Spirocyclic compounds for use in promoting remyelination

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-01525SPIROCYCLIC COMPOUNDS FOR USE IN PROMOTING REMYELINATIONRELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No.: 63 / 722,964, filed November 20, 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) of 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-Komzweig 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 people globally 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 maintainCTQ-01525 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] Several phenotypes (commonly termed types), or patterns of progression, have been described. Phenotypes use the past course of the disease in an attempt to predict the future course. They are important not only for prognosis but also for treatment decisions. Currently, the United States National Multiple Sclerosis Society and the Multiple Sclerosis International Federation, describes four types of MS (revised in 2013):1. Clinically isolated syndrome (CIS)2. Relapsing-remitting MS (RRMS)3. Primary progressive MS (PPMS)4. Secondary progressive MS (SPMS)

[0005] Relapsing-remitting multiple sclerosis is characterized by unpredictable relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits that occur during attacks may either resolve or leave problems, the latter in about 40% of attacks and being more common the longer a person has had the disease. This describes the initial course of 80% of individuals with multiple sclerosis. The relapsing-remitting subtype usually begins with a clinically isolated syndrome (CIS). In CIS, a person has an attack suggestive of demyelination, but does not fulfill the criteria for multiple sclerosis. 30 to 70% of persons experiencing CIS later develop multiple sclerosis.

[0006] Primary progressive multiple sclerosis occurs in approximately 10-20% of individuals, with no remission after the initial symptoms. It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements. The usual age of onset for the primary progressive subtype is later than of the relapsingremitting subtype. It is similar to the age that secondary progressive usually begins in relapsing-remitting multiple sclerosis, around 40 years of age.

[0007] Secondary progressive multiple sclerosis occurs in around 65% of those with initial relapsing-remitting multiple sclerosis, who eventually have progressive neurologic decline between acute attacks without any definite periods of remission. Occasional relapses and minor remissions may appear. The most common length of time between disease onset and conversion from relapsing-remitting to secondary progressive multiple sclerosis is 19 years.CTQ-01525

[0008] At present, there is no cure for myelin-related disorders. Accordingly, there is a need for new therapeutic approaches to the treatment of myelin-related disorders, including the promotion of myelination.

[0009] At present, there is no cure for myelin-related disorders, and no current therapy prevents 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

[0010] In one aspect, the present disclosure relates to compounds, or a pharmaceutically acceptable salts thereof, represented by structural formula (I):wherein:X is 5- to 12-membered heteroaryl;Y is Ce-12 aryl or 5- to 12-membered heteroaryl;G is selected from NR1, O, and S(=O)2;R1is selected from H, Ci-6 alkyl, Ce-i2 aryl, C3-12 cycloalkyl, 5- to 12-membered heteroaryl, C(=O)R2, S(=O)R3, and S(=O)2R4;R2, R3, and R4is each independently selected from C1-6 alkyl, C1-6 haloalkyl, Ce-12 aryl, C3-12 cycloalkyl, 5 to 12-membered heteroaryl, and 4 to 10-membered heterocycloalkyl; and a, b, c, and d is each independently selected from 1, 2, and 3, wherein each C1-6 alkyl, Ce-12 aryl, C1-6 haloalkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C1-6 alkoxy, C1-6 deuteroalkyl, C3-8 cycloalkyl, C3-8 cycloalkoxy, C2-6 alkenyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, (Ci-e) alkylamino(Ci-CTQ-01525 e alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-6 alkoxy(Ci-3)alkyl, C6-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl, whereinR14R15, R18R18a, R20R20aR24and R27is each independently H or C1-6 alkyl;R16and R17is each independently selected from H, C1-6 alkyl, hydroxy(Ci-6)alkyl, and halo(Ci-6)alkyl;R19and R23is each independently C1-6 alkyl or halo(Ci-6)alkyl;R21R22R25anj R26eacindepencienly selected from H, C1-6 alkyl, C1-3 alkoxy(Ci-6)alkyl, hydroxy(Ci-6)alkyl, cyano(Ci-6)alkyl, amino(Ci-6)alkyl, C1-3 alkylamino(Ci-6)alkyl, and di(Ci-3)alkylamino(Ci-6)alkyl; orR21and R22or R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-3 alkoxy, halo(Ci-3)alkoxy, C1-6 alkoxy(Ci-3)alkyl, C6-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0011] In another aspect, the present disclosure relates to pharmaceutical compositions comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient.

[0012] In another aspect, the present disclosure relates to methods of promoting myelination in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0013] 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.

[0014] 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.

[0015] 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.CTQ-01525

[0016] 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.

[0017] In another aspect, the present disclosure provides methods of inhibiting CYP51 (lanosterol demethylase) comprising contacting CYP51 with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the disclosure.DETAILED DESCRIPTION OF THE INVENTION

[0018] Described herein are myelin-promoting compounds of Formula (I), methods of making the compounds, their pharmaceutical compositions, and their use in the treatment of myelin-related disorders.

[0019] The enhancement and / or inducement of the accumulation of A8,9-unsaturated sterol intermediates of the cholesterol biosynthesis pathway in oligodendrocyte progenitor cells (OPCs) can induce oligodendrocyte generation. Enhancement and / or inducement of the accumulation of A8,9-unsaturated sterol intermediates can be provided by modulating and / or inhibiting enzymes within the cholesterol biosynthesis pathway in OPCs that enhance and / or induce A8,9-unsaturated sterol intermediate accumulation and / or for which the A8,9- unsaturated sterol intermediates are substrates as well as directly and / or indirectly administering A8,9-unsaturated sterol intermediates to the OPCs. Enhancement and / or inducement of the accumulation of A8,9-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.

[0020] As such, in some embodiments an agent, such as a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, that can enhance and / or induce accumulation of A8,9-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 a pharmaceutically acceptable salt or solvate thereof, is a compound that inhibits enzyme mediated synthesis of one or more sterol intermediates in the cholesterol biosynthesis pathway of the OPCs and / or promotes accumulation of A8,9-unsaturated sterol intermediates.CTQ-01525

[0021] In certain embodiments, the compound of Formula (I) , or a pharmaceutically 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) 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) can inhibit CYP51, sterol 14-reductase and / or EBP. In certain embodiments, the compound of Formula (I) can inhibit CYP51.

[0022] For example, in certain embodiments, the compound of Formula (I) used in the methods described herein can inhibit CYP51 enzyme activity in the cholesterol biosynthetic pathway. Alternatively, in certain embodiments, the compound of Formula (I) 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.

[0023] CYP51 belongs to the cytochrome P450 (CYP) monooxygenase superfamily and mediates 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 14a- demethylases and are the only invariant P450 present in all sterol biosynthetic pathways.

[0024] Without being bound by a particular theory, it is believed that compounds of Formula (I) , 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 A8,9-unsaturated sterol intermediates. In some embodiments, enhancement and / or inducement of the accumulation of A8,9-unsaturated sterol intermediates can promote OPC differentiation, survival, proliferation 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.CTQ-01525

[0025] In one aspect, the present disclosure relates to compounds, or a pharmaceutically acceptable salts thereof, represented by structural formula (I):wherein:X is 5- to 12-membered heteroaryl;Y is Ce-12 aryl or 5- to 12-membered heteroaryl;G is selected from NR1, O, and S(=O)2;R1is selected from H, Ci-6 alkyl, Ce-i2 aryl, C3-12 cycloalkyl, 5- to 12-membered heteroaryl, C(=O)R2, S(=O)R3, and S(=O)2R4;R2, R3, and R4is each independently selected from C1-6 alkyl, C1-6 haloalkyl, Ce-12 aryl, C3-12 cycloalkyl, 5 to 12-membered heteroaryl, and 4 to 10-membered heterocycloalkyl; and a, b, c, and d is each independently selected from 1, 2, and 3, wherein each C1-6 alkyl, Ce-12 aryl, C1-6 haloalkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C1-6 alkoxy, C1-6 deuteroalkyl, C3-8 cycloalkyl, C3-8 cycloalkoxy, C2-6 alkenyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, (Ci-e) alkylamino(Ci- e)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-6 alkoxy(Ci-3)alkyl, C6-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl, whereinR14R15, R18R18a, R20R20aR24and R27is each independently H or C1-6 alkyl;R16and R17is each independently selected from H, C1-6 alkyl, hydroxy(Ci-e)alkyl, and halo(Ci-e)alkyl;R19and R23is each independently C1-6 alkyl or halo(Ci-6)alkyl;CTQ-01525R2122 25anj 26 JS eac]1inc[epenc[enly selected from H, Ci-6 alkyl, C1-3 alkoxy(Ci-6)alkyl, hydroxy(Ci-6)alkyl, cyano(Ci-6)alkyl, amino(Ci-6)alkyl, C1-3 alkylamino(Ci-6)alkyl, and di(Ci-3)alkylamino(Ci-6)alkyl; orR21and R22or R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-3 alkoxy, halo(Ci-3)alkoxy, C1-6 alkoxy(Ci-3)alkyl, C6-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl.

[0026] In certain embodiments, the compound is represented by structural formula (II):whereinZ is CH or N,Rxis selected from H, F, Cl, Br, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-8 cycloalkyl, and C3-8 cycloalkoxy; andRyis selected from H, F, Cl, Br, C1-6 haloalkyl, C1-6 haloalkoxy, and S(=O)2(Ci-6 alkyl), wherein each C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C3-8 cycloalkoxy is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C1-6 deuteroalkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, (Ci-e) alkylamino(Ci-6)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-3 alkoxy, halo(Ci-3)alkoxy, C1-6 alkoxy(Ci-3)alkyl, C6-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl, whereinR14R15, R18R18a, R20R20aR24and R27is each independently H or C1-6 alkyl;CTQ-01525R16and R17is each independently selected from H, Ci-6 alkyl, hydroxy(Ci-6)alkyl, and halo(Ci-6)alkyl;R19and R23is each independently Ci-6 alkyl or halo(Ci-6)alkyl;R21R22 R25anj R26eac]1inc[epenc[enly selected from H, Ci-6 alkyl, C1-3 alkoxy(Ci-6)alkyl, hydroxy(Ci-6)alkyl, cyano(Ci-6)alkyl, amino(Ci-6)alkyl, C1-3 alkylamino(Ci-6)alkyl, and di(Ci-3)alkylamino(Ci-6)alkyl; orR21and R22or R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-3 alkoxy, halo(Ci- s)alkoxy, C1-6 alkoxy(Ci-3)alkyl, C6-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12- membered heteroaryl.

[0027] In certain embodiments, the Z is N

[0028] In certain embodiments, Z is CH.

[0029] In certain embodiments, the compound is represented by structural formula (III):

[0030] In further embodiments, Rxis selected from H, C1-3 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, and C3-6 cycloalkoxy, wherein each C1-3 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, and C3-6 cycloalkoxy is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, Ci-6deuteroalkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, (Ci-e) alkylamino(Ci- e)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-3 alkoxy, halo(Ci-CTQ-015253)alkoxy, Ci-6 alkoxy(Ci-3)alkyl, Ce-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl, whereinR14R15, R18R18a, R20R20aR24and R27is each independently H or Ci-6 alkyl;R16and R17is each independently selected from H, Ci-6 alkyl, hydroxy(Ci-6)alkyl, and halo(Ci-6)alkyl;R19and R23is each independently Ci-6 alkyl or halo(Ci-6)alkyl;R21R22R25anj R26eacindepencienly selected from H, Ci-6 alkyl, C1-3 alkoxy(Ci-6)alkyl, hydroxy(Ci-6)alkyl, cyano(Ci-6)alkyl, amino(Ci-6)alkyl, C1-3 alkylamino(Ci-6)alkyl, and di(Ci-3)alkylamino(Ci-6)alkyl; orR21and R22or R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-3 alkoxy, halo(Ci- 3)alkoxy, C1-6 alkoxy(Ci-3)alkyl, C6-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12- membered heteroaryl. In certain embodiments, Rxis H. In certain embodiments, Rxis C1-3 alkyl, such as methyl, ethyl, propyl, or isopropyl. For example, Rxis methyl. In certain embodiments, Rxis C3-6 cycloalkyl, such as C3 C4, C5, or Ce cycloalkyl. For example, Rxis cyclopropyl. In certain embodiments, Rxis C1-3 alkoxy, such as methoxy, ethoxy, propoxy, or isopropoxy. For example, Rxis methoxy. In certain embodiments, Rxis C3-6 cycloalkoxy, such as C3 C4, C5, or Ce cycloalkoxy. For example, Rxis cyclopropropoxy. In certain embodiments, Rxis selected from H, C1-3 alkyl, C3-6 cycloalkyl, and C1-3 alkoxy. In certain embodiments, Rxis selected from C1-3 alkyl, C3-6 cycloalkyl, and C1-3 alkoxy.

[0031] In certain embodiments, Ryis selected from F, C1-3 haloalkyl, C1-3 haloalkoxy, and S(=O)2(Ci-6alkyl), wherein each C1-3 haloalkyl and C1-3 haloalkoxy is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C1-6 deuteroalkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, (Cue) alkylamino(Ci-6)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl,CTQ-01525Ci-3 alkoxy, halo(Ci-3)alkoxy, Ci-6 alkoxy(Ci-3)alkyl, Ce-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl, whereinR14R15, R18R18a, R20R20aR24and R27is each independently H or Ci-6 alkyl;R16and R17is each independently selected from H, Ci-6 alkyl, hydroxy(Ci-6)alkyl, and halo(Ci-6)alkyl;R19and R23is each independently Ci-6 alkyl or halo(Ci-6)alkyl;R21R22R25anj R26eacindepencienly selected from H, Ci-6 alkyl, C1-3 alkoxy(Ci-6)alkyl, hydroxy(Ci-6)alkyl, cyano(Ci-6)alkyl, amino(Ci-6)alkyl, C1-3 alkylamino(Ci-6)alkyl, and di(Ci-3)alkylamino(Ci-6)alkyl; orR21and R22or R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-3 alkoxy, halo(Ci- 3)alkoxy, C1-6 alkoxy(Ci-3)alkyl, C6-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12- membered heteroaryl. In certain embodiments, Ryis F. In certain embodiments, Ryis C1-3 haloalkyl, such as Ci haloalkyl, C2 haloalkyl, or C3 haloalkyl. For example, Ryis selected from CF3, CHF2, CH2F, C2F5, C2HF4, C2H2F3, C2H3F2, C2H4F, C3F7, C3HF6, C3H2F5, C3H3F4, C3H4F3, C3H5F2, and C3H6F. For example, Ryis CF3. In certain embodiments, Ryis C1-3 haloalkoxy, such as Ci haloalkoxy, C2 haloalkoxy, or C3 haloalkoxy. For example, Ryis selected from OCF3, OCHF2, OCH2F, OC2F5, OC2HF4, OC2H2F3, OC2H3F2, OC2H4F, OC3F7, OC3HF6, OC3H2F5, OC3H3F4, OC3H4F3, OC3H5F2, and OC3H6F. For example, Ryis OCHF. In certain embodiments, Ryis selected from C1-3 haloalkyl and C1-3 haloalkoxy. In certain embodiments, Ryis selected from CF3 and OCHF2. In certain embodiments, Ryis S(=O)2(Ci-6 alkyl). For example, Ryis selected from S(=0)2(Me), S(=O)2(Et), S(=O)2(n-Pr)>S(=O)2(i-Pr), S(=O)2(n-Bu), S(=O)2(i-Bu)>and S(=O)2(t-Bu). For example, Ryis S(=0)2(Me).

[0032] In certain embodiments, the compound is represented by one of the following structural formulas:CTQ-01525In certain embodiments, the compound is represented by structural formula (Illa). In certain embodiments, the compound is represented by structural formula (Illb). In certain embodiments, the compound is represented by structural formula (IIIc).

[0033] In certain embodiments, the compound is represented by one of the following structural formulas:CTQ-01525(Ille).In certain embodiments, the compound is represented by structural formula (Illd). In certain embodiments, the compound is represented by structural formula (Ille).

[0034] In certain embodiments, the compound is represented by the following structural formula:

[0035] In certain embodiments, a is 1 or 2. In certain embodiments, b is 1 or 2. In certain embodiments, c is 1 or 2. In certain embodiments, d is 1 or 2.

[0036] In certain embodiments, the compound is represented by one of the following structural formulas:CTQ-01525

[0037] In certain embodiments, the compound is represented by structural formula (IVa) or structural formula (IVb). In certain embodiments, the compound is represented by structural formula (IVc) or structural formula (IVd). In certain embodiments, the compound is represented by structural formula (IVa). In certain embodiments, the compound is represented by structural formula (IVb). In certain embodiments, the compound is represented by structural formula (IVc). In certain embodiments, the compound is represented by structural formula (IVd).

[0038] In certain embodiments, G is O. In certain embodiments, G is S(=O)2. In certain embodiments, G is NR1.

[0039] In certain embodiments, R1is selected from H, Ci-6 alkyl, Ce-i2 aryl, 5- to 12- membered heteroaryl, C(=O)R2, and S(=O)2R4. For example, R1is H. For example, R1is H. For example, R1is Ce-i2 aryl. For example, R1is 5- to 12-membered heteroaryl. For example, R1is Ci-6 alkyl. For example, R1is C(=O)R2. For example, R1is S(=O)2R4.CTQ-01525

[0040] In certain embodiments, R1is Ce-12 aryl or 5- to 12-membered heteroaryl, wherein the Ce-12 aryl or 5- to 12-membered heteroaryl is substituted with a substituent selected from CN and S(=O)2(Ci-6 alkyl). For example, R1is Ce -12 aryl, such as phenyl, substituted with CN. For example, R1is Ce-12 aryl, such as phenyl, substituted with S(=O)2(Ci-6 alkyl), such as S(=O)2(Me). For example, R1is 5- to 12-membered heteroaryl, such as pyridyl or pyrimidyl, substituted with CN. For example, R1is 5- to 12-membered heteroaryl, such as pyridyl or pyrimidyl, substituted with S(=O)2(Ci-6 alkyl), such as S(=O)2(Me). In certain embodiments, R1is phenyl or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is substituted with a substituent selected from CN and S(=O)2(Ci-3 alkyl). In some embodiments, R1is a moiety represented by one of the following structural formulas:

[0041] In certain embodiments, R1is C(=O)R2. In certain embodiments, R2is Ci-6 alkyl.In certain embodiments, R2is C1-3 alkyl, such as methyl ethyl, propyl, or isopropyl. In certain embodiments, R2is methyl.

[0042] In certain embodiments, R1is S(=O)2R4. In certain embodiments, R4is C1-6 alkyl. In certain embodiments, R4is C1-3 alkyl, such as methyl ethyl, propyl, or isopropyl. In certain embodiments, R4is methyl.

[0043] In certain embodiments, R1is selected from H and C1-3 alkyl. In certain embodiments, R1is H. In certain embodiments, R1is C1-3 alkyl, such as methyl ethyl, propyl, or isopropyl. In certain embodiments, R1is methyl.

[0044] In certain embodiments, the compound is represented by one of the following structural formulas or a pharmaceutically acceptable form thereof:CTQ-01525CTQ-01525CTQ-01525CTQ-01525CTQ-01525Defmitions

[0045] Definitions of specific functional groups and chemical terms are described in more detail 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 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.

[0046] Compounds described herein can comprise one or more asymmetric centers, and thus can 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 etCTQ-01525 al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York, 1981; Wilen et al., Tetrahedron 332 25 (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.

[0047] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (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.

[0048] Unless otherwise stated, structures depicted herein are also meant to include compounds 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.

[0049] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, "Ci-6 alkyl" is intended to encompass Ci, C2, C3, C4, C5, Ce, 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.

[0050] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0051] The term "alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms ("C1-10 alkyl"). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C1-9 alkyl"). 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 ("C1-6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-5 alkyl"). 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 ("C1-2 alkyl"). In some embodiments, an alkyl groupCTQ-01525 has 1 carbon atom ("Ci alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-6 alkyl"). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3- methyl-2-butanyl, tertiary amyl), and hexyl (Ce) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (Cs), 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 C1-10 alkyl (such as substituted C1-6 alkyl, e.g., -CF3, Bn).

[0052] The term "haloalkyl" refers to a substituted alkyl group, wherein one or more of the hydrogen 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 ("Ci-s haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C1-6 haloalkyl"). In some 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 ("C1-3 haloalkyl"). 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, -CCI3, - CFCh, -CF2CI, and the like.

[0053] The term "deuteroalkyl" refers to an alkyl group, wherein one or more of the hydrogen atoms are independently replaced by deuterium. In some embodiments, the deuteroalkyl moiety has 1 to 8 carbon atoms ("Ci-s deuteroalkyl"). In some embodiments, the deuteroalkyl moiety has 1 to 6 carbon atoms ("C1-6 deuteroalkyl”). 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 ("C1-2 deuteroalkyl"). In some embodiments, the deuteroalkyl moiety is Ci, C2, C3, C4, C5, or Ce deuteroalkyl. A deuteroalkyl moiety having n carbon atoms can have from 1 to 2n+l 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.CTQ-01525

[0054] The term "hydroxyalkyl" is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a hydroxyl. In some embodiments, the hydroxyalkyl moiety has 1 to 8 carbon atoms ("Ci-s hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 6 carbon atoms ("Ci-6 hydroxyalkyl"). In some embodiments, the hydroxyalkyl moiety has 1 to 4 carbon atoms ("Ci-4 hydroxyalkyl"). 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").

[0055] The term "alkoxy" refers to an alkyl group, as defined herein, appended to the parent molecular 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 ("C1-6 alkoxy"). In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms ("C1-4 alkoxy"). In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms ("C1-3 alkoxy"). 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.

[0056] The term "haloalkoxy" refers to a haloalkyl group, as defined herein, appended to the parent 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 ("C1-4 haloalkoxy"). 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.

[0057] The term "alkoxy alkyl" is a substituted alkyl group, wherein one or more of the hydrogen 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 ("C1-6 alkoxyalkyl"). 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 ("C1-2 alkoxyalkyl").

[0058] The term "heteroalkyl" refers to an alkyl group, which further includes at least one 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 moreCTQ-01525 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 ("heteroCi-20 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and lor more heteroatoms within the parent chain ("heteroCi-i8 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 ("heteroCi-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 ("heteroCi-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 ("heteroCi-12 alkyl"). 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 ("heteroCi-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 ("heteroCi-s alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-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 ("heteroCi-4 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain ("heteroCi-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 ("heteroCi-2 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroCi 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 heteroCi-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl.

[0059] The term "alkenyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g.,CTQ-015251, 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 ("C2-7 alkenyl"). 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 ("C2-4 alkenyl"). 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 carboncarbon double bonds can be internal (such as in 2- butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl 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 (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl 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., -CEUCHCH3 ormay be an (E)- or (Z)- double bond.

[0060] The term "heteroalkenyl" refers to an alkenyl group, which further includes at least one 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-io alkenyl"). 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").

[0061] In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-s alkenyl"). 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 1CTQ-01525 or more heteroatoms within the parent chain ("heteroC2-6 alkenyl"). 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 ("heteroC2-5 alkenyl"). 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 ("heteroC2-3 alkenyl"). 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-io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-io alkenyl.

[0062] The term "alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group 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 ("C2-8 alkynyl"). 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 ("C2-5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2-4 alkynyl"). 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 carboncarbon 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 C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), 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 C2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10 alkynyl.CTQ-01525

[0063] The term "heteroalkynyl" refers to an alkynyl group, which further includes at least one 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-io 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 ("heteroC2-9 alkynyl"). 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-s 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 ("heteroC2-7 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more 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 1 or 2 heteroatoms within the parent chain ("heteroC2-4 alkynyl"). 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 ("heteroC2-6 alkynyl"). 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-io alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-io alkynyl.

[0064] The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C3-14 carbocyclyl") 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 ("C3-8 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C3-7 carbocyclyl"). 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 carbocyclylCTQ-01525 group has 5 to 6 ring carbon atoms ("C5-6 carbocyclyl"). 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 (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like.

[0065] Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), 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- IH-indenyl (C9), decahydronaphthal enyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing 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 C3-14 carbocyclyl.

[0066] In some embodiments, "cycloalkyl" is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C3-14 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C3-10 cycloalkyl"). 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 ("C4-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-6 cycloalkyl"). 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 (Ce). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) andCTQ-01525 cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). 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 C3-14 cycloalkyl.

[0067] In some embodiments, "bicycloalkyl" is a bicyclic, saturated carbocyclyl group having 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 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 ("C4-6 bicycloalkyl"). 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 ("C5-10 bicycloalkyl"). Examples of C5-6 bicycloalkyl groups include bicyclopentane (C5) and bicyclohexane (Ce). 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 C3-6 cycloalkyl groups as well as bicycloheptane (C7) and bicyclooctane (Cs). 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 C4-14 bicycloalkyl. In certain embodiments, the bicycloalkyl group is a substituted C4-14 bicycloalkyl.

[0068] The term "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 14- membered non-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 carboncarbon 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 theCTQ-01525 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.

[0069] In some embodiments, a heterocyclyl group is a 4-10 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 ("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.

[0070] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, 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, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, 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. ExemplaryCTQ-015256-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, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1,8- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, l,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-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3- b]pyridinyl, 4, 5, 6, 7 -tetrahydro-lH-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.

[0071] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system e.g., having 6, 10, or 147t electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("Ce-i4 aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("Ce aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("Cio aryl"; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("Ci4 aryl"; 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 Ce-i4 aryl. In certain embodiments, the aryl group is a substituted Ce-i4 aryl.

[0072] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.CTQ-01525

[0073] The term "heteroaryl" refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 n 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 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).

[0074] In some embodiments, a heteroaryl group is a 5-12 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 ("5-12 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 5-6CTQ-01525 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.

[0075] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups 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. Exemplary5-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. Exemplary6-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.

[0076] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.

[0077] The term "unsaturated bond" refers to a double or triple bond.

[0078] The term "unsaturated" or "partially unsaturated" refers to a moiety that includes at least one double or triple bond.

[0079] The term "saturated" refers to a moiety that does not contain a double or triple bond, z.e., the moiety only contains single bonds.CTQ-01525

[0080] 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.

[0081] A group is optionally substituted unless expressly provided otherwise. The term "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.

[0082] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa, -0N(Rbb)2, -N(Rbb)2, -N(Rbb)3X; -N(0Rcc)Rbb, -SH, - SRaa, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORCC)3, -CO^, -OC(=O)Raa, -OCO2Raa, -CTQ-01525C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, - C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, - OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, -Si(Raa)3, -OSi(Raa)3, -C(=S)N(Rbb)2, -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, - 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), Ci-io alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2. 10 alkynyl, heteroCi-io alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, Ce-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 =0, =S, =NN(Rbb)2, =NNRbbC(=0)Raa, =NNRbbC(=0)0Raa, =NNRbbS(=0)2Raa, =NRbbor =NORCC; each instance of Raais, independently, selected from Ci-io alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-io alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, Ce-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(=0)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)0Raa, - 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, CI-IO alkyl, Ci-io perhaloalkyl, C2. io alkenyl, C2-10 alkynyl, heteroCi-io alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, 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, Ci-io alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-io alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, Ce-i4CTQ-01525 aryl, 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, - 0N(Rff)2, -N(Rff)2, -N(Rff)3+X , -N(0Ree)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, Ci-6alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, 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 =0 or =S; wherein X is a counterion; each instance of Reeis, independently, selected from C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, Ce-io 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, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl 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(CI-6alkyl)2, -N(CI-6alkyl)2, -N(CI-6alkyl)3+X , -NH(CI-6alkyl)2+X , -NH2(CI-6alkyl)+X , -NH3+X , -N(OCI-6alkyl)(Ci-6alkyl), -N(0H)(CI-6alkyl), -NH(OH), -SH, -SC1-6 alkyl, -SS(Ci-6alkyl), -C(=O)(Ci-6alkyl), - CO2H, -CO2(Ci-6 alkyl), -OC(=O)(Ci-6alkyl), -OCO2(Ci-6alkyl), -C(=O)NH2, -C(=O)N(CI-6alkyl)2, -OC(=O)NH(CI-6alkyl), -NHC(=O)(CI-6alkyl), -N(CI-6alkyl)C(=O)( Ci-6alkyl), - NHCO2(CI-6alkyl), -NHC(=O)N(CI-6alkyl)2, -NHC(=O)NH(CI-6alkyl), -NHC(=0)NH2, -CTQ-01525C(=NH)0(CI-6 alkyl), -OC(=NH)(CI-6alkyl), -OC(=NH)OCI-6alkyl, -C(=NH)N(CI-6alkyl)2, - C(=NH)NH(CI-6alkyl), -C(=NH)NH2, -OC(=NH)N(CI-6alkyl)2, -OC(=NH)NH(CI-6alkyl), - OC(=NH)NH2, -NHC(=NH)N(CI-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(CI-6alkyl), -SO2N(CI-6alkyl)2, -SO2NH(CI-6alkyl), -SO2NH2, -SO2(CI-6alkyl), -SO2O(Ci-6alkyl), -OSO2(Ci-6alkyl), -SO(Ci-6alkyl), -Si(Ci-6alkyl)3, -OSi(Ci-6alkyl)3, -C(=S)N(CI-6alkyl)2, -C(=S)NH(Ci-6alkyl), -C(=S)NH2, -C(=O)S(CI-6alkyl), -C(=S)SCi-6alkyl, -SC(=S)SCi-6alkyl, - P(=0)(0Ci-6 alkyl)2, -P(=0)(Ci-6 alkyl)2, -OP(=O)(Ci-6alkyl)2, -OP(=O)(OCi-6alkyl)2, Ci-6alkyl, Ci-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-io carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; wherein X is a counterion.

[0083] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0084] 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, -0N(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, - X , -OP(ORCC)2, -OP(ORCC)3+X , -wherein X , Raa, Rbband Rccare as defined herein.

[0085] The term "amino" refers to the group -NH2. The term "substituted amino," by extension, refers to a monosubstituted amino, a disubstituted amino, or a tri substituted amino. In certain embodiments, the "substituted amino" is a monosubstituted amino or a di substituted amino group.

[0086] The term "monosubstituted amino" refers to an amino group wherein the nitrogen 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.CTQ-01525

[0087] The term "di substituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and

[0088] 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 - 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.

[0089] The term "tri substituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected fromwherein Rbband X are as defined herein.

[0090] The term "sulfonyl" refers to a group selected from -SO2N(Rbb)2, -SO2Raa, and- SO2ORaa, wherein Raaand Rbbare as defined herein.

[0091] The term "sulfinyl" refers to the group -S(=O)Raa, wherein Raais as defined herein.

[0092] 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 un substituted, 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 di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two RX1groups taken together form a 5- to 6-membered heterocyclic ring.

[0093] 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,CTQ-01525 heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphati camino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroaryl ami no, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0094] The term "carbonyl" refers a group wherein the carbon directly attached to the parent 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.

[0095] The term "oxo" refers to the group =0, and the term "thiooxo" refers to the group =S.

[0096] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include 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(=O)Raa,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, CI-IO alkyl, C1-10 perhaloalkyl, C2-io alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3- 14 membered heterocyclyl, Ce-14 aryl, 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, heteroalky nyl, 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, Ci-10 alkyl (e.g., aralkyl, heteroaralkyl), C2-io alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl,CTQ-01525 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 Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0097] For example, nitrogen protecting groups such as amide groups (e.g., -C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, tri chloroacetamide, trifluoroacetamide, phenyl acetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o- nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N1- dithiobenzyloxyacylamina)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophen y 1 )propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methy 1 -2-(o- phenyl azophenoxy )propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o-(b enzoy 1 oxy methy l)b enzami de .

[0098] 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)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl- [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), l-(l-adamantyl)-l- methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, 1, 1 -dimethyl -2,2- dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1- methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l- 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-(l ,3- dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-CTQ-01525 dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2- triphenylphosphonioisopropyl carbamate (Ppoc), l,l-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)m ethyl 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 )benzyl carbamate, 1, 1 -dimethyl -3 -(N, N-dimethylcarboxamido )propyl 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, l-methyl-l-(3,5- dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p-phenylazophenyl)ethyl carbamate, 1- methyl-1- phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenyl azo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4- (trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0099] 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.

[0100] 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 -diphenylmal eimide, N-2,5- dimethylpyrrole, N-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted l,3-dimethyl-l,3,5-triazacyclohexan- 2-one, 5-substituted 1,3 -dibenzyl- 1 ,3,5-CTQ-01525 triazacyclohexan- 2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2- (trimethyl silyl)ethoxy ]methylamine (SEM), N-3 -acetoxypropylamine, N-(l-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 yl)mesityl]methyleneamine, N-(N' ,N'-dimethylaminomethylene)amine, N,N'- isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N- 5- chlorosalicylideneamine, N-(5-chloro-2- hydrox yphen yl)phenylmethyleneamine, N - cyclohex ylideneamine, N-(5,5-dimethyl-3-oxo-l- 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), tertbutyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-m ethoxybenzyl (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).

[0101] In certain embodiments, the substituent present on an oxygen atom is an oxygen 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 OrganicCTQ-01525Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0102] 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- methoxy ethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymeth yl (SEMOR), tetrahydropyranyl (TEIP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, l-[(2-chloro-4-meth yl)phenyl]-4-methox ypiperidin-4-yl (CTMP), l,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1 -ethoxy ethyl, 1- (2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 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, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6- di chlorobenzyl, 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 yl)diphen ylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4, 4', 4"- tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol-l- yl)bis(4',4"-dimethoxyphenyl)methyl, l,l-bis(4-methoxyphenyl)-l'-pyrenylmethyl, 9- anthryl, 9- (9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl S,S- dioxido, trimethyl silyl (TMS), tri ethylsilyl (TES), triisopropyl silyl (TIPS), dimethylisopropyl silyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t- butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethyl silyl (DPMS), t-butylmethoxyphenyl silyl (TEMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, tri chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3- phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio )pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-CTQ-01525 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-(phenyl sulfonyl) 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-l-napththyl carbonate, methyl dithiocarb onate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl)benzoate, 2- formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(meth ylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4- ( l,l,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis( l,l-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), triisoproyl silyl (TIPS), triphenyl silyl (TPS), triethylsilyl (TES), trimethyl silyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2- trimethylsilylethyl carbonate, methoxymethyl (MOM), 1 -ethoxy ethyl (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).

[0103] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting 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 Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999,CTQ-01525 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.

[0104] A "counterion" as used herein can be an anionic counterion or a cationic counterion.

[0105] An “anionic counterion" is a negatively charged group associated with a positively 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", CIO4 ", OH ", H2PO4 ", HCO3 ", HSO4 ", sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p- toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthal ene-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", PFe , AsFe", SbFe", B[3,5- (CFs^CeH?] 4", B(CeFs)4 ", BPI14", A1(OC(CF3)3) 4 , and carborane anions (e.g., CB11H12" or (HCBnMesBre)"). 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.

[0106] A “cationic counterion" is a positively charged group associated with a negatively 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(Ci-ealkyl)+, NH2(Ci-ealkyl)2+, NH (Ci-ealkyl)3+, and N+(Ci-ealkyl)4 cations, where the Ci-ealkyl 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

[0107] In another aspect, the present disclosure relates to pharmaceutical compositions comprising a compound disclosed herein, e.g., a compound represented by structural formula (I), (II), (III), (Illa), (Bib), (inc), (Illd), (Ille), (Illf), (Via), (VIb), (Vic), or (Vid), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.CTQ-01525

[0108] Compounds provided herein are usually administered in the form of pharmaceutical 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 Modem Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0109] In some embodiments, the pharmaceutical composition comprises a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula la, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula lb, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula Ila, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula lib, 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.

[0110] The pharmaceutical compositions may be administered in either single or multiple 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.CTQ-01525

[0111] One mode for administration is parenteral, for example, by injection. The forms 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.

[0112] Oral administration may be another route for administration of the compounds described 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, semisolid, 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.

[0113] 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.

[0114] The compositions that include at least one compound described herein or a pharmaceutically 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 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 describedCTQ-01525 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.

[0115] For preparing solid compositions such as tablets, the principal active ingredient 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.

[0116] The tablets or pills of the compounds described herein may be coated or otherwise 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.

[0117] Compositions for inhalation or insufflation may include solutions and suspensions 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 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.

[0118] The specific dose level of a compound of the present application for any particular 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 particularCTQ-01525 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

[0119] In another aspect, the present disclosure relates to methods 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 disclosed herein, a pharmaceutically accept salt thereof, or a composition disclosed herein.

[0120] In another aspect, the present disclosure relates to using the compounds, e.g., compounds represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Hid), (Hie), (Illf), (Via), (VIb), (Vic), or (Vid), pharmaceutically acceptable salts thereof, and compositions disclosed herein for use in treating a disorder in a subject in need thereof.

[0121] In another aspect, the present disclosure relates to using the compounds, e.g., compounds represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Hid), (Hie), (Illf), (Via), (VIb), (Vic), or (Vid), pharmaceutically acceptable salts thereof, and compositions disclosed herein for use in promoting myelination in a subject in need thereof.

[0122] In another aspect, the present disclosure relates to using the compounds, e.g., compounds represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Hid), (Hie), (Illf), (Via), (VIb), (Vic), or (Vid), 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.

[0123] In another aspect, the present disclosure relates to using the compounds, e.g., compounds represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Hid), (Hie),CTQ-01525(I Ilf), (Via), (VIb), (Vic), or (Vid), 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.

[0124] In certain embodiments, the subject has a myelin-related disorder. In certain embodiments, 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. In some embodiments, the multiple sclerosis is clinically isolated syndrome. In some embodiments, the multiple sclerosis is relapsing-remitting multiple sclerosis. In some embodiments, the multiple sclerosis is primary progressive multiple sclerosis. In some embodiments, the multiple sclerosis is secondary progressive multiple sclerosis.

[0125] In another aspect, the present disclosure relates to method of inhibiting CYP51 (lanosterol demethylase) comprising contacting CYP51 with a compound disclosed herein, e.g., compounds represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Hid), (Ille), (Ulf), (Via), (VIb), (Vic), or (Vid), a pharmaceutically accept salt thereof, or a composition disclosed herein.

[0126] Described herein are methods for promoting myelination of central 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 represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (Illf), (Via), (VIb), (Vic), or (Vid) or a pharmaceutical composition comprising the same. In certain embodiments, the subject matter disclosed herein is directed to a compound represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (Illf), (Via), (VIb), (Vic), or (Vid) or a pharmaceutically acceptable salt or solvate thereof, for promoting myelination of centralCTQ-01525 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 represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Hid), (Hie), (I I If), (Via), (VIb), (Vic), or (Vid) 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.

[0127] In certain embodiments, in the methods for promoting myelination of central nervous system neurons in a subject suffering from a myelin-related disorder, compound represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Hid), (Hie), (I I If), (Via), (VIb), (Vic), or (Vid) 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.

[0128] In certain embodiments, in the methods for promoting myelination of central nervous system neurons in a subject suffering from a myelin-related disorder, the compound represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Hid), (Hie), (I I If), (Via), (VIb), (Vic), or (Vid) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, promotes accumulation of A8,9- unsaturated sterol intermediates in the cholesterol biosynthesis pathway.

[0129] In certain embodiments, in the methods for promoting myelination of central nervous system neurons in a subject suffering from a myelin-related disorder, the compound represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Hid), (Hie), (I I If), (Via), (VIb), (Vic), or (Vid) 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 represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (Illf), (Via), (VIb), (Vic), or (Vid) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, inhibits CYP51.

[0130] In certain embodiments, in the methods for promoting myelination of central nervous system neurons in a subject suffering from a myelin-related disorder, the compound represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Hid), (Ille), (I I If), (Via), (VIb), (Vic), or (Vid) 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. InCTQ-01525 certain embodiments, the induction of OPC differentiation is characterized by an increase in myelin basic protein (MBP) expression.

[0131] In certain embodiments, the subject matter described herein is directed to a method 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 represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Hid), (Hie), (I I If), (Via), (VIb), (Vic), or (Vid) 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 II, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IIIc, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illd, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Ille, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illf, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVc, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVd, or a pharmaceutically acceptable salt or solvate thereof.

[0132] In certain embodiments, the subject matter disclosed herein is directed to a compound represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Hid), (Ille), (Illf), (Via), (VIb), (Vic), or (Vid) 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 II, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound ofCTQ-01525Formula I is a compound of Formula Illa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IIIc, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illd, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Ille, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illf, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVc, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVd, or a pharmaceutically acceptable salt or solvate thereof.

[0133] In certain embodiments, the subject matter disclosed herein is directed to the use of a compound represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Hid), (Ille), (Illf), (Via), (VIb), (Vic), or (Vid) 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 II, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IIIc, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illd, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Ille, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illf, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound ofCTQ-01525Formula I is a compound of Formula IVb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVc, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVd, or a pharmaceutically acceptable salt or solvate thereof.

[0134] In certain embodiments, the subject matter disclosed herein is directed to a method of promoting myelination in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (Illf), (Via), (VIb), (Vic), or (Vid) 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 II, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IIIc, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illd, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Ille, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illf, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVc, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVd, or a pharmaceutically acceptable salt or solvate thereof.

[0135] In certain embodiments, the subject matter disclosed herein is directed to a compound represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (Illf), (Via), (VIb), (Vic), or (Vid) 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.CTQ-01525In some embodiments, the compound of Formula I is a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IIIc, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illd, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Ille, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illf, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVc, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVd, or a pharmaceutically acceptable salt or solvate thereof.

[0136] In certain embodiments, the subject matter disclosed herein is directed to use of a compound represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Hid), (Ille), (Illf), (Via), (VIb), (Vic), or (Vid) 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 II, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IIIc, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illd, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound ofCTQ-01525Formula I is a compound of Formula Ille, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illf, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVc, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVd, or a pharmaceutically acceptable salt or solvate thereof.

[0137] In certain embodiments, the subject matter disclosed herein is directed to a method 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 represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (Illf), (Via), (VIb), (Vic), or (Vid) 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.

[0138] 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-Komzweig 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.

[0139] The compound represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (Illf), (Via), (VIb), (Vic), or (Vid) 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., neuronalCTQ-01525 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. In some embodiments, the compound of Formula I is a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IIIc, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illd, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Ille, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula Illf, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVa, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVb, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVc, or a pharmaceutically acceptable salt or solvate thereof. In other embodiments, the compound of Formula I is a compound of Formula IVd, or a pharmaceutically acceptable salt or solvate thereof.

[0140] “Demyelination” as used herein, refers to the act of demyelinating, or the damage 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).

[0141] 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 beCTQ-01525 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.

[0142] “Promoting Myelination” as used herein refers to increasing the rate of myelin 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.

[0143] A “baseline level of myelin production rate” as used herein, refers to the rate of myelin production in subject being treated before the onset of treatment.

[0144] “MS therapeutic agents” as used herein, refers to therapeutic agents known to be used in treating MS. Such therapeutic agents include, but are not limited to, Copaxone (glatiramer acetate), Ocrevus (ocrelizumab), Campath (Lemtrada or alemtuzumab), Gilenya, Ampyra (dalfampridine), Tysabri (natalizumab), Aubagio (teriflunomide), Rebif , Avonex, Betaseron, Plegridy, Interferon Beta- la, dimethyl fumarate, fmgolimod, rituximab, Zinbryta, Ofatumymab, Nerventra (laquinimod), Masitinib, Siponimod, Ozanimod, Ponesimod, ibudilast, vatelizumab, minocycline, ibrutinib, PRN2246, Cladripine, GNBAC1, daclizumab, and MD1003 (biotin).

[0145] In certain embodiments, the compounds of the disclosure and pharmaceutically acceptable salts or solvates thereof can be administered with an MS therapeutic agent. The MS therapeutic agent may be administered simultaneously with the compound of the disclosure. Alternatively, the MS therapeutic agent may be administered prior to administration the compound of the disclosure. Alternatively still, the MS therapeutic agent may be administered following the administration of the compound of the disclosure.

[0146] In certain embodiments, the compounds of the disclosure and pharmaceutically acceptable salts or solvates thereof can be administered in combination with cognitive enhancing (nootropic) agents. Exemplary agents include any drugs, supplements, or otherCTQ-01525 substances that improve cognitive function, particularly executive functions, memory, creativity, or motivation, in healthy individuals. Non-limiting examples include racetams (e.g., piracetam, oxiracetam, and aniracetam), nutraceuticals (e.g., bacopa monnieri, panax ginseng, ginko biloba, and GABA), stimulants (e.g., amphetamine pharmaceuticals, methylphenidate, eugeroics, xanthines, and nicotine), L-Theanine, Tolcapone, Levodopa, Atomoxetine, and Desipramine.

[0147] A further embodiment for treating a subject suffering from a myelin-related disorder is to administer a therapeutically effective amount of a compound described herein along with a therapeutically effective amount of additional oligodendrocyte differentiation and / or proliferation inducing agent(s) and / or anti-neurodegenerative disease agent. Examples of anti-neurodegenerative disease agents include L-dopa, cholinesterase inhibitors, anticholinergics, dopamine agonists, steroids, immunomodulators including interferons, monoclonal antibodies, and glatiramer acetate and modulators (e.g., inhibitors) of SARM1 a new class of NADase enzyme (See, Essuman, Neuron, Vol. 93, Issue 6, pa 1334, March 22, 2017).

[0148] Therefore, in a further aspect of the disclosure, the oligodendrocyte precursor differentiation and / or proliferation inducing compound represented by structural formula (I), (II), (III), (Illa), (Bib), (inc), (Hid), (Ille), (Illf), (Via), (VIb), (Vic), or (Vid) or a pharmaceutically acceptable salt or solvate thereof, can be administered as part of a combination therapy with adjunctive therapies for treating neurodegenerative and myelin related disorders.

[0149] A further embodiment for treating a subject suffering from a myelin-related disorder is to administer a therapeutically effective amount of a compound described herein along with a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor. In some embodiments, the BTK inhibitor is selected from Acalabrutinib, Ibrutinib, Orelabrutinib, Pirtobrutinib, Remibrutinib, Rilzabrutinib, Tirabrutinib, Zanubrutinib, Evobrutinib, Fenebrutinib, Tolebrutinib, Elsubrutinib, Poseltinib, Luxeptinib, Nemtabrutinib, Spebrutinib, Tirabrutinib, Vecabrutinib, Branebrutinib, Catadegbrutinib, Bexodegbrutinib, Sunvozertinib, and Avitinib. In some embodiments, the BTK inhibitor is selected from Evobrutinib, Fenebrutinib, and Tolebrutinib.

[0150] A further embodiment for treating a subject suffering from a myelin-related disorder is to administer a therapeutically effective amount of a compound described herein along with a therapeutically effective amount of Cladribine, Dimethyl fumarate, Diroximel fumarate, Evobrutinib, Fenebrutinib, Fingolimod, Glatiramer acetate, Interferon beta- la,CTQ-01525Mitoxantrone, Monomethyl fumarate, Orelabrutinib, Ponesimod, Remibrutinib, Siponimod, Teriflunomide, or Tolebrutinib.

[0151] The phrase “combination therapy” embraces the administration of the compound represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Hid), (Ille), (I Ilf), (Via), (VIb), (Vic), or (Vid) or a pharmaceutically acceptable salt or solvate thereof and an additional therapeutic agent as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of each. When administered as a combination, the oligodendrocyte precursor differentiation inducing compound described herein and an additional therapeutic agent can be formulated as separate compositions. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).

[0152] “ Combination therapy” is intended to embrace administration of these therapeutic agent (the compound represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (Ulf), (Via), (VIb), (Vic), or (Vid) or a pharmaceutically acceptable salt or solvate thereof and an additional therapeutic agent) in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence wherein the therapeutic agents are administered is not narrowly critical. “Combination therapy” also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients (such as, but not limited to, a second and different therapeutic agent) and non-drug therapies (e.g., surgery).

[0153] In another aspect of the disclosure, the therapeutic agents administered in a combination therapy with the oligodendrocyte differentiation and / or proliferation inducingCTQ-01525 compound described herein (the compound represented by structural formula (I), (II), (III), (Illa), (Illb), (inc), (Illd), (Ille), (Illf), (Via), (VIb), (Vic), or (Vid) or a pharmaceutically acceptable salt or solvate thereof) can include at least one anti-neurodegenerative agent such as but not limited to, an immunotherapeutic agent.

[0154] In certain embodiments of the method described herein (promoting myelination of central nervous system axons in a subject suffering from a myelin-related disorder) the subject is administered the compound described herein for an on-drug segment of the dosing cycle for at least three months. For example, the subject is administered the compound described herein for an on-drug segment of the dosing cycle for at least six months.

[0155] In particular embodiments of the method described herein (promoting myelination of central nervous system axons in a subject suffering from a myelin-related disorder), the subject is administered the compound represented by structural formula (I), (II), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (Illf), (Via), (VIb), (Vic), or (Vid) or a pharmaceutically acceptable salt or solvate thereof using the following dosing cycle: on-drug segment for at least six months; off-drug segment for at least three months; wherein the on-drug and off- drug segments are optionally repeated.

[0156] An “on-drug segment” is the period of time (e.g., number of days or weeks) deemed appropriate by a skilled medical professional that the drug is being administered to the subject, and will vary depending on the nature of the disease, the dose of the drug being administered, the health of the patient, the intended result, and the like. An “off-drug segment” is the period of time between on-drug segments. By way of example, a dosing cycle of treatment regimen for treating multiple sclerosis can be on-drug segment for at least six months, followed by an off drug segment for at least three months, wherein the on-drug and off-drug segments of the dosing cycle are optionally repeated. As will be appreciated by those of skill in the art, a dosing cycle having any combination of the number of “on” and “off’ drug segments can be designed as deemed appropriate by a skilled medical professional.

[0157] Administration methods include administering an effective amount (i.e., an effective amount) of a compound or composition of the disclosure at different times during the course of therapy or concurrently in a combination form. The methods of the disclosure include all known therapeutic treatment regimens. In certain embodiments, the compound or pharmaceutical composition is administered intravenously, intrathecally, subcutaneously, intramuscularly, intranasally, or orally.CTQ-01525PREPARATION OF INTERMEDIATESIntermediate A tert-butyl 2-((4-methoxypyridin-3-yl)amino)-7-azaspiro[3.5]nonane-7-carboxylateTo a solution of 4-methoxypyri din-3 -amine (1.5 g, 12.08 mmol, 1 eq) and tert-butyl 2-oxo-7- azaspiro[3.5]nonane-7-carboxylate (3.47 g, 14.50 mmol, 1.2 eq) in isopropyl acetate (45 mL) was added NaBH(OAc)3 (3.07 g, 14.50 mmol, 1.2 eq) and TFA (4.13 g, 36.25 mmol, 2.68 mL, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 16 hr. LCMS (10-80% acetonitrile in 0.2% NHs FBO / water over 3.0 min): RT = 2.068 min, [M+H]+= 348.3, showed 75% of desired product. The reaction mixture was treated with saturated NaHCCh aq. (25 mL) and stirred for 30 mins. The resulting mixture was extracted with ethyl acetate (10 mL x 3) and the combined organic layer was washed with brine (15 mL x 3). The organic phase was dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 10% MeOH in di chloromethane) to afford the title compound (3.3 g, 79%) as a yellow solid.'HNMR (400 MHz, CDC13): 3 8.04 (d, J= 6.0 Hz, 1H), 7.72 (s, 1H), 6.85 (d, J= 6.0 Hz, 1H), 4.25 (s, 1H), 3.92 (s, 3H), 3.89 - 3.83 (m, 1H), 3.40 - 3.28 (m, 4H), 2.50 - 2.40 (m, 2H), 1.68 - 1.58 (m, 4H), 1.55 -1.51 (m, 2H), 1.47 (s, 9H).Intermediate B7V-(4-(difluoromethoxy)phenyl)-7V-(4-methoxypyridin-3-yl)-7-azaspiro[3.5]nonan-2- amine hydrochlorideCTQ-01525Step 1: tert-butyl 2-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)-7- azaspiro[3.5]nonane-7-carboxylateA mixture of tert-butyl 2-((4-methoxypyridin-3-yl)amino)-7-azaspiro[3.5]nonane-7- carboxylate (100 mg, 287.81 pmol, 1 eq), l-bromo-4-(difluoromethoxy)benzene (128.37 mg, 575.62 pmol, 78.76 uL, 2 eq), t-BusP Pd G2 (chloro[(tri-tert-butylphosphine)-2-(2- aminobiphenyl)] palladium(II), 14.75 mg, 28.78 pmol, 0.1 eq), t-BuONa (82.98 mg, 863.43 pmol, 3 eq) in toluene (5 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 120 °C for 24 hr under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.871 min, [M+H]+= 490.2 showed 54% of desired product. The reaction mixture was concentrated. The residue was purified by flash chromatography on silica gel (0 - 50% ethyl acetate in petroleum ether) to afford the title compound (125 mg, 89%) as a pink solid.Step 2: V-(4-(difluoromethoxy)phenyl)-7V-(4-methoxypyridin-3-yl)-7- azaspiro[3.5]nonan-2-amine hydrochlorideTo a solution of tert-butyl 2-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)-7- azaspiro[3.5]nonane-7-carboxylate (125 mg, 255.33 pmol, 1 eq) in HCl / dioxane (4M / L, 5 mL) was added and at 0 °C. The mixture was stirred at 25 °C for 1.5 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.411 min, [M+H]+= 390.2, showed of 99% desired product. The solution was concentrated under reduced pressure to afford the title compound (102 mg, crude) as a pink solid.CTQ-01525Intermediate C7V-(4-methoxypyridin-3-yl)- V-(4-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonan-2-amine hydrochlorideStep 1: tert-butyl 2-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-7- azaspiro[3.5]nonane-7-carboxylateA mixture of tert-butyl 2-((4-methoxypyridin-3-yl)amino)-7-azaspiro[3.5]nonane-7- carboxylate (450 mg, 1.30 mmol, 1 eq , l-bromo-4-(trifluoromethyl)benzene (582.83 mg, 2.59 mmol, 357.57 pL, 2 eq , t-BusP Pd G2 (66.36 mg, 129.51 pmol, 0.1 eq), t-BuONa (373.40 mg, 3.89 mmol, 3 eq in toluene (10 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 125 °C for 16 hr under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.862 min, [M+H]+= 492.3 showed 39% of desired product. The reaction solution was diluted with brine (50 mL) and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL x 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% EE (ethyl acetate: ethanol = 3: 1) in petroleum ether) to afford the title compound (550 mg, 86%) as a white solid.CTQ-01525Step 2: 7V-(4-methoxypyridin-3-yl)-7V-(4-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonan- 2-amine hydrochlorideTo a solution of tert-butyl 2-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-7- azaspiro[3.5]nonane-7-carboxylate (550 mg, 1.12 mmol, 1 eq was added HCl / dioxane (4 M, 8 mL, 28.60 eq). The mixture was stirred at 25 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.708 min, [M+H]+= 392.3 showed 98% of desired product. The solution was filtered and concentrated under reduced pressure to afford the title compound (437 mg, crude) as a white solid.Intermediate D tert-butyl 7-((4-methoxypyridin-3-yl)amino)-2-azaspiro[3.5]nonane-2-carboxylateRonTo a solution of 4-methoxypyri din-3 -amine (0.85 g, 6.85 mmol, 1 eq) and tert-butyl 7-oxo-2- azaspiro[3.5]nonane-2-carboxylate (1.80 g, 7.53 mmol, 1.1 eq in isopropyl acetate (40 mL) was added NaBH(OAc)3 (1.74 g, 8.22 mmol, 1.2 eq) and TFA (2.34 g, 20.54 mmol, 1.52 mL, 3 eq . The mixture was stirred at 25 °C for 12 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.738 min, [M+H]+= 348.2 showed 68% of desired product. The reaction mixture was treated with saturated NaOH aq. (10 mL) and stirred for 3 mins. The resulting mixture was extracted with ethyl acetate (100 mL x 3) and the combined organic layer was washed with brine (50 mL x 3). The organic phase was dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography on silica gel (0 - 30% EE (ethyl acetate: ethanol = 3: 1) in petroleum ether) to afford the title compound (1.71 g, 72%) as a light white solid.CTQ-01525'H NMR (400 MHz, CD3OD): <5 7.94 (d, J= 6.0 Hz, 1H), 7.85 (s, 1H), 7.21 (d, J= 6.0 Hz, 1H), 4.09 (s, 3H), 3.68 - 3.55 (m, 4H), 3.39 - 3.32 (m, 1H), 2.02 - 1.91 (m, 4H), 1.71 - 1.60 (m, 2H), 1.44 (s, 9H), 1.41 - 1.28 (m, 2H).Intermediate E7V-(4-(difluoromethoxy)phenyl)- V-(4-methoxypyridin-3-yl)-2-azaspiro[3.5]nonan-7- amineStep 1: tert-butyl 7-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)-2- azaspiro[3.5]nonane-2-carboxylateA mixture of tert-butyl 7-((4-methoxypyridin-3-yl)amino)-2-azaspiro[3.5]nonane-2- carboxylate (1.0 g, 2.88 mmol, 1 eq), l-bromo-4-(difluoromethoxy)benzene (1.28 g, 5.76 mmol, 787.56 uL, 2 eq), t-BuONa (829.76 mg, 8.63 mmol, 3 eq) and t-BusP Pd G2 (294.95 mg, 575.62 pmol, 0.2 eq) in toluene (50 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 120 °C for 12 hr under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.865 min, [M+H]+= 490.2 showed 37% of desired product. The reaction mixture was filtered and concentrated. The residue was purified by flash silica gel chromatography on silica gel (0 - 15% EE (ethyl acetate: ethanol = 3: 1) in petroleum ether) to afford the title compound (370 mg, 26%) as a white solid.CTQ-01525Step 2: V-(4-(difluoromethoxy)phenyl)-7V-(4-methoxypyridin-3-yl)-2- azaspiro[3.5]nonan-7-amineA solution of tert-butyl 7-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)-2- azaspiro[3.5]nonane-2-carboxylate (360 mg, 735.36 pmol, 1 eq in 5% TFA / HFIP (5 mL) was stirred at 25 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.675 min, [M+H]+= 390.3 showed 80% of desired product. The reaction mixture was treated with saturated NaHCCh (5 mL) and stirred for 30 mins. The reaction mixture was filtered and concentrated to afford the title compound (286 mg, crude) as a brown solid.Intermediate F7V-(4-methoxypyridin-3-yl)-7V-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.5]nonan-7-amineStep 1: tert-butyl 7-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-2- azaspiro[3.5]nonane-2-carboxylateTo a mixture of tert-butyl 7-((4-methoxypyri din-3 -yl)amino)-2-azaspiro[3.5]nonane-2- carboxylate (400 mg, 1.15 mmol, 1 eq) in toluene (8 mL) was added l-bromo-4- (trifhioromethyl)benzene (518.07 mg, 2.30 mmol, 317.84 pL, 2 eq), Z-BusP Pd G2 (58.99 mg, 115.12 pmol, 0.1 eq and / -BuONa (331.92 mg, 3.45 mmol, 3 eq . The mixture was stirred at 120 °C for 16 hours under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / waterCTQ-01525 over 1.5 min): RT = 0.840 min, [M+H]+= 492.3, showed 68% of desired product. The solution was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (0 - 53% ethyl acetate in petroleum ether) to afford the title compound (560 mg, 98%) as a yellow oil.Step 2: 7V-(4-methoxypyridin-3-yl)-7V-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.5]nonan- 7-amineA mixture of tert-butyl 7-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-2- azaspiro[3.5]nonane-2-carboxylate (560 mg, 1.14 mmol, 1 eq in 5% TFA / HFIP (8 mL) was stirred at 25 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.649 min, [M+H]+= 392.2 showed 96% of desired product. Then the mixture was adjusted to pH = 8 with Na2CC>3 (100 mg) at 0 °C, the mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (30 mL x 3), dried with anhydrous Na2SC>4, filtered and concentrated to afford the title compound (444 mg, crude) as a yellow oil.Intermediate G4-methoxy-7V-(2-oxaspiro[3.5]nonan-7-yl)pyridin-3-amineTo a solution of 4-methoxypyri din-3 -amine (500 mg, 4.03 mmol, 1 eq), 2- oxaspiro[3.5]nonan-7-one (564.60 mg, 4.03 mmol, 1 eq in DMF (15 mL) was added TMSC1 (1.09 g, 10.07 mmol, 1.28 mL, 2.5 eq at 0 °C. The mixture was stirred at 0 °C for 10 min, then BH3 THF (1 M / L in THF, 4.03 mL, 1 eq was added into it at 0 °C, the mixture was stirred at 0 °C for 0.5 hr. LCMS (5-95% acetonitrile in 0.2% NHv^O / water over 1.5 min), RT = 0.65 min, [M+H]+= 249.1 showed 82% of desired product. The reaction mixture was treated with saturated NaOH aq. (10 mL) and stirred for 5 mins. The resulting mixture wasCTQ-01525 extracted with ethyl acetate (50 mL x 4) and the combined organic layer was washed with brine (30 mL x 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 (277 mg, 28%) as a light yellow solid.'HNMR (400 MHz, CDCI3): 3 7.92 (d, J= 5.6 Hz, 1H), 7.88 (s, 1H), 6.67 (d, J= 5.6 Hz, 1H), 4.44 (s, 2H), 4.40 (s, 2H), 3.88 (s, 3H), 3.33 - 3.22 (m, 1H), 2.18 - 2.16 (m, 2H), 2.06- 2.01 (m, 2H), 1.67 - 1.57 (m, 2H), 1.27 - 1.15 (m, 2H).Intermediate H4-methoxy- V-(3-oxaspiro[5.5]undecan-9-yl)pyridin-3-amineAt 0 °C, to the solution of 4-methoxypyri din-3 -amine (0.1 g, 805.54 pmol, 1 eq), 3- oxaspiro[5.5]undecan-9-one (0.1 g, 594.42 pmol, 7.38e-l eq in isopropyl acetate (5 mL) was added NaBH(OAc)s (204.87 mg, 966.65 pmol, 1.2 eq , followed by addition of 2,2,2- trifluoroacetic acid (275.55 mg, 2.42 mmol, 179.51 pL, 3 eq . The mixture was stirred at 0 °C for 1 h and then the solution was stirred at 30 °C for 15 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.608 min, [M+H]+= 277.2 showed 85% of desired product. The mixture was adjusted to pH = 9 with sat. NaHCCL, then extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with brine (20 mL x 3), dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash chromatography on silica gel (0 - 25% EE (ethyl acetate: ethanol = 3: 1) in petroleum ether) to afford the title compound (30 mg, 13%) as a yellow oil.CTQ-01525Intermediate I tert-butyl 2-((4-cyclopropylpyridin-3-yl)amino)-7-azaspiro[3.5]nonane-7-carboxylateciStep 1 pStep 1: tert-butyl 2-((4-chloropyridin-3-yl)amino)-7-azaspiro[3.5]nonane-7-carboxylateTo a solution of 4-chloropyri din-3 -amine (2.0 g, 15.56 mmol, 1 eq) and tert-butyl 2-oxo-7- azaspiro[3.5]nonane-7-carboxylate (4.47 g, 18.67 mmol, 1.2 eq) in isopropyl acetate (20 mL) was added NaBH(OAc)3 (3.96 g, 18.67 mmol, 1.2 eq) and TFA (5.32 g, 46.67 mmol, 3.47 mL, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 16 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min), RT = 0.725 min, [M+H]+= 352.2, showed 77% of desired product. The reaction mixture was treated with saturated NaOH aq. (15 mL) and stirred for 30 mins. The resulting mixture was extracted with ethyl acetate (100 mL x 3) and the combined organic layer was washed with brine (50 mL x 3). The organic phase was dried over Na2SC>4, 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 (3.8 g, 69%) as a yellow oil.Step 2: tert-butyl 2-((4-cyclopropylpyridin-3-yl)amino)-7-azaspiro[3.5]nonane-7- carboxylateTo a solution of tert-butyl 2-((4-chloropyridin-3-yl)amino)-7-azaspiro[3.5]nonane-7- carboxylate (1.0 g, 2.84 mmol, 1 eq) and cyclopropylboronic acid (488.23 mg, 5.68 mmol, 2 eq) in toluene (10 mL) was added CS2CO3 (2.78 g, 8.53 mmol, 3 eq) and Pd(OAc)2 (63.80 mg, 284.20 pmol, 0.1 eq) and / / -BuPAd2 (203.79 mg, 568.39 pmol, 0.2 eq) at 0 °C. TheCTQ-01525 mixture was stirred at 120 °C for 2 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min), RT = 0.751 min, [M+H]+= 358.3 showed 61% of desired product. The reaction was 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 (807 mg, 79%) as a yellow solid.Intermediate J7V-(4-cyclopropylpyridin-3-yl)-7V-(4-(difluoromethoxy)phenyl)-7-azaspiro[3.5]nonan-2- amine hydrochlorideStep 1: tert-butyl 2-((4-cyclopropylpyridin-3-yl)(4-(difluoromethoxy)phenyl)amino)-7- azaspiro[3.5]nonane-7-carboxylateTo a solution of tert-butyl 2-((4-cyclopropylpyridin-3-yl)amino)-7-azaspiro[3.5]nonane-7- carboxylate (0.56 g, 1.57 mmol, 1 eq and l-bromo-4-(difluoromethoxy)benzene (698.70 mg, 3.13 mmol, 428.39 pL, 2 eq) in toluene (2 mL) was added t-BusP Pd G2 (160.53 mg, 313.30 pmol, 0.2 eq and t-BuONa (602.18 mg, 6.27 mmol, 4 eq at 0 °C. The mixture was stirred at 125 °C for 12 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min), RT = 0.867 min, [M+H]+= 500.3 showed 39% of desired product. The solution was 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 (495 mg, 63%) as a yellow oil.CTQ-01525Step 2: 7V-(4-cyclopropylpyridin-3-yl)-7V-(4-(difluoromethoxy)phenyl)-7- azaspiro[3.5]nonan-2-amine hydrochlorideA solution of tert-butyl 2-((4-cy cl opropylpyri din-3 -yl)(4-(difluoromethoxy)phenyl)amino)-7- azaspiro[3.5]nonane-7-carboxylate (495 mg, 990.81 pmol, 1 eq) in HCl / di oxane (4M / L, 10 mL) was stirred at 25 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min), RT = 0.660 min, [M+H]+= 400.3 showed 99% of desired product. The reaction was concentrated under reduced pressure to afford the title compound (395.80 mg, crude) was obtained as a yellow solid.Intermediate K7V-(4-cyclopropylpyridin-3-yl)-7V-(4-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonan-2- amine hydrochlorideStep 1: tert-butyl 2-((4-cyclopropylpyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-7- azaspiro[3.5]nonane-7-carboxylateTo a solution of tert-butyl 2-((4-cyclopropylpyridin-3-yl)amino)-7-azaspiro[3.5]nonane-7- carboxylate (400 mg, 1.12 mmol, 1 eq and l-bromo-4-(trifluoromethyl)benzene (377.64 mg,CTQ-015251.68 mmol, 231.68 pL, 1.5 eq) in toluene (10 mL) was added t-BusP Pd G2 (57.33 mg,111.89 mol, 0.1 eq) and t-BuONa (322.58 mg, 3.36 mmol, 3 eq) at 0 °C. The mixture was stirred at 125 °C for 12 hr under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min), RT = 0.903 min, [M+H]+= 502.3 showed 63% of the desired product. The solution was 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 (446 mg, 79%) as a yellow oil.Step 2: 7V-(4-cyclopropylpyridin-3-yl)-7V-(4-(trifluoromethyl)phenyl)-7- azaspiro[3.5]nonan-2-amine hydrochlorideA solution of tert-butyl 2-((4-cyclopropylpyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-7- azaspiro[3.5]nonane-7-carboxylate (447.78 mg, 892.73 pmol, 1 eq) in HCl / dioxane (4 M, 10 mL) was stirred at 25 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min), RT = 0.707 min, [M+H]+= 402.2 showed 84% of the desired product. The solution was concentrated under reduced pressure to afford the title compound (390 mg, crude) as a yellow solid.Intermediate L tert-butyl 7-((4-cyclopropylpyridin-3-yl)amino)-2-azaspiro[3.5]nonane-2-carboxylateOHStep 1: tert-butyl 7-((4-chloropyridin-3-yl)amino)-2-azaspiro[3.5]nonane-2-carboxylateCTQ-01525To a solution of 4-chloropyri din-3 -amine (1.3 g, 10.11 mmol, 1 eq) and tert-butyl 7-oxo-2- azaspiro[3.5]nonane-2-carboxylate (2.90 g, 12.13 mmol, 1.2 eq) in isopropyl acetate (40 mL) was added NaBH(OAc)3 (2.57 g, 12.13 mmol, 1.2 eq) and TFA (3.46 g, 30.34 mmol, 2.25 mL, 3 eq). The mixture was stirred at 30 °C for 12 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.699 min, [M+H]+= 352.2 showed 95% of desired product. The reaction mixture was adjusted to pH = 8 with saturated NaOH aq. (10 mL), and stirred for 3 mins. The resulting mixture was extracted with ethyl acetate (100 mL x 3) and the combined organic layer was washed with brine (50 mL x 3). The organic phase was dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0 - 25% ethyl acetate in petroleum ether) to afford the title compound (2.69 g, 76%) as a light white oil.'HNMR (400 MHz, CDC13): 3 8.03 (s, 1H), 7.85 (d, J= 5.2 Hz, 1H), 7.18 (d, J= 5.2 Hz, 1H), 4.09 - 4.02 (m, 1H), 3.66 (s, 2H), 3.63 (s, 2H), 3.40 - 3.35 (m, 1H), 2.09 - 2.01 (m, 2H), 1.98 - 1.95 (m, 2H), 1.67 - 1.58 (m, 2H), 1.45 (s, 9H), 1.34 - 1.27 (m, 2H).Step 2: tert-butyl 7-((4-cyclopropylpyridin-3-yl)amino)-2-azaspiro[3.5]nonane-2- carboxylateA mixture of tert-butyl 7-((4-chloropyridin-3-yl)amino)-2-azaspiro[3.5]nonane-2-carboxylate (500 mg, 1.42 mmol, 1 eq), cyclopropylboronic acid (244.12 mg, 2.84 mmol, 2 eq), CS2CO3 (1.39 g, 4.26 mmol, 3 eq), Pd(OAc)2 (31.90 mg, 142.10 pmol, 0.1 eq) and w-BuPAd2 (101.90 mg, 284.20 pmol, 0.2 eq) in toluene (6 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 120 °C for 1 hr under N2 atmosphere in microwave. LCMS (5- 95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.738 min, [M+H]+= 358.3 showed 78% of desired product. The reaction mixture was filtered and concentrated. The residue was purified by flash chromatography on silica gel (0 - 30% ethyl acetate in petroleum ether) to afford the title compound (421 mg, 83%) as a yellow oil.'HNMR (400 MHz, CDCI3): d 8.01 - 7.96 (m, 1H), 7.95 - 7.88 (m, 1H), 6.91 - 6.82 (m, 1H), 3.97 - 3.85 (m, 1H), 3.70 - 3.65 (m, 2H), 3.65 - 3.61 (m, 2H), 3.41 - 3.35 (m, 1H), 2.09 - 2.05 (m, 2H), 1.97 - 1.94 (m, 2H), 1.69 - 1.59 (m, 2H), 1.58 - 1.51 (m, 1H), 1.46 (s, 9H), 1.32 - 1.21 (m, 2H), 1.01 - 0.93 (m, 2H), 0.65 - 0.56 (m, 2H).CTQ-01525Intermediate M7V-(4-cyclopropylpyridin-3-yl)-7V-(4-(difluoromethoxy)phenyl)-2-azaspiro[3.5]nonan-7- amine 2,2,2-trifluoroacetateStep 1: tert-butyl 7-((4-cyclopropylpyridin-3-yl)(4-(difluoromethoxy)phenyl)amino)-2- azaspiro[3.5]nonane-2-carboxylateA mixture of tert-butyl 7-((4-cyclopropylpyridin-3-yl)amino)-2-azaspiro[3.5]nonane-2- carboxylate (440 mg, 1.23 mmol, 1 eq), l-bromo-4-(difluoromethoxy)benzene (548.98 mg, 2.46 mmol, 336.59 pL, 2 eq), t-BuONa (354.84 mg, 3.69 mmol, 3 eq) and t-BusP Pd G2 (126.13 mg, 246.16 pmol, 0.2 eq) in toluene (20 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 125 °C for 12 hr under N2 atmosphere. LCMS (5- 95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.857 min, [M+H]+= 500.3 showed 69% of desired product. The reaction mixture was filtered and concentrated. The residue was purified by flash chromatography on silica gel (0 - 20% ethyl acetate in petroleum ether) to afford the title compound (393 mg, 64%) as a yellow oil.Step 2: 7V-(4-cyclopropylpyridin-3-yl)-7V-(4-(difluoromethoxy)phenyl)-2- azaspiro[3.5]nonan-7-amine 2,2,2-trifluoroacetateCTQ-01525A solution of tert-butyl 7-((4-cyclopropylpyridin-3-yl)(4-(difluoromethoxy)phenyl)amino)-2- azaspiro[3.5]nonane-2-carboxylate (393 mg, 786.64 pmol, 1 eq) in 5% TFA / HFIP (2 mL) was stirred at 25 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.652 min, [M+H]+= 400.2 showed 92% of desired product. The reaction mixture was concentrated to afford the title compound (314 mg, crude) as a yellow oil.Intermediate N7V-(4-cyclopropylpyridin-3-yl)-7V-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.5]nonan-7- amine 2,2,2-trifluoroacetateStep 1: tert-butyl 7-((4-cyclopropylpyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-2- azaspiro[3.5]nonane-2-carboxylateA mixture of tert-butyl 7-((4-cyclopropylpyridin-3-yl)amino)-2-azaspiro[3.5]nonane-2- carboxylate (380 mg, 1.06 mmol, 1 eq , l-bromo-4-(trifluoromethyl)benzene (478.35 mg, 2.13 mmol, 293.47 pL, 2 eq), / -BuONa (306.47 mg, 3.19 mmol, 3 eq and Z-BusP Pd G2 (108.93 mg, 212.59 pmol, 0.2 eq in toluene (20 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 125 °C for 12 hr under N2 atmosphere. LCMS (5- 95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.890 min, [M+H]+= 502.3 showed 31% of desired product. The reaction mixture was filtered and concentrated. The residue was purified by flash chromatography on silica gel (0 - 20% ethyl acetate in petroleum ether) to afford the title compound (530 mg, 99%) as a yellow oil.CTQ-01525Step 2: A-(4-cyclopropylpyridin-3-yl)-A-(4-(trifluoromethyl)phenyl)-2- azaspiro[3.5]nonan-7-amine 2,2,2-trifluoroacetateA solution of tert-butyl 7-((4-cyclopropylpyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-2- azaspiro[3.5]nonane-2-carboxylate (510 mg, 1.02 mmol, 1 eq in 5%TFA / HFIP (2 mL) was stirred at 25 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.635 min, [M+H]+= 402.1 showed 88% of desired product. The reaction mixture was concentrated to afford the title compound (408 mg, crude) as a yellow oil.Intermediate O tert-butyl 7-((4-methylpyridin-3-yl)amino)-2-azaspiro[3.5]nonane-2-carboxylateTo a solution of 4-methylpyri din-3 -amine (200 mg, 1.85 mmol, 1 eq) and tert-butyl 7-oxo-2- azaspiro[3.5]nonane-2-carboxylate (486.85 mg, 2.03 mmol, 1.1 eq in isopropyl acetate (10 mL) was added NaBH(OAc)s (470.36 mg, 2.22 mmol, 1.2 eq) and TFA (632.62 mg, 5.55 mmol, 412.13 pL, 3 eq at 0 °C. The mixture was stirred at 25 °C for 16 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min), RT = 0.689 min, [M+H]+= 332.3 showed 88% of desired product. The reaction mixture was treated with saturated NaOH aq. (25 mL) and stirred for 30 mins. The resulting mixture was extracted with ethyl acetate (10 mL * 3) and the combined organic layer was washed with brine (15 mL x 3). The organic phase was dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 60% ethyl acetate in petroleum ether) to afford the title compound (357 mg, 58%) as a yellow oil.'HNMR (400 MHz, CD3OD): <5 7.84 (s, 1H), 7.70 (d, J= 4.8 Hz, 1H), 7.04 (d, J= 4.8 Hz, 1H), 3.68 - 3.55 (m, 4H), 3.43 - 3.34 (m, 1H), 2.15 (s, 3H), 2.05 - 1.90 (m, 4H), 1.71 - 1.60 (m, 2H), 1.44 (s, 9H), 1.39 - 1.26 (m, 2H).CTQ-01525Intermediate P7V-(4-methylpyridin-3-yl)- V-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.5]nonan-7-amine2,2,2-trifluoroacetateStep 1: tert-butyl 7-((4-methylpyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-2- azaspiro[3.5]nonane-2-carboxylateA mixture of tert-butyl 7-((4-methylpyridin-3-yl)amino)-2-azaspiro[3.5]nonane-2- carboxylate (357 mg, 1.08 mmol, 1 eq), l-bromo-4-(trifluoromethyl)benzene (363.52 mg, 1.62 mmol, 223.02 pL, 1.5 eq), t-BuONa (310.52 mg, 3.23 mmol, 3 eq), t-BusP Pd G2 (55.19 mg, 107.71 pmol, 0.1 eq) in toluene (10 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 120 °C for 16 hr under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min), RT = 0.858 min, [M+H]+= 476.3 showed 55% of desired product. The reaction was 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 (404 mg, 79%) as a white solid.Step 2: 7V-(4-methylpyridin-3-yl)-A-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.5]nonan-7- amine 2,2,2-trifluoroacetateCTQ-01525A solution of tert-butyl 7-((4-methylpyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-2- azaspiro[3.5]nonane-2-carboxylate (202 mg, 424.78 pmol, 1 eq in 5% TFA / HFIP (5 mL) was stirred at 25 °C for 2 hr. The reaction was concentrated under reduced pressure to afford the title compound (159.47 mg, crude) as a brown oil.Intermediate Q7-((4-methoxypyridin-3-yl)amino)-2-thiaspiro[3.5]nonane 2,2-dioxideStep 1: (l,4-dioxaspiro[4.5]decane-8,8-diyl)bis(methylene) bis(4- methylbenzenesulfonate)To a mixture of (l,4-dioxaspiro[4.5]decane-8,8-diyl)dimethanol (2.03 g, 10.04 mmol, 1 eq) in pyridine (20 mL) was added 4-methylbenzenesulfonyl chloride (5.74 g, 30.11 mmol, 3 eq and DMAP (122.62 mg, 1.00 mmol, 0.1 eq at 25 °C. The mixture was stirred at 50 °C for 32 hours. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.919 min, [M+H]+= 511.2 showed 93% of desired product. The reaction was cooled to room temperature, then the solution was diluted with water (35 mL) and stirred for 30 mins. Then the solution was filtered and the filter cake was washed with H2O (100 mL) and ethyl acetate (50 mL) and concentrated in vacuum to afford the title compound (4.81 g, crude) as a white solid. The crude product was used in the next step without purification.CTQ-01525'H NMR (400 MHz, CDCh): <5 7.74 (d, J= 8.0 Hz, 4H), 7.36 (d, J= 8.0 Hz, 4H), 3.89 - 3.84(m, 8H), 2.47 (s, 6H), 1.56 - 1.45 (m, 8H).Step 2: 8,ll-dioxa-2-thiadispiro[3.2.47.24]tridecaneTo a mixture of (l,4-dioxaspiro[4.5]decane-8,8-diyl)bis(methylene) bis(4- methylbenzenesulfonate) (3.65 g, 7.15 mmol, 1 eq in DMSO (9 mL) was added Na2S H2O (2.06 g, 8.58 mmol, 1.44 mL, 1.2 eq) in one portion at 25 °C. The mixture was stirred at 90 °C for 88 hours. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.748 min, [M+H]+= 201.2 showed 87% of desired product. Cooled to room temperature, then the mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (30 mL x 3), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (0 - 20% ethyl acetate in petroleum ether) to afford the title compound (1.01 g, 71%) as colorless liquid.'HNMR (400 MHz, CDCh): d 3.93 (s, 4H), 2.96 (s, 4H), 1.99 - 1.88 (m, 4H), 1.63-1.56 (m, 4H).Step 3: 8,ll-dioxa-2thiadispiro[3.2.47.24]tridecane 2,2-dioxideTo a mixture of 8,1 l-dioxa-2-thiadispiro[3.2.47.24]tridecane (1.78 g, 8.89 mmol, 1 eq in MeOH (40 mL), then Oxone (10.93 g, 17.77 mmol, 2 eq in H2O (40 mL) was added into it at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction was quenched with saturated sodium thiosulfate (10 mL), the mixture was diluted with H2O (60 mL) and extracted with ethyl acetate (100 mL x 3). The combined dried with anhydrous Na2SO4, filtered and concentrated in vacuum to afford the title compound (2.0 g, crude) as a yellow solid. The crude product was used in the next step without purification.'HNMR (400 MHz, CDCh): 3 3.95 (s, 4H), 3.88 (s, 4H), 1.98 (t, J= 6.0 Hz, 4H), 1.64 (t, J = 6.0 Hz, 4H).CTQ-01525Step 4: 2,2-dioxo-2thiaspiro[3.5]nonan-7-oneTo a mixture of 8,1 l-dioxa-2thiadispiro[3.2.47.24]tridecane 2,2-dioxide (2.0 g, 8.61 mmol, 1 eq) in THF (12 mL) was added HC1 (4 M, 10 mL, 4.65 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 1 hour. The mixture was diluted with H2O (80 mL) and extracted with ethyl acetate (120 mL x 3), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum to afford the title compound (1.61 g, crude) as a yellow solid. 'HNMR (400 MHz, CDCI3): d 4.04 (s, 4H), 2.40 (t, J= 6.4 Hz, 4H), 2.24 (t, J= 6.4 Hz, 4H).Step 5: 7-((4-methoxypyridin-3-yl)amino)-2-thiaspiro [3.5] nonane 2,2-dioxideTo a mixture of 2,2-dioxo-2thiaspiro[3.5]nonan-7-one (834.01 mg, 4.43 mmol, 1.1 eq and 4- methoxypyri din-3 -amine (500 mg, 4.03 mmol, 1 eq) in DMF (20 mL) was added TMSC1 (1.09 g, 10.07 mmol, 1.28 mL, 2.5 eq) at 0 °C, then BH3 THF (1 M, 4.83 mL, 1.2 eq) was added into it at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (5-95% acetonitrile in 0.2% NH3'H2O / water over 1.5 min): RT = 0.670 min, [M+H]+= 297.2 showed 97% of desired product. The mixture was adjusted to pH = 8 with NaHCCL (20 ml) at 0 °C. Then the mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (50 mL x 3), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (0 - 30% EE (ethyl acetate: ethanol=3: l) in petroleum ether) to afford the title compound (609.7 mg, 51%) as a yellow solid.'HNMR (400 MHz, DMSO-t / 6): 3 7.85 (s, 1H), 7.78 (d, J= 5.2 Hz, 1H), 6.84 (d, J= 5.2 Hz, 1H), 4.48 - 4.42 (m, 1H), 3.93 (s, 4H), 3.83 (s, 3H), 3.33 - 3.28 (m, 1H), 1.96 - 1.83 (m, 4H), 1.74 - 1.64 (m, 2H), 1.32 - 1.21 (m, 2H).CTQ-01525Intermediate R4-methoxy-7V-(2-oxaspiro[4.5]decan-8-yl)pyridin-3-amineTo a mixture of 4-methoxypyri din-3 -amine (170 mg, 1.37 mmol, 1 eq and 2- oxaspiro[4.5]decan-8-one (211.17 mg, 1.37 mmol, 1 eq) in DMF (8 mL) was added TMSC1 (371.94 mg, 3.42 mmol, 434.51 pL, 2.5 eq) and BH3THF (1 M, 1.64 mL, 1.2 eq) in one portion at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS (5-95% acetonitrile in 0.2% NHs f O / water over 1.5 min): RT = 0.74 min, [M+H]+= 263.2 showed 93% of desired product. The mixture was adjusted to pH = 8 with NaHCCh at 0 °C. Then the mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (30 mL x 3), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (0 - 30% ethyl acetate in petroleum ether) to afford the title compound (340 mg, 94%) as a yellow oil.CTQ-01525EXEMPLIFICATIONExample 16-(2-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)-7-azaspiro[3.5]nonan-7-yl)nicotinonitrileA mixture of 7V-(4-(difluoromethoxy)phenyl)-7V-(4-methoxypyridin-3-yl)-7- azaspiro[3.5]nonan-2-amine hydrochloride (102 mg, 261.92 pmol, 1 eq), 6- fluoronicotinonitrile (47.97 mg, 392.87 pmol, 1.5 eq , K2CO3 (108.60 mg, 785.75 pmol, 3 eq) in MeCN (5 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 80 °C for 24 hr under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min), RT = 0.540 min, M+H]+= 492.2, showed 69% of desired product. The reaction solution was concentrated. The residue was purified by flash chromatography on silica gel (0 - 20% EE (ethyl acetate: ethanol = 3: 1) in petroleum ether) to afford the title compound (47.3 mg, 36%) as a white solid.1H NMR (400 MHz, CDCI3): 3 8.52 (d, J= 5.6 Hz, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 7.61 - 7.56 (m, 1H), 7.00 - 6.93 (m, 3H), 6.63 - 6.58 (m, 4H), 4.45 - 4.34 (m, 1H), 3.82 (s, 3H), 3.68 (t, J= 5.6 Hz, 2H), 3.52 (t, J= 5.6 Hz, 2H), 2.34 - 2.26 (m, 2H), 1.83 - 1.65 (m, 5H), 1.29 - 1.26 (m, 1H).CTQ-01525Example 22-(2-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)-7-azaspiro[3.5]nonan-7-yl)pyrimidine-5-carbonitrileA mixture of A-(4-(difluoromethoxy)phenyl)-N-(4-methoxypyridin-3-yl)-7- azaspiro[3.5]nonan-2-amine hydrochloride (200 mg, 469.60 pmol, 1 eq 2-chloropyrimidine- 5-carbonitrile (72.08 mg, 516.55 pmol, 1.1 eq DIEA (242.76 mg, 1.88 mmol, 327.17 pL, 4 eq in MeCN (10 mL) was stirred at 0 °C for 2 hr. LCMS (10-80% acetonitrile in 0.2% NH3 EEO / water over 3.0 min), RT = 2.020 min, [M+H]+= 493.3 showed 56% desired product. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 20% EE (ethyl acetate: ethanol = 3: 1) in petroleum ether) to afford the title compound (113.4 mg, 47%) as a white solid.'HNMR (400 MHz, CD3OD): 6 8.54 (s, 2H), 8.43 (d, J= 6.0 Hz, 1H), 8.20 (s, 1H), 7.20 (d, J = 5.6 Hz, 1H), 6.93 (d, J= 9.2 Hz, 2H), 6.80 - 6.39 (m, 3H), 4.49 - 4.39 (m, 1H), 3.92 (t, J = 5.2 Hz, 2H), 3.84 (s, 3H), 3.76 (t, J= 5.6 Hz, 2H), 2.37 - 2.28 (m, 2H), 1.78 - 1.64 (m, 4H), 1.51 - 1.45 (m, 2H).CTQ-01525Example 32-(7-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)-2-azaspiro[3.5]nonan-2-yl)pyrimidine-5-carbonitrileTo a solution of A-(4-(difluoromethoxy)phenyl)-7V-(4-m ethoxypyri din-3 -yl)-2- azaspiro[3.5]nonan-7-amine (170 mg, 436.53 pmol, 1 eq and 2-chloropyrimidine-5- carbonitrile (73.10 mg, 523.83 pmol, 1.2 eq) in MeCN (5 mL) was added DIEA (225.67 mg, 1.75 mmol, 304.13 uL, 4 eq . The mixture was stirred at 25 °C for 0.5 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.519 min, [M+H]+= 493.2 showed 40% of desired product. The reaction mixture was filtered and concentrated. The residue was purified by flash chromatography on silica gel (0 - 15% EE (ethyl acetate: ethanol = 3: 1) in petroleum ether) to afford the title compound (54.6 mg, 25%) as a white solid.1H NMR (400 MHz, CD3OD): 6 8.54 (s, 2H), 8.44 (d, J= 5.6 Hz, 1H), 8.16 (s, 1H), 7.21 (d, J = 5.6 Hz, 1H), 6.92 (d, J= 9.2 Hz, 2H), 6.90 - 6.39 (m, 3H), 3.95 - 3.86 (m, 1H), 3.85 - 3.82 (m, 5H), 3.80 - 3.77 (m, 2H), 2.05 - 1.98 (m, 4H), 1.84 - 1.72 (m, 2H), 1.26 - 1.12 (m, 2H).CTQ-01525Example 47V-(4-(difluoromethoxy)phenyl)-7V-(4-methoxypyridin-3-yl)-7-(5-(methylsulfonyl)pyrimidin-2-yl)-7-azaspiro[3.5]nonan-2-amineA mixture of A-(4-(difluoromethoxy)phenyl)-7V-(4-methoxypyridin-3-yl)-7- azaspiro[3.5]nonan-2-amine hydrochloride (200 mg, 469.60 pmol, 1 eq 2-chloro-5- (methylsulfonyl)pyrimidine (63.07 mg, 516.55 pmol, 1.1 eq and DIEA (242.77 mg, 1.88 mmol, 327.18 pL, 4 eq) in MeCN (10 mL) was stirred at 0 °C for 2 hr. LCMS (10-80% acetonitrile in 0.2% NH3 EEO / water over 3.0 min), RT = 1.860 min, [M+H]+= 546.3 showed 53% of desired product. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 20% EE (ethyl acetate: ethanol = 3 : 1 ) in petroleum ether) to afford the title compound (113.1 mg, 49%) as a white solid.'HNMR (400 MHz, CD3OD): 6 8.64 (s, 2H), 8.43 (d, J= 5.6 Hz, 1H), 8.19 (s, 1H), 7.20 (d, J = 5.6 Hz, 1H), 6.93 (d, J= 9.2 Hz, 2H), 6.80 - 6.39 (m, 3H), 4.49 - 4.39 (m, 1H), 3.94 (t, J = 5.6 Hz, 2H), 3.84 (s, 3H), 3.79 (t, J= 5.6 Hz, 2H), 3.11 (s, 3H), 2.38 - 2.30 (m, 2H), 1.79 - 1.64 (m, 4H), 1.52 - 1.45 (m, 2H).CTQ-01525Example 57V-(4-(difluoromethoxy)phenyl)-7V-(4-methoxypyridin-3-yl)-7-(4-(methylsulfonyl)phenyl)-7-azaspiro[3.5]nonan-2-amineA mixture of A-(4-(difluoromethoxy)phenyl)-N-(4-methoxypyridin-3-yl)-7- azaspiro[3.5]nonan-2-amine (215 mg, 552.08 pmol, 1 eq l-bromo-4- (methylsulfonyl)benzene (194.69 mg, 828.12 pmol, 1.5 eq RuPhos Pd G2 (46.17 mg, 55.21 pmol, 0.1 eq / -BuONa (159.17 mg, 1.66 mmol, 3 eq in dioxane (8 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 120 °C for 24 hr under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min), RT = 0.537 min, [M+H]+= 544.2, showed 61% of desired product. The reaction solution was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (0 - 20% EE (ethyl acetate: ethanol = 3: 1) in petroleum ether) to afford the title compound (180.1 mg, 59%) as a white solid. 'H NMR. (400 MHz, CD3OD): d 8.43 (d, J= 5.6 Hz, 1H), 8.20 (s, 1H), 7.69 (d, J= 8.8 Hz, 2H), 7.20 (d, J= 5.6 Hz, 1H), 7.02 (d, J= 8.8 Hz, 2H), 6.93 (d, J= 8.8 Hz, 2H), 6.80 - 6.38 (m, 3H), 4.62 - 4.52 (m, 1H), 3.83 (s, 3H), 3.40 (t, J= 5.2 Hz, 2H), 3.26 (t, J= 5.2 Hz, 2H), 3.03 (s, 3H), 2.35 - 2.28 (m, 2H), 1.83 - 1.78 (m, 2H), 1.71 - 1.61 (m, 2H), 1.56 - 1.51 (m, 2H).CTQ-01525Example 66-(7-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)-2-azaspiro[3.5]nonan-2-yl)nicotinonitrileTo a solution of 7V-(4-(difluoromethoxy)phenyl)-7V-(4-m ethoxypyri din-3 -yl)-2- azaspiro[3.5]nonan-7-amine (200 mg, 513.56 pmol, 1 eq and 6-fluoronicotinonitrile (125.41 mg, 1.03 mmol, 2 eq) in MeCN (6 mL) was added K2CO3 (141.96 mg, 1.03 mmol, 2 eq . The mixture was stirred at 80 °C for 12 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.829 min, [M+H]+= 492.3 showed 62% of desired product. The reaction mixture was filtered and concentrated. The residue was purified by flash chromatography on silica gel (0 - 20% EE (ethyl acetate: ethanol = 3 : 1) in petroleum ether) to afford the title compound (242 mg, 94%) as a yellow solid.'HNMR (400 MHz, CD3OD): 6 8.44 (d, J= 5.6 Hz, 1H), 8.29 (d, J= 2.0 Hz, 1H), 8.16 (s, 1H), 7.66 (dd, J= 8.8, 2.0 Hz, 1H), 7.21 (d, J= 5.6 Hz, 1H), 6.92 (d, J= 8.8 Hz, 2H), 6.80 - 6.48 (m, 3H), 6.40 - 6.36 (m, 1H), 3.96 - 3.94 (m, 1H), 3.92 (s, 3H), 3.89 - 3.79 (m, 4H), 2.05 - 1.99 (m, 4H), 1.83 - 1.73 (m, 2H), 1.25 - 1.13 (m, 2H).CTQ-01525Example 77V-(4-(difluoromethoxy)phenyl)-7V-(4-methoxypyridin-3-yl)-2-(5-(methylsulfonyl)pyrimidin-2-yl)-2-azaspiro[3.5]nonan-7-amineTo a solution of A-(4-(difluoromethoxy)phenyl)-7V-(4-m ethoxypyri din-3 -yl)-2- azaspiro[3.5]nonan-7-amine (170 mg, 436.53 pmol, 1 eq and 2-chloro-5- (methylsulfonyl)pyrimidine (100.90 mg, 523.84 pmol, 1.2 eq) in MeCN (5 mL) was added DIEA (225.67 mg, 1.75 mmol, 304.13 uL, 4 eq . The mixture was stirred at 25 °C for 0.5 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.497 min, [M+H]+= 546.2 showed 58% of desired product. The reaction mixture was filtered and concentrated. The residue was purified by flash silica gel chromatography (0 - 25% EE (ethyl acetate: ethanol = 3 : 1) in petroleum ether) to afford the title compound (82.9 mg, 34%) as a white solid.'HNMR (400 MHz, DMSO-t / 6): 3 8.65 (d, J= 3.2 Hz, 2H), 8.48 (d, J= 5.6 Hz, 1H), 8.17 (s, 1H), 7.22 (d, J= 5.6 Hz, 1H), 7.21 - 6.76 (m, 3H), 6.42 (d, J= 9.2 Hz, 2H), 3.87 - 3.77 (m, 8H), 3.20 (s, 3H), 1.93 - 1.84 (m, 4H), 1.77 - 1.65 (m, 2H), 1.14 - 1.02 (m, 2H).CTQ-01525Example 87V-(4-(difluoromethoxy)phenyl)-7V-(4-methoxypyridin-3-yl)-2-(4-(methylsulfonyl)phenyl)-2-azaspiro[3.5]nonan-7-amineA mixture of A-(4-(difluoromethoxy)phenyl)-7V-(4-methoxypyri din-3 -yl)-2- azaspiro[3.5]nonan-7-amine (200 mg, 513.56 pmol, 1 eq), l-bromo-4- (methylsulfonyl)benzene (241.47 mg, 1.03 mmol, 2 eq , / -BuONa (148.06 mg, 1.54 mmol, 3 eq) and RuPhos Pd G2 (39.89 mg, 51.36 pmol, 0.1 eq in dioxane (5 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 120 °C for 12 hr under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.852 min, [M+H]+= 544.2 showed 37% of desired product. The reaction mixture was filtered and concentrated. The residue was purified by flash chromatography on silica gel (0 - 25% EE (ethyl acetate: ethanol = 3 : 1) in petroleum ether) to afford the title compound (118.1 mg, 41%) as a white solid.'HNMR (400 MHz, CD3OD): 6 8.44 (d, J= 5.6 Hz, 1H), 8.16 (s, 1H), 7.65 (d, J= 8.8 Hz, 2H), 7.21 (d, J= 6.0 Hz, 1H), 6.92 (d, J= 8.8 Hz, 2H), 6.78 - 6.39 (m, 5H), 3.96 - 3.87 (m, 1H), 3.83 (s, 3H), 3.64 - 3.60 (m, 4H), 3.00 (s, 3H), 2.04 - 1.98 (m, 4H), 1.83 - 1.72 (m, 2H), 1.26 - 1.14 (m, 2H).CTQ-01525Example 9 V-(4-fluorophenyl)-4-methoxy-A-(2-oxaspiro[3.5]nonan-7-yl)pyridin-3-amineA mixture of 4-methoxy-7V-(2-oxaspiro[3.5]nonan-7-yl)pyridin-3-amine (70 mg, 281.89 pmol, 1 eq), l-bromo-4-fluorobenzene (59.20 mg, 338.27 pmol, 37.16 pL, 1.2 eq), Z-BusP Pd G2 (14.44 mg, 28.19 pmol, 0.1 eq), / -BuONa (81.27 mg, 845.68 pmol, 3 eq) in toluene (5 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 120 °C for 24 hr under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min), RT = 0.690 min, [M+H]+= 343.2 showed 35% of desired product. Concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18 150*30mm*5um, water (FA)-ACN, 17%-47% B over 7 min) to afford the title compound (66.91 mg, 69%) as a white solid.'H NMR (400 MHz, CD3OD): 6 8.40 (d, J= 5.2 Hz, 1H), 8.13 (s, 1H), 7.18 (d, J= 5.2 Hz, 1H), 6.88 - 6.79 (m, 2H), 6.53 - 6.46 (m, 2H), 4.35 - 4.28 (m, 4H), 3.85 - 3.75 (m, 4H), 2.22 - 2.11 (m, 2H), 1.99 - 1.91 (m, 2H), 1.70 - 1.57 (m, 2H), 1.13 - 0.99 (m, 2H).Example 10 4-methoxy- V-(2-oxaspiro[3.5]nonan-7-yl)-A-(4-(trifluoromethyl)phenyl)pyridin-3-amineA mixture of 4-methoxy-A-(2-oxaspiro[3.5]nonan-7-yl)pyridin-3-amine (170 mg, 684.60 pmol, 1 eq), l-bromo-4-(trifluoromethyl)benzene (308.08 mg, 1.37 mmol, 189.00 pL, 2 eq), / -BuONa (197.37 mg, 2.05 mmol, 3 eq), Z-BusP Pd G2 (35.08 mg, 68.46 pmol, 0.1 eq) inCTQ-01525 toluene (7 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 120 °C for 12 hr under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.748 min, [M+H]+= 393.2 showed 51% of desired product. The reaction mixture was filtered and concentrated. The residue was purified by flash chromatography on silica gel (0 - 30% EE (ethyl acetate: ethanol = 3: 1) in petroleum ether) to afford the title compound (232.5 mg, 86%) as a white solid.'HNMR (400 MHz, CD3OD): 6 8.47 (d, J= 5.6 Hz, 1H), 8.14 (s, 1H), 7.36 (d, J= 8.8 Hz, 2H), 7.23 (d, J= 5.6 Hz, 1H), 6.54 (d, J= 8.8 Hz, 2H), 4.34 - 4.33 (m, 4H), 3.99 - 3.90 (m, 1H), 3.83 (s, 3H), 2.23 - 2.16 (m, 2H), 2.04 - 1.96 (m, 2H), 1.72 - 1.63 (m, 2H), 1.14 - 1.02 (m, 2H).Example 11 7V-(4-(difluoromethoxy)phenyl)-7V-(4-methoxypyridin-3-yl)-2-(methylsulfonyl)-2- azaspiro[3.5]nonan-7-amineTo a solution of 7V-(4-(difluoromethoxy)phenyl)-A-(4-m ethoxypyri din-3 -yl)-2- azaspiro[3.5]nonan-7-amine (167 mg, 428.82 pmol, 1 eq methanesulfonyl chloride (100 mg, 872.97 pmol, 67.57 pL, 2.04 eq in DCM (5 mL) was added TEA (130.18 mg, 1.29 mmol, 179.06 pL, 3 eq). The mixture was stirred at 25 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.850 min, [M+H]+= 468.1, showed 74% of desired product. The residue was diluted with water (30 mL) and extracted with DCM 150 mL (50 mL x 3). The combined organic layers were washed with brine 150 mL (50 mL x 3), filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC ((Petroleum ether: Ethyl acetate = 3: 1): (DCM: MeOH= 10: 1) =1 : 1) to afford the title compound (104.9 mg, 52%) as a white solid.'HNMR (400 MHz, CD3OD): 6 8.44 (d, J= 5.6 Hz, 1H), 8.16 (s, 1H), 7.21 (d, J= 5.6 Hz, 1H), 6.93 (d, J= 8.8 Hz, 2H), 6.79 - 6.39 (m, 3H), 3.94 - 3.85 (m, 1H), 3.81 (s, 3H), 3.61 - 3.55 (m, 4H), 2.91 (s, 3H), 2.06 - 1.97 (m, 4H), 1.75 - 1.66 (m, 2H), 1.21 - 1.09 (m, 2H).CTQ-01525Example 121-(7-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-l-oneTo a solution of A-(4-(difluoromethoxy)phenyl)-7V-(4-m ethoxypyri din-3 -yl)-2- azaspiro[3.5]nonan-7-amine (167 mg, 428.82 pmol, 1 eq acetyl chloride (50.49 mg, 643.23 pmol, 45.74 pL, 1.5 e ) in DCM (5 mL) was added TEA (130.18 mg, 1.29 mmol, 179.06 pL, 3 eq . The mixture was stirred at 25 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.820 min, [M+H]+= 432.2 showed 79% of desired product. The residue was diluted with water (30 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine 150 mL (50 mL x 3), filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC ((Petroleum ether: Ethyl acetate=3: l): (DCM: MeOH= 10: 1) = 1 : 1) to afford the title compound (111.7 mg, 60%) as a white solid.'H NMR (400 MHz, CD3OD): 6 8.44 (d, J= 6.0 Hz, 1H), 8.16 (s, 1H), 7.21 (d, J= 6.0 Hz, 1H), 6.93 (d, J= 9.2 Hz, 2H), 6.78 - 6.49 (m, 3H), 3.95 - 3.84 (m, 6H), 3.62 - 3.52 (m, 2H), 2.04 - 1.95 (m, 4H), 1.86, 1.83 (s, 3H total), 1.77 - 1.69 (m, 2H), 1.22 - 1.09 (m, 2H).Example 13 V-(4-(difluoromethoxy)phenyl)-7V-(4-methoxypyridin-3-yl)-2-azaspiro[3.5]nonan-7- amineA solution of tert-butyl 7-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)-2- azaspiro[3.5]nonane-2-carboxylate (347 mg, 708.81 pmol, 1 eq) in 5% TFA / HFIP (10 mL)CTQ-01525 was stirred at 25 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.572 min, [M+H]+= 390.1, showed 93% of desired product. The mixture was purified by purified by reverse phase chromatography (Xtimate Cl 8 150*40mm*10um, water (FA)- ACN, 7%-37% B over 7 min) to afford the title compound (158.4 mg, 57%) as a white solid. 'HNMR (400 MHz, 400 MHz, CD3OD): 3 8.47 (s, 1H), 7.25 (d, J= 4.4 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.81 - 6.41 (m, 3H), 3.95 - 3.87 (m, 1H), 3.85 (s, 3H), 3.77 - 3.75 (m, 4H), 2.16 - 2.10 (m, 2H), 2.06 - 1.99 (m, 2H), 1.75 (t, J= 12.4 Hz, 2H), 1.19 - 1.08 (m, 2H).Example 14 7V-(4-(difluoromethoxy)phenyl)-4-methoxy-A-(2-oxaspiro[3.5]nonan-7-yl)pyridin-3- amineA mixture of 4-methoxy-7V-(2-oxaspiro[3.5]nonan-7-yl)pyridin-3-amine (200 mg, 805.41 pmol, 1 eq), l-bromo-4-(difluoromethoxy)benzene (359.24 mg, 1.61 mmol, 220.26 pL, 2 eq), / -BuONa (232.20 mg, 2.42 mmol, 3 eq), Z-BusP Pd G2 (82.54 mg, 161.08 pmol, 0.2 eq) in toluene (7 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 120 °C for 12 hr under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.713 min, [M+H]+= 391.2, showed 43% of desired product. The reaction mixture was filtered and concentrated. The residue was purified by flash silica gel chromatography (0 - 30% EE (ethyl acetate: ethanol = 3: 1 in petroleum ether) to afford the title compound (172.6 mg, 54%) as a light yellow solid.'HNMR (400 MHz, CD3OD): 3 8.46 - 8.38 (d, J= 5.6 Hz, 1H), 8.12 (s, 1H), 7.18 (d, J= 5.6 Hz, 1H), 6.90 (d, J= 9.2 Hz, 2H), 6.78 - 6.37 (m, 3H), 4.34 - 4.32 (m, 4H), 3.88 - 3.84 (m, 1H), 3.81 (s, 3H), 2.23 - 2.12 (m, 2H), 2.02 - 1.92 (m, 2H), 1.71 - 1.59 (m, 2H), 1.11 - 1.01 (m, 2H).CTQ-01525Example 157V-(4-(difluoromethoxy)phenyl)-7V-(4-methoxypyridin-3-yl)-2-methyl-2- azaspiro[3.5]nonan-7-amineTo a solution of A-(4-(difluoromethoxy)phenyl)-7V-(4-m ethoxypyri din-3 -yl)-2- azaspiro[3.5]nonan-7-amine (167 mg, 428.82 pmol, 1 eq in MeOH (5 mL) was added AcOH (51.50 mg, 857.65 pmol, 49.10 pL, 2 eq , formaldehyde (104.40 mg, 1.29 mmol, 95.78 pL, 37% purity, 3 eq and NaBHiCN (40.42 mg, 643.23 pmol, 1.5 eq . The mixture was stirred at 25 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.606 min, [M+H]+= 404.2, showed 83% of desired product. The residue was diluted with water (30 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (50 mL x 3), filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18 150*30mm*5um, water (FA)-ACN, 6%-36% B over 7 min) to afford the title compound (26 mg, 15%) as a white solid.'H NMR (400 MHz, CDC13): 3 8.49 (d, J= 5.6 Hz, 1H), 8.21 (s, 1H), 6.95 - 6.87 (m, 3H), 6.56 - 6.18 (m, 3H), 3.80 - 3.71 (m, 4H), 2.99 - 2.90 (m, 4H), 2.31 (s, 3H), 2.02 - 1.90 (m, 4H), 1.59 - 1.49 (m, 2H), 1.15 - 1.04 (m, 2H).CTQ-01525Example 167V-(4-(difluoromethoxy)phenyl)-4-methoxy-7V-(3-oxaspiro[5.5]undecan-9-yl)pyridin-3- amineA mixture of 4-methoxy-7V-(3-oxaspiro[5.5]undecan-9-yl)pyridin-3-amine (70 mg, 254.62 pmol, 1 eq), l-bromo-4-(difluoromethoxy)benzene (112.01 mg, 507.24 pmol, 2 eq), LBuONa (73.33 mg, 763.86 pmol, 3 eq) and Z-BusP Pd G2 (26.02 mg, 50.92 pmol, 0.2 eq) in toluene (4 mL) was stirred at 125 °C for 15 hr under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.759 min, [M+H]+= 419.2 showed 39% of desired product. The solution was filtered and washed ethyl acetate (20 mL) and concentrated to giver a residue. The residue was purified by flash silica gel chromatography (0 - 50% EE (ethyl acetate: ethanol = 3: 1) in petroleum ether) to afford the title compound (53 mg, 50%) as a white solid.'H NMR (400MHz, CDCI3): 3 8.48 (d, J= 5.2 Hz, 1H), 8.25 (s, 1H), 6.98 (d, J= 5.6 Hz, 1H), 6.95 (d, J= 9.2 Hz, 2H), 6.58 - 6.21 (m, 3H), 3.82 - 3.76 (m, 4H), 3.67 - 3.53 (m, 4H), 1.88 - 1.75 (m, 4H), 1.40 - 1.36 (m, 4H), 1.32 - 1.24 (m, 4H).CTQ-01525Example 174-methoxy-7V-(3-oxaspiro[5.5]undecan-9-yl)-7V-(4-(trifluoromethyl)phenyl)pyridin-3- amineA mixture of 4-methoxy-7V-(3-oxaspiro[5.5]undecan-9-yl)pyridin-3-amine (50 mg, 180.91 pmol, 1 eq), l-bromo-4-(trifluoromethyl)benzene (81.41 mg, 361.83 pmol, 2 eq), LBuONa (52.16 mg, 542.74 pmol, 3 eq) and Z-BusP Pd G2 (18.54 mg, 36.18 pmol, 0.2 eq) in toluene (8 mL) was stirred at 125 °C for 15 hr under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.795 min, [M+H]+= 421.2 showed 25% desired product. The mixture was filtered and washed ethyl acetate (20 mL) and concentrated to giver a residue. The residue was purified by flash chromatography on silica gel (0 - 50% EE (ethyl acetate: ethanol = 3: 1) in petroleum ether) to afford the title compound (41 mg, 54%) as a white solid.'H NMR (400MHz, CDCI3): 3 8.63 (d, J= 6.4 Hz, 1H), 8.35 (s, 1H), 7.43 (d, J= 8.8 Hz, 2H), 7.23 (d, J= 6.4 Hz, 1H), 6.55 (d, J= 8.8 Hz, 2H), 3.95 (s, 3H), 3.92 - 3.76 (m, 1H), 3.67 - 3.62 (m, 2H), 3.61 - 3.56 (m, 2H), 1.89 - 1.82 (m, 4H), 1.41 - 1.38 (m, 4H), 1.32 - 1.25 (m, 4H).Example 181-(7-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-l-oneCTQ-01525To a mixture of / f-(4-m ethoxy pyri din-3 -yl)-7V-(4-(trifluoromethyl)phenyl)-2- azaspiro[3.5]nonan-7-amine (222 mg, 567.15 pmol, 1 eq in DCM (3 mL) was added TEA (286.95 mg, 2.84 mmol, 394.70 pL, 5 eq) and acetyl chloride (89.04 mg, 1.13 mmol, 80.65 pL, 2 eq in one portion at 0 °C. The mixture was stirred at 25 °C for 30 minutes. LCMS (5- 95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.728 min, [M+H]+= 434.3 showed 83% of desired product. The mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (40 mL x 3), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by prep-TLC ((dichloromethane / methanol=10: l): (Petroleum ether: EE (Ethyl acetate: ethanol= 3: 1) = 3: 1)) to afford the title compound (81.45 mg, 32%) as white solid.'HNMR (400 MHz, CD3OD): 6 8.48 (d, J= 5.6 Hz, 1H), 8.17 (s, 1H), 7.36 (d, J= 8.8 Hz, 2H), 7.24 (d, J= 5.6 Hz, 1H), 6.57 (d, J= 8.0 Hz, 2H), 4.04 - 3.95 (m, 1H), 3.86 - 3.78 (m, 5H), 3.61 - 3.52 (m, 2H), 2.05 - 1.94 (m, 4H), 1.84, 1.82 (s, 3H total), 1.79 - 1.68 (m, 2H), 1.22 - 1.08 (m, 2H).Example 197V-(4-methoxypyridin-3-yl)-7-(methylsulfonyl)-7V-(4-(trifluoromethyl)phenyl)-7- azaspiro[3.5]nonan-2-amineTo a solution of A-(4-m ethoxypyri din-3 -yl)-A-(4-(trifluoromethyl)phenyl)-7- azaspiro[3.5]nonan-2-amine hydrochloride (218 mg, 509.48 pmol, 1 eq in DCM (5 mL) was added TEA (154.66 mg, 1.53 mmol, 212.74 pL, 3 eq) and methane sulfonyl chloride (87.54 mg, 764.22 pmol, 59.15 pL, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.824 min, [M+H]+= 470.2 showed 97% of desired product. The solution was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 33% EE (ethyl acetate: ethanol = 3: 1) in petroleum ether) to afford the title compound (100 mg, 42%) as a white solid.CTQ-01525'H NMR (400 MHz, CDCh): 3 8.55 (d, J= 5.6 Hz, 1H), 8.27 (s, 1H), 7.38 (d, J= 8.4 Hz, 2H), 6.96 (d, J= 5.6 Hz, 1H), 6.50 (d, J= 8.8 Hz, 2H), 4.48 - 4.27 (m, 1H), 3.81 (s, 3H), 3.21 (t, J= 5.6 Hz, 2H), 3.05 (t, J= 5.6 Hz, 2H), 2.75 (s, 3H), 2.32 - 2.21 (m, 2H), 1.86 - 1.78 (m, 2H), 1.74 - 1.62 (m, 2H), 1.54 - 1.57 (m, 2H).Example 207V-(4-(difluoromethoxy)phenyl)-7V-(4-methoxypyridin-3-yl)-7-(methylsulfonyl)-7- azaspiro[3.5]nonan-2-amineTo a mixture of 7V-(4-(difluoromethoxy)phenyl)-7V-(4-methoxypyridin-3-yl)-7- azaspiro[3.5]nonan-2-amine hydrochloride (200 mg, 469.60 pmol, 1 eq in DCM (3 mL) was added TEA (142.55 mg, 1.41 mmol, 196.08 pL, 3 eq) at 0 °C, then methane sulfonyl chloride (0.170 g, 1.48 mmol, 114.86 pL, 3.16 eq was added into it at 0 °C. The solution was stirred at 0 °C for 0.5 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.793 min, [M+H]+= 468.2 showed 98% of the desired product. The solution was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (0 - 10% methanol in ethyl acetate) to afford the title compound (53.4 mg, 24%) as a white solid.'HNMR (400 MHz, CDCh): <5 8.51 - 8.48 (m, 1H), 8.28 (s, 1H), 6.96 - 6.93 (m, 3H), 6.59 - 6.19 (m, 3H), 4.38 - 4.28 (m, 1H), 3.80 (s, 3H), 3.20 (t, J= 5.2 Hz, 2H), 3.05 (t, J= 5.2 Hz, 2H), 2.75 (s, 3H), 2.28 - 2.19 (m, 2H), 1.82 - 1.54 (m, 6H).CTQ-01525Example 21 l-(2-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)-7-azaspiro[3.5]nonan- 7-yl)ethan-l-oneA mixture of A-(4-(difluoromethoxy)phenyl)-A-(4-methoxypyridin-3-yl)-7- azaspiro[3.5]nonan-2-amine hydrochloride (169 mg, 396.81 pmol, 1 eq), acetyl chloride (46.72 mg, 595.21 pmol, 42.32 pL, 1.5 eq) and TEA (120.46 mg, 1.19 mmol, 165.69 pL, 3 eq in DCM (3 mL) was stirred at 0 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.767 min, [M+H]+= 432.3, showed 87% of the desired product. The solution was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (0 - 10% methanol in ethyl acetate) to afford the title compound (61.29 mg, 36%) as a white solid.'H NMR (400 MHz, CDC13): d 8.50 - 8.47 (m, 1H), 8.30 - 8.26 (m, 1H), 6.99 - 6.90 (m, 3H), 6.63 - 6.15 (m, 3H), 4.36 - 4.34 (m, 1H), 3.80, 3.78 (s, 3H total), 3.58 - 3.51 (m, 1H), 3.42 - 3.34 (m, 2H), 3.32 - 3.18 (m, 1H), 2.27 - 2.17 (m, 2H), 2.08, 2.05 (s, 3H total), 1.68 - 1.58 (m, 4H), 1.50 - 1.36 (m, 2H).Example 22 l-(2-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-7-azaspiro[3.5]nonan- 7-yl)ethan-l-oneTo a solution of A-(4-methoxypyri din-3 -yl)-7V-(4-(trifluorom ethyl)phenyl)-7- azaspiro[3.5]nonan-2-amine hydrochloride (218 mg, 509.48 pmol, 1 eq in DCM (5 mL) wasCTQ-01525 added TEA (169.07 mg, 1.67 mmol, 232.55 pL, 3 eq) and acetyl chloride (65.58 mg, 835.40 pmol, 59.40 pL, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT =0.799 min, [M+H]+= 434.3 showed 95% of desired product. The solution was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 33% EE (ethyl acetate: ethanol = 3: 1) in petroleum ether) to afford the title compound (123.28 mg, 51%) as a white solid.'HNMR (400 MHz, CD3OD): 6 8.49 (d, J= 5.6 Hz, 1H), 8.22 (d, J= 2.4 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.26 (d, J= 5.6 Hz, 1H), 6.58 (d, J= 8.4 Hz, 2H), 4.54 - 4.50 (m, 1H), 3.85 (s, 3H), 3.61 - 3.46 (m, 2H), 3.44 - 3.34 (m, 2H), 2.33 - 2.38 (m, 2H), 2.08, 2.06 (s, 3H total), 1.80 - 1.73 (m, 1H), 1.73 - 1.61 (m, 3H), 1.51 - 1.35 (m, 2H).Example 23 V-(4-methoxypyridin-3-yl)-2-(methylsulfonyl)-A-(4-(trifluoromethyl)phenyl)-2- azaspiro[3.5]nonan-7-amineTo a mixture of A-(4-methoxypyridin-3-yl)-A-(4-(trifluoromethyl)phenyl)-2- azaspiro[3.5]nonan-7-amine (222 mg, 567.15 pmol, 1 eq) in DCM (3 mL) was added TEA (286.95 mg, 2.84 mmol, 394.70 pL, 5 eq) and methane sulfonyl chloride (129.94 mg, 1.13 mmol, 87.79 pL, 2 eq) at 0 °C under N2. The mixture was stirred at 25 °C for 0.5 hour. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.745 min, [M+H]+= 470.2 showed 70% of desired product. The mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (40 mL x 3), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by prep-TLC ((dichloromethane / methanol=10: l): Petroleum ether: EE (Ethyl acetate: ethanol= 3: 1) = 3: 1) to afford the title compound (70.83 mg, 26%) as a white solid.'HNMR (400 MHz, CDCI3): 3 8.55 (d, J= 5.6 Hz, 1H), 8.21 (s, 1H), 7.37 (d, J= 8.8 Hz, 2H), 6.98 (d, J= 5.6 Hz, 1H), 6.47 (d, J= 8.8 Hz, 2H), 3.91 - 3.83 (m, 1H), 3.81 (s, 3H), 3.62CTQ-01525(s, 2H), 3.54 (s, 2H), 2.83 (s, 3H), 2.08 - 1.99 (m, 4H), 1.69 - 1.61 (m, 2H), 1.15 - 1.03 (m, 2H).Example 24 l-(2-((4-cyclopropylpyridin-3-yl)(4-(difluoromethoxy)phenyl)amino)-7- azaspiro[3.5]nonan-7-yl)ethan-l-oneA mixture of A-(4-cyclopropylpyridin-3-yl)-7V-(4-(difluoromethoxy)phenyl)-7- azaspiro[3.5]nonan-2-amine hydrochloride (198 mg, 454.19 pmol, 1 eq acetyl chloride (71.31 mg, 908.39 pmol, 64.59 pL, 2 eq TEA (183.84 mg, 1.82 mmol, 252.87 pL, 4 eq in DCM (3 mL) was stirred at 0 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.730 min, [M+H]+= 442.3 showed 87% of the desired product. The solution was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate (25% EtOH)) = 1 : 1) to afford the title compound (105.07 mg, 51%) as a white solid.'HNMR (400 MHz, CDC13): d 8.42 (s, 1H), 8.21 - 8.18 (m, 1H), 6.96 (d, J= 8.8 Hz, 2H), 6.75 (d, J= 5.2 Hz, 1H), 6.59 - 6.14 (m, 3H), 4.48 - 4.36 (m, 1H), 3.59 - 3.51 (m, 1H), 3.46 - 3.31 (m, 2H), 3.29 - 3.14 (m, 1H), 2.37 - 2.25 (m, 2H), 2.10 - 1.96 (m, 4H), 1.74 - 1.59 (m, 4H), 1.45 - 1.34 (m, 2H), 1.07 - 1.01 (m, 2H), 0.83 - 0.76 (m, 2H).CTQ-01525Example 257V-(4-cyclopropylpyridin-3-yl)-A-(4-(difluoromethoxy)phenyl)-7-(methylsulfonyl)-7- azaspiro[3.5]nonan-2-amineTo a mixture of A-(4-cyclopropylpyridin-3-yl)-7V-(4-(difluoromethoxy)phenyl)-7- azaspiro[3.5]nonan-2-amine hydrochloride (197.9 mg, 453.97 pmol, 1 eq in DCM (3 mL) was added TEA (183.75 mg, 1.82 mmol, 252.75 pL, 4 eq , and then added methane sulfonyl chloride (104.0 mg, 907.94 pmol, 2 eq for 0 °C 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.764 min, [M+H]+= 478.2 showed 61% of the desired product. The solution was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate (25%EtOH) = 1 : 1) to afford the title compound (109.72 mg, 51%) as a white solid.'HNMR (400 MHz, CDC13): 3 8.42 (d, J= 5.2 Hz, 1H), 8.21 (s, 1H), 6.99 (d, J= 9.2 Hz, 2H), 6.83 (d, J= 5.2 Hz, 1H), 6.60 - 6.22 (m, 3H), 4.45 - 4.35 (m, 1H), 3.24 - 3.20 (m, 2H), 3.07 - 3.04 (m, 2H), 2.76 (s, 3H), 2.36 - 2.30 (m, 2H), 2.07 - 1.99 (m, 1H), 1.85 - 1.81 (m, 2H), 1.71 - 1.66 (m, 2H), 1.58 - 1.54 (m, 2H), 1.10 - 1.06 (m, 2H), 0.85 - 0.82 (m, 2H).Example 26 l-(2-((4-cyclopropylpyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-7- azaspiro[3.5]nonan-7-yl)ethan-l-oneA mixture of A-(4-cyclopropylpyridin-3-yl)-A-(4-(trifluoromethyl)phenyl)-7- azaspiro[3.5]nonan-2-amine hydrochloride (195 mg, 445.28 pmol, 1 eq), acetyl chlorideCTQ-01525(69.91 mg, 890.56 pmol, 63.32 pL, 2 eq), TEA (180.23 mg, 1.78 mmol, 247.91 pL, 4 eq) in DCM (3 was stirred at 0 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 2.0 min): RT =1.137 min, [M+H]+= 444.2 showed 70% of the desired product. The solution was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18 150*30mm*5um, water (FA)-ACN, 32%-62% B over 7 min) to afford the title compound (119.73 mg, 60%) as a yellow oil.'HNMR (400 MHz, CDC13): 3 8.47 (d, J= 2.8 Hz, 1H), 8.22 (d, J= 7.2 Hz, 1H), 7.41 (d, J = 8.8 Hz, 2H), 6.81 (d, J= 2.8 Hz, 1H), 6.51 (d, J= 8.8 Hz, 2H), 4.54 - 4.42 (m, 1H), 3.58 - 3.51 (m, 1H), 3.48 - 3.35 (m, 2H), 3.31 - 3.18 (m, 1H), 2.40 - 2.33 (m, 2H), 2.09, 2.05 (s, 3H total), 1.98 - 1.83 (m, 1H), 1.78 - 1.58 (m, 4H), 1.48 - 1.33 (m, 2H), 1.16 - 0.99 (m, 2H), 0.92 - 0.75 (m, 2H).Example 27 l-(7-((4-cyclopropylpyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-2- azaspiro[3.5]nonan-2-yl)ethan-l-oneTo the solution of A-(4-cy cl opropylpyri din-3 -yl)-A-(4-(trifluoromethyl)phenyl)-2- azaspiro[3.5]nonan-7-amine 2,2,2-trifluoroacetate (212 mg, 411.26 pmol, 1 eq) and acetyl chloride (64.57 mg, 822.52 pmol, 58.48 pL, 2 eq) in DCM (5 mL) was added TEA (124.84 mg, 1.23 mmol, 171.73 pL, 3 eq) at 0 °C. The reaction was stirred at 0 °C for 1 hr. LCMS (5- 95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.768 min, [M+H]+= 444.3 showed 56% of desired product. The mixture was quenched with methanol (1 mL), then the reaction mixture was filtered and concentrated. The residue was purified by reverse phase chromatography (Welch Xtimate C18 150*30mm*5um, water (FA)-ACN, 32%-62% B over 7 min) to afford the title compound (99.3 mg, 51%) as a white solid.'HNMR (400 MHz, CDCI3): 3 8.48 (s, 1H), 8.24 (s, 1H), 7.40 (d, J= 8.8, 3.2 Hz, 2H), 6.76 (s, 1H), 6.49 (d, J= 8.8 Hz, 2H), 4.02 - 3.91 (m, 1H), 3.80 - 3.49 (m, 4H), 2.09 - 1.96 (m,CTQ-015254H), 1.92 - 1.89 (m, 1H), 1.88, 1.86 (s, 3H total), 1.75 - 1.62 (m, 2H), 1.17 - 1.03 (m, 4H), 0.83 - 0.80 (m, 2H).Example 287V-(4-cyclopropylpyridin-3-yl)-2-(methylsulfonyl)-7V-(4-(trifluoromethyl)phenyl)-2- azaspiro[3.5]nonan-7-amineTo a solution of A-(4-cy clopropylpyri din-3 -yl)-A-(4-(trifluoromethyl)phenyl)-2- azaspiro[3.5]nonan-7-amine (212 mg, 528.06 pmol, 1 eq and methane sulfonyl chloride (540 mg, 4.71 mmol, 364.86 pL, 8.93 eq) in DCM (5 mL) was added TEA (160.30 mg, 1.58 mmol, 220.50 pL, 3 eq) at 0 °C. The reaction was stirred at 0 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.787 min, [M+H]+= 480.2 showed 61% of desired product. The mixture was quenched with methanol (1 mL), then the reaction mixture was filtered and concentrated. The residue was purified by reverse phase chromatography (Welch Xtimate C18 150*30mm*5um, water (FA)-ACN, 37%-67% B over 7 min) to afford the title compound (105.04 mg, 39%) as a white solid.'HNMR (400 MHz, CDC13): 3 8.48 (s, 1H), 8.23 (s, 1H), 7.40 (d, J= 8.4 Hz, 2H), 6.79 (s, 1H), 6.49 (d, J= 8.4 Hz, 2H), 3.99 - 3.93 (m, 1H), 3.66 - 3.50 (m, 4H), 2.84 (s, 3H), 2.11 - 2.05 (m, 4H), 1.90 - 1.87 (m, 1H), 1.70 - 1.64 (m, 2H), 1.20 - 1.04 (m, 4H), 0.84 - 0.82 (m, 2H).CTQ-01525Example 297-((4-(difluoromethoxy)phenyl)(4-methoxypyridin-3-yl)amino)-2-thiaspiro[3.5]nonane2,2-dioxideTo a mixture of 7-((4-methoxypyridin-3-yl)amino)-2-thiaspiro[3.5]nonane 2,2-dioxide (120 mg, 404.88 pmol, 1 eq in toluene (8 mL) was added Z-BusP Pd G2 (41.49 mg, 80.98 pmol, 0.2 eq), / -BuONa (116.73 mg, 1.21 mmol, 3 eq and l-bromo-4-(difluoromethoxy)benzene (180.59 mg, 809.76 pmol, 110.72 pL, 2 eq . The mixture was stirred at 120 °C for 16 hours under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.706 min, [M+H]+= 439.2 showed 22% of desired product. The solution was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (0 - 52.6% ethyl acetate in petroleum ether) to afford the title compound (105.39 mg, 55%) as yellow solid. 'H NMR (400 MHz, CD3OD): 6 8.43 (d, J= 5.6 Hz, 1H), 8.15 (s, 1H), 7.20 (d, J= 5.6 Hz, 1H), 6.91 (d, J= 9.2 Hz, 2H), 6.79 - 6.38 (m, 3H), 3.97 - 3.89 (m, 1H), 3.86 (s, 2H), 3.82 (s, 3H), 3.78 (s, 2H), 2.08 - 2.00 (m, 4H), 1.89 - 1.80 (m, 2H), 1.22 - 1.10 (m, 2H).Example 307-((4-methoxypyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-2-thiaspiro[3.5]nonane2,2-dioxideCTQ-01525To a mixture of 7-((4-methoxypyridin-3-yl)amino)-2-thiaspiro[3.5]nonane 2,2-dioxide (120 mg, 404.88 pmol, 1 eq) in toluene (8 mL)was added Z-BusP Pd G2 (20.75 mg, 40.49 pmol, 0.1 eq), / -BuONa (116.73 mg, 1.21 mmol, 3 eq andl-bromo-4-(trifluoromethyl)benzene (182.20 mg, 809.76 pmol, 111.78 pL, 2 eq). The mixture was stirred at 120 °C for 16 hours under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.730 min, [M+H]+= 441.2 showed 64% of desired product. The solution was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (0 - 50% ethyl acetate in petroleum ether) to afford the title compound (145.66 mg, 80%) as a yellow solid. 'H NMR (400 MHz, CD3OD): 6 8.48 (d, J= 5.6 Hz, 1H), 8.17 (s, 1H), 7.37 (d, J= 8.8 Hz, 2H), 7.25 (d, J= 5.6 Hz, 1H), 6.57 (d, J= 8.8 Hz, 2H), 4.07 - 3.98 (m, 1H), 3.87 (s, 2H), 3.85 (s, 3H), 3.79 (s, 2H), 2.08 - 2.03 (m, 4H), 1.92 - 1.83 (m, 2H), 1.23 - 1.11 (m, 2H).Example 31 7V-(4-cyclopropylpyridin-3-yl)-7V-(4-(difluoromethoxy)phenyl)-2-(methylsulfonyl)-2- azaspiro[3.5]nonan-7-amineTo the solution of 7V-(4-cy cl opropylpyri din-3 -yl)-A-(4-(difhioromethoxy)phenyl)-2- azaspiro[3.5]nonan-7-amine (157 mg, 393.02 pmol, 1 eq) and methane sulfonyl chloride (90.04 mg, 786.03 pmol, 60.84 pL, 2 eq) in DCM (5 mL) at 0 °C was added TEA (119.31 mg, 1.18 mmol, 164.11 pL, 3 eq). The solution was stirred at 0 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.798 min, [M+H]+= 478.3 showed 86% of desired product. The mixture was quenched with methanol (1 mL), then the residue was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with 4M HC1 (1 mL), filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, (petroleum ether: EE (Ethyl acetate / EtOH = 3 : 1) =1 : 1) to afford the title compound (78.77 mg, 41%) as a white solid.CTQ-01525'H NMR (400 MHz, CDCh): 3 8.43 (s, 1H), 8.21 (s, 1H), 6.96 (d, J= 8.8 Hz, 2H), 6.74 (d, J = 4.8 Hz, 1H), 6.59 - 6.19 (m, 3H), 3.90 - 3.84 (m, 1H), 3.63 - 3.52 (m, 4H), 2.83 (s, 3H), 2.09 - 2.05 (m, 4H), 2.00 - 1.91 (m, 1H), 1.68 - 1.61 (m, 2H), 1.15 - 1.11 (m, 2H), 1.05 - 0.99 (m, 2H), 0.82 - 0.75 (m, 2H).Example 32 l-(7-((4-cyclopropylpyridin-3-yl)(4-(difluoromethoxy)phenyl)amino)-2- azaspiro[3.5]nonan-2-yl)ethan-l-oneTo the solution of 7V-(4-cy cl opropylpyri din-3 -yl)-A-(4-(difluoromethoxy)phenyl)-2- azaspiro[3.5]nonan-7-amine (157 mg, 393.02 pmol, 1 eq and acetyl chloride (61.70 mg, 786.03 pmol, 55.89 pL, 2 eq) in DCM (5 mL) was added TEA (119.31 mg, 1.18 mmol, 164.11 pL, 3 eq) at 0 °C. The solution was stirred at 0 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.733 min, [M+H]+= 442.3 showed 67% of desired product. The mixture was quenched with methanol (1 mL), then the residue was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with 4M HC1 (1 mL), filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, (petroleum ether: EE (Ethyl acetate / EtOH= 3: 1) = 1 : 1) to afford the title compound (76.99 mg, 41%) as a white solid.CTQ-01525Example 33A-(4-cyclopropylpyridin-3-yl)-7-(methylsulfonyl)-A-(4-(trifluoromethyl)phenyl)-7- azaspiro[3.5]nonan-2-amineTo a mixture of A-(4-cyclopropylpyridin-3-yl)-A-(4-(trifluoromethyl)phenyl)-7- azaspiro[3.5]nonan-2-amine hydrochloride (195 mg, 445.28 pmol, 1 eq in DCM (3 mL) was added TEA (135.17 mg, 1.34 mmol, 185.93 pL, 3 e ), and then added methane sulfonyl chloride (0.190 mg, 1.66 pmol, 1.28e-l pL, 3.72e-3 eq) at 0 °C. The reaction was stirred at 0 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.851 min, [M+H]+= 480.3, showed 92% of the desired product. The solution was concentrated under reduced pressure to give a residue. The mixture was purified by reverse phase chromatography (Welch Xtimate C18 150*30mm*5um, water (FA)-ACN, 40%-70% B over 7 min) to afford the title compound (99.94 mg, 46%) as a white solid.'HNMR (400 MHz, CDC13): 3 8.48 (d, J= 5.2 Hz, 1H), 8.23 (s, 1H), 7.42 (d, J= 8.8 Hz, 2H), 6.83 (d, J= 5.2 Hz, 1H), 6.51 (d, J= 8.8 Hz, 2H), 4.56 - 4.44 (m, 1H), 3.26 - 3.19 (m, 2H), 3.09 - 3.02 (m, 2H), 2.76 (s, 3H), 2.41 - 2.31 (m, 2H), 1.95 - 1.89 (m, 1H), 1.87 - 1.83 (m, 2H), 1.70 - 1.66 (m, 2H), 1.57 - 1.53 (m, 2H), 1.13 - 1.04 (m, 2H), 0.89 - 0.81 (m, 2H).Examples 34 and 367V-(4-(difluoromethoxy)phenyl)-4-methoxy-7V-(2-oxaspiro[4.5]decan-8-yl)pyridin-3- amineCTQ-01525To a mixture of 4-methoxy-7V-(2-oxaspiro[4.5]decan-8-yl)pyridin-3-amine (165 mg, 628.94 pmol, 1 eq) in toluene (8 mL) was added LBusP Pd G2 (64.45 mg, 125.79 pmol, 0.2 eq), t- BuONa (181.32 mg, 1.89 mmol, 3 eq and l-bromo-4-(difluorom ethoxy )benzene (280.53 mg, 1.26 mmol, 172.00 pL, 2 eq . The mixture was stirred at 120 °C for 16 hours under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.740 min & 0.840 min, [M+H]+= 405.2 showed 11% & 14% of desired product. Concentrated in vacuum. The residue was purified by flash chromatography on silica gel (0 - 52.6% ethyl acetate in petroleum ether) to afford a residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18 150*25mm*5um, water (NH4HCC>3)-ACN, 60%-70% B over 7 min) to afford compound 34 (the first peak, 17.84 mg, 7%) as a yellow solid and compound 36(the second peak, 17.17 mg, 6%) as a yellow solid.Compound 34: 'H NMR (400 MHz, CDCI3): 3 8.49 (d, J= 5.6 Hz, 1H), 8.25 (s, 1H), 7.00 - 6.91 (m, 3H), 6.60 - 6.18 (m, 3H), 3.85 - 3.76 (m, 6H), 3.47 (s, 2H), 2.03 - 1.95 (m, 2H), 1.69 - 1.65 (m, 2H), 1.63 - 1.60 (m, 2H), 1.54 - 1.50 (m, 2H), 1.30 - 1.19 (m, 2H).Compound 36:XH NMR (400 MHz, CDCI3): 3 8.49 (d, J= 5.6 Hz, 1H), 8.23 (s, 1H), 6.98 - 6.93 (m, 3H), 6.58 - 6.19 (m, 3H), 3.87 - 3.78 (m, 6H), 3.47 - 3.45 (m, 2H), 2.01 - 1.93 (m, 2H), 1.78 - 1.73 (m, 2H), 1.69 - 1.64 (m, 2H), 1.60 - 1.56 (m, 2H), 1.19 - 1.06 (m, 2H).Examples 35 and 37 4-methoxy-7V-(2-oxaspiro[4.5]decan-8-yl)-7V-(4-(trifluoromethyl)phenyl)pyridin-3-amineTo a mixture of 4-methoxy-7V-(2-oxaspiro[4.5]decan-8-yl)pyridin-3-amine (155 mg, 590.82 pmol, 1 eq) in toluene (8 mL) was added LBU3P Pd G2 (30.27 mg, 59.08 pmol, 0.1 eq), t- BuONa (170.33 mg, 1.77 mmol, 3 eq and l-bromo-4-(trifluoromethyl)benzene (265.88 mg, 1.18 mmol, 163.11 pL, 2 eq . The mixture was stirred at 120 °C for 16 hours under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT= 0.772 min & 0.790 min, [M+H]+= 407.2 showed 11% & 10% of desired product. The solution wasCTQ-01525 concentrated in vacuum. The residue was purified by flash chromatography on silica gel (0 - 56% ethyl acetate in petroleum ether) to afford the residue. The residue was purified by reverse phase chromatography (Welch Xtimate C18 150*25mm*5um, water (NH4HCO3)- ACN, 65%-75% B over 7 min) to afford compound 35 (the first peak, 22.57 mg, 9%) as a white solid and compound 37 (the second peak, 19.74 mg, 7%) as a white solid.Compound 35: 'HNMR (400 MHz, CDCI3): 3 8.56 (d, J= 5.6 Hz, 1H), 8.27 (s, 1H), 7.37 (d, J= 8.8 Hz, 2H), 7.01 (d, J= 5.6 Hz, 1H), 6.49 (d, J= 8.8 Hz, 2H), 3.94 - 3.78 (m, 6H), 3.45 (s, 2H), 2.04 - 1.96 (m, 2H), 1.70 - 1.66 (m, 2H), 1.63 - 1.59 (m, 2H), 1.57 - 1.49 (m, 2H), 1.31 - 1.19 (m, 2H).Compound 37:XH NMR (400 MHz, CDCI3): 3 8.61 - 8.49 (m, 1H), 8.25 - 8.17 (m, 1H), 7.37 (d, J= 8.8 Hz, 2H), 7.02 - 6.90 (m, 1H), 6.49 (d, J= 8.8 Hz, 2H), 3.95 - 3.82 (m, 6H), 3.48 - 3.45 (m, 2H), 2.03 - 1.95 (m, 2H), 1.78 - 1.74 (m, 2H), 1.69 - 1.66 (m, 2H), 1.63 - 1.55 (m, 2H), 1.19 - 1.04 (m, 2H).Example 38 l-(7-(pyridin-3-yl(4-(trifluoromethyl)phenyl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-l- one- I l l -CTQ-01525Step 1: tert-butyl 7-(pyridin-3-ylamino)-2-azaspiro[3.5]nonane-2-carboxylateTo a solution of pyri din-3 -amine (200 mg, 2.13 mmol, 1 eq) and tert-butyl 7-oxo-2- azaspiro[3.5]nonane-2-carboxylate (559.41 mg, 2.34 mmol, 1.1 eq) in isopropyl acetate (5 mL) was added NaBH(OAc)3 (540.47 mg, 2.55 mmol, 1.2 eq) and TFA (726.90 mg, 6.38 mmol, 473.55 pL, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 16 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min), RT = 0.676 min, [M+H]+= 318.3 showed 95% of the desired product. The reaction mixture was treated with saturated NaOH aq. (25 mL) and stirred for 30 mins. The resulting mixture was extracted with ethyl acetate (50 mL x 3) and the combined organic layer was washed with brine (20 mL x 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 (663 mg, 98%) as a yellow solid.'H NMR (400 MHz, DMSO-t / 6): d 7.94 (d, J= 2.4 Hz, 1H), 7.70 (d, J= 4.0 Hz, 1H), 7.06 - 7.00 (m, 1H), 6.91 - 6.85 (m, 1H), 5.61 (d, J= 7.6 Hz, 1H), 3.59 - 3.46 (m, 4H), 3.18 - 3.15 (m, 1H), 1.84 - 1.81 (m, 4H), 1.58 - 1.46 (m, 2H), 1.37 (s, 9H), 1.26 - 1.09 (m, 2H).Step 2: tert-butyl 7-(pyridin-3-yl(4-(trifluoromethyl)phenyl)amino)-2- azaspiro[3.5]nonane-2-carboxylateA mixture of tert-butyl 7-(pyridin-3-ylamino)-2-azaspiro[3.5]nonane-2-carboxylate (330 mg, 1.04 mmol, 1 eq), l-bromo-4-(trifluoromethyl)benzene (350.88 mg, 1.56 mmol, 215.26 pL, 1.5 eq), t-BuONa (299.73 mg, 3.12 mmol, 3 eq), t-BusP Pd G2 (53.27 mg, 103.96 pmol, 0.1 eq) in toluene (10 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 125 °C for 16 hr under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min), RT = 0.815 min, [M+H]+= 462.3 showed 58% of the desired product. The solution was concentrated under reduced pressure to give a residue. The residueCTQ-01525 was purified by flash chromatography on silica gel (0 - 40% ethyl acetate petroleum ether) to afford the title compound (374 mg, 80%) as a white solid.Step 3: 7V-(pyridin-3-yl)-7V-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.5]nonan-7-amine 2,2,2-trifluoroacetic acidA solution of tert-butyl 7-(pyridin-3-yl(4-(trifluoromethyl)phenyl)amino)-2- azaspiro[3.5]nonane-2-carboxylate (374 mg, 810.37 pmol, 1 eq) in 5% TFA / HFIP (5 mL) was stirred at 25 °C for 2 hr. The solution was concentrated under reduced pressure to afford the title compound (292.87 mg, crude) as a white solid.Step 4: tert-butyl 7-(pyridin-3-yl(4-(trifluoromethyl)phenyl)amino)-2- azaspiro[3.5]nonane-2-carboxylateA mixture of acetyl chloride (95.42 mg, 1.22 mmol, 86.43 pL, 1.5 eq) in DCM (8 mL) was degassed and purged with N2 3 times, and then TEA (246.00 mg, 2.43 mmol, 338.38 pL, 3 eq was added into it at 0 °C and then the mixture was stirred at 0 °C for 0.15 hr under N2 atmosphere. Then A-(pyridin-3-yl)-A-(4-(trifluoromethyl)phenyl)-2-azaspiro[3 ,5]nonan-7- amine (292.87 mg, 810.37 pmol, 1 eq in DCM (1 mL) was added into it at 0 °C, the solution was stirred at 0 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.0 min): RT = 0.371 min, [M+H]+= 404.1 showed 91% of the desired product. The reaction was 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 (211.95 mg, 65%) as a white solid.'H NMR (400 MHz, CD3OD): 3 8.43 (d, J= 5.2 Hz, 1H), 8.24 (d, J= 2.4 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.53 - 7.45 (m, 3H), 6.80 - 6.67 (m, 2H), 4.11 - 4.00 (m, 1H), 3.83 - 3.76 (m, 2H), 3.60 - 3.51 (m, 2H), 2.06 - 1.97 (m, 4H), 1.87 - 1.74 (m, 5H), 1.20 - 1.05 (m, 2H).CTQ-01525Example 39 l-(7-((4-methylpyridin-3-yl)(4-(trifluoromethyl)phenyl)amino)-2-azaspiro[3.5]nonan-2- yl)ethan-l-oneA mixture of acetyl chloride (50.01 mg, 637.15 pmol, 45.30 pL, 1.5 eq), TEA (128.95 mg, 1.27 mmol, 177.37 pL, 3 eq) and A-(4-methylpyridin-3-yl)-A-(4-(trifluoromethyl)phenyl)-2- azaspiro[3.5]nonan-7-amine (159.47 mg, 424.77 pmol, 1 eq) in DCM (6 mL) was stirred at 0 °C for 1 hr under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.90 min, [M+H]+= 418.2 showed 62 % of the desired product. The reaction mixture was treated with saturated NaHCCh aq. (20 mL) and stirred for 30 mins. The resulting mixture was extracted with ethyl acetate (200 mL x 3) and the combined organic layer was washed with brine (150 mL x 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 (81.71 mg, 46%) as a yellow oil.'HNMR (400 MHz, CDCI3): d 8.58 - 8.44 (m, 1H), 8.27 (d, J= 8.8 Hz, 1H), 7.47 - 7.22 (m, 3H), 6.42 (d, J= 8.4 Hz, 2H), 3.99 - 3.83 (m, 1H), 3.80 - 3.51 (m, 4H), 2.13, 2.12 (s, 3H total), 2.03 - 1.93 (m, 4H), 1.84, 1.83 (s, 3H total), 1.74 - 1.55 (m, 2H), 1.20 - 1.01 (m, 2H).Example 40 l-(7-((4-methylpyridin-3-yl)(4-(methylsulfonyl)phenyl)amino)-2-azaspiro[3.5]nonan-2- yl)ethan-l-oneCTQ-01525Step 1: tert-butyl 7-((4-methylpyridin-3-yl)(4-(methylsulfonyl)phenyl)amino)-2- azaspiro[3.5]nonane-2-carboxylateA mixture of tert-butyl 7-((4-methylpyridin-3-yl)amino)-2-azaspiro[3.5]nonane-2- carboxylate (220 mg, 663.75 pmol, 1 eq)., l-bromo-4-(methylsulfonyl)benzene (156.05 mg, 663.75 pmol, 1 eq t-Bu3P Pd G2 (34.01 mg, 66.37 pmol, 0.1 eq t-BuONa (191.37 mg, 1.99 mmol, 3 eq) in toluene (10 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 125 °C for 16 hr under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min), RT = 0.741 min, [M+H]+= 486.3 showed 29% of the desired product. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 70% ethyl acetate in petroleum ether) to afford the title compound (160 mg, 50%) as a yellow solid.Step 2: 7V-(4-methylpyridin-3-yl)-A-(4-(methylsulfonyl)phenyl)-2-azaspiro[3.5]nonan-7- amine 2,2,2-trifluoroacetateA mixture of tert-butyl 7-((4-methylpyridin-3-yl)(4-(methylsulfonyl)phenyl)amino)-2- azaspiro[3.5]nonane-2-carboxylate (160 mg, 329.46 pmol, 1 eq) in 5% TFA / HFIP (4 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 25 °C for 1 hr under N2 atmosphere. The solution was concentrated under reduced pressure to afford the title compound (164.58 mg, crude) as a white solid.CTQ-01525Step 3: l-(7-((4-methylpyridin-3-yl)(4-(methylsulfonyl)phenyl)amino)-2- azaspiro[3.5]nonan-2-yl)ethan-l-oneTo a mixture of acetyl chloride (38.77 mg, 493.95 pmol, 35.12 pL, 1.5 eq) in DCM (5 mL) was degassed and purged with N2 3 times was added TEA (99.96 mg, 987.90 pmol, 137.50 pL, 3 eq) and then the mixture was stirred at 0 °C for 0.15 hr under N2 atmosphere. Then N- (4-methylpyridin-3-yl)-7V-(4-(methylsulfonyl)phenyl)-2-azaspiro[3.5]nonan-7-amine 2,2,2- trifluoroacetate (164.5 mg, 329.30 pmol, 1 eq) was added into at 0 °C. The solution was stirred at 0 °C for 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.555 min, [M+H]+= 428.2 showed 78% of the desired product. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 -70% EE (ethyl acetate: EtOH= 3:1) in petroleum ether) to afford the title compound (64.75 mg, 43%) as a yellow solid.'HNMR (400 MHz, CDCI3): 3 8.54 (s, 1H), 8.29 (d, J= 6.0 Hz, 1H), 7.74 - 7.63 (m, 2H), 7.37 - 7.29 (m, 1H), 6.46 (d, J= 8.0 Hz, 2H), 4.05 - 3.88 (m, 1H), 3.77 - 3.57 (m, 4H), 3.01 (s, 3H), 2.14, 2.13 (s, 3H total), 2.06 - 1.94 (m, 4H), 1.86, 1.84 (s, 3H), 1.75 - 1.68 (m, 2H), 1.22 - 1.05 (m, 2H).Example 417V-(4-methylpyridin-3-yl)-2-(methylsulfonyl)-7V-(4-(trifluoromethyl)phenyl)-2- azaspiro[3.5]nonan-7-amineCTQ-01525A mixture of A-(4-methylpyridin-3-yl)-A-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.5]nonan- 7-amine 2,2,2-trifluoroacetate (277.9 mg, 567.78 pmol, 1 eq) in DCM (8 mL) was added TEA (172.36 mg, 1.70 mmol, 237.08 pL, 3 eq) and then the mixture was stirred at 0 °C for 5 min. Then MsCl (0.400 g, 3.49 mmol, 270.27 pL, 6.15 eq was added into it at 0 °C 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.762 min, [M+H]+= 454.2 showed 85% of the desired product. The reaction mixture was treated with saturated NaHCCf aq. (50 mL) and stirred for 30 mins. The resulting mixture was extracted with ethyl acetate (200 mL x 3) and the combined organic layer was washed with brine (150 mL x 3). The organic phase was dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel (0 - 15% ethyl acetate in petroleum ether) to afford the title compound (139.42 mg, 53%) as a white solid.'HNMR (400 MHz, CDC13): 3 8.51 (d, J= 4.8 Hz, 1H), 8.28 (s, 1H), 7.38 (d, J= 8.8 Hz, 2H), 7.29 (d, J= 4.8 Hz, 1H), 6.42 (d, J= 8.8 Hz, 2H), 3.98 - 3.86 (m, 1H), 3.63, 3.57 (s, 4H), 2.83 (s, 3H), 2.13 (s, 3H), 2.11 - 1.97 (m, 4H), 1.71 - 1.62 (m, 2H), 1.20 - 1.06 (m, 2H).Example 427V-(4-(difluoromethoxy)phenyl)- V-(4-methylpyridin-3-yl)-2-(methylsulfonyl)-2- azaspiro[3.5]nonan-7-amineStep 1: tert-butyl 7-((4-(difluoromethoxy)phenyl)(4-methylpyridin-3-yl)amino)-2- azaspiro[3.5]nonane-2-carboxylateCTQ-01525A mixture of tert-butyl 7-((4-methylpyridin-3-yl)amino)-2-azaspiro[3.5]nonane-2- carboxylate (250 mg, 754.26 pmol, 1 eq , l-bromo-4-(difluoromethoxy)benzene (336.42 mg, 1.51 mmol, 206.27 pL, 2 eq , Z-BusP Pd G2 (77.30 mg, 150.85 pmol, 0.2 eq), / -BuONa (217.45 mg, 2.26 mmol, 3 eq in toluene (12 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 125 °C for 16 hr under N2 atmosphere. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min), RT = 0.828 min, [M+H]+= 474.3 showed 44% of the desired product. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (0 - 40% ethyl acetate petroleum ether) to afford the title compound (270 mg, 76%) as a white solid.Step 2: 7V-(4-(difluoromethoxy)phenyl)-A-(4-methylpyridin-3-yl)-2-azaspiro[3.5]nonan- 7-amine 2,2,2-trifluoroacetateA mixture of tert-butyl 7-((4-(difluoromethoxy)phenyl)(4-methylpyridin-3-yl)amino)-2- azaspiro[3.5]nonane-2-carboxylate (270 mg, 570.16 pmol, 1 eq in 5% TFA / HFIP (4 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 25 °C for 1 hr under N2 atmosphere. The reaction was concentrated under reduced pressure to afford the title compound (277.93 mg, crude) as a yellow oil.Step 3: V-(4-(difluoromethoxy)phenyl)-A-(4-methylpyridin-3-yl)-2-(methylsulfonyl)-2- azaspiro[3.5]nonan-7-amineTo a mixture of 7V-(4-(difluorom ethoxy )phenyl)-A-(4-methylpyri din-3 -yl)-2- azaspiro[3.5]nonan-7-amine 2,2,2-trifluoroacetate (277.93mg, 570.16 pmol, 1 eq in DCM (8CTQ-01525 mL) was added TEA (173.08 mg, 1.71 mmol, 238.08 pL, 3 eq) and then the mixture was stirred at 0 °C for 5 min. Then MsCl (0.16 g, 1.40 mmol, 108.11 pL, 2.45 eq) was added into at 0 °C. The solution was stirred at 0 °C 1 hr. LCMS (5-95% acetonitrile in 0.04%TFA / water over 1.5 min): RT = 0.714 min, [M+H]+= 452.3 showed 97% of the desired product. The reaction mixture was treated with saturated NaHCCf aq. (50 mL) and stirred for 30 mins. The resulting mixture was extracted with ethyl acetate (200 mL x 3) and the combined organic layer was washed with brine (150 mL x 3). The organic phase was dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (0 - 15% ethyl acetate in petroleum ether) to afford the title compound (111.37 mg, 42%) as a white solid.'HNMR (400 MHz, CDC13): 3 8.45 (d, J= 5.2 Hz, 1H), 8.28 (s, 1H), 7.25 (d, J= 5.2 Hz, 1H), 6.95 (d, J= 8.8 Hz, 2H), 6.57 - 6.20 (m, 3H), 3.91 - 3.79 (m, 1H), 3.62, 3.58 (s, 4H total), 2.83 (s, 3H), 2.12 (s, 3H), 2.10 - 1.93 (m, 4H), 1.69 - 1.62 (m, 2H), 1.19 - 1.05 (m, 2H).Biological ActivityMouse OPC Maturation AssayMouse oligodendrocyte progenitor cells (OPCs) were derived from mouse epiblast stem cells using in vitro differentiation protocols described in Najm et al. (2011, Nature Methods).OPCs were expanded and frozen down in aliquots. OPCs were thawed into growth conditions for at least one passage before use in further assays. OPCs were grown and expanded in poly- L-omithine (PO) and laminin-coated flasks in N2B27 media (DMEMZF12 (Gibco), N2-MAX (R&D Systems), B-27 (ThermoFisher), and GlutaMax (Gibco)) supplemented with FGF2 (10 pg / mL, R&D systems, 233-FB-025) and PDGF-AA (10 pg / mL, R&D systems, 233-AA-050) before harvesting for experiments. The cells were seeded onto poly-L-omithine or poly-D- lysine coated CellCarrier Ultra plates (PerkinElmer) coated with laminin (Sigma, L2020) at a density of 150,000 / cm2in N2B27 media without growth factors. For dose-response testing, a lOOOx compound stock in dimethyl sulphoxide (DMSO) was added to assay plates, resulting in 8-point dose curves. Positive controls and DMSO vehicle controls were included in each assay plate. Cells were incubated under standard conditions (37 °C, 5% CO) for 3 days and fixed with 4% paraformaldehyde (PF A) in phosphate buffered saline (PBS) for 20 min. Fixed plates were washed with PBS, permeabilized with 0.1% Triton X-100, and blocked with 10% donkey serum (v / v) in PBS for 40 min. Then, cells were labelled with MBP antibodies (Abeam, ab7349; 1 :200) overnight at 4°C, washed with PBS, and stained with Alexa FluorCTQ-01525 conjugated secondary antibodies (1 :500) for 45 min. Nuclei were visualized by DAPI staining (Sigma; 1 mg / ml), followed by further PBS washes. Cells and cell culture plates were imaged on the Operetta High Content Imaging and Analysis system (PerkinElmer). Analysis (PerkinElmer Harmony and Columbus software) began by identifying intact nuclei stained by DAPI. The peri-nuclear region of each cell was then cross-referenced with the mature myelin protein (MBP) stain to identify oligodendrocyte nuclei, and from this the percentage of oligodendrocytes was calculated. ECso values were calculated using The Levenberg-Marquardt algorithm to fit a Hill equation to the 8-point dose-response curve. ECso values for mouse OPC maturation (mOPC EC50) are provided in Table 1.GC / MS-based Sterol ProfilingMurine Sterol Profiling AssayMouse oligodendrocyte progenitor cells (OPCs) were derived from mouse epiblast stem cells using in vitro differentiation protocols described in Najm et al. (2011, Nature Methods).OPCs were expanded and frozen down in aliquots. OPCs were thawed into growth conditions for at least one passage before use in further assays. Sterols were monitored using a modified Folch wash protocol similar to that described in Pleshinger et al. (2022, RCS Chem. Biol.). Cells were plated at 100,000 cells per well in PO- and laminin-coated 96-well plates in N2B27 media without growth factors. After 24 hours, cells were rinsed with saline and plates were frozen. Cholesterol-d7 standard was then added to each well before drying under nitrogen stream and silyating with BSTFA-TMCS (N,O-bis(trimethylsilyl)trifluoroacetamide, 1% trimethylchlorosilane). After derivatization, 2 pl was analyzed by gas chromatography / mass spectrometry using an Agilent 5973 Network Mass Selective Detector equipped with a 6890 gas chromatograph system and a HP-5MS capillary column. Samples were analyzed in full scan mode using electron impact ionization; ion fragment peaks were integrated to calculate sterol abundance, and quantitation was relative to cholesterol-d7. The following ion fragments were used to quantitate each metabolite: cholesterol-d7 (465), FF-Mas (482), cholesterol (368), zymostenol (458), zymosterol (456), desmosterol (456, 343), 7- dehydrocholesterol (456, 325), lanosterol (393), lathosterol (458), 14-dehydrozymostenol (456, 351), and dihydrolanosterol (395). All standards were obtained from Avanti Polar Lipids unless otherwise indicated. Calibration curves were generated by injecting varying concentrations of sterol standards and maintaining a fixed amount of cholesterol-D7.Lanosterol accumulation was normalized to in-plate negative and positive controls, and EC50 values were calculated using The Levenberg-Marquardt algorithm to fit a Hill equation to anCTQ-015258-point dose-response curve. EC50 values for lanosterol accumulation in mouse cells (mCYP51 GCMS EC50) are provided in Table 1.Human Sterol Profiling AssayPrimary expanded bone marrow-derived human mesenchymal stem cells (MSCs) were obtained from RoosterBio and cultured in RoosterNourish-MSC media. They were grown under standard culture conditions (37 °C, 5% CO2) on Nunclon delta cell culture treated vessels. MSCs were expanded and frozen down in aliquots. Sterols were monitored using a modified Folch wash protocol similar to that described in Pleshinger et al. (2022, RCS Chem. Biol.). Cells were plated at 50,000 cells per well in Nunc MicroWell 96-well plates in hMSC High Performance Media Kit media (RoosterBio). After 24 hours, cells were rinsed with saline and plates were frozen. Cholesterol-d7 standard was then added to each well before drying under nitrogen stream and silyating with BSTFA-TMCS (N,O- bis(trimethylsilyl)trifluoroacetamide, 1% trimethylchlorosilane). After derivatization, 2 pl was analyzed by gas chromatography / mass spectrometry using an Agilent 5973 Network Mass Selective Detector equipped with a 6890 gas chromatograph system and a HP-5MS capillary column. Samples were analyzed in full scan mode using electron impact ionization; ion fragment peaks were integrated to calculate sterol abundance, and quantitation was relative to chole sterol -d7. The following ion fragments were used to quantitate each metabolite: cholesterol-d7 (465), FF-Mas (482), cholesterol (368), zymostenol (458), zymosterol (456), desmosterol (456, 343), 7-dehydrocholesterol (456, 325), lanosterol (393), lathosterol (458), 14-dehydrozymostenol (456, 351), and dihydrolanosterol (395). All standards were obtained from Avanti Polar Lipids unless otherwise indicated. Calibration curves were generated by injecting varying concentrations of sterol standards and maintaining a fixed amount of cholesterol-D7. Lanosterol accumulation was normalized to in-plate negative and positive controls, and EC50 values were calculated using The Levenberg-Marquardt algorithm to fit a Hill equation to an 8-point dose-response curve. EC50 values for lanosterol accumulation in human cells (hCYP51 GCMS EC50) are provided in Table 1.CTQ-01525Table 1. Biological Activity of Exemplary Compounds Against CYP51CTQ-01525

[0158] The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.CTQ-01525

[0159] While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

CTQ-01525CLAIMSWhat is claimed is:

1. A compound, or a pharmaceutically acceptable salt thereof, represented by structural formula (I):wherein:X is 5- to 12-membered heteroaryl;Y is Ce-12 aryl or 5- to 12-membered heteroaryl;G is selected from NR1, O, and S(=O)2;R1is selected from H, Ci-6 alkyl, Ce-i2 aryl, C3-12 cycloalkyl, 5- to 12-membered heteroaryl, C(=O)R2, S(=O)R3, and S(=O)2R4;R2, R3, and R4is each independently selected from C1-6 alkyl, C1-6 haloalkyl, Ce-12 aryl, C3-12 cycloalkyl, 5 to 12-membered heteroaryl, and 4 to 10-membered heterocycloalkyl; and a, b, c, and d is each independently selected from 1, 2, and 3, wherein each C1-6 alkyl, Ce-12 aryl, C1-6 haloalkyl, C3-12 cycloalkyl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C1-6 alkoxy, C1-6 deuteroalkyl, C3-8 cycloalkyl, C3-8 cycloalkoxy, C2-6 alkenyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, (Ci-e) alkylamino(Ci- e)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-6 alkoxy(Ci-3)alkyl, C6-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl, whereinR14R15, R18R18a, R20R20aR24and R27is each independently H or C1-6 alkyl;R16and R17is each independently selected from H, C1-6 alkyl, hydroxy(Ci-e)alkyl, and halo(Ci-e)alkyl;R19and R23is each independently C1-6 alkyl or halo(Ci-6)alkyl;CTQ-01525R2122 25anj 26 JS eac]1inc[epenc[enly selected from H, Ci-6 alkyl, C1-3 alkoxy(Ci-6)alkyl, hydroxy(Ci-6)alkyl, cyano(Ci-6)alkyl, amino(Ci-6)alkyl, C1-3 alkylamino(Ci-6)alkyl, and di(Ci-3)alkylamino(Ci-6)alkyl; orR21and R22or R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-3 alkoxy, halo(Ci-3)alkoxy, C1-6 alkoxy(Ci-3)alkyl, C6-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl.

2. The compound of claim 1, wherein the compound is represented by structural formulawhereinZ is CH or N,Rxis selected from H, F, Cl, Br, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-8 cycloalkyl, and C3-8 cycloalkoxy; andRyis selected from H, F, Cl, Br, C1-6 haloalkyl, C1-6 haloalkoxy, and S(=O)2(Ci-6 alkyl), wherein each C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C3-8 cycloalkoxy is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C1-6 deuteroalkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, (Ci-e) alkylamino(Ci-6)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-3CTQ-01525 alkoxy, halo(Ci-3)alkoxy, Ci-6 alkoxy(Ci-3)alkyl, Ce-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl, whereinR14R15, R18R18a, R20R20aR24and R27is each independently H or Ci-6 alkyl;R16and R17is each independently selected from H, Ci-6 alkyl, hydroxy(Ci-6)alkyl, and halo(Ci-6)alkyl;R19and R23is each independently Ci-6 alkyl or halo(Ci-e)alkyl;R21R22 R25anj R26eac]1inc[epenc[enly selected from H, Ci-6 alkyl, C1-3 alkoxy(Ci-6)alkyl, hydroxy(Ci-6)alkyl, cyano(Ci-6)alkyl, amino(Ci-6)alkyl, C1-3 alkylamino(Ci-6)alkyl, and di(Ci-3)alkylamino(Ci-6)alkyl; orR21and R22or R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-3 alkoxy, halo(Ci-3)alkoxy, C1-6 alkoxy(Ci-3)alkyl, Ce-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl.

3. The compound of claim 2, wherein Z is N.

4. The compound of claim 2, wherein Z is CH.

5. The compound of claim 2, wherein the compound is represented by structural formulaCTQ-015256. The compound of any one of claims 2-5, wherein Rxis selected from H, C1-3 alkyl, C3- 6 cycloalkyl, C1-3 alkoxy, and C3-6 cycloalkoxy, wherein each C1-3 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, and C3-6 cycloalkoxy is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, Ci-6deuteroalkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, (Ci-e) alkylamino(Ci- e)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-3 alkoxy, halo(Ci- s)alkoxy, C1-6 alkoxy(Ci-3)alkyl, C6-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl, whereinR14R15, R18R18a, R20R20aR24and R27is each independently H or C1-6 alkyl;R16and R17is each independently selected from H, C1-6 alkyl, hydroxy(Ci-6)alkyl, and halo(Ci-6)alkyl;R19and R23is each independently C1-6 alkyl or halo(Ci-6)alkyl;R21R22 R25anj R26eac]1inc[epenc[enly selected from H, C1-6 alkyl, C1-3 alkoxy(Ci-6)alkyl, hydroxy(Ci-6)alkyl, cyano(Ci-6)alkyl, amino(Ci-6)alkyl, C1-3 alkylamino(Ci-6)alkyl, and di(Ci-3)alkylamino(Ci-6)alkyl; orR21and R22or R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-3 alkoxy, halo(Ci-3)alkoxy, C1-6 alkoxy(Ci-3)alkyl, C6-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl.

7. The compound of any one of claim 6, wherein Rxis selected from H, C1-3 alkyl, C3-6 cycloalkyl, and C1-3 alkoxy.

8. The compound of claim 6, wherein Rxis selected from C1-3 alkyl, C3-6 cycloalkyl, and C1-3 alkoxy.CTQ-015259. The compound of any one of claims 2-8 whereinRyis selected from F, C1-3 haloalkyl, C1-3 haloalkoxy, and S(=O)2(Ci-6 alkyl), wherein each C1-3 haloalkyl and C1-3 haloalkoxy is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C1-6 deuteroalkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, (Cue) alkylamino(Ci-6)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, Ci- 3 alkoxy, halo(Ci-3)alkoxy, C1-6 alkoxy(Ci-3)alkyl, C6-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl, whereinR14R15, R18R18a, R20R20aR24and R27is each independently H or C1-6 alkyl;R16and R17is each independently selected from H, C1-6 alkyl, hydroxy(Ci-6)alkyl, and halo(Ci-6)alkyl;R19and R23is each independently C1-6 alkyl or halo(Ci-6)alkyl;R21R22 R25anj R26eac]1inc[epenc[enly selected from H, C1-6 alkyl, C1-3 alkoxy(Ci-6)alkyl, hydroxy(Ci-6)alkyl, cyano(Ci-6)alkyl, amino(Ci-6)alkyl, C1-3 alkylamino(Ci-6)alkyl, and di(Ci-3)alkylamino(Ci-6)alkyl; orR21and R22or R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-3 alkoxy, halo(Ci-3)alkoxy, C1-6 alkoxy(Ci-3)alkyl, C6-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl.

10. The compound of claim 9, wherein Ryis selected from C1-3 haloalkyl and C1-3 haloalkoxy.

11. The compound of any one of claims 5-10, wherein the compound is represented by one of the following structural formulas:CTQ-0152512. The compound of any one of claims 5-10, wherein the compound is represented by one of the following structural formulas:CTQ-0152513. The compound of any one of claims 5-10, wherein the compound is represented by the following structural formula:(Illf).

14. The compound of any one of claims 1-13, wherein a is 1 or 2.

15. The compound of any one of claims 1-14, wherein b is 1 or 2.

16. The compound of any one of claims 1-15, wherein c is 1 or 2.

17. The compound of any one of claims 1-16, wherein d is 1 or 2.

18. The compound of claim 5, wherein the compound is represented by one of the following structural formulas:CTQ-0152519. The compound of claim 19, wherein the compound is represented by structural formula (IVa) or structural formula (IVb).CTQ-0152520. The compound of claim 19, wherein the compound is represented by structural formula (IVc) or structural formula (IVd).

21. The compound of any one of claims 18-20, wherein Rxis selected from H, C1-3 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, and C3-6 cycloalkoxy, wherein each C1-3 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, and C3-6 cycloalkoxy is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, Ci-6deuteroalkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, (Ci-e) alkylamino(Ci- e)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-3 alkoxy, halo(Ci- s)alkoxy, C1-6 alkoxy(Ci-3)alkyl, C6-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl, whereinR14R15, R18R18a, R20R20aR24and R27is each independently H or C1-6 alkyl;R16and R17is each independently selected from H, C1-6 alkyl, hydroxy(Ci-6)alkyl, and halo(Ci-6)alkyl;R19and R23is each independently C1-6 alkyl or halo(Ci-6)alkyl;R21R22 R25anj R26eac]1inc[epenc[enly selected from H, C1-6 alkyl, C1-3 alkoxy(Ci-6)alkyl, hydroxy(Ci-6)alkyl, cyano(Ci-6)alkyl, amino(Ci-6)alkyl, C1-3 alkylamino(Ci-6)alkyl, and di(Ci-3)alkylamino(Ci-6)alkyl; orR21and R22or R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-3 alkoxy, halo(Ci-3)alkoxy, C1-6 alkoxy(Ci-3)alkyl, C6-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl.

22. The compound of claim 21, wherein Rxis selected from H, C1-3 alkyl, C3-6 cycloalkyl, and C1-3 alkoxy.CTQ-0152523. The compound of claim 21, wherein Rxis selected from C1-3 alkyl , C3-6 cycloalkyl, and C1-3 alkoxy.

24. The compound of claim 21, wherein Rxis selected from methyl, cyclopropyl, and methoxy.

25. The compound of any one of claims 18-24, whereinRyis selected from F, C1-3 haloalkyl, C1-3 haloalkoxy, and S(=O)2(Ci-6 alkyl), wherein each C1-3 haloalkyl and C1-3 haloalkoxy is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C1-6 deuteroalkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, (Cue) alkylamino(Ci-6)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, Ci- 3 alkoxy, halo(Ci-3)alkoxy, C1-6 alkoxy(Ci-3)alkyl, C6-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl, whereinR14R15, R18R18a, R20R20aR24and R27is each independently H or C1-6 alkyl;R16and R17is each independently selected from H, C1-6 alkyl, hydroxy(Ci-6)alkyl, and halo(Ci-6)alkyl;R19and R23is each independently C1-6 alkyl or halo(Ci-6)alkyl;R21R22 R25anj R26eac]1inc[epenc[enly selected from H, C1-6 alkyl, C1-3 alkoxy(Ci-6)alkyl, hydroxy(Ci-6)alkyl, cyano(Ci-6)alkyl, amino(Ci-6)alkyl, C1-3 alkylamino(Ci-6)alkyl, and di(Ci-3)alkylamino(Ci-6)alkyl; orR21and R22or R25and R26, together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, CN, OR14, SR15, NR16R17, S(O)R18, S(O)2R18a, NR19S(=O)R20, C(=O)OR20a, C(=O)NR21R22, NR23C(=O)R24, C(=S)NR25R26, C(=O)R27, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, halo(Ci-6)alkyl, C1-3 alkylsulfonylaminoalkyl, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, cyano(Ci-6)alkyl, C1-3 alkylcarbonylamino(Ci-6)alkyl, C1-3 alkoxy, halo(Ci-3)alkoxy, C1-6 alkoxy(Ci-3)alkyl, C6-12 aryl, 4- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl.CTQ-0152526. The compound of claim 25, wherein Ryis selected from C1-3 haloalkyl and C1-3 haloalkoxy.

27. The compound of claim 25, wherein Ryis selected from CF3 and OCHF2.

28. The compound of any one of claims 1-27, wherein G is O.

29. The compound of any one of claims 1-27, wherein G is S(=O)2.

30. The compound of any one of claims 1-27, wherein G is NR1.

31. The compound of claim 30, wherein R1is selected from H, C1-6 alkyl, C6-12 aryl, 5- to12-membered heteroaryl, C(=O)R2, and S(=O)2R4.

32. The compound of claim 30, wherein R1is C6-12 aryl or 5- to 12-membered heteroaryl, wherein the C6-12 aryl or 5- to 12-membered heteroaryl is substituted with a substituent selected from CN and S(=O)2(Ci-6 alkyl).

33. The compound of claim 30, wherein R1is phenyl or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is substituted with a substituent selected from CN and S(=O)2(Ci-3alkyl).

34. The compound of claim 30, wherein R1is a moiety represented by one of the following structural formulas:

35. The compound of claim 30, wherein R1is C(=0)R2.

36. The compound of claim 35, wherein R2is C1-6 alkyl.CTQ-0152537. The compound of claim 35, wherein R2is C1-3 alkyl.

38. The compound of claim 35, wherein R2is methyl.

39. The compound of claim 30, wherein R1is S(=O)2R4.

40. The compound of claim 39, wherein R4is C1-6 alkyl.

41. The compound of claim 39, wherein R4is C1-3 alkyl.

42. The compound of claim 39, wherein R4is methyl.

43. The compound of claim 30, wherein R1is selected from H and C1-3 alkyl.

44. The compound of claim 1, wherein the compound is represented by one of the following structural formulas or a pharmaceutically acceptable form thereof:CTQ-01525CTQ-01525CTQ-01525Isomer 1,Isomer 2,CTQ-01525CTQ-0152545. A pharmaceutical composition comprising a compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

46. 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 1-44, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 45.

47. A compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 45, for use in treating a disorder in a subject in need thereof.

48. A compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 45, for use in promoting myelination in a subject in need thereof.CTQ-0152549. Use of a compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 45, in the manufacture of a medicament for treating a disorder in a subject in need thereof.

50. Use of a compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 45, in the manufacture of a medicament for promoting myelination in a subject in need thereof.

51. The method of claim 46, wherein the subject has a myelin-related disorder.

52. The compound for use of claim 47 or 48, wherein the subject has a myelin-related disorder.

53. The use of claim 49 or 50 wherein the subject has a myelin-related disorder.

54. The method of claim 51, compound for use of claim 52, or use of claim 53, 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.

55. The method of claim 51, compound for use of claim 52, or use of claim 53, wherein the disorder is multiple sclerosis.CTQ-0152556. The method of claim 55, wherein the multiple sclerosis is clinically isolated syndrome.

57. The method of claim 55, wherein the multiple sclerosis is relapsing-remitting multiple sclerosis.

58. The method of claim 55, wherein the multiple sclerosis is primary progressive multiple sclerosis.

59. The method of claim 5, wherein the multiple sclerosis is secondary progressive multiple sclerosis.

60. A method of inhibiting CYP51 (lanosterol demethylase) comprising contacting CYP51 with a compound according to any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 45.

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