 - 3.76 (m, 1H total), 3.72 - 3.52, 3.06 - 2.89 (m, 2H total), 3.47 - 3.36 (m, 1H), 2.50 - 2.12 (m, 2H), 2.01 - 1.84 (m, 1H), 1.74 - 1.71 (m, 1H), 1.64 - 1.37 (m, 3H), 1.22 - 1.05 (m, 2H), 0.93 - 0.59 (m, 2H); LCMS (ESI): m / z 419.0 (M+H)+. SFC (Chiralpak AD-3; CO2 / methanol (0.05% DEA)) showed 46:54.

[0364] The second compound: 1H NMR (400MHz, CD3OD): δ 8.55 - 8.53 (m, 1H),8.32 - 8.27 (m, 1H), 7.50 - 7.40 (m, 2H), 7.19 (d, J = 8.4 Hz, 1H), 6.94 - 6.69 (m, 1H), 5.64 - 5.42 (m, 1H), 5.31 - 5.21, 4.67 - 4.56 (m, 1H total), 4.42 - 4.36, 3.88 - 3.85 (m, 1H total), 4.08 - 3.91 (m, 1H), 3.83 - 3.80 (m, 1H), 3.46 - 3.40, 3.05 - 2.91 (m, 1H total), 2.57 - 2.33 (m, 1H), 1.94 - 1.67 (m, 2H), 1.65 - 1.24 (m, 4H), 1.21 - 1.08 (m, 2H), 0.95 - 0.76 (m, 2H); LCMS (ESI): m / z 419.0 (M+H)+. SFC (Chiralpak AD-3; CO2 / methanol (0.05% DEA)) showed 50:50. Example 45 1-((2R)-2-(hydroxy(4-(oxetan-3-yloxy)pyridin-3-yl)methyl)piperidin-1-yl)-2-(4- (trifluoromethyl)phenyl)ethan-1-one (2 compounds) - 158 -CTQ-01425Step 1: 3-iodo-4-(oxetan-3-yloxy)pyridine

[0365] To a solution of oxetan-3-ol (928.14 mg, 12.53 mmol, 2 eq) in DMF (20 mL)was added NaH (501.12 mg, 12.53 mmol, 60% in mineral oil, 2 eq) at 0 °C. The reaction was stirred at 0 °C for 15 min. Then the solution of 4-chloro-3-iodo-pyridine (1.5 g, 6.26 mmol, 1 eq) in DMF (1 mL) was added into it at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS (RT = 1.371 min, [M+H]+= 278.0) showed 27% of desired product. The mixture was quenched with saturated NH4Cl (10 mL), extracted with ethyl acetate (50 mL × 2). The organic layers were combined, washed with brine (15 mL × 5), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0 - 40% ethyl acetate in petroleum ether) to afford the title compound (1.1 g, 60%) as a yellow oil.1H NMR (400 MHz, CDCl3): δ 8.81 (s, 1H), 8.36 (d, J = 5.6 Hz, 1H), 6.32 (d, J = 5.6 Hz, 1H), 5.34 - 5.32 (m, 1H), 5.05 - 5.02 (m, 2H), 4.86 - 4.83 (m, 2H); LCMS (ESI): m / z 278.0 (M+H)+. Step 2: tert-butyl (2R)-2-(hydroxy(4-(oxetan-3-yloxy)pyridin-3-yl)methyl)piperidine-1- carboxylate - 159 -CTQ-01425

[0366] To a solution of 3-iodo-4-(oxetan-3-yloxy)pyridine (0.82 g, 2.96 mmol, 1.26eq) in THF (10 mL) was added isopropylmagnesium chloride lithium chloride complex (1.3 M in n-hexane, 5.41 mL, 3 eq). The reaction was stirred at 0 °C for 30 min and the reaction solution was stirred at 20 °C for 2 h. A solution of tert-butyl (R)-2-formylpiperidine-1- carboxylate (0.5 g, 2.34 mmol, 1 eq) in THF (0.5 mL) was added into it at 0 °C. The mixture was stirred at 25 °C for 16 h. LCMS (RT = 0.624 min & 0.649 min, [M+H]+= 365.1) showed 25% & 10% of desired product. The mixture was quenched with saturated NH4Cl (10 mL), extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0 - 20% (ethyl acetate / EtOH = 3:1) in petroleum ether gradient) to afford the title compound (250 mg, 28%) as a yellow oil. LCMS (ESI): m / z 365.1 (M+H)+. Step 3: (4-(oxetan-3-yloxy)pyridin-3-yl)((R)-piperidin-2-yl)methanol 2,2,2- trifluoroacetate

[0367] A solution of tert-butyl (2R)-2-(hydroxy(4-(oxetan-3-yloxy)pyridin-3-yl)methyl) piperidine-1-carboxylate (230 mg, 631.11 μmol, 1 eq) in 5% TFA / HFIP (10 mL) was stirred at 20 °C for 1 h. LCMS (RT = 1.285 min & 1.343 min, [M+H]+= 265.2) showed 17% & 23% of desired product. The mixture was concentrated to afford the title compound (166 mg, crude) as a brown oil. LCMS (ESI): m / z 265.2 (M+H)+. Step 4: 1-((2R)-2-(hydroxy(4-(oxetan-3-yloxy)pyridin-3-yl)methyl)piperidin-1-yl)-2-(4- (trifluoromethyl)phenyl)ethan-1-one (2 compounds)- 160 -CTQ-01425 To a solution of (4-(oxetan-3-yloxy)pyridin-3-yl)((R)-piperidin-2-yl)methanol 2,2,2- trifluoroacetate (166 mg, 628.03 μmol, 1 eq) and 2-(4-(trifluoromethyl)phenyl)acetic acid (115.39 mg, 565.23 μmol, 0.9 eq) in DCM (10 mL) was added DIEA (243.50 mg, 1.88 mmol, 328.17 μL, 3 eq) and then HATU (286.55 mg, 753.63 μmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS showed 21% the starting material remained. To the mixture was added 2-(4-(trifluoromethyl)phenyl)acetic acid (100 mg, 489.85 μmol, 0.78 eq) and then HATU (200 mg, 526.00 μmol, 0.84 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h again. LCMS (RT = 2.211 min & 2.339 min, [M+H]+= 451.2) showed 15% & 4% of desired product. The mixture was quenched with water (30 mL), extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with brine (10 mL × 2), dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase chromatography (Welch Xtimate C18150 mm X 30 mm X 5 µm; acetonitrile (40-50% gradient over 7 min) / water-NH4HCO3) to afford the first compound (the first peak, 50.07 mg, ...

Claims

CTQ-01425 CLAIMS What is claimed is:

1. A compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (I):wherein: Ar1is optionally substituted heteroaryl; R1is –OH or –H; L2is (–CH2–)por (–CH2–)p–O–, wherein p is an integer from 1-4; Ar2is optionally substituted aryl, heteroaryl, or bicycloalkyl; Ring B is a 4-10-membered heterocycloalkyl ring, optionally substituted by 1-4 occurrences of Rb; and Rb, independently for each occurrence is alkyl, alkenyl, cycloalkyl, or heterocycloalkyl; or two geminal occurrences of Rb, taken together with the intervening atoms, form a spirocycloalkyl ring on Ring B; or two vicinal occurrences of Rb, taken together with the intervening atoms, form a fused cycloalkyl ring on Ring B.

2. A compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (I):wherein: Ar1is optionally substituted 5-12-membered heteroaryl; R1is–OH or –H; L2is (–CH2–)por (–CH2–)p–O–, wherein p is an integer from 1-4; Ar2is optionally substituted (C6-C12)aryl, 5-12-membered heteroaryl, or (C5- C12)bicycloalkyl; Ring B is a 4-10-membered heterocycloalkyl ring, optionally substituted by 1-4 occurrences of Rb; and - 274 -CTQ-01425 Rb, independently for each occurrence is (C1-C10)alkyl, (C2-C10)alkenyl, (C3- C10)cycloalkyl, or 5-to-12-membered heterocycloalkyl; or two geminal occurrences of Rb, taken together with the intervening atoms, form a (C3- C6)spirocycloalkyl ring on Ring B; or two vicinal occurrences of Rb, taken together with the intervening atoms, form a fused cycloalkyl ring on Ring B.

3. The compound of claim 1 or 2, wherein Ring B is a 4-7-membered heterocycloalkyl ring, optionally substituted by 1-4 occurrences of Rb.

4. The compound of any one of claims 1-3, wherein Ring B is a 4-6-membered heterocycloalkyl ring, optionally substituted by 1-4 occurrences of Rb.

5. The compound of any one of claims 1-4, wherein Ring B is a 5-6-membered heterocycloalkyl ring, optionally substituted by 1-4 occurrences of Rb.

6. The compound of claim 5, wherein Ring B is a 6-membered heterocycloalkyl ring, optionally substituted by 1-4 occurrences of Rb.

7. The compound of claim 1, having the structure of formula (Ia):

8. The compound of any one of claims 1-7, wherein R1is –OH.

9. The compound of any one of claims 1-8, having the structure of formula (Ib):- 275 -CTQ-01425 10. The compound of any one of claims 1-9, having the structure of formula (Ib-1):

11. The compound of any one of claims 1-8, having the structure of formula (Ib-a), (1b- b), (Ib-c), or (1b-d):

12. The compound of claim 11, having the structure of formula (Ib-a).

13. The compound of claim 11, having the structure of formula (Ib-b).

14. The compound of claim 11, having the structure of formula (Ib-c).

15. The compound of claim 11, having the structure of formula (Ib-d).

16. The compound of any one of claims 1-15, wherein L2is –CH2–, –CH2CH2–, or – CH2O–.

17. The compound of any one of claims 1-16, wherein L2is –CH2–. - 276 -CTQ-01425 18. The compound of any one of claims 1-16, wherein L2is –CH2O–.

19. The compound of any one of claims 1-18, wherein Ar1is optionally substituted pyridinyl.

20. The compound of any one of claims 1-19, wherein Ar1isR1ais H, alkyl, cycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy, halo, haloalkoxy, haloalkyl, -NH2, -NH(alkyl), or cyano; and n is an integer from 1-3.

21. The compound of claim 20, wherein.

22. The compound of claim 20 or 21, wherein R1ais alkoxy, cycloalkoxy, heterocycloalkoxy, or cycloalkyl.

23. The compound of any one of claims 1-22, wherein24. The compound of any one of claims 1 and 3-23, wherein Ar2is aryl or heteroaryl, optionally substituted with one or more substituents selected from halo, haloalkyl, alkoxy, alkyl, haloalkoxy, cyano, and –SO2(alkyl). - 277 -CTQ-01425 25. The compound of any one of claims 1 and 3-24, wherein Ar2is aryl or heteroaryl, substituted with at least one substituent selected from halo, haloalkyl, alkoxy, alkyl, haloalkoxy, cyano, and –SO2(alkyl).

26. The compound of any one of claims 1 and 3-25, wherein Ar2is aryl or heteroaryl, substituted with two occurrences of halo.

27. The compound of any one of claims 1 and 3-25, wherein Ar2is aryl or heteroaryl, substituted with one occurrence of haloalkyl.

28. The compound of any one of claims 1-25, wherein Ar2is phenyl, substituted with 1-2 occurrences of R2a, wherein each occurrence of R2ais independently halo, haloalkyl, alkoxy, alkyl, haloalkoxy, cyano, or –SO2(alkyl). 29..

30. The compound of claim 29, wherein Ar2is, ,.

31. The compound of claim 30, wherein Ar2is. - 278 -CTQ-01425 32. The compound of any one of claims 1-31, having the structure of formula (Ib-1a), (Ib- 1b) ̧(Ib-1c), or (Ib-1d):R1ais alkoxy or cycloalkoxy, and v is 0 or 1.

33. The compound of claim 32, having the structure of formula (Ib-1a).

34. The compound of claim 32, having the structure of formula (Ib-1b).

35. The compound of claim 32, having the structure of formula (Ib-1c).

36. The compound of claim 32, having the structure of formula (Ib-1d). - 279 -CTQ-01425 37. The compound of any one of claims 1-25, wherein Ar2is pyridinyl, substituted with 1-2 occurrences of R2a, wherein each occurrence of R2ais independently halo, haloalkyl, alkoxy, alkyl, haloalkoxy, cyano, or –SO2(alkyl).

38. The compound of claim 37, wherein Ar2is.

39. The compound of claim 38, wherein Ar2is.

40. The compound of claim 1 or 2, wherein the compound is:- 280 -CTQ-01425- 281 -CTQ-01425- 282 -CTQ-01425- 283 -CTQ-01425; or a pharmaceutically acceptable salt thereof. - 284 -CTQ-01425 41. The compound of claim 1 or 2, wherein the compound is:- 285 -CTQ-01425- 286 -CTQ-01425- 287 -CTQ-01425or a pharmaceutically acceptable salt thereof. - 288 -CTQ-01425 42. A compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (II):wherein: W, X, Y, and Z are each independently CH, CR1a, or N; wherein at least one of Y, W, X, and Z is N; each R1ais independently alkoxy, alkyl, cycloalkyl, cycloalkoxy, heterocycloalkoxy, halo, haloalkoxy, haloalkyl, -NH2, -NH(alkyl), or cyano; R3is alkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl; R4is alkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, haloalkyl, or alkoxyalkyl; Rcis OH or H; L2is (–CH2–)p or (–CH2–)p–O–, wherein p is an integer from 1-4; and Ar2is optionally substituted aryl, heteroaryl, or bicycloalkyl.

43. A compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (II):wherein: W, X, Y, and Z are each independently CH, CR1a, or N; wherein at least one of Y, W, X, and Z is N; each R1ais independently (C1-C10)alkoxy, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C3- C10)cycloalkoxy, 5-to-12-membered heterocycloalkoxy, halo, halo(C1-C10)alkoxy, halo(C1-C10)alkyl, -NH2, -NH((C1-C10)alkyl), or cyano; Rcis OH or H; R3is (C1-C10)alkyl, (C3-C10)cycloalkyl(C1-C10)alkyl, 5-to-12-membered heterocycloalkyl(C1-C10)alkyl, (C6-C12)aryl(C1-C10)alkyl, 5-to-12-membered - 289 -CTQ-01425 heteroaryl(C1-C10)alkyl, halo(C1-C10)alkyl, (C1-C10)hydroxyalkyl, or (C1- C10)alkoxy(C1-C10)alkyl; R4is (C1-C10)alkyl, (C3-C10)cycloalkyl(C1-C10)alkyl, 5-to-12-membered heterocycloalkyl(C1-C10)alkyl, (C6-C12)aryl(C1-C10)alkyl, 5-to-12-membered heteroaryl(C1-C10)alkyl, halo(C1-C10)alkyl, or (C1-C10)alkoxy(C1-C10)alkyl; L2is (–CH2–)p or (–CH2–)p–O–, wherein p is an integer from 1-4; and Ar2is optionally substituted (C6-C12)aryl, 5-12-membered heteroaryl, or (C5- C12)bicycloalkyl.

44. The compound of claim 42 or 43, wherein one or two of W, X, Y, and Z is N.

45. The compound of claim 44, wherein one of W, X, Y, and Z is N.

46. The compound of any one of claims 42-45, wherein Y is N.

47. The compound of any one of claims 42-46, having the structure of formula (IIa):

48. The compound of any one of claims 42-47, having the structure of formula (IIa-a), (IIa-b), (IIa-c), or (IIa-d):- 290 -CTQ-0142549. The compound of claim 48, having the structure of formula (IIa-a).

50. The compound of claim 48, having the structure of formula (IIa-b).

51. The compound of claim 48, having the structure of formula (IIa-c).

52. The compound of claim 48, having the structure of formula (IIa-d).

53. The compound of any one of claims 42-52, wherein L2is –CH2–, –CH2CH2–, or –CH2O–.

54. The compound of any one of claims 42-53, wherein L2is –CH2–.

55. The compound of any one of claims 42-53, wherein L2is –CH2O–.

56. The compound of any one of claims 42-55, wherein R1ais alkoxy.

57. The compound of claim 56, wherein R1ais methoxy or isopropyloxy.

58. The compound of claim 56, wherein R1ais methoxy.

59. The compound of any one of claims 42-58, wherein R3is methyl. - 291 -CTQ-01425 60. The compound of any one of claims 42-56, having the structure of formula (IIb) or (IIc):c).

61. The compound of any one of claims 42-60, wherein R4is n-propyl.

62. The compound of any one of claims 42-61, having the structure of formula (IIb-a), (IIb-b), (IIb-c), or (IIb-d):wherein R1ais alkoxy.

63. The compound of claim 62, having the structure of formula (IIb-a). - 292 -CTQ-01425 64. The compound of claim 62, having the structure of formula (IIb-b).

65. The compound of claim 62, having the structure of formula (IIb-c).

66. The compound of claim 62, having the structure of formula (IIb-d).

67. The compound of any one of claims 42 or 44-66, wherein Ar2is aryl or heteroaryl, optionally substituted with one or more substituents selected from halo, haloalkyl, alkoxy, alkyl, haloalkoxy, cyano, and –SO2(alkyl).

68. The compound of any one of claims 42 or 44-67, wherein Ar2is aryl or heteroaryl, substituted with at least one substituent selected from halo, haloalkyl, alkoxy, alkyl, haloalkoxy, cyano, and –SO2(alkyl).

69. The compound of any one of claims 42 or 44-68, wherein Ar2is aryl or heteroaryl, substituted with two occurrences of halo.

70. The compound of any one of claims 42 or 44-68, wherein Ar2is aryl or heteroaryl, substituted with one occurrence of haloalkyl.

71. The compound of any one of claims 42-68, wherein Ar2is phenyl, substituted with 1- 2 occurrences of R2a, wherein each occurrence of R2ais independently halo, haloalkyl, alkoxy, alkyl, haloalkoxy, cyano, or –SO2(alkyl).

72. The compound of claim 71, wherein Ar2is; wherein m is an integer from 0-1. - 293 -CTQ-01425 . The compound of claim 72, wherein Ar2is, ,.

74. The compound of claim 73, wherein Ar2is.

75. The compound of any one of claims 42-74, having the structure of formula (IIb-1a), (IIb-1b), (IIb-1c), or (IIb-1d):wherein R1ais alkoxy, and76. The compound of claim 75, having the structure of formula (IIb-1a). - 294 -CTQ-01425 77. The compound of claim 75, having the structure of formula (IIb-1b).

78. The compound of claim 75, having the structure of formula (IIb-1c).

79. The compound of claim 75, having the structure of formula (IIb-1d).

80. The compound of any one of claims 42-68, wherein Ar2is pyridinyl, substituted with 1-2 occurrences of R2a, wherein each occurrence of R2ais independently halo, haloalkyl, alkoxy, alkyl, haloalkoxy, cyano, or –SO2(alkyl).

81. The compound of claim 80, wherein Ar2is.

82. The compound of claim 81, wherein Ar2is.

83. The compound of any one of claims 42-82, wherein Rcis -OH.

84. The compound of claim 42 or 43, wherein the compound is:- 295 -CTQ-01425; or a pharmaceutically aceptable salt thereof. - 296 -CTQ-01425 85. The compound of claim 42 or 43, wherein the compound is:- 297 -CTQ-01425or a pharmaceutically aceptable salt thereof.

86. A pharmaceutical composition comprising a compound of any one of claims 1-85, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

87. A method of promoting myelination in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-85, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 86.

88. A compound of any one of claims 1-85, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 86, for use in treating a disorder in a subject in need thereof.

89. A compound of any one of claims 1-85, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 86, for use in promoting myelination in a subject in need thereof. - 298 -CTQ-01425 90. Use of a compound of any one of claims 1-85, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 86, in the manufacture of a medicament for treating a disorder in a subject in need thereof.

91. Use of a compound of any one of claims 1-85, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 86, in the manufacture of a medicament for promoting myelination in a subject in need thereof.

92. The method of claim 87, wherein the subject has a myelin-related disorder.

93. The compound for use of claim 88 or 89, wherein the subject has a myelin-related disorder.

94. The use of claim 90 or 91 wherein the subject has a myelin-related disorder.

95. The method of claim 92, compound for use of claim 93, or use of claim 94, wherein the myelin-related disorder is multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophy, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander's disease, Pelizaeus Merzbacher disease (PMD), Vanishing White Matter Disease, Wallerian Degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Komzweig syndrome, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barre syndrome, Charcot-Marie-Tooth disease, Bell's palsy, or radiation-induced demyelination.

96. The method of claim 92, compound for use of claim 93, or use of claim 94, wherein the disorder is multiple sclerosis. - 299 -CTQ-01425 97. A method of inhibiting CYP51 (lanosterol demethylase) comprising contacting CYP51 with a compound according to any one of claims 1-85, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 86. - 300 -

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