AZETIDINE AND SPIROAZETIDINE COMPOUNDS AND USES THEREOF Background An incomplete understanding of the molecular perturbations that cause disease, as well as a limited arsenal of robust model systems, has contributed to a failure to generate successful disease-modifying therapies against common and progressive neurological disorders, such as ALS and FTD. Progress is being made on many fronts to find agents that can arrest the progress of these disorders. However, the present therapies for most, if not all, of these diseases provide very little relief. Accordingly, a need exists to develop therapies that can alter the course of neurodegenerative diseases. More generally, a need exists for better methods and compositions for the treatment of neurodegenerative diseases in order to improve the quality of the lives of those afflicted by such diseases. Summary TDP-43 is a nuclear DNA/RNA binding protein involved in RNA splicing. Under pathological cell stress, TDP-43 translocates to the cytoplasm and aggregates into stress granules. These phenotypes are hallmarks of degenerating motor neurons and are found in 97% of all ALS cases. The highly penetrant nature of this pathology indicates that TDP-43 is broadly involved in both familial and sporadic ALS. Additionally, TDP-43 mutations that promote aggregation are linked to higher risk of developing ALS, suggesting protein misfolding and aggregation act as drivers of toxicity. TDP-43 toxicity can be recapitulated in yeast models, where the protein induces a viability deficit and localizes to stress granules. The present inventors have discovered that the CYP51A1 inhibitors described herein are capable of reversing TDP-43 induced toxicity. Accordingly, the present invention describes such CYP51A1 inhibitors and methods of using these compounds for the treatment of disorders related to TDP-43 toxicity such as ALS. In an aspect, the invention provides a compound having the structure: Formula I where R ¹ has the structure: Formula II m is 0, 1, or 2; one X is N, and the remaining X are independently CH, CR ⁵ , or N; A ¹ is a bond, CR ² R ³ , CO, SO2, or NR ² ; R ⁵ is halo, optionally substituted C2-C9 heterocyclyl, optionally substituted amino, optionally substituted C3-C8 cycloalkyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C3-C8 cycloalkoxy, optionally substituted C6-C10 aryloxy, optionally substituted C ₁ -C ₆ alkylsulfonyl; and R ² is hydrogen, halo, optionally substituted amino, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₁ -C ₆ alkoxy, hydroxy, optionally substituted C2-C9 heterocyclyl, optionally substituted C2-C9 heteroaryl, or optionally substituted C6-C10 aryl; or R ² and one R ⁵ , together with the atoms to which they are attached, combine to form optionally substituted C4-C9 heteroaryl; R ³ is hydrogen, optionally substituted C2-C6 alkenyl, or optionally substituted C ₁ -C ₆ alkyl; L ¹ is a bond, -O-, -SO2-, optionally substituted C ₁ -C ₆ alkylene, or -NR ⁷ -; R ⁷ is H or optionally substituted C ₁ -C ₆ alkyl; L ² has the structure: Formula V Formula VI Formula VII where each of n, o, p, q, r, and s is independently 1 or 2; each A is independently N or CR ⁸ ; each R ⁸ is independently hydrogen, hydroxy, cyano, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₁ -C ₆ heteroalkyl, or two geminal R ⁸ groups, together with the carbon atom to which they are attached, combine to form a carbonyl; L ³ is a bond, -O-, or optionally substituted C ₁ -C ₆ alkylene; and R ⁴ is optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, or optionally substituted C2-C9 heteroaryloxy. In some embodiments, R ¹ is: . In some embodiments, R ¹ is: In some embodiments, R ¹ is: In some embodiments, one and only one X is N. In some embodiments, R ¹ is: In some embodiments, R ² is: Formula III Formula IV where X ¹ is CH ₂ or NH; X ² is CH2 or O; X ³ is CH2, CHR ⁶ , C(R ⁶ )2, or NH; each of j and k is independently 1, 2, or 3; l is 0 or 2; R ⁶ is hydrogen or two R ⁶ combine with the atoms to which they are attached to form an optionally substituted C2-C9 heterocyclyl or C3-C8 cycloalkyl; ,

In some embodiments, R ² is hydroxy. some embodiments, R ³ is hydrogen. In some embodiments, L ³ is a bond, -CH2-, , , , or -O-. In some embodiments, L ³ is a bond. In some embodiments, L ² has the structure: . Formula VI In some embodiments, L ² has the structure: . In some embodiments, L ² has the structure: , In some embodiments, L ² has the structure: . In some embodiments, L ² has the structure: . In some embodiments, L ² has the structure: . In some embodiments, L ² has the structure: . In some embodiments, L ² has the structure: . In some embodiments, L ² has the structure: . Formula V In some embodiments, L ² has the structure: . In some embodiments, L ² has the structure: In some embodiments, L ² has the structure: In some embodiments, L ² has the structure: . In some embodiments, L ² has the structure: . In some embodiments, L ² has the structure: . In some embodiments, L ² has the structure: . In some embodiments, L ¹ is a bond, -CH2-, -C(CH3)2-, -N(CH3)-, or -SO2-. In some embodiments, L ¹ is a bond. In some embodiments, R ⁴ is optionally substituted C6-C10 aryl. In some embodiments, R ⁴ is phenyl, naphth-2-yl, 6-methoxy-naphth-2-yl, 3-chloro-phenyl, 4-chloro-phenyl, 3,4-dichloro-phenyl, 3- chloro-4-fluoro-phenyl, 3,5-chloro-phenyl, 2-fluoro-3-chloro-phenyl, 3-fluoro-4-chloro-phenyl, 3,4-difluoro- phenyl, 3-chloro-4-cyano-phenyl, 3-fluoro-4-trifluoromethoxy-phenyl, 2-fluoro-4-chloro-phenyl, 2-fluoro-4- trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 3-methoxy-4-trifluoromethyl-phenyl, 2,4-difluoro-phenyl, 3-fluoro-4-cyano-phenyl, 2-chloro-4-fluoro-phenyl, 2,3-dichloro-phenyl, 2-cyano-5-iodo-phenyl, 2- trifluoromethoxy-5-bromo-phenyl, 2-bromo-5-trifluoromethyl-phenyl, 3-chloro-4-iodo-phenyl, or 2-cyano-5- fluoro-phenyl. In some embodiments, R ⁴ is 3,4-dichloro-phenyl, 3-chloro-4-fluoro-phenyl, or 3,5-chloro- phenyl. In some embodiments, R ⁴ is optionally substituted C2-C9 heteroaryl.

In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof. In some embodiments, R ² is C2-C9 heteroaryl. In some embodiments, R ² is pyridin-3-yl. In some embodiments, R ² is optionally substituted C2-C9 heterocyclyl.

In some embodiments, R ⁴ is 4-trifluoromethyl-pyridin-3-yl. In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof. In some embodiments, . In some embodiments, the compound has the structure , or pharmaceutically acceptable salt thereof. In some embodiments, L ¹ is -NR ⁷ -. In some embodiments, R ⁷ is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ⁷ is methyl. In some embodiments, L ¹ is a bond. In some embodiments, R ⁴ is optionally substituted pyridine-3-yl, optionally substituted pyrimidin- 5-yl, or optionally substituted pyrazinyl. In some embodiments, the compound has the structure: . In some embodiments, . In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof, where R ^5A is H or R ⁵ . In some embodiments, L ¹ is a bond. In some embodiments, L ¹ is optionally substituted C ₁ -C ₆ alkylene. In some embodiments, L ¹ is methylene. In some embodiments, . In some embodiments, R ⁸ is hydroxy. In some embodiments, R ⁸ is cyano. In some embodiments, . In some embodiments, . In some embodiments, In some embodiments, the compound has the structure , or pharmaceutically acceptable salt thereof, where R ^5A is H or R ⁵ . In some embodiments, R ⁸ is optionally substituted C ₁ -C ₆ heteroalkyl. In some embodiments, R ⁸ is -CH2OH. In some embodiments, R ⁸ is -CH2OPh. In some embodiments, R ⁸ is -CH2OCH3.

In some embodiments, R ^5A is H. In some embodiments, R ^5A is optionally substituted C ₁ -C ₆ alkoxy. In some embodiments, R ^5A is methoxy. In some embodiments, the compound has the structure: In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof. In some embodiments, L ¹ is a bond. In some embodiments, L ¹ is optionally substituted C ₁ -C ₆ alkylene. In some embodiments, L ¹ is methylene. In some embodiments, . In some embodiments, R ⁵ is optionally substituted C ₁ -C ₆ alkoxy. In some embodiments, R ⁵ is methoxy. In some embodiments, R ⁵ is optionally substituted C3-C8 cycloalkoxy or optionally substituted C6-C10 aryloxy. In some embodiments, R ⁵ is cyclopropoxy. In some embodiments, R ² is hydroxy. In some embodiments, R ² is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ² is CH2OH. In some embodiments, R ⁴ is optionally substituted C8-C9 heteroaryl (e.g., , ,

In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof. In some embodiments, R ⁴ is optionally substituted C7 heteroaryl. In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof. In some embodiments, X is N or CH. In some embodiments, R ⁴ is optionally substituted C2-C9 heteroaryloxy. In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof, where R ^5A is H or R ⁵ . In some embodiments, R ^5A is H. In some embodiments, R ^5A is optionally substituted C ₁ -C ₆ alkoxy. In some embodiments, R ^5A is methoxy. In some embodiments, R ² is optionally substituted C ₁ -C ₆ heteroalkyl. , In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof. In some embodiments, R ⁵ is optionally substituted C3-C8 heterocyclyl. In some embodiments, In some embodiments, R ⁵ is optionally substituted C2-C9 heteroaryl. In some embodiments, . In some embodiments, R ⁵ is optionally substituted C ₁ -C ₆ alkylsulfonyl. In some embodiments, . In some embodiments, R ⁵ is optionally substituted C3-C8 cycloalkyl. In some embodiments, . In some embodiments, R ⁵ is optionally substituted C3-C8 cycloalkoxy. In some embodiments, . In some embodiments, R ⁵ is ethoxy, propoxy, or trifluoromethoxy. In some embodiments, . In some embodiments, the compound has the structure , or pharmaceutically acceptable salt thereof, where R ^5A is H or R ⁵ . In some embodiments, R ³ is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ³ is methyl, propyl, or benzyl. In some embodiments, R ³ is optionally substituted C ₁ -C ₆ alkenyl. In some embodiments, optionally substituted In some embodiments, R ^5A is H. In some embodiments, R ^5A is optionally substituted C ₁ -C ₆ alkoxy. In some embodiments, R ^5A is methoxy. In some embodiments, the compound has the structure , or pharmaceutically acceptable salt thereof. In some embodiments, L ¹ is optionally substituted C ₁ -C ₆ alkylene. In some embodiments, L ¹ is -C(CH3)2-. In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof. In some embodiments, R ² is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof, where R ^4A is optionally substituted C4 alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, or optionally substituted C3-C8 cycloalkyl. In some embodiments, R ^5A is H. In some embodiments, R ^5A is optionally substituted C ₁ -C ₆ alkoxy. In some embodiments, R ^5A is methoxy. In some embodiments, R ³ is hydrogen. In some embodiments, R ³ is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ³ is methyl. In some embodiments, R ^4A is optionally substituted C4 alkyl. In some embodiments, R ^4A is tert- butyl. In some embodiments, R ^4A is optionally substituted C ₁ -C ₆ heteroalkyl. In some embodiments, R ^4A is methoxy. In some embodiments, R ^4A is optionally substituted C3-C8 cycloalkyl. In some embodiments, . In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof. In some embodiments, A ¹ is CR ² R ³ . In some embodiments, R ² is hydroxyl. In some embodiments, R ² is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ² is -CH2OH. In some embodiments, R ³ is hydrogen. In some embodiments, R ³ is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ³ is methyl. In some embodiments, L ¹ is a singe bond. In some embodiments, L ¹ is optionally substituted C1- C6 alkylene. In some embodiments, L ¹ is methylene. In some embodiments, R ⁴ is optionally disubstituted pyridin-3-yl.

, In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof. . In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof. In some embodiments, R ⁴ is pyridinyl. In some embodiments, R ⁴ is pyrimidinyl. In some embodiments, R ⁴ is pyridazinyl. In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof, where R ^4B is hydrogen or optionally substituted C ₁ -C ₆ alkyl; and R ^4C is hydrogen, halo, cyano, or optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ^4B is hydrogen. In some embodiments, R ^4B is optionally substituted C1- C6 alkyl. In some embodiments, R ^4B is methyl. In some embodiments, R ^4C is hydrogen. In some embodiments, R ^4C is halo. In some embodiments, R ^4C is fluoro. In some embodiments, R ^4C is cyano. In some embodiments, R ^4C is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ^4C is ethyl. In some embodiments, the compound has the structure , or pharmaceutically acceptable salt thereof, where R ^4D is optionally substituted C ₁ -C ₆ alkyl, optionally substituted C3-C8 cycloalkyl, or halo. In some embodiments, R ^4D is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ^4D is methyl. In some embodiments, R ^4D is optionally substituted C3-C8 cycloalkyl. In some embodiments, R ^4D is cyclopropyl. In some embodiments, R ^4D is halo. In some embodiments, R ^4D is. In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof, where t is 0 or 1; and each R ^4E is, independently, optionally substituted C ₁ -C ₆ alkyl or optionally substituted C ₁ -C ₆ heteroalkyl. In some embodiments, R ^4E is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ^4E is trifluoromethyl. In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof. In some embodiments, R ⁴ is optionally substituted pyrazin-2-yl. In some embodiments, . In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof. In some embodiments, R ² is hydroxyl. In some embodiments, R ² is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ² is trifluoromethyl. In some embodiments, R ⁴ is 3-chloro-4-fluoro-phenyl. In some embodiments, R ⁴ is 2-cyano-5- fluoro-phenyl. In some embodiments, R ⁴ is 2-bromo-5-trifluoromethyl-phenyl. In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof, where R ^4F is optionally substituted C ₁ -C ₆ heteroalkyl. In some embodiments, R ^4F is methoxy. In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof. In some embodiments, R ⁵ is optionally substituted C ₁ -C ₆ heteroalkyl. In some embodiments, the compound has the structure: In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof. In some embodiments, R ⁵ is ethoxy, azetidin-1-yl, or cyclopropyl. In some embodiments, . In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof. In some embodiments, R ⁵ is methyl or methoxy. In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof. In some embodiments, R ⁵ is halo. In some embodiments, the compound has the structure: , or pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure: or pharmaceutically acceptable salt thereof. In some embodiments, R ² is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, the compound has the structure: , In some embodiments, the compound has the structure: , thereof. In another aspect, the invention provides a compound having the structure: , or pharmaceutically acceptable salt thereof, where is a single bond, hydrogen; is a single bond, R ¹ is , and R ^1A and R ³ , together with the atom to which they are attached, combine to form an optionally substituted C5-C9 heteroaryl; or is a double bond, absent; and R ² is hydrogen or hydroxyl. embodiments, . In some embodiments, is a single bond. In some embodiments, is a double bond. In some embodiments, R ² is hydrogen. In some embodiments, R ² is hydroxyl. In some embodiments, the compound has the structure or pharmaceutically acceptable salt thereof. In some embodiments, the compound is any one of compounds 1-124, 202, 209, 210, 219, 220, 223, 224, 227, and 378 in Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is any one of compounds 125-201, 203-208, 211-218, 221, 222, 225-266, 268-377, and 379-381 in Table 1 or a pharmaceutically acceptable salt thereof. Table 1. Compounds of the Invention

In an aspect, the invention features a pharmaceutical composition including any of the foregoing compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In an aspect, the invention features a method of treating a neurological disorder (e.g., frontotemporal dementia (FTLD-TDP), chronic traumatic encephalopathy, ALS, Alzheimer’s disease, limbic-predominant age-related TDP-42 encephalopathy (LATE), or frontotemporal lobar degeneration) in a subject in need thereof. This method includes administering an effective amount of any of the foregoing compounds or pharmaceutical compositions. In an aspect, the invention features a method of inhibiting toxicity in a cell (e.g., mammalian neural cell) related to a protein (e.g., TDP-43). This method includes administering an effective amount of any of the foregoing compounds or pharmaceutical compositions. In an aspect, the invention features a method of treating a CYP51A1-associated disorder (e.g., FTLD-TDP, chronic traumatic encephalopathy, ALS, Alzheimer’s disease, LATE, or frontotemporal lobar degeneration) in a subject in need thereof. This method includes administering an effective amount of any of the foregoing compounds pharmaceutical compositions. In an aspect, the invention features a method of inhibiting CYP51A1. This method includes contacting a cell with an effective amount of any of the foregoing compounds or pharmaceutical compositions. In another aspect, the invention features a method of treating a neurological disorder in a patient, such as a human patient, identified as likely to benefit from treatment with a CYP51A1 inhibitor on the basis of TDP-43 aggregation. In this aspect, the method may include (i) determining that the patient exhibits, or is prone to develop, TDP-43 aggregation, and (ii) providing to the patient a therapeutically effective amount of a CYP51A1 inhibitor. In some embodiments, the patient has previously been determined to exhibit, or to be prone to developing, TDP-43 aggregation, and the method includes providing to the patient a therapeutically effective amount of a CYP51A1 inhibitor. The susceptibility of the patient to developing TDP-43 aggregation may be determined, e.g., by determining whether the patient expresses a mutant isoform of TDP-43 containing a mutation that is associated with TDP-43 aggregation and toxicity, such as a mutation selected from Q331K, M337V, Q343R, N345K, R361S, and N390D. This may be performed, for example, by determining the amino acid sequence of a TDP-43 isoform isolated from a sample obtained from the patient or by determining the nucleic acid sequence of a TDP-43 gene isolated from a sample obtained from the patient. In some embodiments, the method includes the step of obtaining the sample from the patient. In an additional aspect, the invention features a method of treating a neurological disorder in a patient, such as a human patient, identified as likely to benefit from treatment with a CYP51A1 inhibitor on the basis of TDP-43 expression. In this aspect, the method includes (i) determining that the patient expresses a mutant form of TDP-43 having a mutation associated with TDP-43 aggregation (e.g., a mutation selected from Q331K, M337V, Q343R, N345K, R361S, and N390D), and (ii) providing to the patient a therapeutically effective amount of a CYP51A1 inhibitor. In some embodiments, the patient has previously been determined to express a mutant form of TDP-43 having a mutation associated with TDP- 43 aggregation, such as a Q331K, M337V, Q343R, N345K, R361S, or N390D mutation, and the method includes providing to the patient a therapeutically effective amount of a CYP51A1 inhibitor. In another aspect, the invention features a method of determining whether a patient (e.g., a human patient) having a neurological disorder is likely to benefit from treatment with a CYP51A1 inhibitor by (i) determining whether the patient exhibits, or is prone to develop, TDP-43 aggregation and (ii) identifying the patient as likely to benefit from treatment with a CYP51A1 inhibitor if the patient exhibits, or is prone to develop, TDP-43 aggregation. In some embodiments, the method further includes the step of (iii) informing the patient whether he or she is likely to benefit from treatment with a CYP51A1 inhibitor. The susceptibility of the patient to developing TDP-43 aggregation may be determined, e.g., by determining whether the patient expresses a mutant isoform of TDP-43 containing a mutation that is associated with TDP-43 aggregation and toxicity, such as a mutation selected from Q331K, M337V, Q343R, N345K, R361S, and N390D. This may be performed, for example, by determining the amino acid sequence of a TDP-43 isoform isolated from a sample obtained from the patient or by determining the nucleic acid sequence of a TDP-43 gene isolated from a sample obtained from the patient. In some embodiments, the method includes the step of obtaining the sample from the patient. In another aspect, the invention features a method of determining whether a patient (e.g., a human patient) having a neurological disorder is likely to benefit from treatment with a CYP51A1 inhibitor by (i) determining whether the patient expresses a TDP-43 mutant having a mutation associated with TDP-43 aggregation (e.g., a mutation selected from Q331K, M337V, Q343R, N345K, R361S, and N390D) and (ii) identifying the patient as likely to benefit from treatment with a CYP51A1 inhibitor if the patient expresses a TDP-43 mutant. In some embodiments, the method further includes the step of (iii) informing the patient whether he or she is likely to benefit from treatment with a CYP51A1 inhibitor. The TDP-43 isoform expressed by the patient may be assessed, for example, by isolated TDP-43 protein from a sample obtained from the patient and sequencing the protein using molecular biology techniques described herein or known in the art. In some embodiments, the TDP-43 isoform expressed by the patient is determined by analyzing the patient’s genotype at the TDP-43 locus, for example, by sequencing the TDP-43 gene in a sample obtained from the patient. In some embodiments, the method includes the step of obtaining the sample from the patient. In some embodiments of any of the above aspects, the CYP51A1 inhibitor is provided to the patient by administration of the CYP51A1 inhibitor to the patient. In some embodiments, the CYP51A1 inhibitor is provided to the patient by administration of a prodrug that is converted in vivo to the CYP51A1 inhibitor. In some embodiments of any of the above aspects, the neurological disorder is a neuromuscular disorder, such as a neuromuscular disorder selected from amyotrophic lateral sclerosis, congenital myasthenic syndrome, congenital myopathy, cramp fasciculation syndrome, Duchenne muscular dystrophy, glycogen storage disease type II, hereditary spastic paraplegia, inclusion body myositis, Isaac's Syndrome, Kearns-Sayre syndrome, Lambert–Eaton myasthenic syndrome, mitochondrial myopathy, muscular dystrophy, myasthenia gravis, myotonic dystrophy, peripheral neuropathy, spinal and bulbar muscular atrophy, spinal muscular atrophy, Stiff person syndrome, Troyer syndrome, and Guillain– Barré syndrome. In some embodiments, the neurological disorder is amyotrophic lateral sclerosis. In some embodiments of any of the above aspects, the neurological disorder is selected from frontotemporal degeneration (also referred to as frontotemporal lobar degeneration and frontotemporal dementia), Alzheimer’s disease, Parkinson’s disease, dementia with Lewy Bodies, corticobasal degeneration, progressive supranuclear palsy, dementia parkinsonism ALS complex of Guam, Huntington’s disease, Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD), sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander disease, and hereditary inclusion body myopathy. In some embodiments, the neurological disorder is amyotrophic lateral sclerosis, and following administration of the CYP51A1 inhibitor to the patient, the patient exhibits one or more, or all, of the following responses: (i) an improvement in condition as assessed using the amyotrophic lateral sclerosis functional rating scale (ALSFRS) or the revised ALSFRS (ALSFRS-R), such as an improvement in the patient’s ALSFRS or ALSFRS-R score within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., an improvement in the patient’s ALSFRS or ALSFRS-R score within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient); (ii) an increase in slow vital capacity, such as an increase in the patient’s slow vital capacity within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., an increase in the patient’s slow vital capacity within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient); (iii) a reduction in decremental responses exhibited by the patient upon repetitive nerve stimulation, such as a reduction that is observed within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., a reduction that is observed within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient); (iv) an improvement in muscle strength, as assessed, for example, by way of the Medical Research Council muscle testing scale (as described, e.g., in Jagtap et al., Ann. Indian. Acad. Neurol. 17:336-339 (2014), the disclosure of which is incorporated herein by reference as it pertains to measuring patient response to neurological disease treatment), such as an improvement that is observed within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., an improvement that is observed within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient); (v) an improvement in quality of life, as assessed, for example, using the amyotrophic lateral sclerosis-specific quality of life (ALS-specific QOL) questionnaire, such as an improvement in the patient’s quality of life that is observed within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., an improvement in the subject’s quality of life that is observed within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient); (vi) a decrease in the frequency and/or severity of muscle cramps, such as a decrease in cramp frequency and/or severity within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., a decrease in cramp frequency and/or severity within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient); and/or (vii) a decrease in TDP-43 aggregation, such as a decrease in TDP-43 aggregation within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., a decrease in TDP- 43 aggregation within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient. Chemical Terms It is to be understood that the terminology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting. Those skilled in the art will appreciate that certain compounds described herein can exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, tautomers) and/or isotopic (e.g., in which one or more atoms has been substituted with a different isotope of the atom, such as hydrogen substituted for deuterium) forms. Unless otherwise indicated or clear from context, a depicted structure can be understood to represent any such isomeric or isotopic form, individually or in combination. In some embodiments, one or more compounds depicted herein may exist in different tautomeric forms. As will be clear from context, unless explicitly excluded, references to such compounds encompass all such tautomeric forms. In some embodiments, tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton. In certain embodiments, a tautomeric form may be a prototropic tautomer, which is an isomeric protonation states having the same empirical formula and total charge as a reference form. Examples of moieties with prototropic tautomeric forms are ketone – enol pairs, amide – imidic acid pairs, lactam – lactim pairs, amide – imidic acid pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. In some embodiments, tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. In certain embodiments, tautomeric forms result from acetal interconversion, e.g., the interconversion illustrated in the scheme below: . Those skilled in the art will appreciate that, in some embodiments, isotopes of compounds described herein may be prepared and/or utilized in accordance with the present invention. “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, an isotopic substitution (e.g., substitution of hydrogen with deuterium) may alter the physiciochemical properties of the molecules, such as metabolism and/or the rate of racemization of a chiral center. As is known in the art, many chemical entities (in particular many organic molecules and/or many small molecules) can adopt a variety of different solid forms such as, for example, amorphous forms and/or crystalline forms (e.g., polymorphs, hydrates, solvates, etc). In some embodiments, such entities may be utilized in any form, including in any solid form. In some embodiments, such entities are utilized in a particular form, e.g., in a particular solid form. In some embodiments, compounds described and/or depicted herein may be provided and/or utilized in salt form. In certain embodiments, compounds described and/or depicted herein may be provided and/or utilized in hydrate or solvate form. At various places in the present specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term “C ₁ -C ₆ alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, where a compound includes a plurality of positions at which substitutes are disclosed in groups or in ranges, unless otherwise indicated, the present disclosure is intended to cover individual compounds and groups of compounds (e.g., genera and subgenera) containing each and every individual subcombination of members at each position. Herein a phrase of the form “optionally substituted X” (e.g., optionally substituted alkyl) is intended to be equivalent to “X, where X is optionally substituted” (e.g., “alkyl, where said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g. alkyl) per se is optional. The term “acyl,” as used herein, represents a hydrogen or an alkyl group, as defined herein that is attached to a parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups include from 1 to 6, from 1 to 11, or from 1 to 21 carbons. The term “alkyl,” as used herein, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms). An alkylene is a divalent alkyl group. The term “alkylsulfonyl,” as used herein, refers to a group of formula -SO2-R, where R is alkyl. An optionally substituted alkylsulfonyl is an alkylsulfonyl that is optionally substituted as described herein for alkyl. The term “alkenyl,” as used herein, alone or in combination with other groups, refers to a straight-chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms). The term “alkynyl,” as used herein, alone or in combination with other groups, refers to a straight-chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms). The term amino, as used herein, represents -N(R ^N1 )2, where each R ^N1 is, independently, H, OH, NO2, N(R ^N2 )2, SO2OR ^N2 , SO2R ^N2 , SOR ^N2 , an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), where each of these recited R ^N1 groups can be optionally substituted; or two R ^N1 combine to form an alkylene or heteroalkylene, and where each R ^N2 is, independently, H, alkyl, or aryl. The amino groups of the invention can be an unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(R ^N1 )2). The term “aryl,” as used herein, refers to an aromatic mono- or polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl. The term “arylalkyl,” as used herein, represents an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C6-10 aryl C ₁ -C ₆ alkyl, C6-10 aryl C1-C10 alkyl, or C6-10 aryl C1-C20 alkyl), such as, benzyl and phenethyl. In some embodiments, the akyl and the aryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective groups. The term “aryloxy,” as used herein, refers to a group of formula -O-R, where R is aryl. An optionally substituted aryloxy is an aryloxy that is optionally substituted as described herein for aryl groups. The term “azido,” as used herein, represents a -N3 group. The term “cyano,” as used herein, represents a CN group. The terms “carbocyclyl,” as used herein, refer to a non-aromatic C3-C12 monocyclic, bicyclic, or tricyclic structure in which the rings are formed by carbon atoms. Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl radicals. The term “cycloalkyl,” as used herein, refers to a saturated, non-aromatic, monovalent mono- or polycarbocyclic radical of three to ten, preferably three to six carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. The term “cycloalkoxy,” as used herein, refers to a group of formula -O-R, where R is cycloalkyl. An optionally substituted cycloalkoxy is a cycloalkoxy that is optionally substituted as described herein for cycloalkyl groups. The term “halo,” as used herein, means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical. The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups. Examples of heteroalkyl groups are an “alkoxy” which, as used herein, refers alkyl-O- (e.g., methoxy and ethoxy). A heteroalkylene is a divalent heteroalkyl group. The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkenyl groups. Examples of heteroalkenyl groups are an “alkenoxy” which, as used herein, refers alkenyl-O-. A heteroalkenylene is a divalent heteroalkenyl group. The term heteroalkynyl, as used herein, refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkynyl groups. Examples of heteroalkynyl groups are an “alkynoxy” which, as used herein, refers alkynyl-O-. A heteroalkynylene is a divalent heteroalkynyl group. The term “heteroaryl,” as used herein, refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring, and containing one, two, or three ring heteroatoms selected from N, O, and S, with the remaining ring atoms being C. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl. The term “heteroarylalkyl,” as used herein, represents an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C2-C9 heteroaryl C ₁ -C ₆ alkyl, C2-C9 heteroaryl C1-C10 alkyl, or C2-C9 heteroaryl C1-C20 alkyl). In some embodiments, the akyl and the heteroaryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective groups. The term “heterocyclyl,” as used herein, denotes a mono- or polycyclic radical having 3 to 12 atoms having at least one ring containing one, two, three, or four ring heteroatoms selected from N, O or S, where no ring is aromatic. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl. The term “heterocyclylalkyl,” as used herein, represents an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocyclylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C2-C9 heterocyclyl C ₁ -C ₆ alkyl, C2-C9 heterocyclyl C1-C10 alkyl, or C2-C9 heterocyclyl C1-C20 alkyl). In some embodiments, the akyl and the heterocyclyl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective groups. The term “hydroxyl,” as used herein, represents an -OH group. The term “N-protecting group,” as used herein, represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 3 ^rd Edition (John Wiley & Sons, New York, 1999). N-protecting groups include acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl, and p-toluenesulfonyl; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, and silyl groups, such as trimethylsilyl. Preferred N-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz). The term “nitro,” as used herein, represents an NO2 group. The term “thiol,” as used herein, represents an -SH group. The alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. When substituted, there will generally be 1 to 4 substituents present, unless otherwise specified. Substituents include, for example, aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxyl, oxo (=O), oxime (=N-OH), heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), cycloalkoxy, aryloxy, heteroaryl, heterocyclyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, or thiol. Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted such as arylalkyl (e.g., substituted and unsubstituted benzyl)). Compounds of the invention can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. The optically active forms can be obtained, for example, by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbent or eluant). That is, certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon. The appropriate technique and/or method for separating an enantiomer of a compound described herein from a racemic mixture can be readily determined by those of skill in the art. "Racemate" or "racemic mixture" means a compound containing two enantiomers, where such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light. “Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis," and "trans," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9%) by weight relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure. Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction pure. Percent purity by mole fraction is the ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer. Similarly, percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms. Definitions In this application, unless otherwise clear from context, (i) the term “a” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and/or”; (iii) the terms “including” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; and (iv) the terms about and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art; and (v) where ranges are provided, endpoints are included. As used herein, the term “administration” refers to the administration of a composition (e.g., a compound, a complex or a preparation that includes a compound or complex as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, in some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal and vitreal. As used herein, the term “animal” refers to any member of the animal kingdom. In some embodiments, “animal” refers to humans, at any stage of development. In some embodiments, “animal” refers to non-human animals, at any stage of development. In some embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, and/or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, and/or worms. In some embodiments, an animal may be a transgenic animal, genetically-engineered animal, and/or a clone. As used herein, the terms “approximately” and “about” are each intended to encompass normal statistical variation as would be understood by those of ordinary skill in the art as appropriate to the relevant context. In certain embodiments, the terms “approximately” or “about” each refer to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of a stated value, unless otherwise stated or otherwise evident from the context (e.g., where such number would exceed 100% of a possible value). Two events or entities are “associated” with one another, as that term is used herein, if the presence, level and/or form of one is correlated with that of the other. For example, a particular entity (e.g., polypeptide) is considered to be associated with a particular disease, disorder, or condition, if its presence, level and/or form correlates with incidence of and/or susceptibility of the disease, disorder, or condition (e.g., across a relevant population). As used herein, the terms “benefit” and “response” are used interchangeably in the context of a subject, such as a human subject undergoing therapy for the treatment of a neurological disorder, for example, amyotrophic lateral sclerosis, frontotemporal degeneration (also referred to as frontotemporal lobar degeneration and frontotemporal dementia), Alzheimer’s disease, Parkinson’s disease, dementia with Lewy Bodies, corticobasal degeneration, progressive supranuclear palsy, dementia parkinsonism ALS complex of Guam, Huntington’s disease, Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD), sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander disease, and hereditary inclusion body myopathy. The terms “benefit” and “response” refer to any clinical improvement in the subject’s condition. Exemplary benefits in the context of a subject undergoing treatment for a neurological disorder using the compositions and methods described herein (e.g., in the context of a human subject undergoing treatment for a neurological disorder described herein, such as amyotrophic lateral sclerosis, with a cytochrome P450 isoform 51A1 (CYP51A1) inhibitor described herein, such as an inhibitory small molecule, antibody, antigen-binding fragment thereof, or interfering RNA molecule) include the slowing and halting of disease progression, as well as suppression of one or more symptoms associated with the disease. Particularly, in the context of a patient (e.g., a human patient) undergoing treatment for amyotrophic lateral sclerosis with a CYP51A1 inhibitor described herein, examples of clinical “benefits” and “responses” are (i) an improvement in the subject’s condition as assessed using the amyotrophic lateral sclerosis functional rating scale (ALSFRS) or the revised ALSFRS (ALSFRS-R) following administration of the CYP51A1 inhibitor, such as an improvement in the subject’s ALSFRS or ALSFRS-R score within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., an improvement in the subject’s ALSFRS or ALSFRS-R score within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the subject, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the subject); (ii) an increase in the subject’s slow vital capacity following administration of the CYP51A1 inhibitor, such as an increase in the subject’s slow vital capacity within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., an increase in the subject’s slow vital capacity within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the subject, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the subject); (iii) a reduction in decremental responses exhibited by the subject upon repetitive nerve stimulation, such as a reduction that is observed within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., a reduction that is observed within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the subject, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the subject); (iv) an improvement in the subject’s muscle strength, as assessed, for example, by way of the Medical Research Council muscle testing scale (as described, e.g., in Jagtap et al., Ann. Indian. Acad. Neurol. 17:336-339 (2014), the disclosure of which is incorporated herein by reference as it pertains to measuring patient response to neurological disease treatment), such as an improvement that is observed within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., an improvement that is observed within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the subject, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the subject); (v) an improvement in the subject’s quality of life, as assessed, for example, using the amyotrophic lateral sclerosis-specific quality of life (ALS-specific QOL) questionnaire, such as an improvement in the subject’s quality of life that is observed within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., an improvement in the subject’s quality of life that is observed within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the subject, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the subject); and (vi) a decrease in the frequency and/or severity of muscle cramps exhibited by the subject, such as a decrease in cramp frequency and/or severity within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., a decrease in cramp frequency and/or severity within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the subject, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the subject). In the practice of the methods of the present invention, an “effective amount” of any one of the compounds of the invention or a combination of any of the compounds of the invention or a pharmaceutically acceptable salt thereof, is administered via any of the usual and acceptable methods known in the art, either singly or in combination. As used herein, the terms “cytochrome P450 isoform 51A1,” “CYP51A1,” and “lanosterol 14- alpha demethylase” are used interchangeably and refer to the enzyme that catalyzes the conversion of lanosterol to 4,4-dimethylcholesta-8(9),14,24-trien-3β-ol, for example, in human subjects. The terms “cytochrome P450 isoform 51A1,” “CYP51A1,” and “lanosterol 14-alpha demethylase” refer not only to wild-type forms of CYP51A1, but also to variants of wild-type CYP51A1 proteins and nucleic acids encoding the same. The amino acid sequence and corresponding mRNA sequence of a wild-type form of human CYP51A1 are provided herein as SEQ ID NOs: 1 and 2, which correspond to GenBank Accession No. AAC50951.1 and NCBI Reference Sequence NO. NM_000786.3, respectively. These sequences are shown in Table 2, below. Table 2. Amino acid and nucleic acid sequences of wild-type human CYP5A1

The terms “cytochrome P450 isoform 51A1,” “CYP51A1,” and “lanosterol 14-alpha demethylase” as used herein include, for example, forms of the human CYP51A1 protein that have an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 1 (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 100% identical to the amino acid sequence of SEQ ID NO: 1) and/or forms of the human CYP51A1 protein that contain one or more substitutions, insertions, and/or deletions (e.g., one or more conservative and/or nonconservative amino acid substitutions, such as up to 5, 10, 15, 20, 25, or more, conservative or nonconservative amino acid substitutions) relative to a wild-type CYP51A1 protein. Similarly, the terms “cytochrome P450 isoform 51A1,” “CYP51A1,” and “lanosterol 14-alpha demethylase” as used herein include, for example, forms of the human CYP51A1 gene that encode an mRNA transcript having a nucleic acid sequence that is at least 85% identical to the nucleic acid sequence of SEQ ID NO: 2 (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 100% identical to the amino acid sequence of SEQ ID NO: 2). As used herein, the terms “cytochrome P450 isoform 51A1 inhibitor,” “CYP51A1 inhibitor,” and “lanosterol 14-alpha demethylase inhibitor” are used interchangeably and refer to substances, such as compounds of Formula I. Inhibitors of this type may, for example, competitively inhibit CYP51A1 activity by specifically binding the CYP51A1 enzyme (e.g., by virtue of the affinity of the inhibitor for the CYP51A1 active site), thereby precluding, hindering, or halting the entry of one or more endogenous substrates of CYP51A1 into the enzyme’s active site. Additional examples of CYP51A1 inhibitors that suppress the activity of the CYP51A1 enzyme include substances that may bind CYP51A1 at a site distal from the active site and attenuate the binding of endogenous substrates to the CYP51A1 active site by way of a change in the enzyme’s spatial conformation upon binding of the inhibitor. In addition to encompassing substances that modulate CYP51A1 activity, the terms cytochrome P450 isoform 51A1 inhibitor, “CYP51A1 inhibitor,” and “lanosterol 14-alpha demethylase inhibitor” refer to substances that reduce the concentration and/or stability of CYP51A1 mRNA transcripts in vivo, as well as those that suppress the translation of functional CYP51A1 enzyme. As used herein, the term “CYP51A1-associated disorder” refers to an undesired physiological condition, disorder, or disease that is associated with and/or mediated at least in part by CYP51A1. In some instances, CYP51A1-associated disorders are associated with excess CYP51A1 levels and/or activity. Exemplary CYP51A1-associated disorders include CYP51A1-associated disorders include but are not limited to central nervous system (CNS) disorders, dementia, Alzheimer's Disease, chronic traumatic encephalopathy, FTLD-TDP, LATE, or frontotemporal lobar degeneration. As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic agents. In some embodiments, two or more compounds may be administered simultaneously; in some embodiments, such compounds may be administered sequentially; in some embodiments, such compounds are administered in overlapping dosing regimens. As used herein, the term “dosage form” refers to a physically discrete unit of an active compound (e.g., a therapeutic or diagnostic agent) for administration to a subject. Each unit contains a predetermined quantity of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen). Those of ordinary skill in the art appreciate that the total amount of a therapeutic composition or compound administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms. As used herein, the term “dosing regimen” refers to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic compound has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen includes a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen includes a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen includes a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen includes a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen). As used herein, the term “neuromuscular disorder” refers to a disease impairing the ability of one or more neurons to control the activity of an associated muscle. Examples of neuromuscular disorders are amyotrophic lateral sclerosis, congenital myasthenic syndrome, congenital myopathy, cramp fasciculation syndrome, Duchenne muscular dystrophy, glycogen storage disease type II, hereditary spastic paraplegia, inclusion body myositis, Isaac's Syndrome, Kearns-Sayre syndrome, Lambert–Eaton myasthenic syndrome, mitochondrial myopathy, muscular dystrophy, myasthenia gravis, myotonic dystrophy, peripheral neuropathy, spinal and bulbar muscular atrophy, spinal muscular atrophy, Stiff person syndrome, Troyer syndrome, and Guillain–Barré syndrome, among others. The term “pharmaceutical composition,” as used herein, represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation. A “pharmaceutically acceptable excipient,” as used herein, refers any ingredient other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients may include, for example, antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration. As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of the compound of formula (I). For example, pharmaceutically acceptable salts of any of the compounds described herein include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting a free base group with a suitable organic acid. The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. The term “pure” means substantially pure or free of unwanted components (e.g., other compounds and/or other components of a cell lysate), material defilement, admixture or imperfection. A variety of clinical indicators can be used to identify a patient as “at risk” of developing a particular neurological disease. Examples of patients (e.g., human patients) that are “at risk” of developing a neurological disease, such as amyotrophic lateral sclerosis, frontotemporal degeneration, Alzheimer’s disease, Parkinson’s disease, dementia with Lewy Bodies, corticobasal degeneration, progressive supranuclear palsy, dementia parkinsonism ALS complex of Guam, Huntington’s disease, Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD), sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander disease, and hereditary inclusion body myopathy, include (i) subjects exhibiting or prone to exhibit aggregation of TAR-DNA binding protein (TDP)-43, and (ii) subjects expressing a mutant form of TDP-43 containing a mutation associated with TDP-43 aggregation and toxicity, such as a mutation selected from Q331K, M337V, Q343R, N345K, R361S, and N390D. Subjects that are “at risk” of developing amyotrophic lateral sclerosis may exhibit one or both of these characteristics, for example, prior to the first administration of a CYP51A1 inhibitor in accordance with the compositions and methods described herein. As used herein, the terms “TAR-DNA binding protein-43” and “TDP-43” are used interchangeably and refer to the transcription repressor protein involved in modulating HIV-1 transcription and alternative splicing of the cystic fibrosis transmembrane conductance regulator (CFTR) pre-mRNA transcript, for example, in human subjects. The terms “TAR-DNA binding protein-43” and “TDP-43” refer not only to wild-type forms of TDP-43, but also to variants of wild-type TDP-43 proteins and nucleic acids encoding the same. The amino acid sequence and corresponding mRNA sequence of a wild-type form of human TDP-43 are provided herein as SEQ ID NOs: 3 and 4, which correspond to NCBI Reference Sequence NOs. NM_007375.3 and NP_031401.1, respectively. These sequences are shown in Table 3, below. Table 3. Amino acid and nucleic acid sequences of wild-type human TDP-43

The terms “TAR-DNA binding protein-43” and “TDP-43” as used herein include, for example, forms of the human TDP-43 protein that have an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 3 (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 100% identical to the amino acid sequence of SEQ ID NO: 3) and/or forms of the human TDP-43 protein that contain one or more substitutions, insertions, and/or deletions (e.g., one or more conservative and/or nonconservative amino acid substitutions, such as up to 5, 10, 15, 20, 25, or more, conservative or nonconservative amino acid substitutions) relative to a wild- type TDP-43 protein. For instance, patients that may be treated for a neurological disorder as described herein, such as amyotrophic lateral sclerosis, frontotemporal degeneration, Alzheimer’s disease, Parkinson’s disease, dementia with Lewy Bodies, corticobasal degeneration, progressive supranuclear palsy, dementia parkinsonism ALS complex of Guam, Huntington’s disease, Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD), sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander disease, and hereditary inclusion body myopathy, include human patients that express a form of TDP-43 having a mutation associated with elevated TDP-43 aggregation and toxicity, such as a mutation selected from Q331K, M337V, Q343R, N345K, R361S, and N390D. Similarly, the terms “TAR-DNA binding protein-43” and “TDP-43” as used herein include, for example, forms of the human TDP-43 gene that encode an mRNA transcript having a nucleic acid sequence that is at least 85% identical to the nucleic acid sequence of SEQ ID NO: 4 (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 100% identical to the amino acid sequence of SEQ ID NO: 4). As used herein, the term “subject” refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition. As used herein, the terms "treat," "treated," or "treating" mean both therapeutic treatment and prophylactic or preventative measures where the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. A “therapeutic regimen” refers to a dosing regimen whose administration across a relevant population is correlated with a desired or beneficial therapeutic outcome. The term “therapeutically effective amount” means an amount that is sufficient, when administered to a population suffering from or susceptible to a disease, disorder, and/or condition in accordance with a therapeutic dosing regimen, to treat the disease, disorder, and/or condition. In some embodiments, a therapeutically effective amount is one that reduces the incidence and/or severity of, and/or delays onset of, one or more symptoms of the disease, disorder, and/or condition. Those of ordinary skill in the art will appreciate that the term “therapeutically effective amount” does not in fact require successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be that amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment. It is specifically understood that particular subjects may, in fact, be “refractory” to a “therapeutically effective amount.” To give but one example, a refractory subject may have a low bioavailability such that clinical efficacy is not obtainable. In some embodiments, reference to a therapeutically effective amount may be a reference to an amount as measured in one or more specific tissues (e.g., a tissue affected by the disease, disorder or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine, etc). Those of ordinary skill in the art will appreciate that, in some embodiments, a therapeutically effective amount may be formulated and/or administered in a single dose. In some embodiments, a therapeutically effective amount may be formulated and/or administered in a plurality of doses, for example, as part of a dosing regimen. Brief Description of the Drawings FIGS.1A – 1C demonstrate that the viability of a yeast TDP-43 model is restored by the Erg11 inhibitor, fluconazole. (FIG.1A) Structure of the Erg11 inhibitor and anti-fungal, fluconazole. (FIG.1B) Fluconazole rescues viability of TDP-43-expressing yeast using a resazurin-reduction endpoint. A 2-fold serial dilution of fluconazole was applied to TDP-43-expressing yeast for 24 hours prior to analysis. (FIG. 1C) Wild-type yeast cultures were treated with fluconazole for eight hours prior to HPLC analysis for lanosterol and ergosterol. Data are expressed as the area under the curve (AUC) normalized to cell mass based on optical density of cultures at 600 nm. Fluconazole treatment reduces ergosterol, while simultaneously leading to an increase in the Erg11 substrate, lanosterol. FIG.2 shows the structures of compounds used in primary rat cortical neuron TDP-43 wild type and Q331K mutant survival studies. FIGS.3A and 3B demonstrate that compound A promotes survival in primary rat cortical neurons transfected with wild-type TDP-43. Rat primary cortical neurons were co-transfected with a red fluorescent protein (RFP) as a morphological marker and either control (empty vector) or wild-type TDP- 43 expression plasmids and treated with vehicle (DMSO) or a titration of compound A. (FIG.3A) Risk of neuron death plots. The lifetime of each neuron was determined by either loss of RFP signal or morphological indicators of death such as loss of neurites and cell blebbing and used to generate cumulative hazard plots of risk of death over time (hrs) post-transfection. (FIG.3B) Forest plots. Hazard ratios for each treatment group (relative to TDP-43 DMSO group) were determined by cox regression analysis and used to generate forest plots. Hazard ratios (HR) < 1 in which the confidence interval (CI) does not encompass 1 represent treatments that significantly reduce probability of neuron death relative to the TDP-43 DMSO control. P, p-value. FIGS.4A and 4B demonstrate that compound A promotes survival in primary rat cortical neurons transfected with Q331K Mutant TDP-43. Rat primary cortical neurons were co-transfected with a red fluorescent protein (RFP) as a morphological marker and either control (empty vector) or Q331K mutant TDP-43 expression plasmids and treated with vehicle (DMSO) or a titration of compound A. (FIG.4A) Risk of neuron death plots. The lifetime of each neuron was determined by either loss of RFP signal or morphological indicators of death such as loss of neurites and cell blebbing and used to generate cumulative hazard plots of risk of death over time (hrs) post-transfection. (FIG.4B) Forest plots. Hazard ratios for each treatment group (relative to TDP-43 DMSO group) were determined by cox regression analysis and used to generate forest plots. Hazard ratios (HR) < 1 in which the confidence interval (CI) does not encompass 1 represent treatments that significantly reduce probability of neuron death relative to the TDP-43 DMSO control. P, p-value. FIGS.5A and 5B demonstrate that compound B promotes survival in primary rat cortical neurons transfected with wild-type TDP-43. Rat primary cortical neurons were co-transfected with a red fluorescent protein (RFP) as a morphological marker and either control (empty vector) or wild type TDP- 43 expression plasmids and treated with vehicle (DMSO) or a titration of compound B. (FIG.5A) Risk of neuron death plots. The lifetime of each neuron was determined by either loss of RFP signal or morphological indicators of death such as loss of neurites and cell blebbing and used to generate cumulative hazard plots of risk of death over time (hrs) post-transfection. (FIG.5B) Forest plots. Hazard ratios for each treatment group (relative to TDP-43 DMSO group) were determined by cox regression analysis and used to generate forest plots. Hazard ratios (HR) < 1 in which the confidence interval (CI) does not encompass 1 represent treatments that significantly reduce probability of neuron death relative to the TDP-43 DMSO control. P, p-value. Detailed Description The present invention features compositions and methods for treating neurological disorders, such as amyotrophic lateral sclerosis and other neuromuscular disorders, as well as frontotemporal degeneration, Alzheimers disease, Parkinsons disease, dementia with Lewy Bodies, corticobasal degeneration, progressive supranuclear palsy, dementia parkinsonism ALS complex of Guam, Huntington’s disease, Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD), sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander disease, and hereditary inclusion body myopathy among others. Particularly, the invention provides inhibitors of cytochrome P450 isoform 51A1 (CYP51A1), also referred to herein as lanosterol 14-alpha demethylase, that may be administered to a patient (e.g., a human patient) so as to treat or prevent a neurological disorder, such as one or more of the foregoing conditions. In the context of therapeutic treatment, the CYP51A1 inhibitor may be administered to the patient to alleviate one or more symptoms of the disorder and/or to remedy an underlying molecular pathology associated with the disease, such as to suppress or prevent aggregation of TAR-DNA binding protein (TDP)-43. The disclosure herein is based, in part, on the discovery that CYP51A1 inhibition modulates TDP- 43 aggregation in vivo. Suppression of TDP-43 aggregation exerts beneficial effects in patients suffering from a neurological disorder. Many pathological conditions have been correlated with TDP-43-promoted aggregation and toxicity, such as amyotrophic lateral sclerosis, frontotemporal degeneration, Alzheimer’s disease, Parkinson’s disease, dementia with Lewy Bodies, corticobasal degeneration, progressive supranuclear palsy, dementia parkinsonism ALS complex of Guam, Huntington’s disease, IBMPFD, sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander disease, and hereditary inclusion body myopathy. Without being limited by mechanism, by administering an inhibitor of CYP51A1, patients suffering from diseases associated with TDP-43 aggregation and toxicity may be treated, for example, due to the suppression of TDP-43 aggregation induced by the CYP51A1 inhibitor. Patients that are likely to respond to CYP51A1 inhibition as described herein include those that have or are at risk of developing TDP-43 aggregation, such as those that express a mutant form of TDP- 43 associated with TDP-43 aggregation and toxicity in vivo. Examples of such mutations in TDP-43 that have been correlated with elevated TDP-43 aggregation and toxicity include Q331K, M337V, Q343R, N345K, R361S, and N390D, among others. The compositions and methods described herein thus provide the additional clinical benefit of enabling the identification of patients that are likely to respond to CYP51A1 inhibitor therapy, as well as processes for treating these patients accordingly. The sections that follow provide a description of exemplary CYP51A1 inhibitors that may be used in conjunction with the compositions and methods disclosed herein. The sections below additionally provide a description of various exemplary routes of administration and pharmaceutical compositions that may be used for delivery of these substances for the treatment of a neurological disorder. CYP51A1 Inhibitors Exemplary CYP51A1 inhibitors described herein include compounds disclosed herein. In some embodiments, the compound has the structure of any one of compounds 1-124, 202, 209, 210, 219, 220, 223, 224, 227, or 378 in Table 1. In some embodiments, the compound has the structure of any one of compounds 125-201, 203- 208, 211-218, 221, 222, 225-266, 268-377, or 379-381 in Table 1. Other embodiments, as well as exemplary methods for the synthesis or production of these compounds, are described herein. Methods of Treatment Suppression of CYP51A1 Activity and TDP-43 Aggregation to Treat Neurological Disorders Using the compositions and methods described herein, a patient suffering from a neurological disorder may be administered a CYP51A1 inhibitor, such as a small molecule, antibody, antigen-binding fragment thereof, or interfering RNA molecule described herein, so as to treat the disorder and/or to suppress one or more symptoms associated with the disorder. Exemplary neurological disorders that may be treated using the compositions and methods described herein are, without limitation, amyotrophic lateral sclerosis, frontotemporal degeneration, Alzheimer’s disease, Parkinson’s disease, dementia with Lewy Bodies, corticobasal degeneration, progressive supranuclear palsy, dementia parkinsonism ALS complex of Guam, Huntington’s disease, IBMPFD, sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander disease, and hereditary inclusion body myopathy, as well as neuromuscular diseases such as congenital myasthenic syndrome, congenital myopathy, cramp fasciculation syndrome, Duchenne muscular dystrophy, glycogen storage disease type II, hereditary spastic paraplegia, inclusion body myositis, Isaac's Syndrome, Kearns-Sayre syndrome, Lambert–Eaton myasthenic syndrome, mitochondrial myopathy, muscular dystrophy, myasthenia gravis, myotonic dystrophy, peripheral neuropathy, spinal and bulbar muscular atrophy, spinal muscular atrophy, Stiff person syndrome, Troyer syndrome, and Guillain–Barré syndrome. The present disclosure is based, in part, on the discovery that CYP51A1 inhibitors, such as the agents described herein, are capable of attenuating TDP-43 aggregation in vivo. TDP-43-promoted aggregation and toxicity have been associated with various neurological diseases. The discovery that CYP51A1 inhibitors modulate TDP-43 aggregation provides an important therapeutic benefit. Using a CYP51A1 inhibitor, such as a CYP51A1 inhibitor described herein, a patient suffering from a neurological disorder or at risk of developing such a condition may be treated in a manner that remedies an underlying molecular etiology of the disease. Without being limited by mechanism, the compositions and methods described herein can be used to treat or prevent such neurological conditions, for example, by suppressing the TDP-43 aggregation that promotes pathology. Additionally, the compositions and methods described herein provide the beneficial feature of enabling the identification and treatment of patients that are likely to respond to CYP51A1 inhibitor therapy. For example, in some embodiments, a patient (e.g., a human patient suffering from or at risk of developing a neurological disease described herein, such as amyotrophic lateral sclerosis) is administered a CYP51A1 inhibitor if the patient is identified as likely to respond to this form of treatment. Patients may be identified as such on the basis, for example, of susceptibility to TDP-43 aggregation. In some embodiments, the patient is identified is likely to respond to CYP51A1 inhibitor treatment based on the isoform of TDP-43 expressed by the patient. For example, patients expressing TDP-43 isoforms having a mutation selected from Q331K, M337V, Q343R, N345K, R361S, and N390D, among others, are more likely to develop TDP-43-promoted aggregation and toxicity relative to patients that do not express such isoforms of TDP-43. Using the compositions and methods described herein, a patient may be identified as likely to respond to CYP51A1 inhibitor therapy on the basis of expressing such an isoform of TDP-43, and may subsequently be administered a CYP51A1 inhibitor so as to treat or prevent one or more neurological disorders, such as one or more of the neurological disorders described herein. Assessing Patient Response A variety of methods known in the art and described herein can be used to determine whether a patient having a neurological disorder (e.g., a patient at risk of developing TDP-43 aggregation, such as a patient expressing a mutant form of TDP-43 having a mutation associated with elevated TDP-43 aggregation and toxicity, for example, a mutation selected from Q331K, M337V, Q343R, N345K, R361S, and N390D) is responding favorably to CYP51A1 inhibition. For example, successful treatment of a patient having a neurological disease, such as amyotrophic lateral sclerosis, with a CYP51A1 inhibitor described herein may be signaled by: (i) an improvement in condition as assessed using the amyotrophic lateral sclerosis functional rating scale (ALSFRS) or the revised ALSFRS (ALSFRS-R), such as an improvement in the patient’s ALSFRS or ALSFRS-R score within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., an improvement in the patient’s ALSFRS or ALSFRS-R score within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient); (ii) an increase in slow vital capacity, such as an increase in the patient’s slow vital capacity within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., an increase in the patient’s slow vital capacity within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient); (iii) a reduction in decremental responses exhibited by the patient upon repetitive nerve stimulation, such as a reduction that is observed within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., a reduction that is observed within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient); (iv) an improvement in muscle strength, as assessed, for example, by way of the Medical Research Council muscle testing scale (as described, e.g., in Jagtap et al., Ann. Indian. Acad. Neurol. 17:336-339 (2014), the disclosure of which is incorporated herein by reference as it pertains to measuring patient response to neurological disease treatment), such as an improvement that is observed within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., an improvement that is observed within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient); (v) an improvement in quality of life, as assessed, for example, using the amyotrophic lateral sclerosis-specific quality of life (ALS-specific QOL) questionnaire, such as an improvement in the patient’s quality of life that is observed within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., an improvement in the subject’s quality of life that is observed within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient); (vi) a decrease in the frequency and/or severity of muscle cramps, such as a decrease in cramp frequency and/or severity within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., a decrease in cramp frequency and/or severity within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient); and/or (vii) a decrease in TDP-43 aggregation, such as a decrease in TDP-43 aggregation within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., a decrease in TDP- 43 aggregation within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient. Combination Formulations and Uses Thereof The compounds of the invention can be combined with one or more therapeutic agents. In particular, the therapeutic agent can be one that treats or prophylactically treats any neurological disorder described herein. Combination Therapies A compound of the invention can be used alone or in combination with other agents that treat neurological disorders or symptoms associated therewith, or in combination with other types of treatment to treat, prevent, and/or reduce the risk of any neurological disorders. In combination treatments, the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6, 2005). In this case, dosages of the compounds when combined should provide a therapeutic effect. Pharmaceutical Compositions The compounds of the invention are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Accordingly, in another aspect, the present invention provides a pharmaceutical composition including a compound of the invention in admixture with a suitable diluent, carrier, or excipient. The compounds of the invention may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the scope of the invention. In accordance with the methods of the invention, the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds of the invention may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time. A compound of the invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, a compound of the invention may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. A compound of the invention may also be administered parenterally. Solutions of a compound of the invention can be prepared in water suitably mixed with a surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2003, 20 ^th ed.) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that may be easily administered via syringe. Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders. Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form includes an aerosol dispenser, it will contain a propellant, which can be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer. Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as sugar, acacia, tragacanth, gelatin, and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter. The compounds of the invention may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice. Dosages The dosage of the compounds of the invention, and/or compositions including a compound of the invention, can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds of the invention may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results may be obtained when the compounds of the invention are administered to a human at a daily dosage of, for example, between 0.05 mg and 3000 mg (measured as the solid form). Dose ranges include, for example, between 10-1000 mg. Alternatively, the dosage amount can be calculated using the body weight of the patient. For example, the dose of a compound, or pharmaceutical composition thereof, administered to a patient may range from 0.1-50 mg/kg. EXAMPLES General Schemes General Scheme 1. An intramolecular SN2 reaction of appropriately substituted chiral alcohol I under basic conditions affords epoxide II. Opening of epoxide II with appropriately substituted amine III affords B-amino alcohol IV. General Scheme 2. Cross coupling of an appropriately substituted ketone I and an appropriately substituted aryl halide II under Buchwald-Hartwig conditions affords ketone intermediate III. Reduction of the ketone to the alcohol IV is realized with a reducing reagent. Alternatively, racemic alcohol IV can be purified using SFC to afford S- and R- enantiomers IV. A palladium catalyzed coupling of an appropriately substituted aryl halide I and a cyclic amine II yields ester intermediate III. The intermediate ester III is reduced to aldehyde intermediate IV using an appropriate reducing agent (e.g. DIBAL-H). The aldehyde IV is then coupled with a pyridine halide V under Grignard conditions to yield alcohol product VI. General Scheme 4. An aldehyde amine with an appropriate protecting group (e.g. PG = Boc) I is coupled with a pyridine halide II under Grignard conditions to afford alcohol intermediate III. Removal of the protecting group under acidic conditions (e.g. HCl) affords the free amine intermediate IV. Alkylation of amine IV with an appropriately substituted halide V under basic conditions affords product VI. General Scheme 5 The spirocyclic ketone I with an appropriate protecting group (e.g. Boc) is homologated to alkene ether II under Wittig conditions. The intermediate II is treated with an acid (e.g. HCl) to reveal spirocyclic aldehyde III. Grignard reaction between aldehyde III and pyridine halide IV under Grignard affords the desired alcohol intermediate V. Removal of the protecting group (e.g. HCl) gives the secondary amine VI. This intermediate VI is coupled with an appropriately substituted aryl halide VII under Buchwald-Hartwig conditions to afford intermediate VIII. This intermediate CXI is subjected to a reducing agent (e.g. sodium borohydride) to produce the appropriately substituted alcohol IX. General Scheme 6 A pyridine sulfonyl halide II is coupled with spirocyclic halide I under basic conditions to afford protected intermediate III. Removal of the protecting group under acid conditions (e.g. HCl) affords secondary amine intermediate IV. Palladium catalyzed coupling of amine IV with appropriately substituted aromatic halide V affords product VI. General Scheme 7 An appropriately substituted spirocyclic amine I is coupled with a appropriately substituted pyridine sulfonyl halide II under basic conditions to afford sulfonamide III. General Scheme 8 A nucleophilic substitution between an appropriately substituted mesylate intermediate I with an amine II affords the spirocyclic product III. Abbreviations: BINAP: (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) BAST: Bis(2-methoxyethyl)aminosulfur trifluoride CDI: 1,1'-Carbonyldiimidazole CMBP: cyanomethylene)tributylphosphorane DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE: 1,2-dichloroethane DCM: Dichloromethane DEAD: Diethyl azodicarboxylate DIAD: Diisopropyl azodicarboxylate DIBAL-H: Diosobutylaluminum hydride DIPEA: Diisopropyl ethylamine DMAP: 4-Dimethylaminopyridine DMF: N,N-dimethylformamide DMP: Des-Martin periodinane DPPA: Diphenylphosphoryl azide EDTA: Ethylenediaminetetraacetic acid GDH: Glucose dehydrogenase HATU: Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium) HgO: Mercury (II) oxide LDA: Lithium diisopropylamide LAH: Lithium aluminium hydride LiHMDS: Lithium hexamethyldisilazide MsCl: Methanesulfonyl chloride NADP: Nicotinamide adenine dinucleotide phosphate NaHMDS: Sodium hexamethyldisilazide NaOAc: Sodium acetate NBS: N-Bromosuccinimide NBS: N-bromosuccinimide NMM: N-Methylmorpholine NMO: N-methylmorpholine oxide P(Cy)3: Tricyclohexylphosphine Pd2(dba)3 : Tris(dibenzylideneacetone)dipalladium(0) RuPhos: 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl SPhos: 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl SFC: Supercritical fluid chromatography TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran TMP: 2,2,6,6-tetramethylpiperidine TsCl: Toluenesulfonyl chloride Preparation of [1-(3,4-dichlorophenyl)-4-piperidyl]-(3-pyridyl)methanol (Compound 1) Step 1: Preparation of tert-Butyl 4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate. To a solution of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (10 g, 43.62 mmol) in dichloromethane (250 mL) was added 1,1'-carbonyldiimidazole (7.07 g, 43.62 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 hour. Then, N-methoxymethanamine hydrochloride (7.45 g, 76.33 mmol) was added to the mixture solution at 25 °C. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was treated with saturate sodium bicarbonate (aq) (200 mL) and the combined organic layers were washed with water (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by ISCO column chromatography (25 g silica, 0- 100 % ethyl acetate in petroleum ether, gradient over 20 minutes) to afford tert-butyl 3- [methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate (10 g, 36.72 mmol, 84%) as a yellow oil. ¹ H NMR (400 MHz, Chloroform-d) δ 4.15 - 4.14 (m, 1H), 3.71 (s, 3H), 3.18 (s, 3H), 2.92 – 2.77 (m, 4H), 1.70 - 1.64 (m, 4H), 1.45 (s, 9H). Step 2: Preparation of bromo(3-pyridyl)magnesium. To a solution of 3-bromopyridine (1.2 g, 7.60 mmol, 731.71 µL) in tetrahydrofuran (10 mL) was added isopropylmagnesium chloride (1.3 M, 7.01 mL). The mixture was stirred at 25 °C for 1 hour and the resultantsolution containing bromo(3-pyridyl)magnesium (1.01 g, crude) (yellow liquid)) was taken to the next step. Step 3: Preparation of tert-butyl 3-(pyridine-3-carbonyl)pyrrolidine-1-carboxylate. To a solution of tert-butyl 3-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate (1 g, 3.67 mmol) in tetrahydrofuran (20 mL) was added chloro(3-pyridyl)magnesium (1.01 g, 7.34 mmol) at 0 °C under nitrogen. The mixture was stirred at 25 °C for 20 hours The reaction mixture was treated with saturate ammonium chloride (aq) (20 mL) and extracted with Ethyl acetate (30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by ISCO column chromatography (25 g silica, 0- 100 % ethyl acetate in petroleum ether, gradient over 20 minutes) to obtain tert-butyl 4-(pyridine-3- carbonyl)piperidine-1-carboxylate (0.5 g, 47%) as a yellow liquid. Step 4: Preparation of 4-piperidyl(3-pyridyl)methanone. A solution of hydrochloric acid in ethyl acetate (10 mL) was added to tert-butyl 4-(pyridine-3- carbonyl)piperidine-1-carboxylate (0.5 g, 1.72 mmol) and the resultant mixture was stirred at 25 °C for 30 minutes. LCMS showed starting material was consumed completely and desired mass was detected. The mixture was then concentrated under reduced pressure to obtain 4-piperidyl(3-pyridyl)methanone.HCl (0.38 g, crude) as a light yellow solid. Step 5: Preparation of [1-(3,4-dichlorophenyl)-4-piperidyl]-(3-pyridyl)methanone. To a solution of 4-bromo-1,2-dichloro-benzene (127 mg, 564 µmol) and 4-piperidyl(3- pyridyl)methanone.HCl (128 mg, 564 mol) in dioxane (5 mL) were added 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene (6 mg, 11 µmol), tris(dibenzylideneacetone)dipalladium(0) (10 mg, 11 µmol) and potassium tert-butoxide (158 mg, 1.41 mmol) at 25 °C under nitrogen. The mixture was stirred at 90 °C for 6 hours. LCMS showed starting material was consumed completely and desired mass was detected. The mixture was filtered, and the filtrate was concentrated. The crude product was purified by ISCO column chromatography (25 g silica, 0-50 % ethyl acetate in petroleum ether, gradient over 20 minutes), The product [1-(3,4-dichlorophenyl)-4-piperidyl]-(3-pyridyl)methanone (150 mg, 71%) was obtained as a light yellow solid. Step 6: Preparation of [1-(3,4-dichlorophenyl)-4-piperidyl]-(3-pyridyl)methanol. To a solution of [1-(3, 4-dichlorophenyl)-4-piperidyl]-(3-pyridyl)methanone (70 mg, 209 µmol) in methanol (5 mL) was added sodium borohydride (16 mg, 418 µmol) at 25 °C. The mixture was stirred at 25 °C for 30 minutes. LCMS and HPLC showed starting material was consumed completely and desired mass was detected. Concentration under reduced pressure followed by prep-HPLC (Boston Green ODS 150*305µ column; 10-40 % acetonitrile in an a 0.04% hydrochloric acid solution in water, 15 minute gradient) afforded [1-(3, 4-dichlorophenyl)-4-piperidyl]-(3-pyridyl)methanol (55 mg, 165 µmol, 79%) as a white solid. ¹ H NMR (400 MHz, Methanol-d6) δ 8.92 (s, 1H), 8.82 (d, J = 6.0 Hz, 1H), 8.70 (d, J = 8.0 Hz, 1H), 8.16 - 8.12 (q, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.52 (t, J = 2.8 Hz, 1H), 4.91 (d, J = 5.2 Hz, 1H ), 3.76 – 3.73 (m, 2H), 3.46 – 3.41 (m, 2H), 2.15 – 1.86 (m, 5H); LCMS (ESI) m/z: 337.1 [M+H] ⁺ . Synthesis of 1-(3,4-dichlorophenyl)pyrrolidin-3-yl]-(3-pyridyl)methanone (Compound 6) and [1- (3,4-dichlorophenyl)pyrrolidin-3-yl]-(3-pyridyl)methanol (Compound 2). Step 1: Preparation of tert-butyl 3-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate. To a solution of 1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (900 mg, 4.18 mmol) in dichloromethane (23 mL) was added 1,1'-carbonyldiimidazole (678 mg, 4.18 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 hour. Then N-methoxymethanamine hydrochloride (713 mg, 7.32 mmol) was added to the mixture at 25 °C and stirred for 16 hours. The reaction mixture was treated with saturated sodium bicarbonate (aq) (20 mL) and the organic layer was washed with water (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by ISCO column chromatogrpahy (25 g silica, 0-100 % ethyl acetate in petroleum ether, gradient over 20 minutes) to obtain tert-butyl 3-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate (900 mg, 3.66 mmol, 87%) as a yellow oil. ¹ H NMR (400 MHz, Chloroform-d) δ 3.72 (s, 3H), 3.59 - 3.51 (m, 2H), 3.44 – 3.42 (m, 1H), 3.38 - 3.34 (m, 2H), 3.20 (s, 3H), 2.17 - 2.08 (m, 2H), 1.46 (s, 3H). Step 2: Preparation of tert-butyl 3-(pyridine-3-carbonyl)pyrrolidine-1-carboxylate. To a solution of tert-butyl 3-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate (600 mg, 2.32 mmol) in tetrahydrofuran (15 mL) was added bromo(3-pyridyl)magnesium (847 mg, 4.65 mmol) at 0 ^° C under nitrogen. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was treated with saturated ammonium chloride (aq) (15 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by ISCO column chromatography (25 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 20 minutes) to afford tert-butyl 3-(pyridine-3-carbonyl)pyrrolidine-1-carboxylate (0.3 g, 47%) as a yellow oil. ¹ H NMR (400 MHz, Chloroform-d) δ 9.18 (s, 1H), 8.81 (s, 1H), 8.25 (d, J = 6.0 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H) 4.02 -3.96 (m, 1H), 3.68 - 3.62 (m, 2H), 3.56 - 3.48 (m, 2H), 2.30 -2.17 (m, 2H), 1.47 (s, 9H). Step 3: Preparation of 3-pyridyl(pyrrolidin-3-yl)methanone. To a solution of hydrochloric acid in ethyl acetate (5 mL) was added to tert-butyl 3-(pyridine-3- carbonyl)pyrrolidine-1-carboxylate (0.3 g, 1.09 mmol) and the mixture was stirred at 25°C for 30 minutes. The reaction mixture was concentrated under reduced pressure to afford 3-pyridyl(pyrrolidin-3- yl)methanone (0.26 g, crude) as a white solid. Step 4: Preparation of 1-(3,4-dichlorophenyl)pyrrolidin-3-yl]-(3-pyridyl)methanone. To a solution of 4-bromo-1,2-dichloro-benzene (205 mg, 908 µmol) and 3-pyridyl(pyrrolidin-3- yl)methanone (160 mg, 908 µmol) in dioxane (7 mL) was added 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (11 mg, 18 µmol), tris(dibenzylideneacetone)dipalladium(0) (17 mg, 18 µmol), and potassium tert-butoxide (255 mg, 2.27 mmol) at 25 ^° C under nitrogen. The mixture was stirred at 90 °C for 16 hours. The mixture was filtered, and the filtrate was concentrated. The crude product was purified by ISCO column chromatography (25 g silica, 0-50 % ethyl acetate in petroleum ether, gradient over 20 minutes) and the product [1-(3,4-dichlorophenyl)pyrrolidin-3-yl]-(3-pyridyl)methanone (0.13 g, 44%) was obtained as a light yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 9.22 (d, J = 1.6 Hz, 1H), 8.84 (t, J = 3.2 Hz, 1H), 8.30 – 8.27 (m, 1H), 7.50 – 7.47 (m, 1H),7.24, (d, J = 8.8, Hz, 1H), 6.64 (d, J = 2.8 Hz, 1H), 6.42, 6.40 (d,d, J = 8.8, 2.8 Hz, 1H), 4.19 – 4.12 (m, 1H), 3.63 (d, J = 7.2 Hz, 2H), 3.43 (t, J = 6.8 Hz, 2H), 2.44 – 2.39 (m, 2H); LCMS (ESI) m/z: 321.0 [M+H] ⁺ . Step 5: Preparation of [1-(3,4-dichlorophenyl)pyrrolidin-3-yl]-(3-pyridyl)methanol . To a solution of [1-(3,4-dichlorophenyl)pyrrolidin-3-yl]-(3-pyridyl)methanone (50 mg, 156 µmol) in methanol (5 mL) was added sodium borohydride (12 mg, 311 µmol) at 25 °C. The mixture was stirred at 25 °C for 30 minutes and the mixture was concentrated. The crude residue was purified by prep-HPLC (Boston Green ODS 150*305µ column; 15-40 % acetonitrile in an a 0.04% hydrochloric acid solution in water, 11 minute gradient). to obtain [1-(3,4-dichlorophenyl)pyrrolidin-3-yl]-(3-pyridyl)methanol (72 mg, 225 µmol, 48%) as a pink solid. ¹ H NMR (400 MHz, Methanol-d6) δ 8.93 (t, J = 4.0 Hz, 1H), 8.80 (d, J = 5.2 Hz, 1H), 8.71 (d,d, J = 8.0, 2.0 Hz, 1H), 8.12 (m, 1H), 7.21 (d,d, J = 9.2, 5.2 Hz, 1H), 6.64 – 6.61 (m, 1H), 6.49 – 6.44 (m, 1 H), 4.99 – 4.94 (m, 1H), 3.34 – 3.22 (m, 4H), 2.80 – 2.78 (m, 1H), 2.12 – 1.95 (m, 2H); LCMS (ESI) m/z: 323.0 [M+H] ⁺ . Preparation of [1-(2-phenylethyl)-4-piperidyl]-(3-pyridyl)methanol (Compound 9). Step 1: Preparation of tert-butyl 4-[hydroxy(3-pyridyl)methyl]piperidine-1-carboxylate. To a solution of 3-bromopyridine (1 g, 4.88 mmol, 452 µL) in tetrahydrofuran (20 mL) was added isopropylmagnesium chloride (2 M, 2.68 mL) at -20 °C, and the mixture was stirred at -20 °C for 0.5 hours. A solution of tert-butyl 4-formylpiperidine-1-carboxylate (1.04 g, 4.88 mmol) in tetrahydrofuran was then added at -20 °C. Then the mixture was warmed up to 20 °C and stirred for 16 hours. Saturated ammonium chloride solution (20 mL) was added to the reaction, and the reaction mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (15 mL) and dried over sodium sulfate, filtered, and concentrated to dryness to obtain the crude product. It was further purified by ISCO column chromatography (20 g silica, 20-100 % ethyl acetate in petroleum ether, gradient over 30 minutes) to obtain tert-butyl 4-[hydroxy(3-pyridyl)methyl]piperidine -1-carboxylate (0.9 g, 3.08 mmol, 63%) as a yellow gum. ¹ H NMR (400 MHz, Chloroform-d) δ 8.58 - 8.50 (m, 2H), 7.67 (br. d, J = 7.9 Hz, 1H), 7.31 (dd, J = 5.0, 7.8 Hz, 1H), 4.47 (d, J = 7.1 Hz, 1H), 4.25 - 4.01 (m, 2H), 2.72 - 2.49 (m, 2H), 2.18 (br. s, 1H), 1.93 (br. d, J = 13.2 Hz, 1H), 1.77 (dtd, J = 3.7, 7.7, 15.4 Hz, 1H), 1.45 (s, 9H), 1.36 - 1.12 (m, 3H). Step 2: Preparation of 4-piperidyl(3-pyridyl)methanol. To a solution of tert-butyl 4-[hydroxy(3-pyridyl)methyl]piperidine-1-carboxylate (0.3 g, 1.03 mmol) in ethyl acetate (5 mL) was added 4M hydrochloric acid in ethyl acetate (10 mL). Then the mixture was stirred at 20 °C for 1 hour and concentrated to obtain 4-piperidyl(3-pyridyl)methanol.HCl (240 mg, crude) as a white solid. LCMS (ESI) m/z: 193.1 [M+H] ⁺ . The crude product was used further without purification. Step 3: Preparation of [1-(2-phenylethyl)-4-piperidyl]-(3-pyridyl)methanol. To a solution of 4-piperidyl(3-pyridyl)methanol.HCl (200 mg, 874 µmol) in dimethylformamide (3 mL) was added 2-bromoethylbenzene (178 mg, 962 µmol) and sodium bicarbonate (220 mg, 2.62 mmol). The resultant mixture was stirred at 80 °C for 1 hour. LCMS showed the reaction was complete. The resultant crude product was purified directly by prep-HPLC (Waters Xbridge Prep OBD C18150*405µ column; 20-50 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 minute gradient) to obtain [1-(2-phenylethyl)-4-piperidyl]-(3-pyridyl)methanol (55 mg, 185 µmol, 21%) as a pale yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.63 - 8.53 (m, 2H), 7.74 (br. d, J = 7.9 Hz, 1H), 7.38 - 7.30 (m, 3H), 7.28 - 7.21 (m, 3H), 4.51 (d, J = 7.3 Hz, 1H), 3.13 (br. d, J = 12.3 Hz, 1H), 3.02 (br. d, J = 11.5 Hz, 2H), 2.89 - 2.80 (m, 2H), 2.65 - 2.57 (m, 2H), 2.10 - 1.93 (m, 3H), 1.76 - 1.66 (m, 1H), 1.56 - 1.48 (m, 1H), 1.42 - 1.34 (m, 2H); LCMS (ESI) m/z: 297.1 [M+H] ⁺ .

Preparation of [1-(4-chlorophenyl)-4-piperidyl]-(3-pyridyl)methanol (Compound 10) Step 1: Preparation of methyl 1-(4-chlorophenyl)piperidine-4-carboxylate. 2,2’-Bis(diphenylphosphino)-1,1’-binapthalene (976 mg, 1.57 mmol), palladium (II) acetate (352 mg, 1.57 mmol) and cesium carbonate (6.81 g, 20.89 mmol) were suspended in dioxane (50 mL) and stirred at 20 °C for 1 hour. Then, 1-bromo-4-chloro-benzene (2 g, 10.45 mmol, 2.00 mL) and methyl piperidine-4-carboxylate (1.50 g, 10.45 mmol) were added as a solution in dioxane (50 mL). The mixture was then heated to 105 °C for 16 hours and cooled. The reaction mixture was filtered, and to the filtrate 20mL of water was added.. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by ISCO column chromatography (40 g silica, 0-10% ethyl acetate in petroleum ether, gradient over 20 minutes) to obtain methyl 1-(4-chlorophenyl)piperidine-4-carboxylate (2.2 g, 8.67 mmol, 83%) as yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 7.22 - 7.16 (m, 2H), 6.88 - 6.81 (m, 2H), 3.71 (s, 3H), 3.64 - 3.52 (m, 2H), 2.84 - 2.72 (m, 2H), 2.52 - 2.39 (m, 1H), 2.09 - 1.98 (m, 2H), 1.94 - 1.79 (m, 2H); LCMS (ESI) m/z: 254.0 [M+H] ⁺ . Step 2: Preparation of 1-(4-chlorophenyl)piperidine-4-carbaldehyde. To a stirred solution of methyl 1-(4-chlorophenyl)piperidine-4-carboxylate (0.5 g, 1.97 mmol) in toluene (10 mL) was added diisobutylalumminum hydride (1 M, 1.97 mL) dropwise at -60 °C under nitrogen, and the mixture was stirred at -60 °C for 1 h. TLC (Petroleum ether : Ethyl acetate=5:1, Rf = 0.37) showed starting material was consumed completely and new spot was formed. The reaction mixture was carefully quenched with methanol (10mL) and brine (50mL) and warmed up to room temperature. The mixture was filtered, and the filtrate was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated undervacuum. The residue was purified by ISCO column chromatography (20 g silica, 0-10% Ethyl acetate in Petroleum ether, gradient over 15 minutes) to obtain 1-(4-chlorophenyl)piperidine-4- carbaldehyde (300 mg, 1.34 mmol, 68%) as a yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 9.70 (s, 1H), 7.25 - 7.15 (m, 2H), 6.90 - 6.81 (m, 2H), 3.61 - 3.49 (m, 2H), 2.94 - 2.76 (m, 2H), 2.49 - 2.33 (m, 1H), 2.05 (s, 2H), 1.87 - 1.70 (m, 2H). Step 3: Preparation of [1-(4-chlorophenyl)-4-piperidyl]-(3-pyridyl)methanol. To a stirred solution of 3-bromopyridine (420 mg, 2.66 mmol, 256 µL) in tetrahydrofuran (2 mL) was added isopropylmagnesium chloride (2 M, 1.33 mL) at 0 °C under nitrogen, and the mixture was warmed up to 20 °C and stirred for 1 hour. To the resultant mixture, a solution of 1-(4- chlorophenyl)piperidine-4-carbaldehyde (297 mg, 1.33 mmol) was added and the mixture was stirred at 20 °C for 1 hour. LCMS showed the starting material was consumed completely and desired product was detected. The reaction mixture was cooled to 0 °C and quenched with saturated ammonium chloride solution followed by the addition of water (5 mL). The aqueous phase was extracted with ethyl acetate (5 mL x 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude residue was purified by prep-HPLC (Nano-micro Kromasil C18 80*253µM column; 35-55% acetonitrile in a 10Mm ammonium bicarbonate solution in water, 10 minute gradient) to obain [1-(4-chlorophenyl)-4-piperidyl]-(3-pyridyl)methanol (107 mg, 343 µmol, 26%) as a white solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.54 (s, 2H), 7.77 - 7.64 (m, 1H), 7.34 - 7.28 (m, 1H), 7.23 - 7.14 (m, 2H), 6.90 - 6.77 (m, 2H), 4.56 - 4.43 (m, 1H), 3.74 - 3.64 (m, 1H), 3.59 (br dd, J = 1.5, 12.1 Hz, 1H), 2.75 - 2.54 (m, 2H), 2.40 (s, 1H), 2.16 - 2.04 (m, 1H), 1.88 - 1.70 (m, 1H), 1.60 - 1.47 (m, 1H), 1.45 - 1.35 (m, 2H); LCMS (ESI) m/z: 303.0 [M+H] ⁺ . The following compounds were synthesized according to the protocol described for the Compound 10: Synthesis of 1-(3,4-dichlorophenyl)-4-(3-pyridylmethyl)piperidin-4-ol (Compound 11): Step 1: tert-butyl 4-hydroxy-4-(3-pyridylmethyl)piperidine-1-carboxylate. To a solution of 3-methylpyridine (1.40 g, 15.06 mmol) in THF (50 mL) at -70 ºC was added LDA (2 M, 11.29 mL) dropwise under N2 atmosphere and stirred for 0.5 h at same temperature. The reaction mixture was then stirred at 0 ºC for 0.5 h before cooling it again to -70 ºC when tert-butyl 4-oxopiperidine- 1-carboxylate (2.5 g, 12.55 mmol) in THF (25 mL) was added. The resulting mixture was stirred at 15 ºC for 14 h. The resultant mixture was quenched with NH4Cl solution (10 mL) and was concentrated. To the resultant mixture was added H2O (20 mL), then the aqueous phase was extracted with EtOAc (50 mL *2). The combined organic layers were washed with H2O (10 mL * 1), dried over Na2SO4, filtered and concentrated under reduced pressure. The resultant crude product was purified by flash column (ISCO 40 g silica, 0-100 % ethyl acetate in petroleum ether, gradient over 20 min) to obtain tert-butyl 4-hydroxy-4-(3- pyridylmethyl)piperidine-1-carboxylate (0.9 g, 2.62 mmol, 21%) as a pale yellow gum. 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.53 - 8.45 (m, 2H), 7.56 (br d, J = 7.6 Hz, 1H), 7.26 - 7.22 (m, 1H), 3.87 (br s, 2H), 3.11 (br t, J = 10.8 Hz, 2H), 2.77 (s, 2H), 1.68 - 1.55 (m, 2H), 1.50 (br s, 2H), 1.46 (s, 9H). LCMS (ESI) m/z: 293.2 [M+H] ⁺ . Step 2: 4-(3-pyridylmethyl)piperidin-4-ol. To a solution of tert-butyl 4-hydroxy-4-(3-pyridylmethyl)piperidine-1-carboxylate (850 mg, 2.91 mmol) in DCM (10 mL) at 0 ºC was added TFA (3.31 g, 29.07 mmol). The mixture was stirred at 15 ºC for 3 h and concentrated. The crude product was purified by prep-HPLC (Waters Xbridge Prep OBD C18 150*40mm*10um column; 1-10% acetonitrile in a 10mM ammonium bicarbonate solution in water, 8 min gradient) (neutral). The product 4-(3-pyridylmethyl)piperidin-4-ol (300 mg, 1.40 mmol, 48 %) was used into the next step as a white solid. LCMS (ESI) m/z: 193.1 [M+H] ⁺ . Step 3: 1-(3,4-dichlorophenyl)-4-(3-pyridylmethyl)piperidin-4-ol. To a solution of 1,2-dichloro-4-iodo-benzene (213 mg, 780 umol) and 4-(3-pyridylmethyl)piperidin- 4-ol (150 mg, 780 umol) in dioxane (3 mL) were added t-BuONa (150 mg, 1.56 mmol), Pd2(dba)3 (36 mg, 39 umol, 0.05 eq) and Sphos (32 mg, 78 umol). The suspension was degassed and purged with nitrogen 3 times and stirred at 100 ºC for 12 h and concentrated. The resultant crude product was purified by prep- HPLC (Waters Xbridge Prep OBD C18 150*40mm*10um column; 35-55 % acetonitrile in a 10mM ammonium bicarbonate solution in water, 8 min gradient) (neutral). The compound 1-(3,4-dichlorophenyl)- 4-(3-pyridylmethyl)piperidin-4-ol (50 mg, 147 umol, 19%) was obtained as a pale yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.57 - 8.47 (m, 2H), 7.62 - 7.55 (m, 1H), 7.30 - 7.27 (m, 1H), 7.26 - 7.24 (m, 1H), 7.00 - 6.96 (m, 1H), 6.80 - 6.73 (m, 1H), 3.47 - 3.37 (m, 2H), 3.16 - 3.05 (m, 2H), 2.81 (s, 2H), 1.88 - 1.76 (m, 2H), 1.69 - 1.58 (m, 2H), 1.35 - 1.22 (m, 1H). LCMS (ESI) for (C17H18Cl2N2O) [M+H] ⁺ : 337.0. Preparation of 1-(4-chloro-3-fluoro-phenyl)-4-piperidyl]-(3-pyridyl)methano l (Compound 12) and its chiral separation into enantiomer 1 (Compound 75) and enantiomer 2 (Compound 16). Compounds 12, 16, and 75 were synthesized according to the synthetic procedure reported for the preparation of compound 17 and 77. The compound 12, [1-(4-chloro-3-fluoro-phenyl)-4-piperidyl]-(3- pyridyl)methanol (12 mg, 36 µmol, 5%) was obtained as a white solid. Both enantiomers were obtained as white solids in 17% and 13% yields respectively. 1H NMR (400 MHz, Dimethylsulfoxide-d6) for compound 12: δ 8.50 (d, J = 1.6 Hz, 1H), 8.45 (dd, J = 1.5, 4.7 Hz, 1H), 7.70 (br. d, J = 7.8 Hz, 1H), 7.35 (dd, J = 4.8, 7.7 Hz, 1H), 7.27 (t, J = 9.0 Hz, 1H), 6.89 (dd, J = 2.7, 13.4 Hz, 1H), 6.73 (dd, J = 2.4, 9.0 Hz, 1H), 5.39 (br. s, 1H), 4.36 (br. d, J = 5.5 Hz, 1H), 3.82 - 3.63 (m, 2H), 2.68 - 2.54 (m, 2H), 1.83 (br. d, J = 12.8 Hz, 1H), 1.75 - 1.63 (m, 1H), 1.36 - 1.20 (m, 3H); LCMS (ESI) m/z: 321.0 [M+H] ⁺ . 1H NMR (400 MHz, Dimethylsulfoxide-d6) for compound 75: δ 8.49 (d, J = 1.6 Hz, 1H), 8.45 (dd, J = 1.5, 4.7 Hz, 1H), 7.70 (br. d, J = 7.8 Hz, 1H), 7.35 (dd, J = 4.8, 7.7 Hz, 1H), 7.27 (t, J = 9.0 Hz, 1H), 6.89 (dd, J = 2.7, 13.4 Hz, 1H), 6.73 (dd, J = 2.4, 8.9 Hz, 1H), 5.40 (br. d, J = 3.2 Hz, 1H), 4.36 (br. d, J = 3.2 Hz, 1H), 3.84 - 3.65 (m, 2H), 2.71 - 2.54 (m, 2H), 1.83 (br. d, J = 11.1 Hz, 1H), 1.75 - 1.61 (m, 1H), 1.37 - 1.19 (m, 3H); LCMS (ESI) m/z: 319.0 [M-H]-. (Rt: 3.71min). 1H NMR (400 MHz, Dimethylsulfoxide-d6) for compound 16: δ 8.49 (d, J = 1.6 Hz, 1H), 8.45 (dd, J = 1.5, 4.7 Hz, 1H), 7.70 (br. d, J = 7.8 Hz, 1H), 7.35 (dd, J = 4.8, 7.7 Hz, 1H), 7.28 (t, J = 9.0 Hz, 1H), 6.89 (dd, J = 2.7, 13.4 Hz, 1H), 6.73 (dd, J = 2.4, 9.0 Hz, 1H), 5.40 (s, 1H), 4.36 (br. d, J = 6.4 Hz, 1H), 3.84 - 3.65 (m, 2H), 2.69 - 2.54 (m, 2H), 1.82 (br. d, J = 12.7 Hz, 1H), 1.68 (br. d, J = 8.3 Hz, 1H), 1.35 - 1.23 (m, 3H); LCMS (ESI) m/z: 319.0 [M-H]-. (Rt: 4.28min). Preparation of 1-[4-[hydroxy(3-pyridyl)methyl]-1-piperidyl]-2-phenyl-ethano ne (Compound 14). To a solution of 4-piperidyl(3-pyridyl)methanol.2HCl (150 mg, 780 µmol) in dimethylformamide (2 mL) was added 2-phenylacetic acid (106 mg, 780 µmol, 98 µL), 1-hydroxybenzotriazole (127 mg, 936 µmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (179 mg, 936 µmol), 4-methylmorpholine (237 mg, 2.34 mmol, 257 µL) andthe mixture stirred at 20 °C for 2 hours. LCMS showed the starting material was consumed completely and desired compound was detected. The resultant crude product was purified directly by prep-HPLC (Waters Xbridge BEH C18100*25mm*5µm column; 10-50 % acetonitrile in a 10mM ammonium bicarbonate solution in water, 8 minute gradient) to obtain1-[4-[hydroxy(3- pyridyl)methyl]-1-piperidyl]-2-phenyl-ethanone (107 mg, 344 µmol, 44%) as a white solid. 1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.44 (dd, J = 1.7, 4.6 Hz, 2H), 7.70 - 7.62 (m, 1H), 7.34 (dd, J = 4.8, 7.7 Hz, 1H), 7.31 - 7.25 (m, 2H), 7.23 - 7.14 (m, 3H), 5.38 (d, J = 4.5 Hz, 1H), 4.46 - 4.27 (m, 2H), 4.03 - 3.86 (m, 1H), 3.69 - 3.63 (m, 2H), 2.96 - 2.79 (m, 1H), 2.46 - 2.31 (m, 1H), 1.79 - 1.65 (m, 2H), 1.28 - 1.13 (m, 1H), 1.09 - 0.90 (m, 2H); LCMS (ESI) m/z: 311.1 [M+H] ⁺ . The following compounds were synthesized according to the protocol described for the Compound 14:

Preparation of 2-[1-(2-phenylethyl)-4-piperidyl]-1-(3-pyridyl)ethanol (Compound 18). Step 1: Preparation of tert-butyl 4-[2-hydroxy-2-(3-pyridyl)ethyl]piperidine-1-carboxylate. To a solution of 3-iodopyridine (1.44 g, 7.04 mmol) in tetrahydrofuran (15 mL) was added isopropylmagnesium chloride (2 M, 3.52 mL) in tetrahydrofuran at 0 °C. The mixture was stirred at 0 °C for 30 minutes. Then, tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (0.8 g, 3.52 mmol) was added at 0 °C. Then the mixture was warmed and stirred at 25 °C for 1.5 hours. Saturated ammonium chloride solution (20 mL) was added to the reaction, and the reaction mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by ISCO column chromatography (10 g silica, 50-100 % ethyl acetate in petroleum ether, gradient over 40 minutes) to obtain tert-butyl 4-[2- hydroxy-2-(3-pyridyl)ethyl]piperidine-1-carboxylate (0.94 g, 3.07 mmol, 87%) as a pale yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J = 1.6 Hz, 1H), 8.41 (dd, J = 1.5, 4.6 Hz, 1H), 7.64 (br. d, J = 7.8 Hz, 1H), 7.26 - 7.19 (m, 1H), 4.76 (dd, J = 4.6, 9.0 Hz, 1H), 4.10 - 3.92 (m, 2H), 2.70 - 2.53 (m, 2H), 1.78 - 1.66 (m, 2H), 1.64 - 1.53 (m, 2H), 1.52 - 1.42 (m, 1H), 1.38 (s, 9H), 1.15 - 1.02 (m, 2H). Step 2: Preparation of 2-(4-piperidyl)-1-(3-pyridyl)ethanol. To a solution of tert-butyl 4-[2-hydroxy-2-(3-pyridyl)ethyl]piperidine-1-carboxylate (0.89 g, 2.90 mmol) in ethyl acetate (10 mL) was added 4M hydrochloric acid in ethyl acetate (30 mL). Then the mixture was stirred at 20 °C for 30 minutes. LCMS showed the reaction was complete. The reaction mixture was concentrated to dryness to obtain the crude product2-(4-piperidyl)-1-(3-pyridyl)ethanol.2HCl (840 mg, crude) as a yellow solid. It was further used without purification. Step 3: Preparation of 2-[1-(2-phenylethyl)-4-piperidyl]-1-(3-pyridyl)ethanol. To a solution of 2-bromoethylbenzene (199 mg, 1.07 mmol, 145 µL) in dimethylformamide (4 mL) was added 2-(4-piperidyl)-1-(3-pyridyl)ethanol.2HCl (0.25 g, 895 µmol) and sodium bicarbonate (226 mg, 2.69 mmol). The resultant mixture was stirred at 80 °C for 1 hour. LCMS showed the reaction was complete. The resultant crude product was purified directly by prep-HPLC (Welch Xtimate C18250*50 10µ column; 10-50 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 10 minute gradient) to obtain 2-[1-(2-phenylethyl)-4-piperidyl]-1-(3-pyridyl)ethanol (32 mg, 104 µmol, 12%) as a pale yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.57 (d, J = 2.0 Hz, 1H), 8.53 (dd, J = 1.6, 4.8 Hz, 1H), 7.77 - 7.66 (m, 1H), 7.32 - 7.27 (m, 3H), 7.23 - 7.15 (m, 3H), 4.85 (br dd, J = 5.0, 8.5 Hz, 1H), 3.06 - 2.94 (m, 2H), 2.87 - 2.75 (m, 2H), 2.62 - 2.52 (m, 2H), 2.32 (br. s, 1H), 2.06 - 1.94 (m, 2H), 1.86 - 1.72 (m, 3H), 1.64 - 1.54 (m, 1H), 1.53 - 1.26 (m, 3H); LCMS (ESI) m/z: 311.1 [M+H] ⁺ .

Preparation of stereoisomer 1 (Compound 20) and stereoisomer 2 (Compound 79) of (3,4- dichlorophenyl)-[3-[hydroxy(3-pyridyl)methyl]pyrrolidin-1-yl ]methanone. Step 1: Preparation of tert-butyl 3-[hydroxy(3-pyridyl)methyl]pyrrolidine-1-carboxylate. To a solution of 3-bromopyridine (1.59 g, 10.04 mmol in tetrahydrofuran (10 mL) was added isopropylmagnesium chloride (2 M, 5.02 mL) at 0 °C under nitrogen. The mixture was stirred at 20 °C for 1 hour, then tert-butyl 3-formylpyrrolidine-1-carboxylate (1 g, 5.02 mmol) was added. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride (10 mL) at 0 °C, water was added and the aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum to give the crude producttert-butyl 3-[hydroxy(3-pyridyl)methyl]pyrrolidine-1-carboxylate (1.0 g, crude) as a red gum; LCMS (ESI) m/z: 279.1 [M+H] ⁺ . Step 2: Preparation of 3-pyridyl(pyrrolidin-3-yl)methanol. To a solution of tert-butyl 3-[hydroxy(3-pyridyl)methyl]pyrrolidine-1-carboxylate (1 g, 3.59 mmol) in ethyl acetate (15 mL) was added hydrochloric acid/ethyl acetate (15 mL, 4 M) at 0 °C. The mixture was warmed and stirred at 20 °C for 2 hours The reaction mixture was concentrated under reduced pressure to obtain the crude product which was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10µm; 1-10% acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 minute gradient). The product 3-pyridyl(pyrrolidin-3-yl)methanol (200 mg, 1.12 mmol, 31% ) was obtained as a white solid. ¹ H NMR (400 MHz, Methanol-d4) δ 8.59 - 8.53 (m, 1H), 8.46 (br. d, J = 4.9 Hz, 1H), 7.89 (br. d, J = 7.7 Hz, 1H), 7.49 - 7.40 (m, 1H), 4.77 - 4.52 (m, 1H), 3.28 - 2.91 (m, 4H), 2.72 - 2.57 (m, 1H), 1.97 - 1.64 (m, 2H); LCMS (ESI) m/z: 179.1 [M+H] ⁺ . Step 3: Preparation of (3,4-dichlorophenyl)-[3-[hydroxy(3-pyridyl)methyl]pyrrolidin -1-yl]methanone. To a solution of 3,4-dichlorobenzoic acid (106 mg, 555 µmol) in dimethylformamide (1 mL) were added 4-methylmorpholine (153 mg, 1.51 mmol, 167 µL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (117 mg, 606 µmol), 1-hydroxybenzotriazole (82 mg, 606 µmol), and 3-pyridyl(pyrrolidin-3-yl)methanol (90 mg, 505 µmol). The mixture was stirred at 20 °C for 3 hours and filtered. The crude product was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10µm; 20-45% acetonitrile in a 10mM ammonium bicarbonate solution in water, 8 minute gradient) to obtain stereoisomer 1 and stereoisomer 2 of (3,4-dichlorophenyl)-[3-[hydroxy(3-pyridyl)methyl]pyrrolidin -1-yl]methanone as pale yellow solids. Compound 20: ¹ H NMR (400 MHz, Methanol-d4) δ 8.71 - 8.43 (m, 2H), 8.02 - 7.83 (m, 1H), 7.81 - 7.59 (m, 2H), 7.58 - 7.40 (m, 2H), 4.77 - 4.50 (m, 1H), 3.92 - 3.47 (m, 4H), 2.77 - 2.55 (m, 1H), 1.89 - 1.63 (m, 2H); LCMS (ESI) m/z: 351.0 [M+H] ⁺ . Compound 79: ¹ H NMR (400 MHz, Chloroform-d) δ 8.65 - 8.45 (m, 2H), 7.65 (br. d, J = 7.7 Hz, 1H), 7.60 - 7.55 (m, 1H), 7.51 - 7.43 (m, 1H), 7.36 - 7.27 (m, 2H), 4.75 - 4.63 (m, 1H), 3.83 - 3.23 (m, 4H), 2.74 - 2.52 (m, 2H), 2.19 - 1.87 (m, 2H); LCMS (ESI) m/z: 351.1 [M+H] ⁺ . Preparation of [2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-(3-pyrid yl)methanol (Compound 23) Step 1: Preparation of [2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-(3-pyrid yl)methanone. To a solution of 2-azaspiro[3.3]heptan-6-yl(3-pyridyl)methanol (0.6 g, 2.94 mmol) in dioxane (6 mL) were added 1,2-dichloro-4-iodo-benzene (802 mg, 2.94 mmol), sodium tert-butoxide (847 mg, 8.81 mmol), tris(dibenzylideneacetone)dipalladium(0) (135 mg, 147 µmol), and 2-dicyclohexylphosphino-2′,6′- diisopropoxybiphenyl (27 mg, 59 µmol) under a nitrogen atmosphere. The mixture was stirred at 100 °C for 20 minutes and concentrated. The resultant crude product was purified by ISCO column chromatography (40 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 20 minutes) to obtain[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-(3 -pyridyl)methanone (0.38 g, 1.09 mmol, 37%) as a pale yellow solid. LCMS (ESI) m/z: 347.1 [M+H] ⁺ . Step 2: Preparation of [2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-(3-pyrid yl)methanol. To a solution of [2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-(3-pyrid yl)methanone (0.36 g, 829 µmol) in methanol (7 mL) was added sodium borohydride (62.75 mg, 1.66 mmol) at 0 °C. The mixture was warmed up and stirred at 25 °C for 2 hours. The reaction mixture was quenched by the addition of water (2 mL), and concentrated under vacuum. The residue was purified by prep-HPLC ( Kromasil C18 (250*50mm*10 µm) column; 35-65 % acetonitrile in a 10mM ammonium bicarbonate solution in water, 10 minute gradient ) to obtain [2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-(3-pyrid yl)methanol (113 mg, 323 µmol, 39%) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.69 - 8.49 (m, 2H), 7.74 - 7.63 (m, 1H), 7.30 (dd, J = 4.8, 7.8 Hz, 1H), 7.23 - 7.18 (m, 1H), 6.45 (d, J = 2.6 Hz, 1H), 6.23 (dd, J = 2.6, 8.6 Hz, 1H), 4.70 - 4.60 (m, 1H), 3.92 - 3.71 (m, 4H), 2.63 - 2.48 (m, 1H), 2.37 - 2.24 (m, 2H), 2.20 - 2.05 (m, 3H); LCMS (ESI) m/z: 349.0 [M+H] ⁺ . Preparation of stereoisomer 1 (Compound 24) and stereoisomer 2 (Compound 22) of [1-[(3,4- dichlorophenyl)methyl]pyrrolidin-3-yl]-(3-pyridyl)methanol. To a solution of 3-pyridyl(pyrrolidin-3-yl)methanol (90 mg, 505 µmol) and 4-(bromomethyl)-1,2- dichloro-benzene (133 mg, 555 µmol) in dimethylformamide (1 mL) was added triethylamine (255 mg, 2.52 mmol, 351 µL). The mixture was stirred at 20 °C for 3 hours. The reaction mixture was filtered to give a clear liquid which was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10µm; 25- 55% acetonitrile in an a 10mM ammonium bicarbonate solution in water, 10 minute gradient) to obtain [1- [(3,4-dichlorophenyl)methyl]pyrrolidin-3-yl]-(3-pyridyl)meth anol (45 mg, 123 µmol, 24%, hydrochloric acid) as a white solid. Compound 24: ¹ H NMR (400 MHz, Methanol-d4) δ 8.95 (br. d, J = 8.9 Hz, 1H), 8.82 (d, J = 5.7 Hz, 1H), 8.72 (br t, J = 7.3 Hz, 1H), 8.17 - 8.08 (m, 1H), 7.87 - 7.77 (m, 1H), 7.70 - 7.61 (m, 1H), 7.58 - 7.48 (m, 1H), 5.16 - 4.99 (m, 1H), 4.51 - 4.33 (m, 2H), 3.77 - 3.42 (m, 2H), 3.41 - 3.33 (m, 1H), 3.41 - 3.33 (m, 1H), 3.28 - 3.18 (m, 1H), 3.16 - 2.88 (m, 1H), 2.28 - 1.79 (m, 1H); LCMS (ESI) m/z: 337.0 [M+H] ⁺ . Compound 22: ¹ H NMR (400 MHz, Methanol-d4) δ 8.51 (d, J = 2.0 Hz, 1H), 8.46 - 8.39 (m, 1H), 7.88 - 7.80 (m, 1H), 7.51 - 7.36 (m, 3H), 7.26 - 7.18 (m, 1H), 4.57 (d, J = 7.7 Hz, 1H), 3.64 - 3.48 (m, 2H), 2.70 - 2.54 (m, 3H), 2.48 - 2.40 (m, 1H), 2.28 - 2.19 (m, 1H), 2.04 - 1.85 (m, 2H); LCMS (ESI) m/z: 337.1 [M+H] ⁺ . Preparation of 2-[1-(3,4-dichlorophenyl)-4-piperidyl]-1-(3-pyridyl)ethanol (Compound 27). Step 1: Preparation of ethyl 2-[1-(3,4-dichlorophenyl)-4-piperidyl]acetate. To a solution of 2,2’-bis(diphenylphosphino)-1,1’-binapthalene (331 mg, 531 µmol) in dioxane (30 mL) was added palladium (II) acetate (119 mg, 531 µmol) and cesium carbonate (3.46 g, 10.62 mmol). The reaction mixture was degassed with nitrogen three times and stirred at 20 °C for 1 hour. Then, 4- bromo-1,2-dichloro-benzene (1.2 g, 5.31 mmol) and ethyl 2-(4-piperidyl)acetate (910 mg, 5.31 mmol) were added to the solution. The mixture was heated to 105°C and stirred for 15h. TLC (Petroleum ether : Ethyl acetate = 5:1, Rf = 0.62) showed the reaction was complete. Water (40 mL) was added to the reaction, and the reaction mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated.. The crude product was purified by ISCO column chromatography (20 g silica, 0-10 % ethyl acetate in petroleum ether, gradient over 30 minutes)to obtain ethyl 2-[1-(3,4-dichlorophenyl)-4-piperidyl]acetate (1.08 g, 3.42 mmol, 64%) as a pale yellow oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.25 (d, J = 9.0 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 6.75 (dd, J = 2.8, 8.9 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.62 (br. d, J = 12.5 Hz, 2H), 2.75 (dt, J = 2.1, 12.3 Hz, 2H), 2.28 (d, J = 7.1 Hz, 2H), 1.96 (ttd, J = 3.7, 7.5, 11.1 Hz, 1H), 1.83 (br. d, J = 13.0 Hz, 2H), 1.39 (dq, J = 3.9, 12.3 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H). Step 2: Preparation of 2-[1-(3,4-dichlorophenyl)-4-piperidyl]acetaldehyde. To a solution of ethyl 2-[1-(3,4-dichlorophenyl)-4-piperidyl]acetate (1 g, 3.16 mmol) in tetrahydrofuran (15 mL) was added diisobutylalumminum hydride (1 M, 6.32 mL) in toluene at -50 °C and the mixture was stirred for 1 hour. TLC (Petroleum ether : Ethyl acetate = 5:1) showed the reaction was complete. Hydrochloric acid (15 mL, 1M) was added to the reaction, and the reaction mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered ,and concentrated to dryness to obtain crude product. The crude product was purified by ISCO column chromatography (10 g silica, 0-10 % ethyl acetate in petroleum ether, gradient over 20 minutes) to obtain 2-[1-(3,4-dichlorophenyl)-4-piperidyl]acetaldehyde (490 mg, 1.80 mmol, 57%) as a pale yellow oil. 1H NMR (400 MHz, Chloroform-d) δ 9.82 (s, 1H), 7.28 - 7.23 (m, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 2.6, 8.8 Hz, 1H), 3.62 (br. d, J = 12.6 Hz, 2H), 2.77 (br t, J = 12.2 Hz, 2H), 2.44 (br. d, J = 6.8 Hz, 2H), 2.16 - 2.01 (m, 1H), 1.83 (br. d, J = 12.8 Hz, 2H), 1.51 - 1.32 (m, 2H). Step 3: Preparation of 2-[1-(3,4-dichlorophenyl)-4-piperidyl]-1-(3-pyridyl)ethanol. To a solution of 3-iodopyridine (331 mg, 1.62 mmol) in tetrahydrofuran (3 mL) was added isopropylmagnesium chloride (2 M, 808 µL) in tetrahydrofuran at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then, 2-[1-(3,4-dichlorophenyl)-4-piperidyl]acetaldehyde (220 mg, 808 µmol) was added at 0 °C. The mixture was warmed and stirred at 25 °C for 1.5 hours. LCMS showed the reaction was complete. Saturated ammonium chloride solution (10 mL) was added to the reaction, and the reaction mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to dryness to obtain crude product. The crude was purified by prep-HPLC (Kromasil C18250*505µ column; 30-70 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 10 minute gradient) to obtain 2-[1-(3,4-dichlorophenyl)-4-piperidyl]-1-(3- pyridyl)ethanol (143 mg, 401 µmol, 50%) as a pale yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 8.58 (d, J = 1.6 Hz, 1H), 8.54 (dd, J = 1.5, 4.8 Hz, 1H), 7.73 (br. d, J = 7.8 Hz, 1H), 7.31 (dd, J = 5.0, 7.6 Hz, 1H), 7.25 (d, J = 9.0 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 6.75 (dd, J = 2.8, 8.9 Hz, 1H), 4.98 - 4.78 (m, 1H), 3.72 - 3.51 (m, 2H), 2.72 (br t, J = 11.9 Hz, 2H), 2.11 (br. s, 1H), 1.96 - 1.79 (m, 3H), 1.71 - 1.63 (m, 1H), 1.62 - 1.55 (m, 1H), 1.49 - 1.32 (m, 2H); LCMS (ESI) m/z: 351.1 [M+H] ⁺ . Preparation of stereoisomer 1 (Compound 36), stereoisomer 2 (Compound 89), stereoisomer 3 (Compound 37) and stereoisomer 4 (Compound 90) of [1-(3,4-dichlorophenyl)pyrrolidin-3-yl]-(3- pyridyl)methanol. Step 1: Preparation of tert-butyl 3-[hydroxy(3-pyridyl)methyl]pyrrolidine-1-carboxylate. To a solution of 3-iodopyridine (5.14 g, 25.09 mmol) in tetrahydrofuran (30 mL) was added isopropylmagnesium chloride (2 M, 12.55 mL) dropwise in 0 °C. The mixture was stirred at 25 °C for 1 hour. Then, tert-butyl 3-formylpyrrolidine-1-carboxylate (2.5 g, 12.55 mmol) in tetrahydrofuran (20 mL) was added dropwise the mixture at 0 °C. The mixture was warmed up and stirred at 25 °C for 3 hours. To the mixture was added water (12 mL), and the aqueous phase was extracted with ethyl acetate (25 mL x 3). The combined organic phase was washed with brine (10 mL*3), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. The product tert-butyl 3-[hydroxy(3-pyridyl)methyl]pyrrolidine-1- carboxylate (3.4 g, crude) was obtained as a yellow gum. LCMS (ESI) m/z: 279.1 [M+H] ⁺ . Step 2: Preparation of 3-pyridyl(pyrrolidin-3-yl)methanol. A mixture of tert-butyl 3-[hydroxy(3-pyridyl)methyl]pyrrolidine-1-carboxylate (3.4 g, 12.22 mmol) in hydrochloric acid/ethyl acetate (4 M, 30 mL) was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude product 3-pyridyl(pyrrolidin-3-yl)methanol (3.2 g, crude, hydrochloric acid) as a yellow gum. Step 3: Synthesis of [1-(3,4-dichlorophenyl)pyrrolidin-3-yl]-(3-pyridyl)methanol and chiral separation into enantiomer 1 (compound 36), enantiomer 2 (compound 89), enantiomer 3 (compound 37) and enantiomer 4 (compound 90). To a solution of 3-pyridyl(pyrrolidin-3-yl)methanol.HCl (999 mg, 4.65 mmol) in dimethylformamide (30 mL) weres added 1,2-dichloro-4-iodo-benzene (900 mg, 3.30 mmol), cesium carbonate (2.15 g, 6.60 mmol), bis(dibenzylideneacetone)palladium(0) (190 mg, 330 µmol), and 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (191 mg, 330 µmol). The mixture was stirred at 120 °C for 16 hours under nitrogen. To the mixture was added water (10 mL), and the aqueous solution was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (25 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by prep-HPLC (Kromasil 250*50mm*10µmcolumn; 40%-60% acetonitrile in an 0.04% ammonium hydroxide and10mM ammonium bicarbonate solution, 10 minute gradient) to obtain the racemic product.100 mg of the racemic compound was subjected to preparative SFC (DAICEL CHIRALPAK AD(250mm*30mm,10µm); column, 40 °C, eluting with 60% ethanol containing 0.1% ammonium hydroxide in a flow of 70 g/min carbon dioxide at 100 bar) to obtain enantiomerically pure compounds. Compound descriptions are given below in the table.

Preparation of (5-fluoro-3-pyridyl)-[2-[6-(trifluoromethyl)-3-pyridyl]-2-az aspiro[3.3]heptan-6- yl]methanol (Compound 38). To a solution of 2-azaspiro[3.3]heptan-6-yl-(5-fluoro-3-pyridyl)methanol (54 mg, 245 µmol) and 5- bromo-2-(trifluoromethyl)pyridine (55 mg, 245 µmol) in dioxane (1.5 mL) was added sodium tert-butoxide (71 mg, 734 µmol), tris(dibenzylideneacetone)dipalladium(0) (11 mg, 12 µmol), and 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (2 mg, 5 µmol). The suspension was degassed and purged with nitrgoen 3 times, and then stirred at 100 °C for 20 minutes. LCMS showed starting material was consumed completely and one main peak with desired mass was detected. The mixture was filtered, and the filtrate was dried in vacuo to afford a crude residue. The residue was purified by prep-HPLC (Waters Xbridge Prep OBD C18150*40mm*10µm column; 35-55 % acetonitrile in a 10mM ammonium bicarbonate solution in water, 8 minute gradient ) to obtain (5-fluoro-3-pyridyl)-[2-[6-(trifluoromethyl)-3- pyridyl]-2-azaspiro[3.3]heptan-6-yl]methanol (22 mg, 59 µmol, 24%) as a pale yellow gum. ¹ H NMR (400 MHz, Chloroform-d) δ 8.41 - 8.38 (m, 1H), 8.36 (s, 1H), 7.83 - 7.80 (m, 1H), 7.47 - 7.41 (m, 2H), 6.69 (dd, J = 2.6, 8.6 Hz, 1H), 4.76 - 4.67 (m, 1H), 4.02 - 3.97 (m, 2H), 3.96 - 3.89 (m, 2H), 2.61 - 2.48 (m, 1H), 2.38 - 2.28 (m, 3H), 2.25 - 2.15 (m, 2H); LCMS (ESI) m/z: 368.0 [M+H] ⁺ . The following compounds were synthesized according to the procedure described for Compound 38:

Preparation of (S)-[2-(1,3-benzothiazol-6-yl)-2-azaspiro[3.3]heptan-6-yl]-( 3-pyridyl)methanol (Compound 42) To a solution of (S)-2-azaspiro[3.3]heptan-6-yl(3-pyridyl)methanol (120 mg, 587 µmol) in dichloromethane (3 mL) was added 1,3-benzothiazol-6-ylboronic acid (105 mg, 587 µmol), copper(II) acetate (128 mg, 705 µmol), and N,N-diisopropylethylamine (304 mg, 2.35 mmol, 409 µL). The mixture was stirred at 40 °C for 16 hours under oxygen (15 Psi. The reaction solution was filtered, and the filtrate was purified directly by prep-HPLC (Phenomenex Gemini-NX 150*305µm column; 15-35 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 minute gradient). The product (S)-[2-(1,3- benzothiazol-6-yl)-2-azaspiro[3.3]heptan-6-yl]-(3-pyridyl)me thanol (12 mg, 35 µmol, 6%) was obtained as a pale yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.67 (s, 1H), 8.60 - 8.52 (m, 2H), 7.91 (d, J = 8.8 Hz, 1H), 7.68 (br. d, J = 7.8 Hz, 1H), 7.30 (dd, J = 4.8, 7.9 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H), 6.63 (dd, J = 2.2, 8.8 Hz, 1H), 4.66 (br. d, J = 7.0 Hz, 1H), 3.98 - 3.90 (m, 2H), 3.89 - 3.82 (m, 2H), 2.63 - 2.52 (m, 1H), 2.39 - 2.27 (m, 2H), 2.22 - 2.09 (m, 2H), 1.96 (br. s, 1H); LCMS (ESI) m/z: 338.2 [M+H] ⁺ . Preparation of [2-(3-chloro-4-fluoro-phenyl)-2-azaspiro[3.3]heptan-6-yl]-py ridazin-3-yl-methanol (Compound 44). Compound 44 was synthesized according to the synthetic procedure reported for the Preparation of compound 95. It was obtained as a pale yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 9.16 (dd, J = 2.1, 4.3 Hz, 1H), 7.57 - 7.42 (m, 2H), 6.97 (t, J = 8.9 Hz, 1H), 6.41 (dd, J = 2.8, 6.1 Hz, 1H), 6.24 (td, J = 3.3, 8.9 Hz, 1H), 4.92 (d, J = 5.4 Hz, 1H), 4.01 - 3.72 (m, 5H), 2.73 - 2.62 (m, 1H), 2.43 (dd, J = 8.3, 11.8 Hz, 1H), 2.33 - 2.22 (m, 2H), 2.15 - 2.03 (m, 1H); LCMS (ESI) m/z: 334.1 [M+H] ⁺ . Synthesis of N-[(R)-[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-( 3- pyridyl)methyl]methanesulfonamide (Compound 45): Step 1: (S)-[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-(3-p yridyl)methanol. To a solution of 1,2-dichloro-4-iodo-benzene (668 mg, 2.45 mmol) in DMSO (10 mL) were added K2CO3 (1.35 g, 9.79 mmol), CuI (93 mg, 490 mol), pyrrolidine-2-carboxylic (113 mg, 979 umol) and (S)-2- azaspiro[3.3]heptan-6-yl(3-pyridyl)methanol (500 mg, 2.45 mmol) under N2. The mixture was stirred at 90 ºC for 12 h, filtered, and the filtrate was purified directly by prep-HPLC (Kromasil C18 (250*50mm*10 um)column; 40-70 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 10 min gradient). The compound (S)-[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-(3-p yridyl)methanol (122 mg, 349 umol, 14%) was obtained as a pale yellow solid. LCMS (ESI) m/z: 349.1 [M+H] ⁺ . Step 2: 6-[(R)-azido(3-pyridyl)methyl]-2-(3,4-dichlorophenyl)-2-azas piro[3.3]heptane. To a solution of (S)-[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-(3-p yridyl)methanol (120 mg, 344 umol) in THF (1.5 mL) were added DPPA (104 mg, 378 umol), DIAD (76 mg, 378 umol) and PPh3 (99 mg, 378 umol, 1.1 eq). The mixture was stirred at 20 ºC for 12 h and concentrated in vacuum. The crude product was purity by prep-TLC (Petroleum ether: Ethyl acetate = 2:1 and Petroleum ether: Ethyl acetate = 0:1, Rf =0.43) to obtain 6-[(R)-azido(3-pyridyl)methyl]-2-(3,4-dichlorophenyl)-2- azaspiro[3.3]heptane (130 mg, 327 umol, 953%) was obtained as a colorless gum. LCMS (ESI) m/z: 374.1 [M+H] ⁺ . Step 3: (R)-[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-(3-p yridyl)methanamine. To a solution of 6-[(R)-azido(3-pyridyl)methyl]-2-(3,4-dichlorophenyl)-2-azas piro[3.3]heptane (120 mg, 321 umol) in THF (2 mL) and H2O (0.2 mL) was added PPh3 (126 mg, 481 umol). The mixture was stirred at 50 ºC for 12 h and concentrated. The crude product was purified by Prep-TLC (Dichloromethane: Methanol = 5:1, Rf =0.5) to obtain (R)-[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6- yl]-(3-pyridyl)methanamine (80 mg, 224 umol, 70%) as a colorless gum. LCMS (ESI) m/z: 348.1 [M+H] ⁺ . Step 4: N-[(R)-[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-( 3-pyridyl)methyl]methanesulfonamide. To a solution of (R)-[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-(3-p yridyl)methanamine (40 mg, 115 umol) in DCM (1 mL) was added Et3N (23 mg, 230 umol) and MsCl (26 mg, 230 umol) at 0 ºC. The mixture was stirred at 20 ºC for 2 h and was quenched by addition H2O (0.5 mL) and the resultant mixture was concentrated in vacuum. The residue was purified by prep-HPLC (Waters Xbridge 150*255u column; 41-71 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 10 min gradient) to obtain N-[(R)-[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-( 3-pyridyl)methyl]methanesulfonamide (15 mg, 36 umol, 31%) was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.65 - 8.55 (m, 2H), 7.66 - 7.58 (m, 1H), 7.39 - 7.30 (m, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.44 (d, J = 2.6 Hz, 1H), 6.26 - 6.18 (m, 1H), 5.01 - 4.92 (m, 1H), 4.44 - 4.32 (m, 1H), 3.90 - 3.69 (m, 4H), 2.69 - 2.62 (s, 3H), 2.61 - 2.40 (m, 2H), 2.29 - 2.18 (m, 1H), 2.16 - 2.04 (m, 1H), 2.01 - 1.92 (m, 1H). LCMS (ESI) for (C19H21Cl2N3O2S) [M+H]+: 426.1. Preparation of 6-(3-pyridylmethyl)-2-[6-(trifluoromethyl)-3-pyridyl]-2-azas piro[3.3]heptane (Compound 47) To a solution of 3-pyridyl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3] heptan-6-yl]methanol (300 mg, 859 µmol) in acetic acid (1.5 mL) was added palladium on activated charcoal (101 mg, 86 µmol, 10% purity) and perchloric acid (388 mg, 3.86 mmol) under hydrogen. The mixture was stirred at 20 °C for 18 hours. The mixture was then filtered, and the filtrate was dried over in vacuo to afford the crude product. It then was purified by prep-HPLC (Waters Xbridge BEH C18100*30mm*10µm column; 25-55 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 6 minute gradient) to afford 6-(3- pyridylmethyl)-2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[ 3.3]heptane (16 mg, 46 µmol, 5%) as a pale yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.50 - 8.45 (m, 1H), 8.42 (d, J = 1.6, 1H), 7.82 (d, J = 2.6 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.22 (ddd, J = 0.8, 4.8, 7.8 Hz, 1H), 6.71 - 6.65 (m, 1H), 3.99 (s, 2H), 3.89 (s, 2H), 2.75 - 2.68 (m, 2H), 2.57 - 2.43 (m, 1H), 2.42 - 2.32 (m, 2H), 2.05 - 1.95 (m, 2H). LCMS (ESI) m/z: 334.1 [M+H] ⁺ . Preparation of pyridin-3-yl(7-(6-(trifluoromethyl)pyridin-3-yl)-7-azaspiro[ 3.5]nonan-2-yl)methanol (Compound 49). Step 1: Preparation of tert-butyl 2-(hydroxy(pyridin-3-yl)methyl)-7-azaspiro[3.5]nonane-7-carb oxylate. To a solution of 3-iodopyridine (728 mg, 3.55 mmol) in tetrahydrofuran (6 mL) was added isopropylmagnesium chloride (2 M, 1.78 mL) in tetrahydrofuran dropwise by syringe at 0 °C. The mixture was stirred at 0 °C for 1 hour. Then, tert-butyl 2-formyl-7-azaspiro[3.5]nonane-7-carboxylate (600 mg, 2.37 mmol) was added to the solution at 0 °C under nitrogen. The reaction mixture was warmed up and stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude product which was purified by ISCO column chromatography (10 g silica,20-50% ethyl acetate in petroleum ether, gradient over 20 minutes). The product tert-butyl 2-[hydroxy(3-pyridyl)methyl]-7- azaspiro[3.5]nonane-7-carboxylate (480 mg, crude) was obtained as a yellow oil. LCMS (ESI) m/z: 333.3 [M+H] ⁺ . Step 2: Preparation of pyridin-3-yl(7-azaspiro[3.5]nonan-2-yl)methanol. A solution of tert-butyl 2-[hydroxy(3-pyridyl)methyl]-7-azaspiro[3.5]nonane-7-carboxy late (480 mg, 1.44 mmol) in hydrochloric acid/ethyl acetate (4 M, 4.80 mL) was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 7-azaspiro[3.5]nonan-2-yl(3-pyridyl)methanol (360 mg, crude, Hydrochloric acid) as a white solid. LCMS (ESI) m/z: 233.1 [M+H] ⁺ . The crude product was used further without purification. Step 3: Preparation of pyridin-3-yl(7-(6-(trifluoromethyl)pyridin-3-yl)-7-azaspiro[ 3.5]nonan-2-yl)methanol. To a solution of 1,8-iazabicyclo[5.4.0]undec-7-ene (170 mg, 1.12 mmol, 168 µL) in dimethylsulfoxide (2 mL) was added 5-fluoro-2-(trifluoromethyl)pyridine (92 mg, 558 µmol) and 7- azaspiro[3.5]nonan-2-yl(3-pyridyl)methanol (150 mg, 558 µmol, hydrochloric acid). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by prep-HPLC (Waters Xbridge Prep OBD C18 150*40mm*10µm column; 25-60% acetonitrile in an a 10mM ammonium bicarbonate solution in water, 10 minute gradient). The product 3-pyridyl-[7-[6-(trifluoromethyl)-3-pyridyl]-7-azaspiro[3.5] nonan-2- yl]methanol (68 mg, 180 µmol, 32% ) was obtained as a pale yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.59 - 8.49 (m, 2H), 8.30 (d, J = 2.8 Hz, 1H), 7.68 (br. d, J = 7.8 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.30 - 7.27 (m, 1H), 7.16 (dd, J = 2.6, 8.7 Hz, 1H), 4.65 (br. d, J = 5.9 Hz, 1H), 3.33 - 3.15 (m, 4H), 2.62 (sxt, J = 8.4 Hz, 1H), 2.24 (br. d, J = 2.3 Hz, 1H), 2.03 - 1.93 (m, 1H), 1.90 - 1.82 (m, 1H), 1.81 - 1.72 (m, 3H), 1.69 - 1.61 (m, 3H); LCMS (ESI) m/z: 378.2 [M+H] ⁺ . The following Compound 105 was synthesized according to the protocol described for the Compound 49. Preparation of 2-[1-[(3,4-dichlorophenyl)methyl]azetidin-3-yl]-1-(3-pyridyl )ethanol (Compound 50) To a solution of 2-(azetidin-3-yl)-1-(3-pyridyl)ethanol (200 mg, 1.12 mmol) in dichloromethane (4 mL) was added 3,4-dichlorobenzaldehyde (196 mg, 1.12 mmol). The mixture was stirred at 20 °C for 2 hours. Then, sodium triacetoxyborohydride (476 mg, 2.24 mmol) was added and the mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated to dryness to give the crude product. The crude product was purified by prep-HPLC (Waters Xbridge Prep OBD C18150*4010µ column; 35-65 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 minute gradient) to obtain2-[1-[(3,4- dichlorophenyl)methyl]azetidin-3-yl]-1-(3-pyridyl)ethanol (116 mg, 343 µmol, 31%) as a pale yellow gum. 1H NMR (400 MHz, Chloroform-d) δ 8.59 - 8.49 (m, 2H), 7.70 (br. d, J = 7.9 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.31 - 7.27 (m, 1H), 7.09 (dd, J = 1.8, 8.2 Hz, 1H), 4.81 (dd, J = 5.1, 8.2 Hz, 1H), 3.51 (s, 2H), 3.43 - 3.30 (m, 2H), 2.99-2.96(t, 1 H), 2.86-2.83 (t, 1H), 2.66-2.60 (m, 1H), 2.09 - 1.90 (m, 2H); LCMS (ESI) m/z: 337.1 [M+H] ⁺ . Preparation of 1-(3-pyridyl)-2-[1-[5-(trifluoromethoxy)-2-pyridyl]azetidin- 3-yl]ethanol (Compound 54) and its chiral separation into enantiomer 1 (Compound 26) and enantiomer 2 (Compound 29). To a solution of 2-(azetidin-3-yl)-1-(3-pyridyl)ethanol (200 mg, 1.12 mmol) in dimethylsulfoxide (3 mL) weres added potassium carbonate (620 mg, 4.49 mmol), copper(I) iodide (36 mg, 191 µmol), pyrrolidine-2-carboxylic acid (39 mg, 337 µmol), and 2-bromo-5-(trifluoromethoxy)pyridine (272 mg, 1.12 mmol). The mixture was stirred at 90 °C for 12 hours under nitrogen. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 4). The combined organic layer was concentrated to dryness to give the crude product which was purified by prep-HPLC (Waters Xbridge Prep OBD C18150*4010µm column; 25-55 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 minute gradient) to afford the racemic compound 1-(3-pyridyl)-2-[1-[5- (trifluoromethoxy)-2-pyridyl]azetidin-3-yl]ethanol (167 mg) as a pale yellow gum. The racemic product was subjected to preparative SFC (DAICEL CHIRALPAK AD (250mm*30mm,10µm) column, 40 °C, eluting with 40% methanol containing 0.1% ammonium hydroxide in a flow of 70 g/min carbon dioxide at 100 bar) to obtain enantiomer 1 and 2 in pure form. 1H NMR (400 MHz, Chloroform-d) for compound 54: for δ 8.61 - 8.50 (m, 2H), 8.03 (d, J = 2.6 Hz, 1H), 7.75 - 7.67 (m, 1H), 7.31 (dd, J = 4.6, 7.7 Hz, 2H), 6.20 (d, J = 9.0 Hz, 1H), 4.84 - 4.76 (m, 1H), 4.17 - 4.05 (m, 2H), 3.74 - 3.58 (m, 2H), 2.99 - 2.85 (m, 1H), 2.27 (d, J = 2.6 Hz, 1H), 2.25 - 2.15 (m, 1H), 2.08 (ddd, J = 5.3, 7.9, 13.7 Hz, 1H); LCMS (ESI) m/z: 340.2 [M+H] ⁺ . 1H NMR (400 MHz, Chloroform-d) for compound 26: δ 8.60 - 8.50 (m, 2H), 8.02 (d, J = 2.7 Hz, 1H), 7.71 (td, J = 1.8, 7.8 Hz, 1H), 7.35 - 7.27 (m, 2H), 6.19 (d, J = 9.0 Hz, 1H), 4.80 (dd, J = 5.2, 7.8 Hz, 1H), 4.17 - 4.04 (m, 2H), 3.74 - 3.59 (m, 2H), 2.99 - 2.85 (m, 1H), 2.44 (br. s, 1H), 2.26 - 2.02 (m, 2H); LCMS (ESI) m/z: 340.2 [M+H] ⁺ . HPLC retention time: 2.47min ¹ H NMR (400 MHz, Chloroform-d) for compound 29: δ 8.63 - 8.48 (m, 2H), 8.02 (d, J = 2.4 Hz, 1H), 7.76 - 7.66 (m, 1H), 7.35 - 7.27 (m, 2H), 6.19 (d, J = 9.0 Hz, 1H), 4.79 (dd, J = 5.2, 7.6 Hz, 1H), 4.18 - 4.02 (m, 2H), 3.75 - 3.58 (m, 2H), 3.00 - 2.84 (m, 1H), 2.53 (br. s, 1H), 2.29 - 1.98 (m, 2H); LCMS (ESI) m/z: 340.2 [M+H] ⁺ . HPLC retention time: 2.91min Preparation of 1-(2-(3-chloro-4-fluorophenyl)-2-azaspiro[3.3]heptan-6-yl)-1 -(pyridin-3-yl)ethanol (Compound 57). Step 1: Preparation of (2-(3-chloro-4-fluorophenyl)-2-azaspiro[3.3]heptan-6-yl)(pyr idin-3-yl)methanone. To a solution of 2-azaspiro[3.3]heptan-6-yl(3-pyridyl)methanol (800 mg, 3.92 mmol) in dioxane (10 mL), was added 2-chloro-1-fluoro-4-iodo-benzene (913 mg, 3.56 mmol) sodium tert-butoxide (1.03 g, 10.68 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (33 mg, 71 µmol), and tris(dibenzylideneacetone)dipalladium(0) (163 mg, 178 µmol). Tthe mixture was stirred at 100 °C for 20 min under nitrogen. LCMS showed the starting material was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give obtain crude product. The crude product was purified by ISCO column chromatography (40 g silica,60-80 % ethyl acetate in petroleum ether, gradient over 20 minutes) to obtain[2-(3-chloro-4-fluoro-phenyl)-2-azaspiro[3.3]heptan-6- yl]-(3-pyridyl)methanone (130 mg, 393 µmol, 11%) as a yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 9.08 (s, 1H), 8.78 (br. d, J = 4.3 Hz, 1H), 8.20 (br. d, J = 7.6 Hz, 1H), 7.49 - 7.38 (m, 1H), 7.02 - 6.84 (m, 1H), 6.46 - 6.32 (m, 1H), 6.27 - 6.17 (m, 1H), 3.97 - 3.87 (m, 3H), 3.77 (s, 2H), 2.69 - 2.55 (m, 4H); LCMS (ESI) m/z: 331.2 [M+H] ⁺ . Step 2: Preparation of 1-(2-(3-chloro-4-fluorophenyl)-2-azaspiro[3.3]heptan-6-yl)-1 -(pyridin-3-yl)ethanol. To a solution of [2-(3-chloro-4-fluoro-phenyl)-2-azaspiro[3.3]heptan-6-yl]-(3 -pyridyl)methanone (120 mg, 363 µmol) in tetrahydrofuran (1.5 mL), was added methylmagnesium bromide solution (3 M, 157 µL) at 0 °C. The mixture was warmed up to 20 °C and stirred for 1 hour. Concentration under reduced pressure and purification by prep-HPLC (Waters Xbridge BEH C18100*25mm*5µm column; 40%-70% acetonitrile in an a 10mM ammonium bicarbonate solution, 10 minute gradient) afforded product 1-[2-(3- chloro-4-fluoro-phenyl)-2-azaspiro[3.3]heptan-6-yl]-1-(3-pyr idyl)ethanol (56 mg, 161 µmol, 44%) as a colorless gum. ¹ H NMR (400 MHz, Chloroform-d) δ 8.65 (d, J = 1.9 Hz, 1H), 8.47 (dd, J = 1.5, 4.8 Hz, 1H), 7.76 (td, J = 1.9, 8.0 Hz, 1H), 7.26 (s, 1H), 6.94 (t, J = 8.9 Hz, 1H), 6.37 (dd, J = 2.8, 6.1 Hz, 1H), 6.20 (td, J = 3.3, 8.8 Hz, 1H), 3.84 - 3.81 (m, 1H), 3.78 - 3.75 (m, 1H), 3.71 - 3.64 (m, 2H), 2.58 (quin, J = 8.6 Hz, 1H), 2.34 - 2.20 (m, 2H), 2.16 - 2.07 (m, 2H), 1.87 (ddd, J = 3.8, 8.2, 11.8 Hz, 1H), 1.50 (s, 3H); LCMS (ESI) m/z: 347.1 [M+H] ⁺ . Preparation of 2-[1-(4-chloro-2-fluoro-phenyl)azetidin-3-yl]-1-(3-pyridyl)e thanol (Compound 65) and its chiral resolution into enantiomer 1 (compound 101) and enantiomer 2 (compound 52). To a solution of 2-(azetidin-3-yl)-1-(3-pyridyl)ethanol (200 mg, 1.12 mmol) in dioxane (3 mL) were added 4-chloro-2-fluoro-1-iodo-benzene (96 mg, 374 µmol), 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene (43 mg, 75 µmol), cesium carbonate (487 mg, 1.50 mmol), and Tris(dibenzylideneacetone)dipalladium(0) (51 mg, 56 µmol). The resultant mixture was stirred at 100 °C for 4 hours under nitrogen. Water (10 mL) was added to the reaction, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by prep-HPLC (Waters Xbridge Prep OBD C18150*4010µm column; 35-55 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 minute gradient) to afford2-[1-(4-chloro-2-fluoro-phenyl)azetidin-3-yl]-1-(3-pyr idyl)ethanol (57 mg) as a yellow gum. The racemic mixture was purified by preparative SFC DAICEL CHIRALPAK IG (250mm*30mm,10µm) column, 40 °C, eluting with 50% methanol containing 0.1% ammonium hydroxide in a flow of 70 g/min carbon dioxide at 100 bar) to afford enantiomerically pure compounds 101 and 52. 1H NMR (400 MHz, Chloroform-d) for compound 65: δ 8.62 - 8.52 (m, 2H), 7.71 (td, J = 1.8, 7.8 Hz, 1H), 7.31 (dd, J = 4.8, 7.7 Hz, 1H), 7.01 - 6.89 (m, 2H), 6.38 - 6.28 (m, 1H), 4.80 (dd, J = 5.3, 7.6 Hz, 1H), 4.12 - 3.98 (m, 2H), 3.66 - 3.48 (m, 2H), 2.95 - 2.81 (m, 1H), 2.23 - 1.99 (m, 3H); LCMS (ESI) m/z: 307.1 [M+H] ⁺ . 1H NMR (400 MHz, Chloroform-d) for compound 101: δ 8.60 - 8.51 (m, 2H), 7.75 - 7.68 (m, 1H), 7.30 (dd, J = 4.9, 7.9 Hz, 1H), 6.99 - 6.90 (m, 2H), 6.33 (t, J = 8.9 Hz, 1H), 4.79 (dd, J = 5.2, 7.8 Hz, 1H), 4.11 - 3.97 (m, 2H), 3.63 - 3.48 (m, 2H), 2.88 (quind, J = 7.1, 14.1 Hz, 1H), 2.21 - 2.01 (m, 3H); LCMS (ESI) m/z: 307.1 [M+H] ⁺ . 1H NMR (400 MHz, Chloroform-d) for compound 52: δ 8.62 - 8.49 (m, 2H), 7.77 - 7.66 (m, 1H), 7.30 (dd, J = 4.9, 7.7 Hz, 1H), 6.97 - 6.90 (m, 2H), 6.33 (t, J = 8.9 Hz, 1H), 4.79 (dd, J = 5.3, 7.7 Hz, 1H),4.10 -3.98 (m, 2H), 3.64 - 3.49 (m, 2H), 2.88 (quind, J = 7.1, 14.2 Hz, 1H), 2.27 - 2.01 (m, 3H); LCMS (ESI) m/z: 307.1 [M+H] ⁺ . The following compounds were synthesized according to the protocol described for the Compound 65.

The following compounds were chirally separated using the conditions described for the Compounds 101 and 52. Synthesis of (1S)-2-[3-(3,4-dichlorophenyl)azetidin-1-yl]-1-(3-pyridyl)et hanol (Compound 67) Step 1: Preparation of tert-butyl 3-(3,4-dichlorophenyl)azetidine-1-carboxylate. To a solution of (3,4-dichlorophenyl)boronic acid (809 mg, 4.24 mmol) in isopropyl alcohol (10 mL) was added diiodonickel (66 mg, 212 µmol), (1R,2R)-2-aminocyclohexanol;hydrochloride (32 mg, 212 µmol), sodium bis(trimethylsilyl)amide (1 M, 7.06 mL) and tert-butyl 3-iodoazetidine-1-carboxylate (1 g, 3.53 mmol). The mixture was stirred at 80 °C for 2 hours. TLC (Petroleum ether : Ethyl acetate = 5:1, Rf = 0.43) showed the reaction was complete. The reaction mixture was concentrated to dryness to give the crude product. The crude product was purified by ISCO column chromatography (40 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 30 minutes) to obtain tert-butyl 3-(3,4-dichlorophenyl)azetidine- 1-carboxylate (680 mg) as a pale yellow oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.44 - 7.41 (m, 2H), 7.16 (dd, J = 2.1, 8.3 Hz, 1H), 4.33 (t, J = 8.7 Hz, 2H), 3.95 - 3.91 (m, 2H), 3.68 (tt, J = 5.8, 8.7 Hz, 1H), 1.47 (s, 9H). Step 2: Preparation of 3-(3,4-dichlorophenyl)azetidine. Tert-butyl 3-(3,4-dichlorophenyl)azetidine-1-carboxylate (650 mg, 2.15 mmol) was dissolved in 4M hydrochloric acid in ethyl acetate (20 mL). The mixture was stirred at 25 °C for 1 hour. TLC (Petroleum ether : Ethyl acetate = 3:1, Rf = 0.00) showed the reaction was complete. The reaction mixture was concentrated to dryness to obtain 3-(3,4-dichlorophenyl)azetidine (490 mg, 2.05 mmol, 95%) as hydrochloride salt. It was used further without purification. Step 3: Preparation of (1S)-2-[3-(3,4-dichlorophenyl)azetidin-1-yl]-1-(3-pyridyl)et hanol. To a solution of 3-(3,4-dichlorophenyl)azetidine.HCl (150 mg, 629 µmol,) in ethanol (2 mL) was added (1S)-2-bromo-1-(3-pyridyl)ethanol (127 mg, 629 µmol) and triethylamine(191 mg, 1.89 mmol, 263 µL). The mixture was stirred at 80 °C for 16 hours. LCMS showed the reaction was complete. The mixture was concentrated and purified by prep-HPLC (Xtimate C18150*405µ column; 35-55 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 10 minute gradient) to obtain (1S)-2-[3-(3,4- dichlorophenyl)azetidin-1-yl]-1-(3-pyridyl)ethanol (41 mg, 124 µmol, 20%) as a yellow gum. ¹ H NMR (400 MHz, Chloroform-d) δ 8.60 (d, J = 1.98 Hz, 1H), 8.54 (dd, J = 1.65, 4.74 Hz, 1H), 7.70-7.77 (m, 1H), 7.40 (dd, J = 2.98, 5.18 Hz, 2H), 7.30 (dd, J = 4.96, 7.83 Hz, 1H), 7.15 (dd, J = 1.98, 8.16 Hz, 1H), 4.63 (dd, J = 5.18, 7.83 Hz, 1H), 3.82-3.90 (m, 1H), 3.62-3.78 (m, 3H), 3.32 (t, J = 6.17 Hz, 1H), 3.25 (t, J = 6.73 Hz, 1H), 2.67-2.77 (m, 2H); LCMS (ESI) m/z: 323.0 [M+H] ⁺ .

The following compound was synthesized according to the protocol described for the compound 67: Preparation of 4-[(R)-[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-( 3- pyridyl)methyl]morpholine (Compound 69) Step 1: Preparation of [(S)-[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-(3- pyridyl)methyl] methanesulfonate. To a solution of (S)-[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-(3-p yridyl)methanol (300 mg, 859 µmol) and triethylamine (261 mg, 2.58 mmol, 359 µL) in dichloromethane (3 mL) was added methanesulfonyl chloride (118 mg, 1.03 mmol, 80 µL) dropwise at 0 °C. The mixture was stirred at 15 °C for 1 hour. The reaction mixture was concentrated in vacuo and the crude product was dissolved in ethyl acetate (10 mL) and water (5mL), organic layer separated, and aqueous layer was extracted with ethyl acetate (10 mL x 2). The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The compound [(S)-[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-(3- pyridyl)methyl] methanesulfonate (500 mg, crude) was obtained as a yellow gum. Step 2: Preparation of 4-[(R)-[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-( 3- pyridyl)methyl]morpholine. To a solution of [(S)-[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-(3- pyridyl)methyl] methanesulfonate (120 mg, 281 µmol) in dimethylsulfoxide (1 mL) was added morpholine (147 mg, 1.68 mmol). The mixture was stirred at 60 °C for 3 hours. The mixture was filtered, and the filtrate was purified by prep-HPLC (Phenomenex Luna C18100*30mm*5µm column; 20-50 % acetonitrile in a 0.225% formic acid solution in water, 9 minute gradient) to obtain4-[(R)-[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6 - yl]-(3-pyridyl)methyl]morpholine (7 mg, 15% formic acid) as a white solid. ¹ H NMR (400 MHz, Methanol- d4) δ 8.44 (br. d, J = 2.6 Hz, 2H), 7.80 - 7.75 (m, 1H), 7.42 (dd, J = 4.9, 7.8 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 6.49 (d, J = 2.6 Hz, 1H), 6.32 (dd, J = 2.7, 8.7 Hz, 1H), 3.91 - 3.85 (m, 1H), 3.83 - 3.78 (m, 1H), 3.71 - 3.66 (m, 1H), 3.64 - 3.60 (m, 5H), 3.28 (s, 1H), 2.78 (br. d, J = 8.8 Hz, 1H), 2.56 - 2.41 (m, 3H), 2.40 - 2.32 (m, 2H), 2.23 (dd, J = 8.7, 11.7 Hz, 1H), 1.81 (br. s, 1H), 1.72 - 1.62 (m, 1H); LCMS (ESI) m/z: 418.2 [M+H] ⁺ . Preparation of [1-(3-chloro-4-fluoro-phenyl)-4-piperidyl]-(3-pyridyl)methan ol (Compound 71) and its chiral separation into enantiomer 1 (compound 17) and enantiomer 2 (compound 77). Step 1: Preparation of [1-(3-chloro-4-fluoro-phenyl)-4-piperidyl]-(3-pyridyl)methan one. To a solution of 4-piperidyl(3-pyridyl)methanone.2HCl (0.5 g, 1.90 mmol) in dioxane (8 mL) was added 2-chloro-1-fluoro-4-iodo-benzene (585 mg, 2.28 mmol), sodium tert-butoxide (548 mg, 5.70 mmol), tris(dibenzylideneacetone)dipalladium (0) (87 mg, 95 µmol), and 2-dicyclohexylphosphino-2’,6’- dimethoxybiphenyl (78 mg, 190 µmol). The reaction mixture was bubbled with nitrogen for 10 seconds then stirred at 100 °C for 12 hours. TLC (Petroleum ether : Ethyl acetate = 0:1, Rf = 0.43) showed the reaction was complete. The reaction mixture was cooled to 20 °C followed by addition of water (15 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated to dryness to obtain crude product. The crude product was purified by ISCO column chromatography (10 g silica, 10-60 % ethyl acetate in petroleum ether, gradient over 30 minutes) to obtain [1-(3-chloro-4-fluoro-phenyl)-4-piperidyl]-(3-pyridyl)methan one (470 mg, 1.47 mmol, 78%) as a pale yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 9.19 (d, J = 1.8 Hz, 1H), 8.81 (dd, J = 1.5, 4.9 Hz, 1H), 8.25 (td, J = 2.0, 8.0 Hz, 1H), 7.46 (dd, J = 4.9, 7.9 Hz, 1H), 7.03 (t, J = 8.8 Hz, 1H), 6.95 (dd, J = 3.0, 6.3 Hz, 1H), 6.80 (td, J = 3.4, 9.0 Hz, 1H), 3.64 (td, J = 3.1, 12.4 Hz, 2H), 3.43 - 3.30 (m, 1H), 2.87 (dt, J = 3.3, 11.7 Hz, 2H), 2.07 - 1.90 (m, 4H). Step 2: Preparation of [1-(3-chloro-4-fluoro-phenyl)-4-piperidyl]-(3-pyridyl)methan ol, and chiral separation to enantiomer 1 and enantiomer 2. To a solution of [1-(3-chloro-4-fluoro-phenyl)-4-piperidyl]-(3-pyridyl)methan one (250 mg, 784 µmol) in methanol (4 mL) was added sodium borohydride (59 mg, 1.57 mmol). The mixture was stirred at 20 °C for 1 hour. LCMS showed the reaction was complete. The reaction mixture was concentrated to dryness to give the crude product. The crude was purified by prep-HPLC (Welch Xtimate C18250*5010µ column; 30-70 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 10 minute gradient). to obtain [1-(3-chloro-4-fluoro-phenyl)-4-piperidyl]-(3-pyridyl)methan ol (140 mg) as a white solid. For the chiral resolution an amount 120 mg of racemic product was purified by preparative SFC [DAICEL CHIRALPAK AD (250mm*30mm,10µm) column, 40°C, eluting with 45% methanol containing 0.1% ammonium hydroxide in a flow of 70 g/min carbon dioxide at 100 bar]. Enantiomer 1 and enantiomer 2 were obtained as white solids in 24% and 17% yields. 1H NMR (400 MHz, Dimethylsulfoxide-d6) for compound 71: δ 8.50 (d, J = 1.6 Hz, 1H), 8.45 (dd, J = 1.4, 4.7 Hz, 1H), 7.71 (br. d, J = 7.8 Hz, 1H), 7.36 (dd, J = 4.8, 7.6 Hz, 1H), 7.19 (t, J = 9.2 Hz, 1H), 7.01 (dd, J = 2.9, 6.3 Hz, 1H), 6.88 (td, J = 3.5, 9.0 Hz, 1H), 5.40 (d, J = 4.5 Hz, 1H), 4.45 - 4.30 (m, 1H), 3.74 - 3.53 (m, 2H), 2.62 - 2.52 (m, 2H), 1.85 (br. d, J = 11.5 Hz, 1H), 1.64 (br. d, J = 7.2 Hz, 1H), 1.40 - 1.21 (m, 3H); LCMS (ESI) m/z: 321.0 [M-H] ⁺ . 1H NMR (400 MHz, Dimethylsulfoxide-d6) for compound 17: δ 8.50 (d, J = 1.6 Hz, 1H), 8.45 (dd, J = 1.5, 4.7 Hz, 1H), 7.71 (br. d, J = 7.8 Hz, 1H), 7.36 (dd, J = 4.7, 7.6 Hz, 1H), 7.19 (t, J = 9.1 Hz, 1H), 7.03 - 6.99 (m, 1H), 6.88 (td, J = 3.5, 9.1 Hz, 1H), 5.39 (d, J = 4.5 Hz, 1H), 4.37 (dd, J = 4.9, 6.5 Hz, 1H), 3.73 - 3.54 (m, 2H), 2.61 - 2.51 (m, 2H), 1.85 (br. d, J = 11.2 Hz, 1H), 1.72 - 1.56 (m, 1H), 1.39 - 1.21 (m, 3H); LCMS (ESI) m/z: 321.0 [M+H] ⁺ . (Rt: 3.26min). 1H NMR (400 MHz, Dimethylsulfoxide-d6) for compound 77: δ 8.50 (d, J = 1.6 Hz, 1H), 8.45 (dd, J = 1.5, 4.8 Hz, 1H), 7.71 (br. d, J = 7.8 Hz, 1H), 7.36 (dd, J = 4.8, 7.7 Hz, 1H), 7.19 (t, J = 9.2 Hz, 1H), 7.01 (dd, J = 2.9, 6.4 Hz, 1H), 6.93 - 6.81 (m, 1H), 5.39 (d, J = 4.4 Hz, 1H), 4.42 - 4.32 (m, 1H), 3.73 - 3.55 (m, 2H), 2.62 - 2.51 (m, 2H), 1.89 - 1.80 (m, 1H), 1.72 - 1.57 (m, 1H), 1.40 - 1.22 (m, 3H); LCMS (ESI) m/z: 321.0 [M-H] ⁺ . (Rt: 3.77min). Preparation of 1-(3,4-dichlorophenyl)-4-[hydroxy(3-pyridyl)methyl]piperidin -2-one (Compound 72) To a solution of [1-(3,4-dichlorophenyl)-4-piperidyl]-(3-pyridyl)methanol (60 mg, 178 µmol) in water (3 mL) was added mercury (II) oxide (39 mg, 178 µmol) and 2-[2-[bis(carboxymethyl)amino]ethyl- (carboxymethyl)amino]acetic acid (52 mg, 178 µmol). The resultant mixture was stirred at 100 °C for 1 hour. LCMS showed the reaction was complete. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated. to dryness to afford the crude product. The crude product was further purified by prep-HPLC (Welch Xtimate C18150*255µ column; 30-60 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 10 minute gradient) To obtiain 1-(3,4- dichlorophenyl)-4-[hydroxy(3-pyridyl)methyl]piperidin-2-one (10 mg, 27 µmol, 15%) as a pale yellow solid. ¹ H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.56 (s, 1H), 8.48 (dd, J = 1.5, 4.8 Hz, 1H), 7.81 - 7.71 (m, 1H), 7.67 - 7.56 (m, 2H), 7.39 (dd, J = 4.8, 7.8 Hz, 1H), 7.30 (dd, J = 2.3, 8.7 Hz, 1H), 5.62 (br. s, 1H), 4.60 - 4.46 (m, 1H), 3.71 - 3.51 (m, 2H), 2.35 - 2.24 (m, 2H), 2.10 - 1.99 (m, 1H), 1.74 - 1.57 (m, 2H); LCMS (ESI) m/z: 350.9 [M+H] ⁺ . Preparation of enantiomer 1 (Compound 76) and enantiomer 2 (Compound 15) of [1-(3,4- dichlorophenyl)-4-piperidyl]-(3-pyridyl)methanol. Compound 15 and compound 76 were synthesized according to the synthetic procedure reported for the preparation of compounds 17 and 77. The enantiomer 1 product [1-(3,4-dichlorophenyl)-4- piperidyl]-(3-pyridyl)methanol (27 mg, 80 µmol, 11%) was obtained as a white solid. The enantiomer 2 product [1-(3,4-dichlorophenyl)-4-piperidyl]-(3-pyridyl)methanol (42 mg, 122 µmol, 16%) was obtained as a white solid. 1H NMR (400 MHz, Dimethylsulfoxide-d6) for compound 76 δ 8.50 (d, J = 1.7 Hz, 1H), 8.45 (dd, J = 1.5, 4.7 Hz, 1H), 7.70 (br. d, J = 7.8 Hz, 1H), 7.43 - 7.26 (m, 2H), 7.06 (d, J = 2.8 Hz, 1H), 6.88 (dd, J = 2.9, 9.0 Hz, 1H), 5.39 (d, J = 4.5 Hz, 1H), 4.37 (dd, J = 4.8, 6.5 Hz, 1H), 3.83 - 3.60 (m, 2H), 2.73 - 2.55 (m, 2H), 1.90 - 1.77 (m, 1H), 1.75 - 1.60 (m, 1H), 1.37 - 1.17 (m, 3H); LCMS (ESI) m/z: 335.0 [M-H] ⁺ . (Rt: 3.44min) 1H NMR (400 MHz, Dimethylsulfoxide-d6) for compound 15: δ 8.50 (d, J = 1.7 Hz, 1H), 8.45 (dd, J = 1.5, 4.6 Hz, 1H), 7.70 (br. d, J = 7.8 Hz, 1H), 7.42 - 7.28 (m, 2H), 7.06 (d, J = 2.7 Hz, 1H), 6.88 (dd, J = 2.8, 9.0 Hz, 1H), 5.38 (d, J = 4.6 Hz, 1H), 4.45 - 4.28 (m, 1H), 3.84 - 3.65 (m, 2H), 2.70 - 2.53 (m, 2H), 1.88 - 1.77 (m, 1H), 1.75 - 1.61 (m, 1H), 1.37 - 1.17 (m, 3H); LCMS (ESI) m/z: 335.0 [M-H] ⁺ . (Rt: 3.79min). Preparation of [1-[(3,4-dichlorophenyl)methyl]-4-piperidyl]-(3-pyridyl)meth anol (Compound 78). To a stirred solution of 4-piperidyl(3-pyridyl)methanol (150 mg, 780 µmol) in tetrahydrofuran (2 mL) was added 3,4-dichlorobenzaldehyde (137 mg, 780 µmol), acetic acid (94 mg, 1.56 mmol, 89 µL), and sodium triacetoxyborohydride (331 mg, 1.56 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour and warmed up to 20 °C and stirred further for 1 h. LCMS showed the starting material was consumed completely and desired compound was detected. The resultant crude product was purified directly by prep-HPLC (Waters Xbridge BEH C18100*30mm*10µm column; 27-57 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 10 minute gradient) to obtain [1-[(3,4-dichlorophenyl)methyl]-4- piperidyl]-(3-pyridyl)methanol (53 mg, 150 µmol, 19%) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.54 (br. d, J = 2.6 Hz, 2H), 7.66 (br. d, J = 7.9 Hz, 1H), 7.42 (d, J = 1.3 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.32 - 7.28 (m, 1H), 7.14 (br. d, J = 7.8 Hz, 1H), 4.48 (br. d, J = 7.2 Hz, 1H), 3.42 (s, 2H), 2.91 (br. d, J = 10.9 Hz, 1H), 2.82 (br. d, J = 10.6 Hz, 1H), 2.07 - 1.83 (m, 4H), 1.60 (br. s, 1H), 1.48 - 1.38 (m, 1H), 1.37 - 1.26 (m, 2H); LCMS (ESI) m/z: 351.0 [M+H] ⁺ . Preparation of [1-[(2,3-dichlorophenyl)methyl]-4-piperidyl]-(3-pyridyl)meth anol (Compound 80). To a solution of 4-piperidyl(3-pyridyl)methanol.HCl (100 mg, 437 µmol) and 1-(bromomethyl)-2,3- dichloro-benzene (115 mg, 481 µmol) in dimethylformamide (1 mL) was added triethylamine (221 mg, 2.19 mmol, 304 µL). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was filtered and the resultant product was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10µm; 35-65% acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 minute gradient). Product [1-[(2,3-dichlorophenyl)methyl]-4-piperidyl]-(3-pyridyl)meth anol (90 mg, 252 µmol, 57%) was obtained as a pale yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.61 - 8.51 (m, 2H), 7.73 - 7.66 (m, 1H), 7.45 - 7.29 (m, 3H), 7.23 - 7.14 (m, 1H), 4.50 (d, J = 7.2 Hz, 1H), 3.61 (s, 2H), 2.98 (br. d, J = 11.2 Hz, 1H), 2.93 - 2.83 (m, 1H), 2.19 - 1.90 (m, 4H), 1.74 - 1.62 (m, 1H), 1.53 - 1.39 (m, 1H), 1.39 - 1.28 (m, 2H); LCMS (ESI) m/z: 351.1 [M+H] ⁺ . Preparation of [1-(4,5-dichlorothiazol-2-yl)-4-piperidyl]-(3-pyridyl)methan ol (Compound 81). Step 1: Preparation of 2,4,5-trichlorothiazole. To a solution of 2,4-dichlorothiazole (0.5 g, 3.25 mmol) in chloroform (7 mL) was added sulfuryl chloride (876 mg, 6.49 mmol, 649 µL) and the resultant mixture was stirred at 70 °C for 3 hours. The reaction mixture was concentrated to dryness to obtain 2,4,5-trichlorothiazole (540 mg, 2.87 mmol, 88%) as a colorless oil. The crude product was used further without purification. Step 2: Preparation of [1-(4,5-dichlorothiazol-2-yl)-4-piperidyl]-(3-pyridyl)methan ol. To a solution of 2,4,5-trichlorothiazole (0.2 g, 1.06 mmol) in acetonitrile (5 mL) was added 4- piperidyl(3-pyridyl)methanol (243 mg, 1.06 mmol, hydrochloric acid) and potassium carbonate (587 mg, 4.24 mmol). The mixture was stirred at 20 °C for 16 hours. The crude was purified by prep-HPLC (Waters Xbridge Prep OBD C18150*4010µ column; 40-60 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 minute gradient) to obtain [1-(4,5-dichlorothiazol-2-yl)-4-piperidyl]-(3-pyridyl)methan ol (121 mg, 351 µmol, 33%) as a pale yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.59 - 8.48 (m, 2H), 7.68 (br. d, J = 7.9 Hz, 1H), 7.32 (dd, J = 4.9, 7.7 Hz, 1H), 4.50 (br. d, J = 7.1 Hz, 1H), 3.98 - 3.78 (m, 2H), 3.02 - 2.82 (m, 2H), 2.48 (br. s, 1H), 2.11 - 2.01 (m, 1H), 1.86 (dtd, J = 3.7, 7.6, 11.3 Hz, 1H), 1.52 - 1.30 (m, 3H); LCMS (ESI) m/z: 344.0 [M+H] ⁺ . Synthesis of (1S)-2-[4-(3,4-dichlorophenoxy)-1-piperidyl]-1-(3-pyridyl)et hanol (Compound 83): Step 1: tert-butyl 4-(3,4-dichlorophenoxy)piperidine-1-carboxylate. To a solution of 3,4-dichlorophenol (1 g, 6.13 mmol) and tert-butyl 4-hydroxypiperidine-1- carboxylate (1.36 g, 6.75 mmol) in THF (30 mL) was added PPh3 (3.22 g, 12.27 mmol). Then the mixture was cooled to 0 ºC and DIAD (2.48 g, 12.27 mmol) was added drop wise to the above solution and the resultant mixture was stirred at 25 ºC for 48 h. The reaction mixture was concentrated to give crude product which was purified by flash column (ISCO 40 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 20 min) to afford tert-butyl 4-(3,4-dichlorophenoxy)piperidine-1-carboxylate (1.4g) as a colorless oil. Step 2: 4-(3,4-dichlorophenoxy)piperidine. To a solution of tert-butyl 4-(3,4-dichlorophenoxy)piperidine-1-carboxylate (1.3 g, 3.75 mmol) in EtOAc (10 mL) was added HCl/EtOAc (4 M, 10 mL). The mixture was stirred at 25 ºC for 2h, filtered and the solids were dried over in vacuo to afford 4-(3,4-dichlorophenoxy)piperidine (0.8 g, 3.25 mmol, 87%) as a white solid. Step 3: (1S)-2-[4-(3,4-dichlorophenoxy)-1-piperidyl]-1-(3-pyridyl)et hanol. To a solution of 4-(3,4-dichlorophenoxy)piperidine (0.25 g, 1.02 mmol) in n-BuOH (5 mL) was added Et3N (123 mg, 1.22 mmol) and then (1S)-2-bromo-1-(3-pyridyl)ethanol (205 mg, 1.02 mmol) was added to the mixture. The resultant mixture was stirred at 120 ºC for 12h and concentrated. The crude product was purified by prep-HPLC (Welch Xtimate C18250*50mm*10um column; 30-55 % acetonitrile in a 10mM ammonium bicarbonate solution in water, 10 min gradient) (neutral) to obtain (1S)-2-[4-(3,4- dichlorophenoxy)-1-piperidyl]-1-(3-pyridyl)ethanol (79 mg, 216 umol, 11%) as a brown solid. An additional regioisomer was also isolated during this step. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.63 - 8.58 (m, 1H), 8.57 - 8.51 (m, 1H), 7.78 - 7.72 (m, 1H), 7.35 - 7.28 (m, 2H), 7.02 (d, J = 2.8 Hz, 1H), 6.77 (dd, J = 2.8, 8.8 Hz, 1H), 4.83 - 4.74 (m, 1H), 4.35 (tt, J = 3.4, 7.0 Hz, 1H), 4.08 (s, 1H), 3.07 - 2.95 (m, 1H), 2.77 - 2.64 (m, 2H), 2.63 - 2.56 (m, 1H), 2.52 - 2.44 (m, 1H), 2.39 (ddd, J = 3.3, 8.1, 11.4 Hz, 1H), 2.10 - 1.96 (m, 2H), 1.95 - 1.81 (m, 2H). LCMS (ESI) for (C18H20Cl2N2O) [M+H]+: 367.0. Preparation of pyridin-3-yl(1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3 -yl)methanol (Compound 84) and separation of stereoisomer 1 (Compound 378) and stereoisomer 2 (Compound 28). To a solution of 2,2’-bis(diphenylphosphino)-1,1’-binapthalene (140 mg, 224.43 µmol) in dioxane (10 mL) was added palladium (II) acetate (50 mg, 24 µmol) and cesium carbonate (1.46 g, 4.49 mmol). The reaction mixture was degassed with nitrogen three times, and the mixture was stirred at 20 °C for 1 hour. Then, 3-pyridyl(pyrrolidin-3-yl)methanol (400 mg, 2.24 mmol) and 5-bromo-2 - trifluoromethyl)pyridine (507 mg, 2.24 mmol) were added to the reaction, the mixture was heated to 105 °C and stirred for 15 hours The reaction mixture was concentrated in vacuum to obtain the compound 84. This was further subjected to prep-HPLC ( Waters Xbridge BEH C18100*25mm*5µm column; 28- 40% acetonitrile in a 10mM ammonium bicarbonate solution in water, 8 minute gradient)(neutral) to obtain stereoisomer 1 of pyridin-3-yl(1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3 -yl)methanol (65 mg, 199 µmol, 9%) was obtained as a pale yellow gum and the stereoisomer 2 (52 mg, 160 µmol, 7%) was obtained as a white solid. 1H NMR (400 MHz, Chloroform-d) for compound 378: δ 8.62 - 8.50 (m, 2H), 7.93 - 7.87 (m, 1H), 7.76 (td, J = 1.8, 7.8 Hz, 1H), 7.47 - 7.40 (m, 1H), 7.32 (dd, J = 4.8, 7.8 Hz, 1H), 6.73 (dd, J = 2.4, 8.6 Hz, 1H), 4.74 (d, J = 7.2 Hz, 1H), 3.55 - 3.31 (m, 2H), 3.26 - 3.08 (m, 2H), 2.78 (s, 1H), 2.34 - 2.22 (m, 1H), 2.16 (br. d, J = 8.8 Hz, 1H); LCMS (ESI) m/z: 324.0 [M+H] ⁺ . 1H NMR (400 MHz, Chloroform-d) for compound 28: δ 8.63 - 8.52 (m, 2H), 8.02 - 7.96 (m, 1H), 7.82 - 7.75 (m, 1H), 7.52 - 7.45 (m, 1H), 7.39 - 7.32 (m, 1H), 6.87 - 6.80 (m, 1H), 4.67 (d, J = 8.6 Hz, 1H), 3.64 (dd, J = 7.6, 9.6 Hz, 1H), 3.53 - 3.41 (m, 2H), 3.33 (d, J = 8.2 Hz, 1H), 3.08 - 2.91 (m, 1H), 2.75 (br. d, J = 7.6 Hz, 1H), 1.91 - 1.73 (m, 2H); LCMS (ESI) m/z: 324.0 [M+H] ⁺ . Preparation of (1-benzyl-4-piperidyl)-(3-pyridyl)methanol (Compound 85). To a solution of 4-piperidyl(3-pyridyl)methanol.HCl (300 mg, 1.13 mmol) in dimethylformamide (3 mL) was added bromomethylbenzene (213 mg, 1.24 mmol) and triethylamine (572 mg, 5.66 mmol, 787 µL). The mixture was stirred at 25 °C for 3 hours. The reaction mixture was filtered, concentrated and was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5µm; 25-50% acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 minute gradient) to afford (1-benzyl-4-piperidyl)-(3- pyridyl)methanol (121 mg, 420 µmol, 37%) as a pink solid. ¹ H NMR (400 MHz, Methanol-d4) δ 8.59 - 8.34 (m, 2H), 7.80 (br. d, J = 7.8 Hz, 1H), 7.53 - 7.16 (m, 6H), 4.42 (br. d, J = 7.2 Hz, 1H), 3.49 (s, 2H), 3.07 - 2.77 (m, 2H), 2.14 - 1.83 (m, 3H), 1.72 - 1.54 (m, 1H), 1.51 - 1.18 (m, 3H); LCMS (ESI) m/z: 283.2 [M+H] ⁺ . Preparation of 2-[1-(3,4-dichlorophenyl)azetidin-3-yl]-1-(3-pyridyl)ethanol (Compound 86) and chiral separation into enantiomer 1 (compound 31) and enantiomer 2 (compound 32). Step 1: Preparation of methyl 2-[1-(3,4-dichlorophenyl)azetidin-3-yl]acetate. To a solution of 1,2-dichloro-4-iodo-benzene (1.68 g, 6.17 mmol) and methyl 2-(azetidin-3- yl)acetate.TFA (1.8 g, 7.40 mmol) in dimethylformamide (20 mL) were added cesium carbonate (6.03 g, 18.50 mmol), bis(dibenzylideneacetone)palladium(0) (142 mg, 247 µmol), and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (357 mg, 617 µmol). The mixture was stirred at 120 °C for 2 hours.. The resultant reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL), then extracted with ethyl acetate (50 mL * 2). The organic phase was separated, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by ISCO column chromatography (10 g silica, 0-40% ethyl acetate in petroleum ether, gradient over 20 minutes) to afford methyl 2-[1-(3,4- dichlorophenyl)azetidin-3-yl]acetate (1.2 g, 4.38 mmol, 71%) as a red oil. ¹ H NMR (400 MHz, Chloroform- d) δ 7.22 (d, J = 8.6 Hz, 1H), 6.47 (d, J = 2.3 Hz, 1H), 6.30 - 6.18 (m, 1H), 4.10 - 3.98 (m, 2H), 3.71 (s, 3H), 3.55 (br t, J = 6.3 Hz, 2H), 3.17 - 3.02 (m, 1H), 2.71 (br. d, J = 7.7 Hz, 2H); LCMS (ESI) m/z: 274.0 [M+H] ⁺ . Step 2: Preparation of 2-[1-(3,4-dichlorophenyl)azetidin-3-yl]acetaldehyde. To a solution of methyl 2-[1-(3,4-dichlorophenyl)azetidin-3-yl]acetate (1.1 g, 4.01 mmol) in dichloromethane (50 mL) was added diisobutylalumminum hydride (1 M, 12 mL). The mixture was stirred at -78 °C for 1 hour And reaction mixture was quenched by addition water (20 mL) at 0 °C, and then extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product was purified by ISCO column chromatography (40 g silica, 0-20% ethyl acetate in petroleum ether, gradient over 20 minutes). The product 2-[1-(3,4-dichlorophenyl)azetidin-3-yl]acetaldehyde (0.8 g, 3.28 mmol, 82%) was obtained as a yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 9.82 (s, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.46 (d, J = 2.6 Hz, 1H), 6.27 - 6.20 (m, 1H), 4.15 - 4.03 (m, 2H), 3.56 - 3.46 (m, 2H), 3.21 - 3.06 (m, 1H), 2.95 - 2.87 (m, 2H). Step 3: Preparation of 2-[1-(3,4-dichlorophenyl)azetidin-3-yl]-1-(3-pyridyl)ethanol and chiral separation into enantiomer 1 and enantiomer 2. To a solution of 3-iodopyridine (1 g, 4.92 mmol) in tetrahydrofuran (2 mL) was added a solution of isopropylmagnesium chloride (2 M, 2.46 mL) dropwise at 0 °C. The mixture was stirred at 25 °C for 1 hour. Then the mixture was cooled to 0 °C and in was added 2-[1-(3,4-dichlorophenyl)azetidin-3- yl]acetaldehyde (600 mg, 2.46 mmol). The mixture was stirred at 25 °C for 2 hours and was quenched by addition water (20 mL) at 0 °C, and then extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude residue was purified by prep-HPLC (column: Kromasil C18 (250*50mm*10 µm); 40-65% acetonitrile in an a 10mM ammonium bicarbonate solution in water, 10 minute gradient). The product 2-[1-(3,4-dichlorophenyl)azetidin-3-yl]-1-(3- pyridyl)ethanol (130 mg, 402 µmol, 16%) was obtained as a pale yellow gum. A portion of the compound 2-[1-(3,4-dichlorophenyl)azetidin-3-yl]-1-(3-pyridyl)ethanol was subjected to chiral purification using SFC (column: DAICEL CHIRALPAK IC(250mm*30mm,10µm); mobile phase: [0.1% ammonium:isopropyl alcohol]; B%: 45%-45%, 6 minutes) to afford enantiomers 1 and 2. ¹ H NMR (400 MHz, Chloroform-d) for compound 86 δ 8.59 - 8.50 (m, 2H), 7.76 - 7.68 (m, 1H), 7.35 - 7.29 (m, 1H), 7.20 (d, J = 8.8 Hz, 1H), 6.44 (d, J = 2.6 Hz, 1H), 6.25 - 6.18 (m, 1H), 4.86 - 4.77 (m, 1H), 4.03 - 3.89 (m, 2H), 3.56 - 3.47 (m, 1H), 3.47 - 3.39 (m, 1H), 2.98 - 2.84 (m, 1H), 2.32 - 2.12 (m, 2H), 2.12 - 2.00 (m, 1H); LCMS (ESI) m/z: 323.0 [M+H] ⁺ . 1H NMR (400 MHz, Chloroform-d) for compound 31 δ 8.68 - 8.45 (m, 2H), 7.82 - 7.63 (m, 1H), 7.37 - 7.29 (m, 1H), 7.24 - 7.16 (m, 1H), 6.44 (d, J = 2.6 Hz, 1H), 6.28 - 6.17 (m, 1H), 4.92 - 4.73 (m, 1H), 4.09 - 3.86 (m, 2H), 3.62 - 3.37 (m, 2H), 3.00 - 2.82 (m, 1H), 2.29 - 2.12 (m, 2H), 2.11 - 1.97 (m, 1H); LCMS (ESI) m/z: 323.0 [M+H] ⁺ . 1H NMR (400 MHz, Chloroform-d) for compound 32 δ 8.66 - 8.44 (m, 2H), 7.82 - 7.63 (m, 1H), 7.36 - 7.29 (m, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.48 - 6.40 (m, 1H), 6.27 - 6.17 (m, 1H), 4.88 - 4.73 (m, 1H), 4.09 - 3.86 (m, 2H), 3.59 - 3.37 (m, 2H), 2.99 - 2.83 (m, 1H), 2.51 - 2.26 (m, 1H), 2.25 - 2.12 (m, 1H), 2.11 - 1.98 (m, 1H); LCMS (ESI) m/z: 323.0 [M+H] ⁺ . Preparation of [1-(3,4-dichlorophenyl)pyrrolidin-3-yl]-pyridazin-3-yl-metha nol (Compound 87). Step 1: Preparation of tert-butyl 3-[hydroxy(pyridazin-3-yl)methyl]pyrrolidine-1-carboxylate. To a solution of 2,2,6,6-tetramethylpiperidine (1.06 g, 7.53 mmol, 1.28 mL) in tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M, 3.01 mL) dropwise at -30 °C. The mixture was stirred at 0 °C for 30 minutes. Then, tert-butyl 3-formylpyrrolidine-1-carboxylate (1 g, 5.02 mmol) in tetrahydrofuran (2 mL) and pyridazine (442 mg, 5.52 mmol, 398 µL) in tetrahydrofuran (2 mL) were added simultaneously to a cold solution of lithium tetramethylpiperidide at -70 °C. Then the mixture was stirred at -70 °C for 4 hours. To the mixture was added water (10 mL), and the mixture was extracted with ethyl acetate (20 mL x 6). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to give crude product. The crude product was purified by ISCO column chromatography (20 g silica, 80-100 % ethyl acetate in petroleum ether, gradient over 20 minutes). Product tert-butyl 3-[hydroxy(pyridazin-3- yl)methyl]pyrrolidine-1-carboxylate (600 mg, 2.15 mmol, 43%) was obtained as a brown oil. LCMS (ESI) m/z: 280.2 [M+H] ⁺ . Step 2: Preparation of pyridazin-3-yl(pyrrolidin-3-yl)methanol. A mixture of tert-butyl 3-[hydroxy(pyridazin-3-yl)methyl]pyrrolidine-1-carboxylate (600 mg, 2.15 mmol) in ethyl acetate (5 mL) was added hydrochloric acid/ethyl acetate (2 mL). The mixture was stirred at 25 °C for 30 minutes. The mixture was concentrated to give crude product which was carried onto the next step without purification. Step 3: Preparation of [1-(3,4-dichlorophenyl)pyrrolidin-3-yl]-pyridazin-3-yl-metha nol. To a solution of pyridazin-3-yl(pyrrolidin-3-yl)methanol (330 mg, 1.53 mmol, hydrochloric acid) in dimethylformamide (6 mL) was added 1,2-dichloro-4-iodo-benzene (459 mg, 1.68 mmol), cesium carbonate (997 mg, 3.06 mmol), bis(dibenzylideneacetone)palladium(0) (88 mg, 153 µmol), and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (89 mg, 153 µmol). The mixture was stirred at 120 °C for 15 hours under nitrogen. Then to the mixture was added water (10 mL), and the mixture was extracted with ethyl acetate (20 mL x 4). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated to give crude product. The crude product was purified by prep-HPLC (Kromasil C18 (250*50mm*10 µm) column; 35-60 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 10 minute gradient) to afford[1-(3,4-dichlorophenyl)pyrrolidin-3-yl]-pyridazin-3-yl - methanol (56 mg, 173 µmol, 11%) as a yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 9.20 (dt, J = 1.8, 4.4 Hz, 1H), 7.63 - 7.51 (m, 2H), 7.22 (d, J = 8.8 Hz, 1H), 6.59 (t, J = 2.4 Hz, 1H), 6.39 - 6.33 (m, 1H), 5.11 - 4.96 (m, 1H), 3.91 - 3.67 (m, 1H), 3.45 - 3.20 (m, 4H), 2.93 - 2.77 (m, 1H), 2.19 - 1.96 (m, 2H) LCMS (ESI) m/z: 324.0 [M+H] ⁺ . Preparation of [6-[hydroxy(3-pyridyl)methyl]-2-azaspiro[3.3]heptan-2-yl]-[6 -(trifluoromethyl)-3- pyridyl]methanone (Compound 91) To a solution of 6-(trifluoromethyl)pyridine-3-carboxylic acid (66 mg, 343 µmol) in dimethylformamide (2 mL) was added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (156 mg, 411 µmol), N,N-diisopropylethylamine (133 mg, 1.03 mmol, 179 µL), and 2-azaspiro[3.3]heptan-6-yl(3-pyridyl)methanol (70 mg, 343 µmol). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated in vacuum and the residue was purified by prep-HPLC (Waters Xbridge Prep OBD C18150*40mm*10µm column; 15-45 % acetonitrile in a 10mM ammonium bicarbonate solution in water, 8 minute gradient) to obtain [6-[hydroxy(3-pyridyl)methyl]-2- azaspiro[3.3]heptan-2-yl]-[6-(trifluoromethyl)-3-pyridyl]met hanone (11 mg, 29 µmol, 8%) as a yellow gum. ¹ H NMR (400 MHz, Methanol-d4) δ 8.94 (s, 1H), 8.50 (br. s, 1H), 8.45 - 8.39 (m, 1H), 8.26 (br. d, J = 8.2 Hz, 1H), 7.95 - 7.87 (m, 1H), 7.85 - 7.78 (m, 1H), 7.46 - 7.37 (m, 1H), 4.58 (t, J = 7.4 Hz, 1H), 4.46 - 4.36 (m, 1H), 4.35 - 4.27 (m, 1H), 4.25 - 4.17 (m, 1H), 4.16 - 4.07 (m, 1H), 2.59 - 2.40 (m, 1H), 2.35 - 2.24 (m, 2H), 2.21 - 2.09 (m, 2H); LCMS (ESI) m/z: 378.1 [M+H] ⁺ . Preparation of 6-(3,4-dichlorophenyl)-2-(3-pyridylsulfonyl)-2,6-diazaspiro[ 3.3]heptane (Compound 94) Step 1: Preparation of tert-butyl 6-(3,4-dichlorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxyl ate. To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (500 mg, 2.52 mmol) in dioxane (5 mL) was added 1,2-dichloro-4-iodo-benzene (688 mg, 2.52 mmol), sodium tert-butoxide (727 mg, 7.57 mmol) , tris(dibenzylideneacetone)dipalladium(0) (115 mg, 126 µmol), and 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (24 mg, 50 µmol). The mixture was stirred at 100 °C for 20 minutes under nitrogen. Water (10 mL) was added to the reaction, and the reaction mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated to dryness to give the crude product which was purified by ISCO column chromatography (10 g silica, 0-10 % ethyl acetate in petroleum ether, gradient over 20 minutes). The product tert-butyl 6-(3,4-dichlorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxyl ate (0.36 g, 1.05 mmol, 42%) was obtained as a white solid. ¹ H NMR (400 MHz, Chloroform-d) δ 7.23 (d, J = 8.6 Hz, 1H), 6.49 (d, J = 2.6 Hz, 1H), 6.27 (dd, J = 2.8, 8.7 Hz, 1H), 4.10 (s, 4H), 3.96 (s, 4H), 1.46 (s, 9H). Step 2: Preparation of 2-(3,4-dichlorophenyl)-2,6-diazaspiro[3.3]heptane. To a solution of tert-butyl 6-(3,4-dichlorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxyl ate (200 mg, 583 µmol) in dichloromethane (4 mL) was added trifluoroacetic acid (930 mg, 8.16 mmol, 604 µL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated to dryness to give the crude product. Product 2-(3,4-dichlorophenyl)-2,6-diazaspiro[3.3]heptane (0.42 g, crude, trifluoroacetic acid) was obtained as a brown solid. LCMS (ESI) m/z: 242.9 [M+H] ⁺ . Step 3: Preparation of 6-(3,4-dichlorophenyl)-2-(3-pyridylsulfonyl)-2,6-diazaspiro[ 3.3]heptane. To a solution of 2-(3,4-dichlorophenyl)-2,6-diazaspiro[3.3]heptane (200 mg, 560 µmol, trifluoroacetic acid) in dichloromethane (5 mL) was added pyridine-3-sulfonyl chloride (199 mg, 1.12 mmol) and triethylamine(227 mg, 2.24 mmol). The mixture was stirred at 20 °C for 1 hour andconcentrated to dryness to give the crude product. The crude product was purified by prep-HPLC (Waters Xbridge Prep OBD C18150*4010µM column; 40-70 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 minute gradient). The product 6-(3,4-dichlorophenyl)-2-(3-pyridylsulfonyl)- 2,6-diazaspiro[3.3]heptane (56 mg, 147 µmol, 26%) was obtained as a gray solid. ¹ H NMR (400 MHz, Chloroform-d) δ 9.09 (s, 1H), 8.91 (d, J = 4.8 Hz, 1H), 8.15 (br. d, J = 7.9 Hz, 1H), 7.56 (dd, J = 4.9, 7.9 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 6.43 (d, J = 2.3 Hz, 1H), 6.21 (dd, J = 2.4, 8.7 Hz, 1H), 4.02 (s, 4H), 3.86 (s, 4H); LCMS (ESI) m/z: 384.1 [M+H] ⁺ . Preparation of pyridazin-3-yl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro [3.3]heptan-6-yl]methanol (Compound 95). Step 1: Preparation of tert-butyl 6-[hydroxy(pyridazin-3-yl)methyl]-2-azaspiro[3.3]heptane-2-c arboxylate. To a solution of 2,2,6,6-tetramethylpiperidine (941 mg, 6.66 mmol, 1.13 mL) in tetrahydrofuran (15 mL) was added dropwise n-butyllithium (2.5 M, 2.66 mL) at -30 °C. Then the mixture was warmed up to 0 °C and stirred for 30 minutes. The mixture was then cooled to -70 °C followed by the addition of pyridazine (391 mg, 4.88 mmol, 352 µL) in tetrahydrofuran (1 mL), tert-butyl 6-formyl-2- azaspiro[3.3]heptane-2-carboxylate (1 g, 4.44 mmol), and 2,2,6,6-tetramethylpiperidine (941 mg, 6.66 mmol, 1.13 mL) in tetrahydrofuran (3 mL). The mixture was stirred at -70 °C for 2 hours. The mixture was then quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 5).The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated to give crude product. The crude product was purified by ISCO column chromatography (20 g silica, 90-100 % ethyl acetate in petroleum ether, gradient over 10 minutes) to affordtert-butyl 6-[hydroxy(pyridazin-3-yl)methyl]-2- azaspiro[3.3]heptane-2-carboxylate (0.6 g, 1.96 mmol, 44%) as a yellow oil. LCMS (ESI) m/z: 306.2 [M+H] ⁺ . Step 2: Preparation of 2-azaspiro[3.3]heptan-6-yl(pyridazin-3-yl)methanol. To a solution of tert-butyl 6-[hydroxy(pyridazin-3-yl)methyl]-2-azaspiro[3.3]heptane-2-c arboxylate (0.6 g, 1.96 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (1.57 g, 13.75 mmol, 1.02 mL). The mixture was stirred at 20 °C for 1 hour. LCMS showed the reaction was complete. The reaction mixture was concentrated to dryness to give the crude product 2-azaspiro[3.3]heptan-6-yl(pyridazin-3- yl)methanol (0.8 g, crude, trifluoroacetic acid salt) as a brown oil which was used further without purification. LCMS (ESI) m/z: 206.2 [M+H] ⁺ . Step 3: Preparation of pyridazin-3-yl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro [3.3]heptan-6- yl]methanone. To a solution of 2-azaspiro[3.3]heptan-6-yl(pyridazin-3-yl)methanol. (0.2 g, 626 µmol, trifluoroacetic acid salt) in dioxane (2 mL) were added 5-bromo-2-(trifluoromethyl)pyridine (142 mg, 626 µmol), sodium tert-butoxide (181 mg, 1.88 mmol), tris(dibenzylideneacetone)dipalladium(0) (29 mg, 31 µmol), and 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (6 mg, 13 µmol). The mixture was stirred at 100 °C for 20 minutes. LCMS showed the reaction was complete. Water (15 mL) was added to the reaction, and the reaction mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated to give crude product. The crude product was purified by prep-HPLC (Phenomenex Gemini-NX 150*305µ column; 16- 46 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 minute gradient) to afford pyridazin-3-yl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro [3.3]heptan-6-yl]methanone (10 mg, 29 µmol, 5%) as a pale yellow solid. LCMS (ESI) m/z: 349.0 [M+H] ⁺ . Step 4: Preparation of pyridazin-3-yl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro [3.3]heptan-6-yl]methanol. To a solution of pyridazin-3-yl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro [3.3]heptan-6- yl]methanone (10 mg, 29 µmol) in methanol (2 mL) was added sodium borohydride (2 mg, 57 µmol). The mixture was stirred at 20 °C for 30 minutes. LCMS showed the reaction was complete. The reaction mixture was concentrated to dryness to give the crude product. The crude was purified by prep-HPLC (Phenomenex Gemini-NX 150*305µ column; 15-45 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 11 minute gradient) to affordpyridazin-3-yl-[2-[6-(trifluoromethyl)-3-pyridyl]-2- azaspiro[3.3]heptan-6-yl]methanol (2 mg, 7 µmol, 23%) as a white solid. ¹ H NMR (400 MHz, Chloroform- d) δ 9.20 - 9.12 (m, 1H), 7.83 (d, J = 2.7 Hz, 1H), 7.59 - 7.39 (m, 3H), 6.69 (dd, J = 2.5, 8.5 Hz, 1H), 4.93 (t, J = 4.8 Hz, 1H), 4.03 - 3.89 (m, 5H), 2.74 - 2.63 (m, 1H), 2.48 (dd, J = 7.9, 11.6 Hz, 1H), 2.39 - 2.25 (m, 2H), 2.16 - 2.06 (m, 1H); LCMS (ESI) m/z: 351.1 [M+H] ⁺ . Preparation of 3-pyridyl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.5] nonan-7-yl]methanol (Compound 97). Step 1: Preparation of tert-butyl 7-[hydroxy(3-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-carboxy late. To a solution of 3-iodopyridine (947 mg, 4.62 mmol) in tetrahydrofuran (15 mL) was added isopropylmagnesium chloride (2 M, 2.31 mL) in tetrahydrofuran dropwise by syringe at 0 °C. The mixture was stirred at 0°C for 30 minutes. To the reaction was added tert-butyl 7-formyl-2-azaspiro[3.5]nonane-2- carboxylate (780 mg, 3.08 mmol) 0 °C. The solution was stirred at 20 °C for 1.5 hours. Saturated ammonium chloride solution (5 mL) was added to the reaction, and the reaction mixture was extracted with Ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to to obtin the crude product which was purified by ISCO column chromatography (10 g silica, 0-5 % methanol in dichloromethane, gradient over 20 min). The product tert-butyl 7-[hydroxy(3-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-carboxy late (0.8 g, 2.41 mmol, 78%) was obtained as a white solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.53 - 8.47 (m, 2H), 7.66 (br. d, J = 7.7 Hz, 1H), 7.31 - 7.28 (m, 1H), 4.42 (d, J = 7.1 Hz, 1H), 3.60 - 3.49 (m, 4H), 2.55-2.47 (m, 1H), 1.98 - 1.82 (m, 3H), 1.63 - 1.52 (m, 1H), 1.43 (s, 9H), 1.41 - 1.30 (m, 3H), 1.15 - 0.93 (m, 2H). Step 2: Preparation of 2-azaspiro[3.5]nonan-7-yl(3-pyridyl)methanol. A mixture of tert-butyl 7-[hydroxy(3-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-carboxy late (0.4 g, 1.20 mmol) in hydrochloric acid/methanol (4M, 4 mL) was stirred at 20 °C for 1 hour The reaction mixture was concentrated to dryness to give the crude product. Product 2-azaspiro[3.5]nonan-7-yl(3- pyridyl)methanol (380 mg, crude, hydrochloric acid) was obtained as a pale yellow gum. LCMS (ESI) m/z: 233.1 [M+H] ⁺ . Step 3: Preparation of 3-pyridyl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.5] nonan-7-yl]methanol. To a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (157 mg, 1.03 mmol, 156 µL) in dimethylsulfoxide (1.5 mL) was added 2-azaspiro[3.5]nonan-7-yl(3-pyridyl)methanol (120 mg, 517 µmol) and 5-fluoro-2-(trifluoromethyl)pyridine (128 mg, 775 µmol). The mixture was stirred at 80 °C for 2 hours. The reaction solution was filtered, and the filtrate was purified directly using prep-HPLC (Phenomenex Gemini-NX 150*305µM column; 20%-50% acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 minute gradient).to afford 3-pyridyl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.5] nonan-7- yl]methanol (77 mg, 203 µmol, 39%) as a white solid. ¹ H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.48 (d, J = 1.8 Hz, 1H), 8.44 (dd, J = 1.5, 4.8 Hz, 1H), 7.86 (d, J = 2.6 Hz, 1H), 7.68 (br. d, J = 7.9 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.34 (dd, J = 4.8, 7.8 Hz, 1H), 6.86 (dd, J = 2.5, 8.5 Hz, 1H), 5.32 (d, J = 4.5 Hz, 1H), 4.37 - 4.30 (m, 1H), 3.71 - 3.55 (m, 4H), 1.98 - 1.71 (m, 3H), 1.57 - 1.25 (m, 4H), 1.14 - 0.98 (m, 2H); LCMS (ESI) m/z: 378.2 [M+H] ⁺ . The following compound was synthesized according to the protocol described for the Compound 97. Synthesis of N-(pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)-2-azasp iro[3.3]heptan-6-amine (Compound 98): Step 1: preparation of tert-butyl 6-(pyridin-3-ylamino)-2-azaspiro[3.3]heptane-2-carboxylate. To a solution of 3-iodopyridine (386 mg, 1.88 mmol) in dioxane (4 mL) were added tert-butyl 6- amino-2-azaspiro[3.3]heptane-2-carboxylate (400 mg, 1.88 mmol), t-BuONa (543 mg, 5.65 mmol, 3 eq), Pd2(dba)3 (86 mg, 94 umol, 0.05 eq) and RuPhos (18 mg, 38 umol), then the mixture was stirred at 100 °C for 20 min under N2. The reaction mixture was diluted with 2 mL H2O and extracted with EtOAc(5 mL *3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column (ISCO 40 g silica,67-80% ethyl acetate in petroleum ether, gradient over 20 min) to obtain tert-butyl 6-(3-pyridylamino)-2-azaspiro[3.3]heptane-2- carboxylate (630 mg, crude) was obtained as a red solid. 1H NMR (400MHz, CHLOROFORM-d) δ 8.32 (dd, J=1.2, 4.6 Hz, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.90 (d, J=4.4 Hz, 1H), 7.24 - 7.12 (m, 1H), 6.99 - 6.91 (m, 1H), 4.11 (q, J=7.2 Hz, 1H), 3.93 - 3.78 (m, 2H), 2.75 - 2.52 (m, 2H), 2.16 - 1.97 (m, 3H), 1.46 - 1.35 (m, 9H), 1.25 (t, J=7.2 Hz, 1H). LCMS (ESI) m/z: 290.2 [M+H] ⁺ . Step 2: preparation of N-(pyridin-3-yl)-2-azaspiro[3.3]heptan-6-amine. To a solution of tert-butyl 6-(3-pyridylamino)-2-azaspiro[3.3]heptane-2-carboxylate (600 mg, 2.07 mmol) in DCM (6 mL), was added TFA (9.46 g, 82.94 mmol) and the resultant mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain N-(3-pyridyl)-2- azaspiro[3.3]heptan-6-amine (830 mg, crude, TFA) as a brown oil. LCMS (ESI) m/z: 190.3 [M+H] ⁺ . Step 3: preparation of N-(pyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)-2-azasp iro[3.3]heptan-6-amine. To a solution of DBU (322 mg, 2.11 mmol) in DMSO (3 mL), were added 5-fluoro-2- (trifluoromethyl)pyridine (174 mg, 1.06 mmol) and N-(3-pyridyl)-2-azaspiro[3.3]heptan-6-amine (200 mg, 1.06 mmol) and then the mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The crude product was purified by prep-HPLC ( Phenomenex Luna C18200*40mm*10um column; 20-50% acetonitrile in an a 0.2% formic acid solution in water, 8 min gradient) to give N-(3-pyridyl)-2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3 .3]heptan-6-amine (29 mg, 77 umol, 7% FA) as a pale yellow solid. 1H NMR (400MHz, METHANOL-d4) δ 7.94 - 7.72 (m, 3H), 7.54 (d, J=8.6 Hz, 1H), 7.18 (dd, J=4.8, 8.3 Hz, 1H), 7.01 (br d, J=8.6 Hz, 1H), 6.91 (br d, J=8.4 Hz, 1H), 4.11 (s, 2H), 3.99 (s, 2H), 3.88 (quin, J=7.4 Hz, 1H), 2.78 (ddd, J=2.5, 7.4, 10.1 Hz, 2H), 2.23 - 2.09 (m, 2H). LCMS (ESI for C17H17F3N4 [M+H] ⁺ : 335.1.

Preparation of 2-(3,4-dichlorophenyl)-6-(3-pyridylsulfonyl)-2-azaspiro[3.3] heptane (Compound 99). Step 1: Preparation of tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate. A solution of sodium sulfite (936 mg, 7.43 mmol) and sodium bicarbonate (624 mg, 7.43 mmol) in water (5 mL) was heated to 75 °C, and pyridine-3-sulfonyl chloride (594 mg, 3.34 mmol) was added dropwise . The reaction mixture was stirred at 75 °C for 1 h. The mixture was concentrated in vacuo. Dimethylformamide (5 mL), sodium bicarbonate (624 mg, 7.43 mmol, 289 µL), and tert-butyl 6-iodo-2- azaspiro[3.3]heptane-2-carboxylate (1.20 g, 3.71 mmol) were added to the residue. The reaction mixture was stirred at 75 °C for 2 hours. The mixture was filtered and washed with dimethylformamide (1 mL) to give filtrate. The crude product was purified by prep-HPLC (Kromasil C18 (250*50mm*10 µm column; 20%-50% acetonitrile in 10mM ammonium acetate bicarbonate in water, 10 minute gradient). Product 6- (3-pyridylsulfonyl)-2-azaspiro[3.3]heptane-2-carboxylate (310 mg, 916 µmol, 25%) was obtained as a white solid. LCMS (ESI) m/z: 339.2 [M+H] ⁺ . Step 2: Preparation of 6-(3-pyridylsulfonyl)-2-azaspiro[3.3]heptane. A solution of tert-butyl 6-(3-pyridylsulfonyl)-2-azaspiro[3.3]heptane-2-carboxylate (280 mg, 827 µmol) in trifluoroacetic acid (0.5 mL) and dichloromethane (0.5 mL) was stirred at 15 °C for 1 hour. The mixture was concentrated in vacuo and dissolved in methanol (4 mL). The solution was basified by ion exchange resin. Product 6-(3-pyridylsulfonyl)-2-azaspiro[3.3]heptane (220 mg, crude) was obtained as a yellow gum. LCMS (ESI) m/z: 239.1 [M+H] ⁺ . Step 3: Preparation of 2-(3,4-dichlorophenyl)-6-(3-pyridylsulfonyl)-2-azaspiro[3.3] heptane. To a solution of 6-(3-pyridylsulfonyl)-2-azaspiro[3.3]heptane (200 mg, 839 µmol), 1,2-dichloro-4- iodo-benzene (229 mg, 839 µmol), and sodium tert-butoxide (323 mg, 3.36 mmol) in dioxane (3 mL) was added tris(dibenzylideneacetone)dipalladium(0) (38 mg, 42 µmol) and 2-dicyclohexylphosphino-2′,6′- diisopropoxybiphenyl (8 mg, 17 µmol). The suspension was stirred at 100°C for 30 minutes under nitrogen.. The mixture was filtered and filtrate was concentrated. The crude product was purified by prep- HPLC (Waters Xbridge BEH C18100*25mm*5µm column; 45%-75% acetonitrile in an10mM ammonium acetate bicarbonate in water, 10 minute gradient). The product 2-(3,4-dichlorophenyl)-6-(3- pyridylsulfonyl)-2-azaspiro[3.3]heptane (50 mg, 129 µmol, 15%) was obtained as a white solid. ¹ H NMR (400 MHz, Chloroform-d-d) δ 9.01~9.09 (s, 1H), 8.92 - 8.90 (d, 1H), 8.20 - 8.17 (m, 1H), 7.56 – 7.53 (m, 1H), 7.23 - 7.21 (s, 1H), 6.46 – 6.45 (d, 1H), 6.25 – 6.23 (m, 1H), 3.90 - 3.84 (m, 2H), 3.80 – 3.76 (m, 2H), 3.75 - 3.71 (m, 1H), 2.85 – 2.80 (m, 2H), 2.57 – 2.51 (m, 2H); LCMS (ESI) m/z: 383.1 [M+H] ⁺ . Preparation of (S)-(2-(3-chloro-2-fluorophenyl)-2-azaspiro[3.3]heptan-6-yl) (pyridin-3-yl)methanol (Compound 107) To a solution of (S)-2-azaspiro[3.3]heptan-6-yl(3-pyridyl)methanol (150 mg, 734 µmol) in dimethylsulfoxide (4 mL), was added 1-chloro-2-fluoro-3-iodo-benzene (188 mg, 734 µmol), potassium carbonate (477 mg, 3.45 mmol), pyrrolidine-2-carboxylic acid (34 mg, 294 µmol), and copper(I) iodide (28 mg, 147 µmol). The mixture was stirred at 90 °C for 3 hours. LCMS showed the starting material was consumed completely and desired mass was detected. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. Purification by prep-HPLC ( Waters Xbridge Prep OBD C18 150*40mm*10µm column; 30%-70% acetonitrile in an a 0.04% ammonium hydroxide and 10mM ammonium bicarbonate solution, 8 minute gradient) afforded(S)-[2-(3-chloro-2-fluoro-phenyl)-2- azaspiro[3.3]heptan-6-yl]-(3-pyridyl)methanol (25 mg, 74 µmol, 10% as a pale yellow gum. ¹ H NMR (400 MHz, Chloroform-d) δ 8.53 (br. s, 2H), 7.67 (br. d, J = 7.9 Hz, 1H), 7.28 (br. d, J = 4.9 Hz, 1H), 6.92 - 6.83 (m, 1H), 6.76 - 6.67 (m, 1H), 6.29 (dt, J = 1.3, 8.1 Hz, 1H), 4.62 (d, J = 7.1 Hz, 1H), 4.01 - 3.93 (m, 2H), 3.92 - 3.84 (m, 2H), 2.60 - 2.47 (m, 1H), 2.38 - 2.22 (m, 3H), 2.19 - 2.04 (m, 2H); LCMS (ESI) m/z: 333.1 [M+H] ⁺ . The following compounds were synthesized according to the protocol described for the Compound 107. Preparation of (S)-[2-(6-bromopyridazin-3-yl)-2-azaspiro[3.3]heptan-6-yl]-( 3-pyridyl)methanol (Compound 112) and (S)-3-pyridyl-[2-[6-(trifluoromethoxy)pyridazin-3-yl]-2-azas piro[3.3]heptan-6- yl]methanol (Compound 7). Step 1: Preparation of 3-bromo-6-(trifluoromethoxy)pyridazine. To a solution of 6-bromopyridazin-3-ol (1 g, 5.71 mmol) in nitromethane (15 mL) was added 1- (trifluoromethyl)-1,2-benziodoxol-3-one (903 mg, 2.86 mmol). The mixture was stirred at 100 °C for 5 hours. The reaction mixture was concentrated in vacuum and the crude product was purified by ISCO column chromatography (20 g silica, 0-18 % ethyl acetate in petroleum ether, gradient over 20 minutes) to obtain 3-bromo-6-(trifluoromethoxy)pyridazine (150 mg, 432 µmol, 15%) as a white solid. LCMS (ESI) m/z: 243.1 [M+H] ⁺ . Step 2: Preparation of (S)-3-pyridyl-[2-[6-(trifluoromethoxy)pyridazin-3-yl]-2-azas piro[3.3]heptan-6- yl]methanol, (S)-[2-(6-bromopyridazin-3-yl)-2-azaspiro[3.3]heptan-6-yl]-( 3-pyridyl)methanol. To a solution of (S)-2-azaspiro[3.3]heptan-6-yl(3-pyridyl)methanol (120 mg, 588 µmol) in dimethylsulfoxide (3 mL) were added copper(I) iodide (22 mg, 118 µmol), 3-bromo-6- (trifluoromethoxy)pyridazine (143 mg, 588 µmol), potassium carbonate (325 mg, 2.35 mmol), and pyrrolidine-2-carboxylic acid (27 mg, 235 µmol) under nitrogen. The mixture was stirred at 90 °C for 3 hours and concentrated.The resultant crude product was purified by prep-HPLC (Waters Xbridge Prep OBD C18150*40mm*10µm column; 1-60 % acetonitrile in an a 0.05% ammonia solution in water, 8 minute gradient). The product (S)-3-pyridyl-[2-[6-(trifluoromethoxy)pyridazin-3-yl]-2-azas piro[3.3]heptan-6- yl]methanol (7 mg, 18 µmol, 3%) was obtained as a pale yellow solid and the product (S)-[2-(6- bromopyridazin-3-yl)-2-azaspiro[3.3]heptan-6-yl]-(3-pyridyl) methanol (16 mg, 42 µmol, 7%) was obtained as a pale yellow solid. 1H NMR (400 MHz, Chloroform-d) for compound 7 δ 8.59 - 8.48 (m, 2H), 7.72 - 7.65 (m, 1H), 7.32 - 7.27 (m, 1H), 7.03 - 6.95 (m, 1H), 6.65 - 6.58 (m, 1H), 4.71 - 4.62 (m, 1H), 4.17 - 4.09 (m, 2H), 4.09 - 4.02 (m, 2H), 2.67 - 2.50 (m, 2H), 2.37 - 2.30 (m, 2H), 2.24 - 2.13 (m, 2H). LCMS (ESI) m/z: 367.2 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d) for compound 112 δ 8.55 - 8.51 (m, 2H), 7.72 - 7.66 (m, 1H), 7.32 - 7.27 (m, 1H), 7.25 (s, 1H), 6.37 (d, J = 9.2, 1H), 4.66 (d, J = 6.8 Hz, 1H), 4.15 - 4.07 (m, 2H), 4.07 - 3.99 (m, 2H), 2.67 - 2.50 (m, 2H), 2.38 - 2.29 (m, 2H), 2.24 - 2.11 (m, 2H); LCMS (ESI) m/z: 361.0 [M+H] ⁺ . Preparation of 2-[3-ethyl-1-[6-(trifluoromethyl)-3-pyridyl]azetidin-3-yl]-1 -(3-pyridyl)ethanol (Compound 113) and its chiral separation into enantiomer 1 (compound 116) and enantiomer 2 (compound 46). Step 1: Preparation of tert-butyl 3-ethyl-3-(hydroxymethyl)azetidine-1-carboxylate. To a solution of 1-tert-butyl-3-methyl 3-ethylazetidine-1,3-dicarboxylate (8 g, 32.88 mmol) in tetrahydrofuran (100 mL) was added lithium borohydride (5.01 g, 230.17 mmol). The mixture was stirred at 20 °C for 3 hours. The mixture was quenched by ice-water (50 mL), and the aqueous solution was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by ISCO column chromatography (40 g silica, 0-40 % ethyl acetate in petroleum ether, gradient over 30 minutes) to obtain tert-butyl 3-ethyl-3-(hydroxymethyl)azetidine-1-carboxylate (6.5 g, 30.19 mmol, 92%) was obtained as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ 3.71 - 3.67 (m, 2H), 3.66 - 3.62 (m, 2H), 3.57 (d, J = 8.6 Hz, 2H), 1.73 - 1.56 (m, 2H), 1.48 - 1.37 (m, 9H), 0.93 - 0.83 (m, 3H). Step 2: Preparation of tert-butyl 3-ethyl-3-(methylsulfonyloxymethyl)azetidine-1-carboxylate. To a solution of tert-butyl 3-ethyl-3-(hydroxymethyl)azetidine-1-carboxylate (6.2 g, 28.80 mmol) in dichloromethane (100 mL) were added triethylamine (5.83 g, 57.60 mmol, 8.02 mL), and methanesulfonyl chloride (3.96 g, 34.56 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour and the mixture was quenched by water (30 mL) at 0°C, and the aqueous solution was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by ISCO column chromatography (40 g silica, 0-40 % ethyl acetate in petroleum ether, gradient over 20 minutes) to obtain tert-butyl 3-ethyl-3-(methylsulfonyloxymethyl)azetidine-1-carboxylate (8 g, 27.27 mmol, 95%) was obtained as a pale yellow oil. ¹ H NMR (400 MHz, Chloroform-d) δ 4.24 (s, 2H), 3.74 - 3.68 (m, 2H), 3.67 - 3.61 (m, 2H), 3.04 (s, 3H), 1.79 - 1.61 (m, 2H), 1.43 (s, 9H), 0.99 - 0.82 (m, 3H). Step 3: Preparation of tert-butyl 3-(cyanomethyl)-3-ethyl-azetidine-1-carboxylate. To a solution of tert-butyl 3-ethyl-3-(methylsulfonyloxymethyl)azetidine-1-carboxylate (4 g, 13.63 mmol) in dimethylsulfoxide (8 mL) was added sodium cyanide (935 mg, 19.09 mmol). The mixture was stirred at 80 °C for 16 h. To the mixture was added water (10 mL), and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by ISCO column chromatography (40 g silica, 0-80 % ethyl acetate in petroleum ether, gradient over 20 minutes) to obtaintert-butyl 3-(cyanomethyl)-3-ethyl-azetidine-1-carboxylate (2.6 g, 11.59 mmol, 85%) as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ 3.80 - 3.62 (m, 4H), 2.61 (s, 2H), 1.78 (q, J = 7.5 Hz, 2H), 1.44 (s, 9H), 0.94 (t, J = 7.5 Hz, 3H). Step 4: Preparation of tert-butyl 3-ethyl-3-(2-oxoethyl)azetidine-1-carboxylate. To a solution of tert-butyl 3-(cyanomethyl)-3-ethyl-azetidine-1-carboxylate (1 g, 4.46 mmol) in dichloromethane (12 mL) was added diisobutylalumminum hydride (1 M, 11.15 mL) at -70 °C. The mixture was warmed to 20 °C and stirred at 20 °C for 12 hours. The mixture was then quenched with saturated ammonium chloride (4 mL) and extracted with dichloromethane (10 mL x 3). The organic layer was washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated to give crude product. The crude product was purified by ISCO column chromatography (4 g silica, 20-50 % ethyl acetate in petroleum ether, gradient over 20 minutes) to obtain tert-butyl 3-ethyl-3-(2-oxoethyl)azetidine-1- carboxylate (0.13 g, 572 µmol, 13%) as a yellow oil. ¹ H NMR (400 MHz, Chloroform-d) δ 9.72 (t, J = 1.6 Hz, 1H), 3.70 - 3.62 (m, 4H), 2.67 (d, J = 1.6 Hz, 2H), 1.70 - 1.61 (m, 2H), 1.37 (s, 9H), 0.81 (t, J = 7.4 Hz, 3H). Step 5: Preparation of tert-butyl 3-ethyl-3-[2-hydroxy-2-(3-pyridyl)ethyl]azetidine-1-carboxyl ate. To a solution of 3-iodopyridine (152 mg, 744 µmol) in tetrahydrofuran (5 mL) was added isopropylmagnesium chloride (2 M, 372 µL) at 0 °C. The mixture was stirred at 0 °C for 30 minutes. Then, tert-butyl 3-ethyl-3-(2-oxoethyl)azetidine-1-carboxylate (130 mg, 572 µmol) in tetrahydrofuran (0.5 mL) was added dropwise to the reaction. The mixture was stirred at 20 °C for 3 hours and was quenched with water (5 mL) and extracted with ethyl acetate (15 mL x 4). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated to give crude product. The crude product was purified by ISCO column chromatography (10 g silica, 50-70 % ethyl acetate in petroleum ether, gradient over 20 minutes) to obtain tert-butyl 3-ethyl-3-[2-hydroxy-2-(3-pyridyl)ethyl]azetidine-1-carboxyl ate (240 mg, crude) as a yellow oil. ¹ H NMR (400 MHz, Chloroform-d) δ 8.52 - 8.42 (m, 2H), 7.66 (br. d, J = 7.9 Hz, 1H), 7.23 (dd, J = 4.8, 7.8 Hz, 1H), 4.78 (dd, J = 3.4, 9.7 Hz, 1H), 3.83 (d, J = 8.6 Hz, 1H), 3.56 (d, J = 8.8 Hz, 1H), 3.53 - 3.43 (m, 2H), 2.11 - 1.99 (m, 1H), 1.81 - 1.68 (m, 3H), 1.36 (s, 9H), 0.86 (t, J = 7.4 Hz, 3H). Step 6: Preparation of 2-(3-ethylazetidin-3-yl)-1-(3-pyridyl)ethanol. A mixture of tert-butyl 3-ethyl-3-[2-hydroxy-2-(3-pyridyl)ethyl]azetidine-1-carboxyl ate (240 mg, 783 µmol) in dichloromethane (2 mL) and trifluoroacetic aid (1 mL) was stirred at 20 °C for 1.5 hours. The mixture was concentrated to obtain the crude product. Then the crude product was dissolved in methanol (10 ml), basified by ion exchange resin, and the turbid liquid was filtered to remove the insoluble solids and the filtrate was concentrated in vacuo. The product 2-(3-ethylazetidin-3-yl)-1-(3-pyridyl)ethanol (130 mg, 630 µmol, 80%) was obtained as yellow oil. LCMS (ESI) m/z: 207.2 [M+H] ⁺ . Step 7: Preparation of 2-[3-ethyl-1-[6-(trifluoromethyl)-3-pyridyl]azetidin-3-yl]-1 -(3-pyridyl)ethanol and its chiral separation into pure enantiomers. To a solution of 2-(3-ethylazetidin-3-yl)-1-(3-pyridyl)ethanol (130 mg, 630 µmol) in dimethylformamide (2 mL) were added 5-fluoro-2-(trifluoromethyl)pyridine (114 mg, 693 µmol) and triethylamine (128 mg, 1.26 mmol). The mixture was stirred at 70 °C for 12 hours and concentrated. The resultant crude product purified directly by prep-HPLC Phenomenex Gemini-NX 150*30mm*5µm column; 21-51 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 minute gradient) to obtain the racemic compound 2-[3-ethyl-1-[6-(trifluoromethyl)-3-pyridyl]azetidin-3-yl]-1 -(3-pyridyl)ethanol. Then the racemic compound was subjected to preparative SFC (DAICEL CHIRALPAK AD(250mm*30mm,10µm) column, 40°C, eluting with 40% ethanol containing 0.1% ammonium hydroxide in a flow of 65 g/min carbon dioxide at 100 bar) to obtain enantiomer 1 (Rt=1.210min) and enantiomer 2 (Rt=1.344min). The product 2-[3-ethyl-1-[6-(trifluoromethyl)-3-pyridyl]azetidin-3-yl]-1 -(3-pyridyl)ethanol (67 mg, 190 µmol, 30%) was obtained as a pale yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.58 (d, J = 1.8 Hz, 1H), 8.54 (d, J = 3.6 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.76 (br. d, J = 7.9 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.32 (dd, J = 4.8, 7.8 Hz, 1H), 6.70 (dd, J = 2.6, 8.5 Hz, 1H), 4.94 (br. d, J = 8.4 Hz, 1H), 4.03 (d, J = 7.8 Hz, 1H), 3.77 (d, J = 7.6 Hz, 1H), 3.72 (d, J = 7.4 Hz, 1H), 3.63 (d, J = 7.4 Hz, 1H), 2.50 (br. s, 1H), 2.22 (dd, J = 9.9, 14.6 Hz, 1H), 2.02 - 1.88 (m, 3H), 1.03 - 0.94 (t, 3H) LCMS (ESI) m/z: 352.2 [M+H] ⁺ . Enantiomer 1 (20 mg, 57 µmol) was obtained as a pale yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.59 (d, J = 1.9 Hz, 1H), 8.55 (dd, J = 1.4, 4.7 Hz, 1H), 7.83 (d, J = 2.6 Hz, 1H), 7.75 (br. d, J = 7.9 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.31 (dd, J = 4.8, 7.8 Hz, 1H), 6.69 (dd, J = 2.6, 8.6 Hz, 1H), 4.94 (br. d, J = 9.9 Hz, 1H), 4.02 (d, J = 7.8 Hz, 1H), 3.77 (d, J = 7.6 Hz, 1H), 3.72 (d, J = 7.4 Hz, 1H), 3.61 (d, J = 7.4 Hz, 1H), 2.27 - 2.11 (m, 2H), 2.01 - 1.83 (m, 3H), 1.01 (t, J = 7.4 Hz, 3H) LCMS (ESI) m/z: 352.2 [M+H] ⁺ . Enantiomer 2 (22 mg, 61 µmol) was obtained as a pale yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.59 (d, J = 1.9 Hz, 1H), 8.55 (dd, J = 1.5, 4.8 Hz, 1H), 7.83 (d, J = 2.6 Hz, 1H), 7.75 (br. d, J = 7.9 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.32 (dd, J = 4.8, 7.8 Hz, 1H), 6.69 (dd, J = 2.6, 8.5 Hz, 1H), 4.94 (br. d, J = 9.8 Hz, 1H), 4.02 (d, J = 7.7 Hz, 1H), 3.77 (d, J = 7.6 Hz, 1H), 3.72 (d, J = 7.4 Hz, 1H), 3.61 (d, J = 7.3 Hz, 1H), 2.26 - 2.13 (m, 2H), 2.03 - 1.84 (m, 3H), 1.01 (t, J = 7.4 Hz, 3H)LCMS (ESI) m/z: 352.2 [M+H] ⁺ . Preparation of (4-methoxypyridin-3-yl)(2-(6-(trifluoromethyl)pyridin-3-yl)- 2-azaspiro[3.3]heptan-6- yl)methanol (Compound 114) and its chiral separation into enantiomer 1 (Compound 100) and enantiomer 2 (Compound 51). Step 1: Preparation of tert-butyl 6-(hydroxy(4-methoxypyridin-3-yl)methyl)-2-azaspiro[3.3]hept ane-2- carboxylate. To a solution of 3-iodo-4-methoxy-pyridine (390 mg, 1.66 mmol) in tetrahydrofuran (5 mL) was added isopropylmagnesium chloride (2 M, 1.24 mL) in tetrahydrofuran dropwise by syringe at 0 °C. The mixture was stirred at 0 °C for 1 hour. Then, tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (374 mg, 1.66 mmol) was added to the solution at 0 °C under nitrogen. The solution was stirred at 20 °C for 1 hour and was diluted with ammonium chloride (2 mL) and extracted with ethyl acetate (10mL x 3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO column chromatography (10 g silica, 70-100% ethyl acetate in petroleum ether, gradient over 20 minutes) to obtain tert-butyl 6-[hydroxy-(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]hepta ne-2-carboxylate (550 mg, 1.64 mmol, 99%) as a pale yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.49 - 8.29 (m, 2H), 6.76 (d, J = 5.6 Hz, 1H), 4.76 (br. d, J = 7.0 Hz, 1H), 3.92 - 3.85 (m, 5H), 3.84 - 3.77 (m, 2H), 2.97 - 2.84 (m, 1H), 2.57 (qd, J = 7.8, 15.6 Hz, 1H), 2.19 (br. d, J = 7.9 Hz, 2H), 2.10 - 1.96 (m, 2H), 1.41 (s, 9H); LCMS (ESI) m/z: 335.2 [M+H] ⁺ . Step 2: Preparation of (4-methoxypyridin-3-yl)(2-azaspiro[3.3]heptan-6-yl)methanol. To a solution of tert-butyl 6-[hydroxy-(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]hepta ne-2- carboxylate (500 mg, 1.50 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (2.39 g, 20.93 mmol). The mixture was stirred at 20 °C for 2 hours. The mixture was basified by ion exchange resin to pH ~9 at 0 °C and concentrated to obtain 2-azaspiro[3.3]heptan-6-yl-(4-methoxy-3-pyridyl)methanol (380 mg, 1.30 mmol, 87%, crude) as a white solid. LCMS (ESI) m/z: 235.1 [M+H] ⁺ . It was taken to the next step without purification. Step 3: Preparation of (4-methoxypyridin-3-yl)(2-(6-(trifluoromethyl)pyridin-3-yl)- 2-azaspiro[3.3]heptan-6- yl)methanol. To a solution of 1,8-Diazabicyclo[5.4.0]undec-7-ene (390 mg, 2.56 mmol, 386 µL) in dimethylsulfoxide (5 mL) were added 5-fluoro-2-(trifluoromethyl)pyridine (211 mg, 1.28 mmol) and 2- azaspiro[3.3]heptan-6-yl-(4-methoxy-3-pyridyl)methanol (300 mg, 1.28 mmol). The mixture was stirred at 60 °C for 12 hours. The reaction was filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by prep-HPLC (Kromasil C18 (250*50mm*10 µm column; 20-50% acetonitrile in an a 10mM ammonium bicarbonate solution in water, 10 minute gradient) to obtain (4-methoxy-3-pyridyl)-[2- [6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptan-6-yl]m ethanol (100% purity) ( total 471 mg ) as a pale yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.45 (s, 1H), 8.40 (s, 1H), 7.82 (d, J = 2.6 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 6.81 (d, J = 5.7 Hz, 1H), 6.68 (dd, J = 2.6, 8.6 Hz, 1H), 4.81 (br. d, J = 5.5 Hz, 1H), 4.03 - 3.96 (m, 2H), 3.96 - 3.88 (m, 5H), 2.69 (sxt, J = 7.8 Hz, 1H), 2.43 - 2.38 (m, 1H), 2.35 - 2.30 (m, 1H), 2.27 - 2.09 (m, 2H); LCMS (ESI) m/z: 380.2 [M+H] ⁺ . Step 4: Chiral separation of (4-methoxy-3-pyridyl)-[2-[6-(trifluoromethyl)-3-pyridyl]-2-a zaspiro[3.3]heptan- 6-yl]methanol to enantiomer 1 and enantiomer 2. The racemic (4-methoxy-3-pyridyl)-[2-[6-(trifluoromethyl)-3-pyridyl]-2-a zaspiro[3.3]heptan-6- yl]methanol (454 mg, 1.20 mmol) was subjected to chiral chromatography: SFC (column: Lux Cellulose-2 (50×4.6 mm,I.D.,3um);mobile phase: [0.05%ammonium:ethanol];B%: 5%-50%, minutes). The enantiomer 1 was obtained as white solid in 46% yield and enantiomer 2 was obtained in 48% yield as white solid. 1H NMR (400 MHz, Chloroform-d) for compound 100: δ 8.42 -8.39 (m, 2H), 7.82 (d, J = 2.6 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 6.81 (d, J = 5.7 Hz, 1H), 6.68 (dd, J = 2.6, 8.6 Hz, 1H), 4.81 (br. d, J = 5.5 Hz, 1H), 4.03 - 3.96 (m, 2H), 3.96 - 3.88 (m, 5H), 2.69 (sxt, J = 7.8 Hz, 1H), 2.43 - 2.30 (m, 2H), 2.27 - 2.09 (m, 2H); LCMS (ESI) m/z: 380.2 [M+H] ⁺ ; (Rt: 1.430min). 1H NMR (400 MHz, Chloroform-d) for compound 51: δ 8.45 - 8.40 (m, 2H), 7.82 (d, J = 2.6 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 6.81 (d, J = 5.7 Hz, 1H), 6.68 (dd, J = 2.6, 8.6 Hz, 1H), 4.81 (br. d, J = 5.5 Hz, 1H), 4.03 - 3.96 (m, 2H), 3.96 - 3.88 (m, 5H), 2.69 (sxt, J = 7.8 Hz, 1H), 2.43 - 2.30 (m, 2H), 2.27 - 2.09 (m, 2H); LCMS (ESI) m/z: 380.2 [M+H] ⁺ ; (Rt: 1.509min).

Preparation of 1-(3-pyridyl)-1-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspir o[3.3]heptan-6-yl]ethanol (Compound 117) Step 1: Preparation of 3-pyridyl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3] heptan-6-yl]methanone. To a solution of 3-pyridyl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3] heptan-6-yl]methanol (0.9 g, 2.58 mmol) in ethylene dichloride (18 mL) was added manganese(IV) oxide (2.24 g, 25.76 mmol). The mixture was stirred at 60 °C for 40 hours. The mixture was filtered, and the filtrate was dried over in vacuo to afford the crude product 3-pyridyl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3] heptan-6- yl]methanone (0.55 g, 1.58 mmol, 62%, crude) which was used into the next step without further purification. Step 2: Preparation of 1-(3-pyridyl)-1-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspir o[3.3]heptan-6-yl]ethanol. To a solution of 3-pyridyl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3] heptan-6-yl]methanone (60 mg, 173 µmol) in tetrahydrofuran (0.5 mL) was added methylmagnesium bromide (3 M, 115 µL, in tetrahydrofuran) at 0 °C. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched by addition of ammonium chloride (1 mL) and the reaction mixture was concentrated in vacuum. The residue was purified by prep-HPLC (Waters Xbridge 150*255µm column; 40-60 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 10 minute gradient) to obtain1-(3- pyridyl)-1-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3 ]heptan-6-yl]ethanol (31 mg, 86 µmol, 25%) was obtained as a pale yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.67 (d, 1H), 8.51 (d, J = 4, 1H), 7.81 (d, J = 2.4, 1H), 7.80 - 7.73 (m, 1H), 7.47 - 7.40 (m, 1H), 7.29 (br. d, J = 4.8 Hz, 1H), 6.70 - 6.64 (m, 1H), 4.03 - 3.92 (m, 2H), 3.90 - 3.83 (m, 2H), 2.66 - 2.53 (m, 1H), 2.42 - 2.26 (m, 2H), 2.22 - 2.12 (m, 1H), 1.98 - 1.83 (m, 2H), 1.52 (s, 3H). LCMS (ESI) m/z: 364.1 [M+H] ⁺ . Preparation of 6-[fluoro(3-pyridyl)methyl]-2-[6-(trifluoromethyl)-3-pyridyl ]-2-azaspiro[3.3]heptane (Compound 118) To a solution of 3-pyridyl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3] heptan-6-yl]methanol (200 mg, 573 µmol) in dichloromethane (4 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (253 mg, 1.14 mmol) under nitrogen. The mixture was stirred at -70 °C for 1.5 hours, then was stirred at -10 °C for 30 minutes The reaction mixture was concentrated in vacuum and the resultant crude product was purified by prep-HPLC (Phenomenex Gemini-NX 150*30mm*5µm column; 35-55 % acetonitrile in a 10mM ammonium bicarbonate solution in water, 8 minute gradient). Then the product was purified again by prep-HPLC (Phenomenex Luna C18100*30mm*5µm column; 15-45 % acetonitrile in an a 0.225% formic acid solution in water, 9 minute gradient). The product 6-[fluoro(3-pyridyl)methyl]-2-[6- (trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptane (12 mg, 34 µmol, 6%) was obtained as a pale yellow gum. ¹ H NMR (400 MHz, Chloroform-d) δ 8.63 - 8.58 (m, 1H), 8.57 - 8.53 (m, 1H), 7.86 - 7.81 (m, 1H), 7.67 - 7.62 (m, 1H), 7.47 - 7.42 (m, 1H), 7.36 - 7.30 (m, 1H), 6.73 - 6.65 (m, 1H), 5.50 - 5.36 (m, 1H), 4.04 - 3.98 (m, 2H), 3.97 - 3.90 (m, 2H), 2.82 - 2.64 (m, 1H), 2.43 - 2.26 (m, 4H). LCMS (ESI) m/z: 352.1 Synthesis of (3aR,6aS)-2-(3,4-dichlorophenyl)-5-(3-pyridylsulfonyl)-1,3,3 a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole (Compound 121): Step 1: tert-butyl (3aR,6aS)-2-(3,4-dichlorophenyl)-1,3,3a,4,6,6a-hexahydropyrr olo[3,4-c]pyrrole-5- carboxylate. To a solution of tert-butyl (3aR,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5 - carboxylate (400 mg, 1.88 mmol) in dioxane (4 mL) were added t-BuONa (543 mg, 5.65 mmol), Pd2(dba)3 (86 mg, 94 umol, 0.05 eq), RuPhos (18 mg, 38 umol) and 1,2-dichloro-4-iodo-benzene (514 mg, 1.88 mmol) and the resultant mixture was stirred at 100 °C for 20 min under N2.10 mL of water was added to the reaction mixture and the reaction mixture was extracted with Ethyl acetate (20 mL*3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated. The crude product was purified by flash column (ISCO 10 g silica, 0-15 % ethyl acetate in petroleum ether, gradient over 20 min). tert-butyl (3aR,6aS)-2-(3,4-dichlorophenyl)-1,3,3a,4,6,6a-hexahydropyrr olo[3,4-c]pyrrole-5- carboxylate (360 mg, 1.01 mmol, 53%) was obtained as a pale yellow solid. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.23 (d, J=8.9 Hz, 1H), 6.59 (d, J=2.8 Hz, 1H), 6.37 (dd, J=2.8, 8.8 Hz, 1H), 3.65 (br s, 2H), 3.50 (br s, 2H), 3.36 (br d, J=9.4 Hz, 1H), 3.26 (br s, 1H), 3.18 (dd, J=3.9, 9.6 Hz, 2H), 3.01 (br s, 2H), 1.46 (s, 9H) Step 2: (3aR,6aS)-5-(3,4-dichlorophenyl)-2,3,3a,4,6,6a-hexahydro-1H- pyrrolo[3,4-c]pyrrole. To a solution of tert-butyl (3aR,6aS)-2-(3,4-dichlorophenyl)-1,3,3a,4,6,6a-hexahydropyrr olo[3,4- c]pyrrole-5-carboxylate (340 mg, 952 umol) in DCM (4 mL) was added TFA (1.52 g, 13.32 mmol) at 0 °C, then the mixture was stirred at 20 °C for 2 h and concentrated. The crude product (3aR,6aS)-5-(3,4- dichlorophenyl)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyr role (760 mg, crude, TFA) was obtained as a brown gum. Step 3: (3aR,6aS)-2-(3,4-dichlorophenyl)-5-(3-pyridylsulfonyl)-1,3,3 a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrole. To a solution of (3aR,6aS)-5-(3,4-dichlorophenyl)-2,3,3a,4,6,6a-hexahydro-1H- pyrrolo[3,4- c]pyrrole (300 mg, 1.17 mmol) in DCM (4 mL) was added pyridine-3-sulfonyl chloride (414 mg, 2.33 mmol) and Et3N (472 mg, 4.67 mmol), then the mixture was stirred at 20 °C for 1h and concentrated. The resultant crude product was purified by prep-HPLC (Phenomenex Gemini-NX C1875*303u column; 30- 60 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 6 min gradient) to obtain (3aR,6aS)-2-(3,4-dichlorophenyl)-5-(3-pyridylsulfonyl)-1,3,3 a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole (32 mg, 76 umol, 7%) was obtained as a white solid. 1H NMR (400MHz, DMSO-d6) δ = 8.97 (d, J=1.9 Hz, 1H), 8.87 (dd, J=1.4, 4.8 Hz, 1H), 8.22 (td, J=1.8, 8.1 Hz, 1H), 7.66 (dd, J=4.8, 7.8 Hz, 1H), 7.32 (d, J=8.9 Hz, 1H), 6.62 (d, J=2.8 Hz, 1H), 6.44 (dd, J=2.8, 8.9 Hz, 1H), 3.42 (br dd, J=6.8, 10.1 Hz, 2H), 3.31 - 3.27 (m, 2H), 3.11 (dd, J=3.2, 10.2 Hz, 2H), 3.00 - 2.90 (m, 4H). LCMS (ESI) for C17H17Cl2N3O2S [M+H]+: 398.1

Preparation of 2,2,2-trifluoro-1-(3-pyridyl)-1-[2-[6-(trifluoromethyl)-3-py ridyl]-2-azaspiro[3.3]heptan- 6-yl]ethanol (Compound 122) To a solution of 3-pyridyl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3] heptan-6-yl]methanone (150 mg, 432 µmol) in tetrahydrofuran (3 mL) were added trimethyl(trifluoromethyl)silane (246 mg, 1.73 mmol) and cesium fluoride (72 mg, 475 µmol, 18 µL). The mixture was stirred at 60 °C for 12 hours. The reaction mixture was concentrated in vacuum and the crude product was purified by prep-HPLC (Phenomenex Gemini-NX C1875*30mm*3µm column; 40-60 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 minute gradient) to afford2,2,2-trifluoro-1-(3-pyridyl)-1-[2-[6- (trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptan-6-yl]etha nol (30 mg, 72 µmol, 17%) as a pale yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.78 - 8.73 (m, 1H), 8.61 (d, J = 3.8 Hz, 1H), 7.92 - 7.85 (m, 1H), 7.84 - 7.77 (m, 1H), 7.49 - 7.41 (m, 1H), 7.40 - 7.32 (m, 1H), 6.68 (dd, J = 2.6, 8.6 Hz, 1H), 4.15 - 3.96 (m, 2H), 3.94 - 3.78 (m, 2H), 3.75 - 3.48 (m, 1H), 3.23 - 3.06 (m, 1H), 2.62 - 2.48 (m, 1H), 2.47 - 2.34 (m, 1H), 2.20 - 2.03 (m, 1H), 2.02 - 1.87 (m, 1H). LCMS (ESI) m/z: 418.1 [M+H] ⁺ . Synthesis of 3-pyridyl-[2-[2-(trifluoromethyl)pyrimidin-5-yl]oxyspiro[3.3 ]heptan-6-yl]methanol (Compound 124): Step 1: preparation of methyl 2-[2-(trifluoromethyl)pyrimidin-5-yl]oxyspiro[3.3]heptane-6- carboxylate. To a solution of methyl 2-hydroxyspiro[3.3]heptane-6-carboxylate (1 g, 5.88 mmol) in DMF (15 mL) was added NaH (235 mg, 5.88 mmol, 60% purity) at 0 °C . The mixture was stirred at 20 °C for 30 min, 5-bromo-2-(trifluoromethyl)pyrimidine (1.33 g, 5.88 mmol) was added and the mixture was stirred at 20 °C for 12 h.15 mL of water was added to the reaction, the reaction mixture was extracted with ethyl acetate (30 mL*2). The combined organic layers were washed with brine (15 mL) and dried over Na2SO4 and concentrated. The crude product was purified by flash column (ISCO 10 g silica, 0-15 % ethyl acetate in petroleum ether, gradient over 20 min) to obtain methyl 2-[2-(trifluoromethyl)pyrimidin-5- yl]oxyspiro[3.3]heptane-6-carboxylate (580 mg, 1.83 mmol, 31%) as a yellow solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.39 (s, 2H), 4.72 (quin, J=6.8 Hz, 1H), 3.69 (s, 3H), 3.09 (quin, J=8.4 Hz, 1H), 2.76 - 2.56 (m, 2H), 2.48 - 2.19 (m, 6H) Step 2: preparation of 2-[2-(trifluoromethyl)pyrimidin-5-yl]oxyspiro[3.3]heptane-6- carbaldehyde. To a solution of methyl 2-[2-(trifluoromethyl)pyrimidin-5-yl]oxyspiro[3.3]heptane-6- carboxylate (500 mg, 1.58 mmol) in DCM (10 mL) was added DIBALH (1 M, 3.16 mL, 2 eq) in toluene at -60 °C. The mixture was stirred at -60 °C for 1h followed by the addition of 15 mL of water. The reaction mixture was extracted with DCM (30 mL*2), organic layers were washed with brine (15 mL) and dried over Na2SO4. Concentration and purification of the crude product by flash column (ISCO 10 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 20 min) afforded 2-[2-(trifluoromethyl)pyrimidin-5- yl]oxyspiro[3.3]heptane-6-carbaldehyde (130 mg, 454 umol, 29%) as a colorless oil. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 9.75 (d, J=1.8 Hz, 1H), 8.39 (s, 2H), 4.73 (quin, J=6.8 Hz, 1H), 3.26 - 3.10 (m, 1H), 2.78 - 2.67 (m, 1H), 2.59 (td, J=5.9, 12.0 Hz, 1H), 2.49 - 2.19 (m, 6H) Step 3: preparation of 3-pyridyl-[2-[2-(trifluoromethyl)pyrimidin-5-yl]oxyspiro[3.3 ]heptan-6-yl]methanol. To a solution of 3-iodopyridine (143 mg, 699 umol) in THF (2 mL) was added i-PrMgCl (2 M, 349 uL) in THF at 0 °C and the mixture was stirred at 0 °C for 0.5 h.2-[2-(trifluoromethyl)pyrimidin-5- yl]oxyspiro[3.3]heptane-6-carbaldehyde (100 mg, 349 umol) was then added at 0 °C. Then the mixture was warmed up and stirred at 25 °C for 1.5 h.10 mL of Saturated ammonium chloride solution was added to the reaction mixture and was extracted with ethyl acetate (20 mL*2). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4 and concentrated to dryness. The crude was purified by prep-HPLC (Phenomenex Gemini-NX C1875*303u column; 27-47 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 6 min gradient) to afford 3-pyridyl-[2-[2- (trifluoromethyl)pyrimidin-5-yl]oxyspiro[3.3]heptan-6-yl]met hanol (72 mg, 197 umol, 56%) as a white solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.59 - 8.48 (m, 2H), 8.37 (s, 2H), 7.67 (br d, J=7.9 Hz, 1H), 7.32 - 7.26 (m, 2H), 4.77 - 4.56 (m, 2H), 2.76 - 2.43 (m, 3H), 2.32 - 2.13 (m, 4H), 2.10 (br s, 1H), 2.03 - 1.90 (m, 2H). LCMS (ESI) for C18H18F3N3O2 [M+H]+: 366.2. Synthesis of pyridazin-3-yl-[2-[2-(trifluoromethyl)pyrimidin-5-yl]oxyspir o[3.3]heptan-6-yl]methanol (Compound 125) To a solution of 2,2,6,6-tetramethylpiperidine (111 mg, 786 umol) in THF (2 mL) was added n- BuLi (2.5 M, 314 uL, in hexane) at -30 °C, then the mixture was stirred at 0 °C for 30 min. Then pyridazine (46 mg, 576 umol) in THF (0.5 mL) and 2-[2-(trifluoromethyl)pyrimidin-5-yl]oxyspiro[3.3]heptane-6- carbaldehyde (150 mg, 524 umol) in THF (1 mL) were added simultaneously to a cold solution of LTMP at -70 °C. Then the mixture was stirred at -70 °C for 1.5 h. To the resultant mixture was added H2O (10 mL), extracted with EtOAc (30 mL*2), organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated to give crude product. The crude was purified by prep-HPLC (Phenomenex Gemini-NX C18 75*303u column; 20-40 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 6 min gradient) to afford pyridazin-3-yl-[2-[2-(trifluoromethyl)pyrimidin-5-yl]oxyspir o[3.3]heptan-6-yl]methanol (26 mg, 71 umol, 13%) as a pale yellow solid. 1H NMR (400MHz, CHLOROFORM-d) δ 9.21 - 9.07 (m, 1H), 8.37 (s, 2H), 7.53 - 7.43 (m, 2H), 4.89 (t, J=5.9 Hz, 1H), 4.79 - 4.63 (m, 1H), 2.76 - 2.50 (m, 3H), 2.36 - 1.89 (m, 6H). LCMS (ESI) for C17H17F3N4O2 [M+H]+: 367.1. The following compound(s) were synthesized according to the protocol described for the Compound 125: The following enantiopure compounds were separated using preparative SFC (Chiralpak AD-H 250x30mm, 10µm column, 40°C, eluting with 60% ethanol containing 0.1% ammonium hydroxide in a flow of 65 g/min CO2 at 100 bar) to give stereoisomer 1 of 3-pyridyl-[2-[[6-(trifluoromethyl)-3- pyridyl]oxy]spiro[3.3]heptan-6-yl]methanol (15 mg, 38 umol, 17%) as a yellow oil, SFC (rt=1.55); Stereoisomer 2 of 3-pyridyl-[2-[[6-(trifluoromethyl)-3-pyridyl]oxy]spiro[3.3]h eptan-6-yl]methanol (14 mg, 39 umol, 18%) was obtained as a yellow solid, SFC (rt=1.89); Stereoisomer 3 of 3-pyridyl-[2-[[6- (trifluoromethyl)-3-pyridyl]oxy]spiro[3.3]heptan-6-yl]methan ol (7 mg, 20 umol, 9%) was obtained as a white solid, SFC (rt=2.23); Stereoisomer 4 of 3-pyridyl-[2-[[6-(trifluoromethyl)-3- pyridyl]oxy]spiro[3.3]heptan-6-yl]methanol (3 mg, 7 umol, 3%) was obtained as a yellow solid, SFC (rt=2.38).

Synthesis of [4-(cyclobutoxy)-3-pyridyl]-[2-[6-(trifluoromethyl)-3-pyridy l]-2-azaspiro[3.3]heptan-6- yl]methanol (compound 131). Step 1: 4-(cyclobutoxy)-3-iodo pyridine. To a stirred solution of cyclobutanol (783 mg, 10.86 mmol, 1.3 eq) in THF (20 mL) was added t- BuOK (1.41 g, 12.53 mmol, 1.5eq) and 4-chloro-3-iodo-pyridine (2 g, 8.35 mmol, 1 eq). The reaction was stirred at 80 °C for 3 h. The resultant mixture was filtered and the filtrate was concentrated under reduce pressure afford crude product. The crude product was purified by flash column (ISCO 20 g silica, 0-15 % ethyl acetate in petroleum ether, gradient over 15 min) to obtain 4-(cyclobutoxy)-3-iodo-pyridine (1.9 g, 6.77 mmol, 81%) as a pale yellow oil. 1H NMR (400MHz, CHLOROFORM-d) δ 8.74 (s, 1H), 8.32 (d, J = 5.6 Hz, 1H), 6.58 (d, J = 5.5 Hz, 1H), 4.76 (quin, J = 7.0 Hz, 1H), 2.57 - 2.44 (m, 2H), 2.28 (ddq, J = 2.7, 7.5, 9.9 Hz, 2H), 2.01 - 1.85 (m, 1H), 1.82 - 1.68 (m, 1H).LCMS (ESI) m/z: 276.0 [M+H] ⁺ . Step 2: tert-butyl 6-[[4-(cyclobutoxy)-3-pyridyl]-hydroxy-methyl]-2-azaspiro[3. 3]heptane-2-carboxylate. To a stirred solution of 4-(cyclobutoxy)-3-iodo-pyridine (879 mg, 3.20 mmol, 1.2 eq) in THF (6 mL) was added i-PrMgCl (2 M, 1.60 mL, 1.2 eq) at 0 ºC, the mixture was stirred at 20 ºC for 1 h. Then tert- butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (600 mg, 2.66 mmol, 1 eq) in THF (2 mL) was added dropwise to the above solution and the mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (8 mL X 3). The combined organic phase was dried over Na2SO4 and concentrated. The crude product was purified by flash column (ISCO 20 g silica, 0-40 % ethyl acetate in petroleum ether, gradient over 20 min). tert-butyl 6-[[4-(cyclobutoxy)-3-pyridyl]- hydroxy-methyl]-2 azaspiro[3.3]heptane-2-carboxylate (800 mg, 2.14 mmol, 80%) was obtained as pale yellow oil. 1H NMR (400MHz, CHLOROFORM-d) δ 8.52 - 8.21 (m, 2H), 6.61 (d, J = 5.6 Hz, 1H), 4.87 - 4.61 (m, 2H), 3.95 - 3.81 (m, 4H), 2.65 - 2.55 (m, 1H), 2.55 - 2.46 (m, 2), 2.31 - 2.14 (m, 4H), 2.12 - 1.99 (m, 2H), 1.98 - 1.87 (m, 1H), 1.83 - 1.70 (m, 1H), 1.43 (s, 9H). LCMS (ESI) m/z: 375.2 [M+H] ⁺ . Step 3: 2-azaspiro[3.3]heptan-6-yl-[4-(cyclobutoxy)-3-pyridyl]methan ol. To a stirred solution of tert-butyl 6-[[4-(cyclobutoxy)-3-pyridyl]-hydroxy-methyl]-2- azaspiro[3.3]heptane-2-carboxylate (700 mg, 1.87 mmol, 1 eq) in DCM (6 mL) was added dropwise trifluoroacetic acid (3.59 g, 31.51 mmol). The mixture was stirred at 20 °C for 1 h and concentrated and the residue was further dissolved in MeOH (5mL), then was added AMbersep 900(OH),ion exchange resin(4g) let the pH to 8. The mixture was filtered and the filtrate was concentrated to dryness to give the product 2-azaspiro[3.3]heptan-6-yl-[4-(cyclobutoxy)-3-pyridyl]methan ol (500 mg, 1.82 mmol, 97%) as yellow oil. Step 4: [4-(cyclobutoxy)-3-pyridyl]-[2-[6-(trifluoromethyl)-3-pyridy l]-2-azaspiro[3.3]heptan-6-yl]methanol. To a stirred solution of 2-azaspiro[3.3]heptan-6-yl-[4-(cyclobutoxy)-3-pyridyl]methan ol (500 mg, 1.82 mmol, 1 eq) in N,N-dimethylformamide (5 mL) was added triethylamine (369 mg, 3.64 mmol) and 5- fluoro-2-(trifluoromethyl)pyridine (301 mg, 1.82 mmol, 1 eq). The mixture was stirred at 80 °C for 3 h. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (Waters Xbridge Prep OBD C18 150*40mm*10um column; 35-65 % acetonitrile in a 10mM ammonium hydroxide solution in water, 8 min gradient). The compound [4-(cyclobutoxy)-3-pyridyl]-[2-[6-(trifluoromethyl)-3-pyridy l]-2- azaspiro[3.3]heptan-6-yl]methanol (224 mg, 534 umol, 29%) was obtained as pale yellow solid. 1H NMR (400MHz, CHLOROFORM-d) δ 8.43 - 8.35 (m, 2H), 7.83 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 6.69 - 6.63 (m, 2H), 4.84 (m, 1H), 4.75 (br t, J = 7.1 Hz, 1H), 4.02 - 3.92 (m, 4H), 2.71 - 2.54 (m, 1H), 2.53 - 2.52 (m, 2H), 2.36 - 2.34 (m, 2H), 2.18 -2.23 (m, 4H),2.01 – 1.79 (m, 2H), 1.76 (quin, J = 9.4 Hz, 1H). LCMS (ESI) for C22H24F3N3O2 [M+H] ⁺ : 420.1.

The following compounds were synthesized according to the protocol described for the Compound 131:

Synthesis of (4-pyrazol-1-yl-3-pyridyl)-[2-[6-(trifluoromethyl)-3-pyridyl ]-2-azaspiro[3.3]heptan-6- yl]methanol (Compound 175). To a solution of 1H-pyrazole (35 mg, 521 umol) in DMF (1 mL) was added t-BuOK (70 mg, 625 umol) and (4-chloro-3-pyridyl)-[2-[6-(trifluoromethyl)-3-pyridyl]-2-az aspiro[3.3]heptan-6-yl]methanol (80 mg, 208 umol) and the mixture was stirred at 100 °C for 3 h. The resultant mixture was filtered and the filtrate was purified by prep-HPLC(Phenomenex Gemini-NX C18 75*30mm*3um column; 30%-60% acetonitrile in an a 0.05% ammonium hydroxide and 10mM sodium bicarbonate solution in water, 8min gradient). The compound (4-pyrazol-1-yl-3-pyridyl)-[2-[6-(trifluoromethyl)-3-pyridyl ]-2-azaspiro[3.3]heptan- 6-yl]methanol (32 mg, 76 umol, 36% was obtained as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.71 (s, 1H), 8.68 - 8.62 (m, 1H), 7.96 - 7.90 (m, 1H), 7.90 - 7.85 (m, 1H), 7.84 - 7.79 (m, 1H), 7.48 - 7.40 (m, 1H), 7.31 - 7.28 (m, 1H), 6.70 - 6.65 (m, 1H), 6.65 - 6.61 (m, 1H), 5.70 - 5.47 (m, 1H), 4.71 - 4.53 (m, 1H), 4.06 - 3.95 (m, 2H), 3.95 - 3.82 (m, 2H), 2.74 - 2.61 (m, 1H), 2.60 - 2.49 (m, 1H), 2.48 - 2.37 (m, 1H), 2.28 - 2.15 (m, 1H), 1.98 - 1.90 (m, 1H). LCMS (ESI for C21H20F3N5O) m/z: 416.2 [M+H] ⁺ The following compounds were synthesized according to the protocol described for Compound 175:

Synthesis of (4-methylsulfonyl-3-pyridyl)-[2-[6-(trifluoromethyl)-3-pyrid yl]-2-azaspiro[3.3]heptan-6- yl]methanol (Compound 181): To a solution of (4-chloro-3-pyridyl)-[2-[6-(trifluoromethyl)-3-pyridyl]-2-az aspiro[3.3]heptan-6- yl]methanol (130 mg, 339 umol) and azetidine;hydrochloride (475 mg, 5.08 mmol) in DMSO (1.5 mL) was added DIPEA (219 mg, 1.69 mmol). The mixture was stirred at 110 °C for 18 h. To the reaction was added an additional amount of azetidine;hydrochloride (158.45 mg, 1.69 mmol) and DIPEA (87.56 mg, 677.45 umol) and stirred further at 110 °C for 24 h. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (Phenomenex Gemini-NX C1875*30mm*3um column; 30-60 % acetonitrile in an a 0.05% ammonium hydroxide and 10mM ammonium bicarbonate solution in water, 8 min gradient) to obtain (4-methylsulfonyl-3-pyridyl)-[2-[6-(trifluoromethyl)-3-pyrid yl]-2-azaspiro[3.3]heptan-6-yl]methanol (6 mg, 13 umol, 4%) as pale yellow solid. This is a byproduct of the reaction where the source of the sulfone moiety is likely DMSO. 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.92 (s, 1H), 8.85 (d, J = 5.3 Hz, 1H), 7.88 (d, J = 5.1 Hz, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 6.72 (br d, J = 8.8 Hz, 1H), 5.40 (d, J = 6.8 Hz, 1H), 4.07 - 3.92 (m, 4H), 3.25 (s, 3H), 2.97 - 2.76 (m, 1H), 2.56 - 2.38 (m, 2H), 2.38 - 2.10 (m, 2H). LCMS (ESI) for C19H20F3N3O3S [M+H] ⁺ : 428.1 Synthesis of (4-cyclopropyl-3-pyridyl)-[2-[6-(trifluoromethyl)-3-pyridyl] -2-azaspiro[3.3]heptan-6- yl]methanol (Compound 182): To a solution of (4-chloro-3-pyridyl)-[2-[6-(trifluoromethyl)-3-pyridyl]-2-az aspiro[3.3]heptan-6- yl]methanol (130 mg, 339 umol) and cyclopropylboronic acid (58 mg, 677 umol) in dioxane (0.6 mL) and MeCN (0.6 mL) was added K2CO3 (140 mg, 1.02 mmol), P(Cy)3 (14 mg, 51 umol) and Pd2(dba)3 (31 mg, 34 umol). The mixture was bubbled with nitrogen for 1min and the resulting mixture was stirred at 110°C for 15h. The reaction mixture was concentrated to dryness to afford the crude product which was purified by prep-HPLC (Phenomenex Gemini-NX C1875*30mm*3um column; 35%-65% acetonitrile in an a 0.05% ammonium hydroxide and 10mM sodium bicarbonate solution in water, 8min gradient). The compound (4- cyclopropyl-3-pyridyl)-[2-[6-(trifluoromethyl)-3-pyridyl]-2- azaspiro[3.3]heptan-6-yl]methanol (52 mg, 129 umol, 38%) was obtained as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.65 (s, 1H), 8.36 (d, J = 5.5 Hz, 1H), 7.80 (d, J = 2.7 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 6.82 (d, J = 5.5 Hz, 1H), 6.65 (dd, J = 2.4, 8.6 Hz, 1H), 5.21 (d, J = 5.4 Hz, 1H), 3.97 (d, J = 11.0 Hz, 4H), 2.80 - 2.68 (m, 1H), 2.42 (dd, J = 7.9, 11.7 Hz, 1H), 2.35 - 2.22 (m, 3H), 2.15 - 2.07 (m, 1H), 1.22 (td, J = 4.0, 8.1 Hz, 2H), 0.93 - 0.85 (m, 2H). LCMS (ESI for C21H22F3N3O) [M+H] ⁺ : 390.2 Synthesis of 6-[methoxy(3-pyridyl)methyl]-2-[6-(trifluoromethyl)-3-pyridy l]-2-azaspiro[3.3]heptane (Compound 183): To a mixture of 3-pyridyl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3] heptan-6-yl]methanol (150 mg, 429 umol, 1 eq) in THF (2 mL) was added NaH (69 mg, 1.72 mmol, 60% purity) in one portion at 0 °C under nitrogen atmorphere. The mixture was stirred for 5 minutes. Then iodomethane (244 mg, 1.72 mmol) was added to the reaction solution. The mixture was warmed up and stirred at 25°C for 1 h. The reaction mixture was then cooled and quenched with water (0.5 ml) at 0°C. The crude residue was purified by prep-HPLC(Waters Xbridge Prep OBD C18150*40mm*10um; 40-70 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 min gradient to obtain 6-[methoxy(3-pyridyl)methyl]-2- [6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptane (92 mg, 253 umol, 59%) as a white solid. 1H NMR (400MHz, CHLOROFORM-d) δ 8.57 (br d, J = 3.4 Hz, 1H), 8.51 (s, 1H), 7.82 (d, J = 2.5 Hz, 1H), 7.60 (br d, J = 7.9 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.31 (dd, J = 4.9, 7.6 Hz, 1H), 6.67 (dd, J = 2.3, 8.4 Hz, 1H), 4.06 (d, J = 6.6 Hz, 1H), 4.00 - 3.94 (m, 2H), 3.93 - 3.84 (m, 2H), 3.26 (s, 3H), 2.56 - 2.41 (m, 1H), 2.31 (br d, J = 8.0 Hz, 2H), 2.12 (br d, J = 8.4 Hz, 2H). LCMS (ESI) for C19H20F3N3O [M+H] ⁺ : 364.1. The following compounds were synthesized according to the procedure described for the Compound 183.

Synthesis of [2-[5-fluoro-6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]h eptan-6-yl]-(3- pyridyl)methanol, (Compound 193). To a solution of 5-bromo-3-fluoro-2-(trifluoromethyl)pyridine (60 mg, 245 umol) in dioxane (1 mL) was added 2-azaspiro[3.3]heptan-6-yl(3-pyridyl)methanol (50 mg, 245 umol), Pd2(dba)3 (11 mg, 12 umol), RuPhos (2 mg, 5 umol) and t-BuONa (71mg, 734 umol) and the mixture was stirred at 100 °C for 15min under nitrogen atmosphere. The reaction mixture was then extracted with EtOAc (20 mL X 3) and the combined organic layers were washed with brine (15 mL) and dried over Na2SO4. The crude product was purified by prep-HPLC column: Phenomenex Luna C1875*30mm*3um; 20 %-40 % acetonitrile in an a 0.225% formic acid solution in water, 8 min gradient) to obtain [2-[5-fluoro-6-(trifluoromethyl)-3-pyridyl]-2- azaspiro[3.3]heptan-6-yl]-(3-pyridyl)methanol (8 mg, 21 umol, 9% ) as a yellow gum. 1H NMR (400MHz, CHLOROFORM-d) δ 8.60 - 8.50 (m, 2H), 7.69 (br d, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.31 (dd, J = 4.9, 7.7 Hz, 1H), 6.43 - 6.31 (m, 1H), 4.67 (d, J = 6.5 Hz, 1H), 4.05 - 3.98 (m, 2H), 3.97 - 3.90 (m, 2H), 2.63 - 2.51 (m, 1H), 2.39 - 2.27 (m, 2H), 2.26 - 2.14 (m, 2H). LCMS (ESI) for (C18H19F4N3O) [M+H] ⁺ : 368.1 Synthesis of (2-(5-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-azaspiro[3.3 ]heptan-6-yl)(pyridin-3- yl)methanol (Compound 194) and (2-(5-chloro-2-(trifluoromethyl)pyridin-3-yl)-2- azaspiro[3.3]heptan-6-yl)(pyridin-3-yl)methanol (Compound 195). To a solution of 2-azaspiro[3.3]heptan-6-yl(3-pyridyl)methanol (200 mg, 979 umol) in DMF (5 mL) was added 3,5-dichloro-2-(trifluoromethyl)pyridine (211 mg, 979 umol) and Et3N (198 mg, 2 mmol) and the mixture was stirred at 90 °C for 12 h. The resultant reaction mixture was extracted with EtOAc (20 mL*3), the combined organic layers were washed with brine (15 mL), dried over Na2SO4 and concentrated. The products were separated by column chromatography: (Phenomenex Luna C18 75*30mm*3um; 30-42 % acetonitrile in an a 0.225% formic acid solution in water, 8 min gradient) to obtain the regioisomers. [2-[5-chloro-6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]h eptan-6-yl]-(3-pyridyl)methanol (22mg, 57 umol, 6%) was obtained as a brown solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ 8.62 - 8.49 (m, 2H), 7.74 - 7.62 (m, 2H), 7.31 (dd, J = 4.9, 7.7 Hz, 1H), 6.68 (d, J = 2.1 Hz, 1H), 4.67 (d, J = 6.5 Hz, 1H), 4.08 - 3.98 (m, 2H), 3.97 - 3.88 (m, 2H), 2.66 - 2.50 (m, 1H), 2.42 - 2.28 (m, 2H), 2.26 - 2.14 (m, 2H). LCMS (ESI) for (C18H17ClF3N3O) [M+H] ⁺ : 384.1 Compound [2-[5-chloro-2-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]h eptan-6-yl]-(3- pyridyl)methanol (8 mg, 22 umol,1%) was obtained as a yellow solid. ¹ H NMR (400MHz, CHLOROFORM- d) δ 8.59 (br s, 2H), 7.92 (d, J = 1.8 Hz, 1H), 7.73 (br d, J = 8.1 Hz, 1H), 7.35 (br s, 1H), 6.76 (d, J = 1.6 Hz, 1H), 4.68 (d, J = 6.6 Hz, 1H), 4.08 (s, 2H), 4.04 - 3.97 (m, 2H), 2.62 - 2.50 (m, 1H), 2.32 (d, J = 7.9 Hz, 2H), 2.26 - 2.13 (m, 2H) LCMS (ESI) for (C18H17ClF3N3O) [M+H] ⁺ : 384.1. The following compounds were synthesized according to the protocol described for the Compound 107:

The following stereoisomers were separated similar to the conditions described for the compounds 100 and 51 using the one of the conditions mentioned below. General chiral prep HPLC conditions. Condition A: SFC (DAICEL CHIRALPAK IC(250mm*30mm,5um column, 40°C, eluting with organic solvent containing 0.1% ammonium hydroxide in a flow of 65 g/min CO2 at 100 bar). Condition B: SFC (Phenomenex-Cellulose-2 (250mm*30mm,10um) column, 40°C, eluting with organic solvent containing 0.1% ammonium hydroxide in a flow of 65 g/min CO2 at 100 bar). Organic solvent: 25-60% methanol, ethanol or isopropanol. The retention times mentioned for the possible stereoisomers are based on the order they are eluted from the column under the same condition. In the table below, * on the structure denotes a stereogenic center which is enantiomerically pure (either R or S). Confirmation of structure of Compound 34: Step 1: tert-butyl 6-[hydroxy(3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbox ylate. To a solution of 3-iodopyridine (32.76 g, 159.80 mmol) in THF (350 mL) was added i-PrMgCl (2 M, 79.90 mL) at 0 ºC and the mixture was stirred at 20 ºC for 1 h, then tert-butyl 6-formyl-2- azaspiro[3.3]heptane-2-carboxylate (18 g, 79.90 mmol) in THF (50 mL) was added to the mixture at 0 ºC. The resultant mixture was stirred at 20 ºC for 1h and quenched by the addition NH4Cl (300 mL), extracted with ethyl acetate (500 mL *4). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product which was purified by flash column (ISCO 100 g silica, 70-100% ethyl acetate in petroleum ether, gradient over 20 min). The product tert-butyl 6- [hydroxy(3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carboxyl ate (16 g, 52.57 mmol, 66%) was obtained as a pale yellow solid. Step 2: tert-butyl 6-(pyridine-3-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate . To a solution of tert-butyl 6-[hydroxy(3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbox ylate (7 g, 23.00 mmol) in DCE (120 mL) was added MnO2 (19.99 g, 229.97 mmol). The mixture was stirred at 60 ºC for 36 h, filtered and the filtrate was concentrated in vacuum. The crude product was purified by flash column (ISCO 40 g silica, 56-80% ethyl acetate in petroleum ether, gradient over 20 min) to afford tert- butyl 6-(pyridine-3-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate (6.2 g, 19.89 mmol, 87%) as a pale yellow gum. LCMS (ESI) m/z: 247.1 [M-56+H] ⁺ . Step 3: tert-butyl 6-[(S)-hydroxy(3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-ca rboxylate. To a solution of glucose dehydrogenase (GDH) (313 mg, 20.50 mmol),NADP (150 mg, 20.50 mmol), glucose (11.18 g, 20.50 mmol) and keto reductase (1.25 g, 20.50 mmol) in buffer (190 mL) was added drop wise tert-butyl 6-(pyridine-3-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate (6.2 g, 20.50 mmol, 1 eq) in DMSO (19 mL). Then the mixture was stirred at 30 ºC for 12h (pH was maintained around 7 using 4M NaOH). The mixture was filtered and the filtrate was extracted with ethyl acetate (80 mL*4). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the crude product. The compound tert-butyl 6-[(S)-hydroxy(3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2- carboxylate (6 g, 19.71 mmol, 96%) was obtained as a pale yellow solid. Note: Buffer: A mixture of NaH2PO4.2H2O (3.96 g) and Na2HPO4.12H2O (11.1 g) were dissolved in H2O (500 mL) to make 0.1 M (pH = 7) aqueous solution. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.51 - 8.41 (m, 2H), 7.7 - 7.6 (m, 1H), 7.26 - 7.18 (m, 1H), 4.59 – 4.50 (m, 1H), 3.94 - 3.71 (m, 4H), 2.5 – 2.35 (m, 1H), 2.24 – 2.12 (m, 2H), 2.09 - 1.95 (m, 2H), 1.48 - 1.35 (s, 9H). LCMS (ESI) m/z: 305.2 [M+H] ⁺ . Step 4: (S)-2-azaspiro[3.3]heptan-6-yl(3-pyridyl)methanol. To a solution of tert-butyl 6-[(S)-hydroxy(3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-ca rboxylate (5 g, 16.43 mmol) in DCM (34 mL) was added TFA (26.22 g, 229.97 mmol). The mixture was stirred at 15 ºC for 1h and concentrated. MeOH (10 mL) was added and the mixture was basified by resin AMBERSEP(R)900OH until pH > 7. Then the mixture was filtered and the filtrate was concentrated to obtain (S)-2-azaspiro[3.3]heptan-6-yl(3-pyridyl)methanol (4.5 g, crude) as a yellow gum. The crude product was used in the next steps without further purification. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.53 (s, 1H), 8.43 – 8.42 (m, 1H), 7.9 - 7.76 (m, 1H), 7.45 – 7.36 (m, 1H), 4.64 - 4.56 (m, 1H), 4.02 – 3.97 (d, 4H), 2.57 – 2.43 (m, 1H), 2.34 – 2.12 (m, 4H). LCMS (ESI) m/z: 205.2 [M+H] ⁺ . SFC (Rt =2.282) method: AD_IPA_DEA_5_40_34_35_4min. Step 5: (S)-[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-(3-p yridyl)methanol. To a solution of (S)-2-azaspiro[3.3]heptan-6-yl(3-pyridyl)methanol (150 mg, 734 umol) in DMSO (2 mL) was added K2CO3 (406 mg, 2.94 mmol), 1,2-dichloro-4-iodo-benzene (200 mg, 734 umol), pyrrolidine-2-carboxylic acid (34 mg, 294 umol) and CuI (28 mg, 147 umol) under N2. The mixture was stirred at 90 ºC for 3 h and concentrated in vacuum. The residue was purified by prep-HPLC (Waters Xbridge Prep OBD C18150*40mm*10um column;35-65% acetonitrile in an a 0.04% ammonia solution in water, 8 min gradient) to obtain (S)-[2-(3,4-dichlorophenyl)-2-azaspiro[3.3]heptan-6-yl]-(3- pyridyl)methanol (75 mg, 215 umol, 29%) as a pale yellow solid. LCMS (ESI) m/z: 349.2 [M+H] ⁺ , SFC (Rt =2.120) method: AD_MeOH_DEA_40_4_35. The chiral purity and enantiomeric form was confirmed by HPLC and X-ray crystallography respectively.

Synthesis of 6-[2-methoxy-1-(3-pyridyl)ethyl]-2-[6-(trifluoromethyl)-3-py ridyl]-2- azaspiro[3.3]heptane, (Compound 284). Step 1: tert-butyl 6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylate. To a solution of methoxymethyl(triphenyl)phosphonium;chloride (64.91 g, 189.34 mmol) in THF (400 mL) was added drop wise LDA (2 M, 94.67 mL, in THF/n-hexane) under nitrogen atmosphere at 0 ºC. The reaction mixture was stirred at 25 ºC for 2 h. Then a solution of tert-butyl 6-oxo-2- azaspiro[3.3]heptane-2-carboxylate (20 g, 94.67 mmol) in THF (150 mL) was added drop wise to the mixture at 0 ºC. The reaction mixture was stirred further at 60 ºC for 2 h. The mixture was poured into ice- water (200 mL) and the aqueous phase was extracted with ethyl acetate (300 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by flash column (ISCO 80 g silica, 0-15 % ethyl acetate in petroleum ether, gradient over 20 min) to obtain tert-butyl 6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylate (22 g, 82.74 mmol, 87%) as a yellow oil. Step 2: tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate. To a solution of tert-butyl 6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylate (20 g, 83.57 mmol, 1 eq) in dichloromethane (200 mL) and water (100 mL) was added 2,2,2-trichloroacetic acid (54.62 g, 334.29 mmol). Then the mixture was stirred at 25 ºC for 1 h followed by the addition of NaHCO3 solution to maintain pH above 7. The organic layer was collected and the aqueous phase was extracted with dichloromethane (300 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (17 g, 67.91 mmol, 81.6%) as a pale yellow solid. The crude product was used directly for the next step without purification 1H NMR (400 MHz, CHLOROFORM-d) δ 9.76 - 9.68 (m, 1H), 3.94 (s, 2H), 3.83 (s, 2H), 3.16 - 3.03 (m, 1H), 2.52 - 2.26 (m, 4H), 1.42 (s, 9H). Step 3: tert-butyl 6-[hydroxy(3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbox ylate. To a solution of 3-iodopyridine (17.74 g, 86.56 mmol) in THF (200 mL) was added i-PrMgCl (2 M, 43.28 mL in THF) at 0 ºC, then the mixture was warmed up and stirred at 25 ºC for 1 h. The mixture was cooled again to 0 ºC and tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (15 g, 66.58 mmol) was added. The resultant reaction mixture was warmed up and stirred at 25 ºC for 2 h and was quenched by the addition H2O (200 mL). The organics were separated and the aqueous phase was then extracted with ethyl acetate (400 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. It was then purified by flash column (ISCO 80 g silica, 80-100 % ethyl acetate in petroleum ether,gradient over 20 min) to afford tert-butyl 6- [hydroxy(3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carboxyl ate (10.5 g, 34.50 mmol, 52%) as a yellow gum. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.47 - 8.45 (m, 2H), 7.66 - 7.64 (m, 1H), 7.27-7.25 (m, 1H), 4.60 - 4.53 (m, 1H), 3.92 - 3.77 (m, 4H), 2.51 - 2.39 (m, 1H), 2.26 - 2.15 (m, 2H), 2.04 - 1.98 (m, 2H), 1.41 (s, 9H). Step 4: 2-azaspiro[3.3]heptan-6-yl(3-pyridyl)methanol. To a solution of tert-butyl 6-[hydroxy(3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbox ylate (9.5 g, 31.21 mmol) in dichloromethane (70 mL) was added trifluoroacetic acid (49.82 g, 436.95 mmol). The mixture was stirred at 25 ºC for 1 h. The reaction mixture was concentrated under vacuum and 50mL of MeOH was added followed by Ambersep|r 900(OH), ion exchange resin to maintain pH＞7. Then it was filtered and the filtrate was concentrated under reduced pressure to afford the desired product. The crude product 2-azaspiro[3.3]heptan-6-yl(3-pyridyl)methanol (8.6 g, crude) was taken to the next step without further purification. Step 5: 3-pyridyl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3] heptan-6-yl]methanol. To a solution of 2-azaspiro[3.3]heptan-6-yl(3-pyridyl)methanol (6 g, 29.37 mmol) in DMF (60 mL) was added Et3N (5.94 g, 58.75 mmol) and 5-fluoro-2-(trifluoromethyl)pyridine (4.12 g, 24.97 mmol) and then the mixture was stirred at 80 ºC for 2 h. The thus obtained reaction mixture was concentrated under vacuum and the crude product was purified by flash column (ISCO 40g silica, 70-100 % ethyl acetate in petroleum ether, gradient over 20 min). The compound 3-pyridyl-[2-[6-(trifluoromethyl)-3-pyridyl]-2- azaspiro[3.3]heptan-6-yl]methanol (4 g, 11.45 mmol, 39%) was obtained as a pale yellow gum. LCMS (ESI) m/z: 350.1 [M+H] ⁺ . Step 6: 3-pyridyl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3] heptan-6-yl]methanone. To a solution of 3-pyridyl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3] heptan-6-yl]methanol (3 g, 8.59 mmol) in dichloromethane (40 mL) was added Dess–Martin periodinane (7.28 g, 17.17 mmol) at 0 ºC. The reaction mixture was warmed up and stirred at 25 ºC for 1 h. The reaction mixture was then quenched by the addition of a solution of Na2SO3 (20 mL) and then stirred at 25 ºC for 0.5 h. The resultant mixture was extracted with Ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. It was purified by flash column (ISCO 40 g silica, 40-80% ethyl acetate in petroleum ether,gradient over 20 min) to obtain 3-pyridyl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3] heptan-6- yl]methanone (2.4 g, 6.91 mmol, 81%) as a pale yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.12 - 9.05 (m, 1H), 8.84 - 8.75 (m, 1H), 8.25 - 8.17 (m, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.50 - 7.39 (m, 2H), 6.71 (dd, J = 2.4, 8.4 Hz, 1H), 4.10 (s, 2H), 4.00 - 3.90 (m, 3H), 2.75 - 2.59 (m, 4H). LCMS (ESI) m/z: 348.1 [M+H] ⁺ . Step 7: 6-[(E)-2-methoxy-1-(3-pyridyl)vinyl]-2-[6-(trifluoromethyl)- 3-pyridyl]-2-azaspiro[3.3]heptane. To a solution of methoxymethyl(triphenyl)phosphonium.chloride (3.26 g, 9.50 mmol) in THF (12 mL) was added lithium diisopropylamide (2 M, 4.75 mL, in THF/n-hexane) at 0 ºC and then the mixture was stirred further at 25 ºC for 1 h. Then 3-pyridyl-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3] heptan- 6-yl]methanone (1.1 g, 3.17 mmol) in THF (5 mL) was added to the above solution at 0 ºC and the mixture was warmed up and stirred further at 25 ºC for 12 h. The reaction mixture was cooled to 0 ºC, H2O (10 mL) was added, extracted with ethyl acetate (50 mL x 4). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. It was purified by flash column chromatography (ISCO 40 g silica, 60-70% ethyl acetate in petroleum ether, gradient over 20 min) to afford 6-[(E)-2-methoxy-1-(3-pyridyl)vinyl]-2-[6- (trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptane (2 g, crude). It was taken to the next step without further purification. LCMS (ESI) m/z: 376.2 [M+H] ⁺ . Step 8: 2-(3-pyridyl)-2-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspir o[3.3]heptan-6-yl]acetaldehyde. To a solution of 6-[(E)-2-methoxy-1-(3-pyridyl)vinyl]-2-[6-(trifluoromethyl)- 3-pyridyl]-2- azaspiro[3.3]heptane (2.5 g, 6.66 mmol) in dichloromethane (25 mL) was added trifluoroacetic acid (7.59 g, 66.60 mmol), then the mixture was stirred at 25 ºC for 16h. The reaction mixture was quenched by the addition of Na2CO3 solution to adjust pH > 7, organic layer separated, and aqueous phase was extracted with dichloromethane (50mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product 2-(3-pyridyl)-2-[2-[6-(trifluoromethyl)-3- pyridyl]-2-azaspiro[3.3]heptan-6-yl]acetaldehyde (2.5g) as a pale yellow gum, which was taken into the next step without purificaton. LCMS (ESI) m/z: 362.2 [M+H]+. Step 9: 2-(3-pyridyl)-2-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspir o[3.3]heptan-6-yl]ethanol To a solution of 2-(3-pyridyl)-2-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspir o[3.3]heptan-6- yl]acetaldehyde (2.2 g, 6.09 mmol) in MeOH (40 mL) was added NaBH4 (691 mg, 18.26 mmol) at 0 ºC and the reaction mixture was warmed up and stirred at 25 ºC for 1 h. The mixture was then quenched by the addition of H2O (20 mL) at 0 ºC and extracted with ethyl acetate (50 mL x 3). The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. It was purified by flash column (ISCO 40 g silica, 90-100% ethyl acetate in petroleum ether, gradient over 20 min) to afford 2-(3-pyridyl)-2-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspir o[3.3]heptan-6-yl]ethanol (650 mg, 1.70 mmol, 28%) as a pale yellow solid. LCMS (ESI) m/z: 364.1 [M+H] ⁺ . Step 10: 6-[2-methoxy-1-(3-pyridyl)ethyl]-2-[6-(trifluoromethyl)-3-py ridyl]-2-azaspiro[3.3]heptane. To a solution of 2-(3-pyridyl)-2-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspir o[3.3]heptan-6-yl]ethanol (60 mg, 165.12 umol) in THF (2 mL) was added NaH (13 mg, 330 umol, 60% suspension) at 0 ºC .The mixture was further stirred at 0 ºC for 0.5 h and CH3I (23 mg, 165 umol) was added. The resultant mixture was stirred at 25 ºC for 1h, then cooled to 0 ºC and quenched with H2O. The aqueous phase was then extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by prep-HPLC (Waters Xbridge BEH C18100*30mm*10um column; 30-60% acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 min gradient) to afford 6-[2- methoxy-1-(3-pyridyl)ethyl]-2-[6-(trifluoromethyl)-3-pyridyl ]-2-azaspiro[3.3]heptane (21 mg, 55 umol, 33%) was obtained as a yellow gum. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.50 - 8.49 (m, 1H), 8.47 - 8.44 (m, 1H), 7.82 (d, J = 2.6 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.46 - 7.41 (m, 1H), 7.27 - 7.23 (m, 1H), 6.70 - 6.64 (m, 1H), 4.06 - 3.95 (m, 2H), 3.89 - 3.79 (m, 2H), 3.55 - 3.49 (m, 2H), 3.29 (s, 3H), 2.81 - 2.72 (m, 1H), 2.63 - 2.45 (m, 2H), 2.15 - 2.05 (m, 2H), 1.87 - 1.78 (m, 1H). LCMS (ESI for C20H22F3N3O) [M+H]+: 378.2. The following compounds were synthesized according to the protocol described for the Compound 284

Synthesis of 6-[2-methoxy-1-(4-methoxy-3-pyridyl)ethyl]-2-[6-(trifluorome thyl)-3-pyridyl]-2- azaspiro[3.3]heptane (compound 289). To a solution of 6-[(E)-2-methoxy-1-(4-methoxy-3-pyridyl)vinyl]-2-[6-(trifluo romethyl)-3-pyridyl]-2- azaspiro[3.3]heptane (150 mg, 185 umol) in MeOH (2 mL) was added Pd/C (15 mg, 10%, 1.00 eq) and the resultant mixture was stirred at 25 °C for 2 h under H2 balloon. The mixture was filtered and the filtrate was concentrated under vacuum. The crude product was purified by prep-HPLC (Phenomenex Luna C18 200*40mm*10um column; 20-60 % acetonitrile in an a 0.2% formic acid solution in water, 8 min gradient) to afford 6-[2-methoxy-1-(4-methoxy-3-pyridyl)ethyl]-2-[6-(trifluorome thyl)-3-pyridyl]-2- azaspiro[3.3]heptane (23 mg, 55 umol, 30%) as a pale yellow gum. 1H NMR (400MHz, CHLOROFORM-d) δ 8.47 (d, J = 6.2 Hz, 1H), 8.39 (s, 1H), 7.82 (d, J = 2.6 Hz, 1H), 7.46 - 7.43 (m, 1H), 7.12 - 7.03 (m, 1H), 6.69 (dd, J = 2.4, 8.6 Hz, 1H), 4.07 (s, 3H), 4.05 - 4.02 (m, 1H), 4.01 - 3.97 (m, 1H), 3.92 - 3.87 (m, 1H), 3.87 - 3.81 (m, 1H), 3.56 - 3.49 (m, 1H), 3.47 - 3.41 (m, 1H), 3.33 - 3.24 (m, 4H), 2.72 - 2.59 (m, 1H), 2.53-2.47 (m, 1H), 2.17 - 2.02 (m, 2H), 1.78-1.73 (m, 1H). LCMS (ESI for C21H24F3N3O2 [M+H] ⁺ : 408.1. Synthesis of 1-(4-methoxy-3-pyridyl)-1-[2-[6-(trifluoromethyl)-3-pyridyl] -2-azaspiro[3.3]heptan-6- yl]propan-2-one (Compound 290) and 1-(4-methoxy-3-pyridyl)-2-methyl-1-[2-[6-(trifluoromethyl)-3 - pyridyl]-2-azaspiro[3.3]heptan-6-yl]propan-2-ol (Compound 291). Step 1: 1-(4-methoxy-3-pyridyl)-1-[2-[6-(trifluoromethyl)-3-pyridyl] -2-azaspiro[3.3]heptan-6-yl]propan-2-ol. To a solution of 2-(4-methoxy-3-pyridyl)-2-[2-[6-(trifluoromethyl)-3-pyridyl] -2-azaspiro[3.3]heptan- 6-yl]acetaldehyde (900 mg, 1.15 mmol) in THF (10 mL) at 0 °C was added bromo(methyl)magnesium (3 M, 1.15 mL) drop-wise with stirring at 0° C. The reaction was stirred at 0° C for 2h. The mixture poured into ice-water(10 mL), and the aqueous phase was extracted with DCM (10 mL*3). The combined organic phase was washed with brine (5 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to afford crude product. The crude product was purified by flash column (ISCO 10 g silica, 0-20 % MeOH in DCM, gradient over 20 min) to afford 1-(4-methoxy-3-pyridyl)-1-[2-[6-(trifluoromethyl)-3-pyridyl] -2- azaspiro[3.3]heptan-6-yl]propan-2-ol (330 mg, 810umol, 70%) as a yellow gum. Step 2: 1-(4-methoxy-3-pyridyl)-1-[2-[6-(trifluoromethyl)-3-pyridyl] -2-azaspiro[3.3]heptan-6-yl]propan-2- one. To a solution of 1-(4-methoxy-3-pyridyl)-1-[2-[6-(trifluoromethyl)-3-pyridyl] -2-azaspiro[3.3]heptan- 6-yl]propan-2-ol (330 mg, 810 umol, 1 eq) in DCM (6 mL) was added to Des-Martin periodinane (687 mg, 1.62 mmol) at 0 °C. Then the mixture was stirred at 25°C for 2h. The mixture was poured into sat.Na2CO3 (5 mL) and sat. Na2SO3 (5mL) at 0°C and stirred for 2h and the aqueous phase was extracted with Ethyl acetate (15 mL*3). The combined organic phase was washed with brine (10 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to afford crude product. The crude product was purified by flash column (ISCO 12 g silica, 0-80 % ethyl acetate in petroleum ether, gradient over 20 min) to give 280 mg crude product.20 mg crude product was purified by prep-HPLC (Phenomenex Luna C18 75*30mm*3um column; 15-50 % acetonitrile in an a 0.2% formic acid solution in water, 8 min gradient) to give 11 mg product as white solid. The reminder of the 260 mg was used directly in the next step without further purification. ¹ H NMR (400MHz, CHLOROFORM-d) δ 8.47 (br d, J = 5.5 Hz, 1H), 8.25 (s, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 6.85 (d, J = 5.7 Hz, 1H), , 4.09 - 4.03 (m, 1H), 4.01 - 3.96 (m, 1H), 3.92 (s, 3H), 3.91 - 3.79 (m, 3H), 3.00 - 2.84 (m, 1H), 2.61 (ddd, J = 4.4, 7.7, 12.0 Hz, 1H), 2.19 - 2.09 (m, 1H), 2.07 - 1.95 (m, 4H), 1.89 - 1.74 (m, 1H). LCMS (ESI for C21H22F3N3O2 [M+H] ⁺ : 406.1. Step 2: 1-(4-methoxy-3-pyridyl)-2-methyl-1-[2-[6-(trifluoromethyl)-3 -pyridyl]-2-azaspiro[3.3]heptan-6- yl]propan-2-ol. A solution of 1-(4-methoxy-3-pyridyl)-1-[2-[6-(trifluoromethyl)-3-pyridyl] -2-azaspiro[3.3]heptan-6- yl]propan-2-one (50 mg, 123 umol) in THF (1 mL) was degassed and purged with N2 three times and cooled to 0 °C. Bromo(methyl)magnesium (3 M, 82 uL, 2 eq) was added and the mixture was stirred at 0 °C for 2 h under N2 atmosphere. The resultant mixture was poured into ice-water (2 mL), the aqueous phase was extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (2 ml), dried with anhydrous Na2SO4, filtered and concentrated to afford crude product. The crude residue was purified by prep-HPLC (Phenomenex Luna C1875*30mm*3um column; 35-60% MeOH in an a 0.2% formic acid solution in water, 8 min gradient) to obtain 1-(4-methoxy-3-pyridyl)-2-methyl-1-[2-[6- (trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptan-6-yl]prop an-2-ol (50 mg, 116 umol, 31%) as a white solid. 1H NMR (400MHz, CHLOROFORM-d) δ 8.47 - 8.38 (m, 1.8H), 7.81 (d, J = 2.6 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 6.1 Hz, 0.8H), , 6.67 (dd, J = 2.6, 8.5 Hz, 1H), 4.10 - 4.04 (m, 1H), 4.03 - 3.93 (m, 4H), 3.87 - 3.80 (m, 1H), 3.78 - 3.70 (m, 1H), 3.28 (d, J = 10.9 Hz, 1H), 2.93 (br dd, J = 8.5, 17.4 Hz, 1H), 2.70 - 2.58 (m, 1H), 2.26 - 2.09 (m, 1H), 2.06 - 1.95 (m, 1H), 1.49 (t, J = 10.7 Hz, 1H), 1.32 - 1.23 (m, 3H), 1.10 - 1.00 (m, 3H). LCMS (ESI for C22H26F3N3O2 [M+H] ⁺ : 422.1. Synthesis of 2-(3-chloro-4-fluoro-phenyl)-6-[(4-methoxy-3-pyridyl)methyl] -2-azaspiro[3.3]heptan-6- ol (compound 292): Step 1: tert-butyl 6-[chloro-(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]heptan e-2-carboxylate. To a solution of tert-butyl 6-[hydroxy-(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]hepta ne-2- carboxylate (2 g, 5.98 mmol) in DCM (60 mL) was added Et3N (3.03 g, 29.90 mmol) followed by drop- wise addition of MsCl (2.71 g, 23.66 mmol) at 0~5 ºC The resultant mixture stirred at 20 ºC for 58 h under N2 and was quenched by addition H2O (50 mL) at 0 ºC. The organic phase was collected, and the H2O phase was then extracted with ethyl acetate (150 mL *2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product tert-butyl 6-[chloro-(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]heptan e-2- carboxylate (6 g, crude) was taken to the next step without further purification. LCMS (ESI) m/z: 353.3 [M+H] ⁺ . Step 2: tert-butyl 6-[(4-methoxy-3-pyridyl)methylene]-2-azaspiro[3.3]heptane-2- carboxylate. Tert-butyl 6-[chloro-(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]heptan e-2-carboxylate (1 g, 2.83 mmol) and DBU (1.52 g, 9.95 mmol) were taken up into a microwave tube in dioxane (10 mL). The sealed tube was heated at 120 °C for 3 h under microwave. The reaction mixture was quenched by addition H2O (10 mL) and the H2O phase was then extracted with EtOAc (30 mL *3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain tert-butyl 6-[(4-methoxy-3-pyridyl)methylene]-2-azaspiro[3.3]heptane-2- carboxylate (1 g, 3.16 mmol, 19%) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.37 - 8.29 (m, 2H), 6.83 - 6.78 (m, 1H), 6.39 - 6.33 (s, 1H), 4.01 - 3.96 (m, 4H), 3.90 (s, 3H), 3.18 - 3.13 (m, 2H), 3.10 - 3.04 (m, 2H), 1.46 - 1.43 (s, 9H). LCMS (ESI) m/z: 317.3 [M+H] ⁺ . Step 3: tert-butyl 1-(4-methoxy-3-pyridyl)-2-oxa-7-azadispiro[2.1.35.13]nonane- 7-carboxylate. To a solution of tert-butyl 6-[(4-methoxy-3-pyridyl)methylene]-2-azaspiro[3.3]heptane-2- carboxylate (400 mg, 1.26 mmol) in H2O (6 mL) and t-BuOH (3 mL) was added NBS (225 mg, 1.26 mmol). Then the mixture was stirred at 50 ºC for 2 h followed by the addition of NaOH (152 mg, 3.79 mmol) and the mixture was stirred at 25 ºC for 1 h. The the resultant reaction mixture was added H2O (2 mL), then the H2O phase was then extracted with DCM (3 mL *2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl 1-(4-methoxy-3- pyridyl)-2-oxa-7-azadispiro[2.1.35.13]nonane-7-carboxylate (350 mg, 1.05 mmol, 83%) which was used in the next step without further purification. Step 4: tert-butyl 6-hydroxy-6-[(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]hep tane-2-carboxylate. To a solution of tert-butyl 1-(4-methoxy-3-pyridyl)-2-oxa-7-azadispiro[2.1.35.13]nonane- 7- carboxylate (330mg, 993 umol) in MeOH (6 mL) was added Pd/C (300 mg, 10% purity). Then the mixture was then stirred under hydrogen atmosphere at 20 ºC for 1.5 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain tert-butyl 6-hydroxy-6-[(4-methoxy-3-pyridyl)methyl]- 2-azaspiro[3.3]heptane-2-carboxylate (330 mg, 790 umol, 80%) as a pale yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.68 - 8.62 (s, 1H), 8.56 - 8.49 (m, 1H), 7.21 - 7.14 (m, 1H), 4.16 - 4.06 (s, 3H), 4.01 - 3.94 (m, 2H), 3.94 - 3.89 (m, 2H), 2.98 - 2.92 (m, 2H), 2.38 - 2.26 (m, 4H), 1.48 - 1.43 (s, 9H). LCMS (ESI) m/z: 335.4 [M+H] ⁺ . Step 5: 6-[(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]heptan-6-ol. To a solution of tert-butyl 6-hydroxy-6-[(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]hep tane-2- carboxylate (320 mg, 957 umol) in DCM (3 mL) was added TFA (2.24 g, 19.65 mmol) and the mixture was stirred at 20 ºC for 1 h. The reaction mixture was concentrated under reduced pressure and methanol (5 mL) was added followed by Ambersep|r 900(OH), ion exchange resin to increase pH＞7. The resultant mixture was filtered and the filtrate was concentrated in vacuum. Compound 6-[(4-methoxy- 3-pyridyl)methyl]-2-azaspiro[3.3]heptan-6-ol (180 mg, 768 umol, 80%) was obtained as a pale yellow gum. LCMS (ESI) m/z: 235.3 [M+H] ⁺ Step 6: 2-(3-chloro-4-fluoro-phenyl)-6-[(4-methoxy-3-pyridyl)methyl] -2-azaspiro[3.3]heptan-6-ol. To a solution of 6-[(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]heptan-6-ol (80 mg, 342 umol, 1 eq) in DMSO (3 mL) were added 2-chloro-1-fluoro-4-iodo-benzene (88 mg, 342 umol), CuI (26 mg, 137 umol), K2CO3 (142 mg, 1.02 mmol) and DL-PROLINE (16 mg, 137 umol), then the mixture was stirred at 90 ºC for 2 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by prep-HPLC (Phenomenex Luna C1875*30mm*3um column;10-40 % acetonitrile in an a 0.2% formic acid solution in water, 8 min gradient ) to obtain 2-(3-chloro-4-fluoro-phenyl)-6-[(4-methoxy-3- pyridyl)methyl]-2-azaspiro[3.3]heptan-6-ol (22 mg, 53 umol, 16%) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.78 - 8.07 (m, 2H), 6.97 (br t, J = 8.8 Hz, 2H), 6.48 - 6.35 (m, 1H), 6.29 - 6.21 (m, 1H), 5.62 - 5.43 (m, 1H), 4.06 (br s, 3H), 3.90 - 3.77 (m, 4H), 3.18 - 2.80 (m, 2H), 2.45 (br d, J = 12.0 Hz, 4H). LCMS (ESI for C19H20ClFN2O2) [M+H] ⁺ : 363.0. The following compounds were synthesized according to the protocol described for the Compound 292:

Synthesis of 2-(3-chloro-4-fluoro-phenyl)-6-(3-pyridylmethyl)-2-azaspiro[ 3.3]heptane-6-carbonitrile (compound 299). Step 1: tert-butyl 6-(p-tolylsulfonyloxy)-2-azaspiro[3.3]heptane-2-carboxylate. To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (5 g, 23.44 mmol) in DCM (50 mL) were added TsCl (5.81 g, 30.48 mmol), Et3N (4.74 g, 46.89 mmol) and DMAP (573 mg, 4.69 mmol). Then the mixture was stirred at 20 °C for 16 h. The mixture was filtered and concentrated in vacuum, and dried in vacuo to afford crude product. The crude product was purified by flash column (ISCO 40 g silica, 0-80 % ethyl acetate in petroleum ether, gradient over 20 min) to obtain tert-butyl 6-(p- tolylsulfonyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (8.6 g, 23.40 mmol, 99.%) as a pale yellow solid. LCMS (ESI) m/z: 312.2.0 [M-56+H] ⁺ Step 2: tert-butyl 6-cyano-2-azaspiro[3.3]heptane-2-carboxylate. To a solution of tert-butyl 6-(p-tolylsulfonyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (8 g, 21.77 mmol) in DMSO (90 mL) was added KCN (2.59 g, 39.78 mmol). Then the mixture was stirred at 100 °C for 12 h. The mixture was cooled to 0°C and then poured into ice-water (100 mL), the aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with brine (50 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to afford crude product. The crude product was purified by flash column (ISCO 40 g silica, 0-80 % ethyl acetate in petroleum ether, gradient over 20 min) to afford tert-butyl 6-cyano-2-azaspiro[3.3]heptane-2-carboxylate (3 g, 13.50 mmol, 62%) as a white solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ 3.95 (d, J = 4.3 Hz, 4H), 3.08 - 2.88 (m, 1H), 2.68 - 2.47 (m, 4H), 1.43 (s, 9H) Step 3: tert-butyl 6-cyano-6-(3-pyridylmethyl)-2-azaspiro[3.3]heptane-2-carboxy late. To a solution of tert-butyl 6-cyano-2-azaspiro[3.3]heptane-2-carboxylate (2 g, 9.00 mmol) in THF (20 mL) was added LiHMDS (1 M, 18.00 mL) drop-wise at -70 °C. Then the mixture was stirred at -70 °C for 30 min. Then 3-(chloromethyl)pyridine (1.72 g, 13.50 mmol) in THF (5 mL) was added dropwise to the above solution and the mixture was stirred at -70 °C for 3 h. To the mixture was added H2O (20 mL) and extracted with etOAc (30 mL*3). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated to give crude product. The crude product was purified by flash column (ISCO 10 g silica, 90-100% ethyl acetate in petroleum ether, gradient over 20 min) to afford tert-butyl 6-cyano-6-(3- pyridylmethyl)-2-azaspiro[3.3]heptane-2-carboxylate (2 g, 6.38 mmol, 71%) as a pale yellow solid ¹ H NMR (400MHz, CHLOROFORM-d) δ 8.60 (d, J = 4.9 Hz, 1H), 8.57 - 8.52 (m, 1H), 7.76 (br d, J = 7.0 Hz, 1H), 7.46 - 7.34 (m, 1H), 4.07 (s, 2H), 3.94 (s, 2H), 2.98 (s, 2H), 2.70 (br d, J = 13.3 Hz, 2H), 2.41 (br d, J = 10.3 Hz, 2H), 1.44 (s, 9H). Step 4: 6-(3-pyridylmethyl)-2-azaspiro[3.3]heptane-6-carbonitrile. To a solution oftert-butyl 6-cyano-6-(3-pyridylmethyl)-2-azaspiro[3.3]heptane-2-carboxy late (400 mg, 1.28 mmol) in DCM (3 mL) was added TFA (1.54 g, 13.51 mmol) dropwise, the mixture was stirred at 20°C for 2 h. The reaction mixture was then concentrated to dryness to give the crude product which was dissolved in MeOH (5mL) followed by the addition of AMbersep 900(OH),ion exchange resin(2g) to adjust pH to 8. The mixture was filtered and the filtrate was concentrated to dryness to give 6-(3- pyridylmethyl)-2-azaspiro[3.3]heptane-6-carbonitrile (250 mg, 1.17 mmol, 92%) as a pale yellow oil. Step 5: 2-(3-chloro-4-fluoro-phenyl)-6-(3-pyridylmethyl)-2-azaspiro[ 3.3]heptane-6-carbonitrile. To a solution of 6-(3-pyridylmethyl)-2-azaspiro[3.3]heptane-6-carbonitrile (120 mg, 563 umol) in DMSO (2 mL) were added 2-chloro-1-fluoro-4-iodo-benzene (144 mg, 563 umol), CuI (43 mg, 225 umol), DL- PROLINE (26 mg, 225 umol) and K2CO3 (233 mg, 1.69 mmol).The resultant mixture was stirred at 80°C for 12 h. The crude product was purified by prep-HPLC (Waters Xbridge Prep OBD C18 150*40mm*10um column;33-53 % acetonitrile in an a 0.05% ammonia solution and an a 10mM ammonium bicarbonate solution in water, 8 min gradient) to afford 2-(3-chloro-4-fluoro-phenyl)-6-(3- pyridylmethyl)-2-azaspiro[3.3]heptane-6-carbonitrile (61 mg, 179 umol, 32%) as a white solid. 1H NMR (400MHz, CHLOROFORM-d) δ 8.83 - 8.43 (m, 2H), 7.68 (br d, J = 7.1 Hz, 1H), 7.34 (br s, 1H), 6.98 (br t, J = 8.7 Hz, 1H), 6.41 (br d, J = 3.3 Hz, 1H), 6.24 (br d, J = 8.4 Hz, 1H), 3.98 (s, 2H), 3.82 (s, 2H), 2.99 (br s, 2H), 2.75 (br d, J = 12.6 Hz, 2H), 2.50 (br d, J = 12.6 Hz, 2H). LCMS (ESI for C19H17ClFN3 [M+H] ⁺ : 342.0. The following compounds were synthesized according to the protocol described for the Compound 299.

Synthesis of [2-[5-chloro-6-(trifluoromethyl)-3-pyridyl]-6-(3-pyridylmeth yl)-2-azaspiro[3.3]heptan-6- yl]methanol (Compound 307) and [2-[5-chloro-2-(trifluoromethyl)-3-pyridyl]-6-(3-pyridylmeth yl)-2- azaspiro[3.3]heptan-6-yl]methanol (Compound 308): Step 1: tert-butyl 6-formyl-6-(3-pyridylmethyl)-2-azaspiro[3.3]heptane-2-carbox ylate. To a solution of tert-butyl 6-cyano-6-(3-pyridylmethyl)-2-azaspiro[3.3]heptane-2-carboxy late (1 g, 3.19 mmol) in DCM (10 mL) was added DIBAL-H (1 M, 9.57 mL) at -70~-65 °C. Then the mixture was stirred at -70~-65 °C for 1h. To the mixture was added H2O (10 mL), and EtOAc (20 mL) and the mixture was filtered. The filtered cake was separated and the aqueous layer was extracted with EtOAc (15 mL*3). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated. Compound tert- butyl 6-formyl-6-(3-pyridylmethyl)-2-azaspiro[3.3]heptane-2-carbox ylate (800 mg, 2.53 mmol, 79%) was obtained as a pale yellow oil. LCMS (ESI) m/z: 317.2 [M+H] ⁺ . Step 2: tert-butyl 6-(hydroxymethyl)-6-(3-pyridylmethyl)-2-azaspiro[3.3]heptane -2-carboxylate. To a solution of tert-butyl 6-formyl-6-(3-pyridylmethyl)-2-azaspiro[3.3]heptane-2-carbox ylate (800 mg, 2.53 mmol) in MeOH (10 mL) was added NaBH4 (182 mg, 4.81 mmol) at 0 °C. Then the mixture was stirred at 20 °C for 2 h. The mixture was concentrated to give crude product. The crude product was purified by flash column (ISCO 10 g silica, 80-100 % ethyl acetate in petroleum ether, gradient over 20 min. The compound tert-butyl 6-(hydroxymethyl)-6-(3-pyridylmethyl)-2-azaspiro[3.3]heptane -2- carboxylate (340 mg, 1.07 mmol, 42%) was obtained as a pale yellow gum. LCMS (ESI) m/z: 319.2 [M+H] ⁺ Step 3: [6-(3-pyridylmethyl)-2-azaspiro[3.3]heptan-6-yl]methanol. To a solution of tert-butyl 6-(hydroxymethyl)-6-(3-pyridylmethyl)-2-azaspiro[3.3]heptane -2- carboxylate (330 mg, 1.04 mmol) in DCM (3 mL) was added TFA (1.54 g, 13.51 mmol). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated to dryness and was further dissolved in MeOH(8 mL), then was added AMbersep 900(OH), ion exchange resin(2 g) to adjust pH to 7. The mixture was filtered and the filtrate was concentrated to dryness to give the crude product. [6-(3-pyridylmethyl)-2- azaspiro[3.3]heptan-6-yl]methanol (300 mg, 962 umol, 93%) was obtained as yellow oil. LCMS (ESI) m/z: 219.2 [M+H] ⁺ Step 4: preparation of [2-[5-chloro-6-(trifluoromethyl)-3-pyridyl]-6-(3-pyridylmeth yl)-2-azaspiro[3.3]heptan- 6-yl]methanol and [2-[5-chloro-2-(trifluoromethyl)-3-pyridyl]-6-(3-pyridylmeth yl)-2-azaspiro[3.3]heptan-6- yl]methanol. To a solution of [6-(3-pyridylmethyl)-2-azaspiro[3.3]heptan-6-yl]methanol (290 mg, 930 umol, 1 eq) and 3,5-dichloro-2-(trifluoromethyl)pyridine (201 mg, 930 umol, 1 eq) in DMF (3 mL) was added Et3N (282 mg, 2.79 mmol, 388 uL, 3 eq). The mixture was stirred at 100 °C for 2 h. LCMS showed the starting material was consumed and desired MS was detected. The reaction mixture was concentrated to dryness to give the crude. The reaction mixture was purified by normal phase(Welch Ultimate XB NH210u 100*30mm column; 5%-40% the solution of ethyl alcohol and Heptane,10 min gradient). [2-[5-chloro-6- (trifluoromethyl)-3-pyridyl]-6-(3-pyridylmethyl)-2-azaspiro[ 3.3]heptan-6-yl]methanol (35 mg, 87 umol) was obtained as white solid. [2-[5-chloro-2-(trifluoromethyl)-3-pyridyl]-6-(3-pyridylmeth yl)-2- azaspiro[3.3]heptan-6-yl]methanol (8 mg, 21 umol) was obtained as white solid. For compound 307: ¹ H NMR (400MHz, CHLOROFORM-d) δ 8.54 - 8.44 (m, 2H), 7.61 (d, J = 2.2 Hz, 1H), 7.54 (br d, J = 7.9 Hz, 1H), 7.25 (d, J = 5.0 Hz, 1H), 6.65 (d, J = 1.5 Hz, 1H), 3.99 (s, 2H), 3.86 (s, 2H), 3.45 (s, 2H), 2.85 - 2.75 (m, 2H), 2.22 (s, 4H). LCMS (ESI for C19H19ClF3N3O) [M+H] ⁺ : 398.0 For compound 308: ¹ H NMR (400MHz, CHLOROFORM-d) δ 8.53 - 8.42 (m, 2H), 7.92 - 7.82 (m, 1H), 7.52 (br d, J = 7.7 Hz, 1H), 7.23 (br d, J = 4.8 Hz, 1H), 6.70 (s, 1H), 4.03 (s, 2H), 3.91 (s, 2H), 3.42 (s, 2H), 2.78 (s, 2H), 2.22 - 2.12 (m, 4H). LCMS (ESI for C19H19ClF3N3O) [M+H] ⁺ : 398.0 Synthesis of [2-(3-chloro-4-fluoro-phenyl)-6-(3-pyridylmethyl)-2-azaspiro [3.3]heptan-6-yl]methanol (Compound 309): To a solution of [6-(3-pyridylmethyl)-2-azaspiro[3.3]heptan-6-yl]methanol (100 mg, 458.10 umol) and 2-chloro-1-fluoro-4-iodo-benzene (117 mg, 458 umol) in DMSO (1 mL) were added CuI (17 mg, 92 umol), pyrrolidine-2-carboxylic acid (21 mg, 183 umol) and K2CO3 (127 mg, 916.20 umol). Then the mixture was stirred at 90 °C for 12 h and the resultant crude product was purified by prep-HPLC column: Phenomenex Gemini-NX C1875*30mm*3um;mobile phase: [water(10mM NH4HCO3)-ACN];B%: 33%- 53%,6min to give [2-(3-chloro-4-fluoro-phenyl)-6-(3-pyridylmethyl)-2-azaspiro [3.3]heptan-6-yl]methanol (28 mg, 80 umol, 17%) as a white solid. 1H NMR (400MHz, CHLOROFORM-d) δ 8.50 (br s, 2H), 7.56 (br d, J=7.6 Hz, 1H), 7.28 - 7.23 (m, 1H), 6.97 (t, J=8.9 Hz, 1H), 6.38 (dd, J=2.8, 6.1 Hz, 1H), 6.22 (td, J=3.3, 8.8 Hz, 1H), 3.81 (s, 2H), 3.71 (s, 2H), 3.45 (s, 2H), 2.82 (s, 2H), 2.22 - 2.07 (m, 4H) LCMS (ESI for C19H20ClFN2O [M+H]+: 352.2 The following compound was synthesized according to the protocol described for the Compound 309: Synthesis of [2-(3-chloro-4-fluoro-phenyl)-6-[(4-methoxy-3-pyridyl)methyl ]-2-azaspiro[3.3]heptan-6- yl]methanol (compound 311): Step 1: methyl 4-methoxypyridine-3-carboxylate. A mixture of 4-chloropyridine-3-carboxylic acid (30 g, 190.41 mmol) in SOCl2 (98.40 g, 827.10 mmol) was stirred at 80 °C for 2 h. The reaction mixture was concentrated in vacuum. Then MeOH (47.51 g, 1.48 mol) was added to it and the mixture was stirred at 70 °C for 12 h. The mixture was filtered and the solids were was washed with MeOH (60mL*3) and dried. The compound methyl 4-methoxypyridine- 3-carboxylate (22.6 g, 128.44 mmol, 67%) was obtained as a white solid. LCMS (ESI) m/z: 168.1[M+H] ⁺ Step 2: (4-methoxy-3-pyridyl)methanol. To a mixture of methyl 4-methoxypyridine-3-carboxylate (8 g, 47.86 mmol, 1 eq) in THF (80 mL) was added LiAlH ₄ (3.63 g, 95.72 mmol) in portions at 0 °C for 2 h under N ₂ atmosphere. To the resultant reaction mixture was added 3.7 mL H2O and 3.7 mL 15% NaOH dropwise at 0 °C. Then 11.1 mL H2O was added to the mixture. Then the mixture was filtered and the filtrate was concentrated under reduced pressure to afford the desired product. The crude product was purified by flash column (ISCO 40 g silica, 0-100 % ethyl acetate in petroleum ether, gradient over 20 min). The compound (4-methoxy-3- pyridyl)methanol (1.46 g, 10.49 mmol, 22%) was obtained as a yellow solid. LCMS (ESI) m/z: 140.2[M+H] ⁺ Step 3: 3-(chloromethyl)-4-methoxy-pyridine. To a solution of (4-methoxy-3-pyridyl)methanol (1.46 g, 10.49 mmol) in CHCl3 (50 mL) was added thionyl chloride (1.90 g, 15.96 mmol) drop wise at 0 °C under N2 atmosphere. Then the mixture was stirred at 20 °C for 1 h. The mixture was concentrated and the resultant residue was dissolved in EtOAc followed by the addition of saturated aqueous sodium bicarbonate until PH=9~10 and extracted further with EtOAc(20 mL*3). The organic layer was washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated. The compound 3-(chloromethyl)-4-methoxy-pyridine (1.35 g, 7.97 mmol, 76%) was obtained as a yellow solid. LCMS (ESI) m/z: 158.2[M+H] ⁺ Step 4: tert-butyl 6-cyano-6-[(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]hepta ne-2-carboxylate. A mixture of tert-butyl 6-cyano-2-azaspiro[3.3]heptane-2-carboxylate (1.90 g, 8.57 mmol) in THF (20 mL) was degassed with N ₂ 3 times, then LiHMDS (1 M, 17.13 mL, in THF) was added to the above solution drop wise at -70 ~ -65 °C, and the mixture was stirred at -70 °C for 0.5 h. Then 3-(chloromethyl)- 4-methoxy-pyridine (1.35 g,8.57 mmol) in THF (10 mL) was added to the above solution dropwise at - 70 °C and the mixture was stirred for 3 h. The mixture was quenched with H2O (20 mL), extracted with EtOAc (30 mL*3). The organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated to give crude product. The crude product was purified by flash column (ISCO 40 g silica, 0-80 % ethyl acetate in petroleum ether, gradient over 20 min) to obtain tert-butyl 6-cyano-6-[(4-methoxy-3- pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.9 g, 5.26 mmol, 61%) as a pale yellow solid. LCMS (ESI) m/z: 344.3[M+H] ⁺ Step 5: tert-butyl 6-formyl-6-[(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]hept ane-2-carboxylate. To a solution of tert-butyl 6-cyano-6-[(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]hepta ne-2- carboxylate (1 g, 2.91 mmol) in DCM (10 mL) was added dropwise DIBAL-H (1 M, 8.74 mL, in toluene) at 0 °C. The mixture was stirred at 20 °C for 4 h. The mixture was quenched with 10 mL H ₂ O at 0 °C and stirred for 0.5 h. It was filtered and the filtrate was extracted with ethyl acetate (15 mL*2). The combined organic layers were dried over Na2SO4 and concentrated. The compound tert-butyl 6-formyl-6-[(4- methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carboxyla te (300 mg, 866 umol, 30%) was obtained as a pale yellow solid. LCMS (ESI) m/z: 347.3[M+H] ⁺ Step 6: tert-butyl 6-(hydroxymethyl)-6-[(4-methoxy-3-pyridyl)methyl]-2-azaspiro [3.3]heptane-2- carboxylate. To a solution of tert-butyl 6-formyl-6-[(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]hept ane-2- carboxylate (300 mg, 866 umol) in MeOH (5 mL) was added NaBH ₄ (66 mg, 1.73 mmol) in portions at 0 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched by the addition 5 mL H2O at 0 °C and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was extracted with ethyl acetate (5 mL*2), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by flash column (ISCO 20 g silica, 0-90 % ethyl acetate in petroleum ether, gradient over 20 min) to obtain tert-butyl 6- (hydroxymethyl)-6-[(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3 .3]heptane-2-carboxylate (67 mg, 192 umol, 22%) as a yellow gum. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.44 - 8.33 (m, 1H), 8.28 (br d, J = 4.4 Hz, 1H), 6.86 - 6.74 (m, 1H), 3.90 (br dd, J = 4.3, 11.1 Hz, 7H), 3.32 - 3.18 (m, 2H), 2.81 - 2.67 (m, 2H), 2.21 - 1.93 (m, 4H), 1.51 - 1.33 (m, 9H), 1.27 (br s, 1H), LCMS (ESI) m/z: 349.3[M+H] ⁺ Step 7: [6-[(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]heptan-6-yl] methanol. To a solution of tert-butyl 6-(hydroxymethyl)-6-[(4-methoxy-3-pyridyl)methyl]-2- azaspiro[3.3]heptane-2-carboxylate (67 mg, 192 umol) in DCM (2 mL) was added TFA (1.54 g, 13.51 mmol). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuum and the residue was dissolved in MeOH (2 mL) followed by the addition of resin (Ambersep900, 0.3 g) until pH > 7. The mixture was then filtered and the filtrate was dried over in vacuo to afford the desired product. The compound [6-[(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]heptan-6-yl] methanol (47 mg crude) was obtained as a yellow oil. LCMS (ESI) m/z: 249.2[M+H] ⁺ Step 8: [2-(3-chloro-4-fluoro-phenyl)-6-[(4-methoxy-3-pyridyl)methyl ]-2-azaspiro[3.3]heptan-6-yl]methanol. A mixture of [6-[(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]heptan-6-yl] methanol (40 mg, 161 umol), 2-chloro-1-fluoro-4-iodo-benzene (41 mg, 161 umol), CuI (12 mg, 64 umol), DL-PROLINE (7 mg, 64 umol) and K2CO3 (67 mg, 483 umol) in DMSO (1 mL) was degassed and purged with N23 times, and then the mixture was stirred at 90 °C for 12 h under N2 atmosphere. The residue was purified by prep- HPLC (Waters Xbridge BEH C18100*30mm*10um column; 35-60% acetonitrile in an a 10mM ammonium bicarbonate solution in water, 10min gradient) to obtain [2-(3-chloro-4-fluoro-phenyl)-6-[(4- methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]heptan-6-yl]methano l (7 mg, 19 umol, 12%) as a green solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.62 (br s, 1H), 6.96 (t, J = 8.9 Hz, 2H), 6.38 (dd, J = 2.6, 6.0 Hz, 1H), 6.22 (td, J = 3.2, 8.6 Hz, 1H), 3.89 (br s, 3H), 3.79 (br d, J = 12.6 Hz, 4H), 3.34 (br s, 2H), 3.13 - 2.66 (m, 2H), 2.60 - 2.32 (m, 1H), 2.27 - 1.99 (m, 4H). LCMS (ESI) for (C20H22ClFN2O2) [M+H]+: 377.2 Synthesis of 6-(phenoxymethyl)-6-(3-pyridylmethyl)-2-[6-(trifluoromethyl) -3-pyridyl]-2- azaspiro[3.3]heptane (Compound 312). To a solution of [6-(3-pyridylmethyl)-2-[6-(trifluoromethyl)-3-pyridyl]-2-aza spiro[3.3]heptan-6- yl]methanol (15 mg, 41 umol) in toluene (1 mL) was added phenol (8 mg, 82.56 umol), 2-(tributyl-λ5- phosphanylidene)acetonitrile (30 mg, 124 umol) under N2. The mixture was stirred at 80°C for 3 h. Concentration followed by the purification of the crude product by prep-HPLC (Phenomenex Gemini-NX C1875*30mm*3um column;30-60 % acetonitrile in an a 0.05% ammonia solution and an a 10mM ammonium bicarbonate solution in water, 8 min gradient) afforded 6-(phenoxymethyl)-6-(3-pyridylmethyl)- 2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptane (18 mg, 42 umol, 50%) as a yellow gum. 1H NMR (400MHz, CHLOROFORM-d) δ 8.56 - 8.39 (m, 2H), 7.83 (d, J = 2.6 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.32 (t, J = 7.9 Hz, 2H), 7.22 (dd, J = 4.8, 7.6 Hz, 1H), 7.02 - 6.97 (m, 1H), 6.91 (d, J = 8.0 Hz, 2H), 6.68 (dd, J = 2.5, 8.6 Hz, 1H), 4.03 (s, 2H), 3.93 (s, 2H), 3.71 (s, 2H), 2.93 (s, 2H), 2.34 (s, 4H). LCMS (ESI for C25H24F3N3O) [M+H] ⁺ : 440.1 Synthesis of 6-(methoxymethyl)-6-(3-pyridylmethyl)-2-[6-(trifluoromethyl) -3-pyridyl]-2- azaspiro[3.3]heptane (Compound 313): To a solution of [6-(3-pyridylmethyl)-2-[6-(trifluoromethyl)-3-pyridyl]-2-aza spiro[3.3]heptan-6- yl]methanol (25 mg, 69 umol) in THF (0.5 mL) was added NaH (6 mg, 138 umol, 60% suspension) at 0 °C. The mixture was stirred at 20°C for 0.1h followed by the addition of iodomethane (20 mg, 138 umol) was added at 0°C. The mixture was warmed up and stirred at 20°C for 2 h.1ml H2O was added to the reaction solution at 0°C and the resultant crude residue was purified by prep-HPLC (Phenomenex Luna C1875*30mm*3um column;20-50 % acetonitrile in an a 0.2% formic acid solution in water, 8 min gradient). The compound 6-(methoxymethyl)-6-(3-pyridylmethyl)-2-[6-(trifluoromethyl) -3-pyridyl]-2- azaspiro[3.3]heptane (13 mg, 35 umol, 25% y) was obtained as a white solid. 1H NMR (400MHz, METHANOL-d4) δ = 8.41 (dt, J = 1.6, 5.4 Hz, 2H), 7.77 - 7.71 (m, 2H), 7.53 (d, J = 8.5 Hz, 1H), 7.42 - 7.34 (m, 1H), 6.87 (dd, J = 2.6, 8.6 Hz, 1H), 3.99 (s, 2H), 3.92 (s, 2H), 3.37 (s, 3H), 3.13 (s, 2H), 2.84 (s, 2H), 2.35 - 2.24 (m, 2H), 2.22 - 2.11 (m, 2H). LCMS (ESI for C20H22F3N3O) [M+H] ⁺ : 378.1 Synthesis of [6-[(4-methoxy-3-pyridyl)methyl]-2-[6-(trifluoromethyl)-3-py ridyl]-2- azaspiro[3.3]heptan-6-yl]methanol (Compound 314) and 6-[(4-methoxy-3-pyridyl)methyl]-6- (phenoxymethyl)-2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro [3.3]heptane (Compound 315): Step 1: [6-[(4-methoxy-3-pyridyl)methyl]-2-[6-(trifluoromethyl)-3-py ridyl]-2-azaspiro[3.3]heptan-6- yl]methanol To a solution of [6-[(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]heptan-6-yl] methanol (80 mg, 322 umol) in DMF (2 mL) was added Et3N (98 mg, 966 umol) and 5-fluoro-2-(trifluoromethyl)pyridine (53 mg, 322 umol). The mixture was stirred at 90 °C for 2 h. The residue was purified by prep-HPLC (Waters Xbridge BEH C18100*30mm*10um column; 40-70% acetonitrile in an a 10mM ammonium bicarbonate solution in water, 10 min gradient) to obtain [6-[(4-methoxy-3-pyridyl)methyl]-2-[6-(trifluoromethyl)-3- pyridyl]-2-azaspiro[3.3]heptan-6-yl]methanol (20 mg, 52 umol, 16%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.42 (d, J = 5.8 Hz, 1H), 8.31 (s, 1H), 7.82 (d, J = 2.8 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 6.84 (d, J = 5.8 Hz, 1H), 6.67 (dd, J = 2.6, 8.4 Hz, 1H), 3.98 (s, 2H), 3.95 - 3.89 (m, 5H), 3.35 (s, 2H), 2.81 (s, 2H), 2.27 - 2.12 (m, 4H). LCMS (ESI) for (C20H22F3N3O2) [M+H] ⁺ : 394.2 Step 2: 6-[(4-methoxy-3-pyridyl)methyl]-6-(phenoxymethyl)-2-[6-(trif luoromethyl)-3-pyridyl]-2- azaspiro[3.3]heptane. To a solution of [6-[(4-methoxy-3-pyridyl)methyl]-2-[6-(trifluoromethyl)-3-py ridyl]-2- azaspiro[3.3]heptan-6-yl]methanol (8 mg, 20.34 umol) in toluene (0.5 mL) was added phenol (4 mg, 41 umol, 4uL, 2 eq), 2-(tributyl-λ5-phosphanylidene)acetonitrile (15 mg, 61umol) under N2. The mixture was stirred at 80°C for 3h and concentrated to obtain the crude product which was purified by prep-HPLC ( Phenomenex Gemini-NX C1875*30mm*3um column;35-75 % acetonitrile in an a 0.05% ammonia solution and an a 10mM ammonium bicarbonate solution in water, 8 min gradient). The compound 6-[(4- methoxy-3-pyridyl)methyl]-6-(phenoxymethyl)-2-[6-(trifluorom ethyl)-3-pyridyl]-2-azaspiro[3.3]heptane (8 mg, 17 umol, 86% ) was obtained as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.42 (s, 1H), 8.28 (s, 1H), 7.83 (d, J = 2.8 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.30-7.27 (m, 2H), 7.03-6.95 (m, 1H), 6.89-6.81 (m, 3H), 6.69-6.67 (m, 1H), 4.03 (s, 2H), 3.2 (s, 2H), 3.78 (s, 3H),3.75 (s, 2H), 2.93 (s, 2H), 2.38 - 2.31 (m, 4H). LCMS (ESI) for (C26H26F3N3O2) [M+H] ⁺ : 470.1 Synthesis of 6-(3-pyridyl)-2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3 .3]heptan-6-ol (Compound 316). Step 1: tert-butyl 6-hydroxy-6-(3-pyridyl)-2-azaspiro[3.3]heptane-2-carboxylate . To a solution of 3-iodopyridine (970 mg, 5 mmol) in THF (10 mL) was added i-PrMgCl (2 M, 2.49 mL in THF) dropwise at 0 °C. Then the mixture was stirred at 0 °C for 1 h. Then tert-butyl 6-oxo-2- azaspiro[3.3]heptane-2-carboxylate (1 g, 5 mmol) in THF (10 mL) was added to the mixture and the reaction was stirred at 20°C for 12 h. The mixture was quenched with saturated NH4Cl solution (30 mL), extracted with EtOAc (50 mL*3) and the combined organic layers were washed with brine (20 mL) and dried over Na2SO4. The crude product was purified by flash column (ISCO 20 g silica, 0~80% ethyl acetate in petroleum ether, gradient over 30 min) to obtain tert-butyl 6-hydroxy-6-(3-pyridyl)-2- azaspiro[3.3]heptane-2-carboxylate (300 mg, 1 mmol, 22 %) as a yellow oil. LCMS (ESI) for (C16H22N2O3) [M+H] ⁺ : 291.0 Step 2: 6-(3-pyridyl)-2-azaspiro[3.3]heptan-6-ol. To a solution of tert-butyl 6-hydroxy-6-(3-pyridyl)-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 861 umol) in DCM (12 mL) was added TFA (9.24 g, 81 mmol) and the reaction was stirred at 15 °C for 1 h. The mixture was concentrated under reduced pressure, then was added MeOH (15 ml) and resin (Ambersep900, ca.2g) until PH=10.The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 6-(3-pyridyl)-2-azaspiro[3.3]heptan-6-ol (220 mg, crude) as a yellow oil. ¹ H NMR (400MHz, CHLOROFORM-d) δ 8.62 (d, J = 2.2 Hz, 1H), 8.47 (d, J = 4.2 Hz, 1H), 7.74 (br d, J = 7.9 Hz, 1H), 7.30 (dd, J = 4.8, 7.9 Hz, 1H), 4.09 (s, 2H), 3.84 (s, 2H), 2.79 - 2.69 (m, 2H), 2.64 - 2.54 (m, 2H). Step 3: 6-(3-pyridyl)-2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3 .3]heptan-6-ol. To a solution of 6-(3-pyridyl)-2-azaspiro[3.3]heptan-6-ol (60 mg, 315 umol) in DMF (1.5 mL) was added 5-fluoro-2-(trifluoromethyl)pyridine (52 mg, 315 umol) and TEA (64 mg, 631 umol). The reaction was stirred at 80 °C for 2 h followed by the addition of 5-fluoro-2-(trifluoromethyl)pyridine (52 mg, 315 umol) and the reaction was stirred at 80 °C for 2 h. The mixture was cooled to room temperature, concentrated under reduced pressure. The crude product was purified by prep-HPLC (Phenomenex Luna C1875*30mm*3um;mobile; 20-42 % acetonitrile in an a 0.225% formic acid solution in water, 6 min gradient) to afford 6-(3-pyridyl)-2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3 .3]heptan-6-ol (8 mg, 24 umol, 7 %) as a pale yellow solid. 1H NMR (400MHz, CHLOROFORM-d) δ 8.76 (s, 1H), 8.61 (br d, J = 3.9 Hz, 1H), 7.90 - 7.78 (m, 2H), 7.49 (d, J = 8.6 Hz, 1H), 7.40 (dd, J = 4.9, 7.9 Hz, 1H), 6.74 (dd, J = 2.7, 8.6 Hz, 1H), 4.24 (s, 2H), 3.98 (s, 2H), 2.95 - 2.87 (m, 2H), 2.79 - 2.71 (m, 2H). LCMS (ESI) for (C17H16F3N3O) [M+H] ⁺ : 336.1

The following compounds were synthesized according to the protocol described for the Compound 316: Synthesis of 6-[(4-methoxy-3-pyridyl)methylene]-2-[6-(trifluoromethyl)-3- pyridyl]-2- azaspiro[3.3]heptane (Compound 320). Step 1: 6-[(4-methoxy-3-pyridyl)methylene]-2-azaspiro[3.3]heptane. To a solution of tert-butyl 6-[(4-methoxy-3-pyridyl)methylene]-2-azaspiro[3.3]heptane-2- carboxylate (100 mg, 316 umol) in DCM (2 mL) was added TFA (1.54 g, 13.51 mmol) and the mixture was stirred at 20 ºC for 1h. The reaction mixture was concentrated in vacuum and to the residue was added MeOH (3 mL) and resin (Ambersep|r 900(OH)) to adjust pH＞7. The obtained mixture was filtered and filtrate was concentrated under reduced pressure to afford the desired product 6-[(4-methoxy-3- pyridyl)methylene]-2-azaspiro[3.3]heptane (100 mg, crude) as a yellow gum. Step 2: 6-[(4-methoxy-3-pyridyl)methylene]-2-[6-(trifluoromethyl)-3- pyridyl]-2-azaspiro[3.3]heptane. To a solution of 6-[(4-methoxy-3-pyridyl)methylene]-2-azaspiro[3.3]heptane (100 mg, 462.37 umol) in DMF (2 mL) was added 5-fluoro-2-(trifluoromethyl)pyridine (76 mg, 462 umol) and Et3N (140 mg, 1.39 mmol) and the mixture was stirred at 80 ºC for 2 h. The reaction mixture was concentrated in vacuum and the residue was purified by prep-HPLC (Phenomenex Gemini-NX C1875*30mm*3um column; 40-60% acetonitrile in an a 10mM ammonium bicarbonate solution in water and in an a 0.05% ammonia solution in water, 8 min gradient) to obtain 6-[(4-methoxy-3-pyridyl)methylene]-2-[6- (trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptane (36 mg, 98 umol, 21%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.41 - 8.25 (m, 2H), 7.93 - 7.81 (m, 1H), 7.53 - 7.41 (m, 1H), 6.88 - 6.67 (m, 2H), 6.47 - 6.37 (m, 1H), 4.14 - 4.01 (m, 4H), 3.98 - 3.83 (m, 3H), 3.31 - 3.22 (m, 2H), 3.21 - 3.12 (m, 2H). LCMS (ESI for C19H18F3N3O) [M+H] ⁺ : 362.1.

Synthesis of 7-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptan-6 -yl]-5,6-dihydropyrrolo[1,2- c]imidazol-7-ol (compound 321): Step 1: tert-butyl 6-[hydroxy-(3-tritylimidazol-4-yl)methyl]-2-azaspiro[3.3]hep tane-2-carboxylate. To a solution of 5-iodo-1-trityl-imidazole (9.78 g, 22.42 mmol) in DCM (80 mL), was added EtMgBr (3 M, 7.47 mL) at -15 ºC, and the mixture was stirred at -15 ºC for 1h. To the resultant mixture was added tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (5 g, 22.19 mmol, 1 eq) in DCM (10 mL) and stirred at 20°C for 1 h. The reaction mixture was poured into saturated NH4Cl (80 mL) at 0°C and the resulting mixture was extracted with DCM (30mL * 3). The combined organic phase was dried over Na2SO4 and concentrated. The residue was purified by flash column (ISCO 40g silica, 0-100 % ethyl acetate in petroleum ether, gradient over 15 min, 0-7 % methanol in dichloromethane, gradient over 10min) to afford tert-butyl 6-[hydroxy-(3-tritylimidazol-4-yl)methyl]-2-azaspiro[3.3]hep tane-2-carboxylate (8.5 g, 14.60 mmol, 66%) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.31 - 7.29 (m, 10H), 7.10 - 7.06 (m, 6H), 6.55 (br s, 1H), 4.46 (br s, 1H), 3.82 - 3.72 (dbr s, 4H), 2.46 (br s, 1H), 2.07 - 2.00 (m, 2H), 1.98 – 1.94 (m, 2H), 1.40 (s, 9H). LCMS (ESI) m/z: 536.4 [M+H] ⁺ Step 2: tert-butyl 6-(3-tritylimidazole-4-carbonyl)-2-azaspiro[3.3]heptane-2-ca rboxylate. A solution of tert-butyl 6-[hydroxy-(3-tritylimidazol-4-yl)methyl]-2-azaspiro[3.3]hep tane-2- carboxylate (8.5 g, 15.87 mmol) in DCM (80 mL) was cooled to 0 °C and was added DMP (13.46 g, 31.74 mmol). The mixture was stirred at 20 °C for 12h. The reaction mixture was added sat.Na2SO3 let the KI test paper test negative for blue and to the mixture was added sat.NaHCO ₃ turn pH to 8. The resulting mixture was extracted with DCM (3*30mL). The organic phase was concentrated to dryness to give the crude product. The crude product was purified by flash column (ISCO 40 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 28 min) to obtain tert-butyl 6-(3-tritylimidazole-4-carbonyl)-2- azaspiro[3.3]heptane-2-carboxylate (4.8 g, 8.99 mmol, 57%) as colourless gum. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.58 (d, J = 1.1 Hz, 1H), 7.48 - 7.39 (m, 1H), 7.39 - 7.29 (m, 9H), 7.15 - 7.07 (m, 6H), 4.05 (m, 1H), 4.03 - 3.98 (s, 2H), 3.98 - 3.85 (s, 2H), 2.57 - 2.41 (m, 4H), 1.43 (s, 9H). Step 3: tert-butyl 6-[1-hydroxy-3-methoxy-3-oxo-1-(3-tritylimidazol-4-yl)propyl ]-2-azaspiro[3.3]heptane-2- carboxylate. To a solution of methyl acetate (3.33 g, 44.97 mmol) in THF (50 mL) was added LDA (2 M, 13.49 mL, 3 eq) dropwise at -70 °C under N2. The mixture was stirred at -70°C for 30 min and to that was added tert-butyl 6-(3-tritylimidazole-4-carbonyl)-2-azaspiro[3.3]heptane-2-ca rboxylate (4.8 g, 8.99 mmol) in THF (5 mL). The mixture was stirred at -70 °C for 2 h. The reaction mixture was poured to sat.NH4Cl (50mL) in the ice bath. The resulting mixture was extracted with ethyl acetate (30mL*3, organic layers were washed with brine (30mL) and dried over Na2SO4 and concentrated. The crude product was purified by flash column (ISCO 40 g silica, 0-90 % ethyl acetate in petroleum ether, gradient over 25 min) to obtain tert- butyl 6-[1-hydroxy-3-methoxy-3-oxo-1-(3-tritylimidazol-4-yl)propyl ]-2-azaspiro[3.3]heptane-2-carboxylate (3.4 g, 5.59 mmol, 62%) as yellow oil. LCMS (ESI) m/z: 608.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.39 - 7.29 (m, 10H), 7.14 - 7.08 (m, 6H), 6.75 (s, 1H), 4.28 (s, 1H), 3.90 - 3.84 (m, 2H), 3.73(s.2H), 3.65 - 3.60 (m, 3H), 2.99 - 2.95 (d, 1H), 2.64 - 2.52 (d, 1H), 2.22(m,1H), 2.20 - 2.10 (m, 2H), 1.77 (m, 1H), 1.43 (s, 9H). Step 4: tert-butyl 6-[1,3-dihydroxy-1-(3-tritylimidazol-4-yl)propyl]-2-azaspiro [3.3]heptane-2-carboxylate. To a solution of tert-butyl 6-[1-hydroxy-3-methoxy-3-oxo-1-(3-tritylimidazol-4-yl)propyl ]-2- azaspiro[3.3]heptane-2-carboxylate (3.4 g, 5.59 mmol) in THF (35 mL) was added LAH (318 mg, 8.39 mmol) at 0°C under N2. The mixture was stirred at 20°C for 2h. To the reaction mixture was added slowly Na2SO4.10H2O (3.24 g, 10.07 mmol) in the ice bath and then was stirred at 20°C for 30min. The resulting mixture was filtered and the filtrate was concentrated to dryness. The crude product was purified by flash column (ISCO 20 g silica, 0-100 % ethyl acetate in petroleum ether, gradient over 15 min;0-30 % methanol in dichloromethane, gradient over 15 min) to obtain tert-butyl 6-[1,3-dihydroxy-1-(3- tritylimidazol-4-yl)propyl]-2-azaspiro[3.3]heptane-2-carboxy late (2 g, 3.45 mmol, 62%) as white solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.41 - 7.32 (m, 10H), 7.17 - 7.09 (m, 6H), 6.66 (s, 1H), 3.88 (q, J = 8.4 Hz, 2H), 3.81 - 3.64 (m, 4H), 2.54 (m, 1H), 2.52 (quin, J = 8.5 Hz, 1H), 2.28 - 2.15 (m, 1H), 2.19 – 2.09 (m, 2H), 2.04 – 1.99 (m, 2H), 1.80 - 1.77 (m, 2H), 1.43 (s, 9H). LCMS (ESI) m/z: 580.4 [M+H] ⁺ Step 5: tert-butyl 6-[1,3-dihydroxy-1-(1H-imidazol-5-yl)propyl]-2-azaspiro[3.3] heptane-2-carboxylate To a solution of tert-butyl 6-[1,3-dihydroxy-1-(3-tritylimidazol-4-yl)propyl]-2-azaspiro [3.3]heptane- 2-carboxylate (800 mg, 1.38 mmol) in MeOH (10 mL) was added Pd/C (600 mg, 10% purity) under N2 atmosphere. The suspension was degassed and purged with hydrogen 3 times. The mixture was stirred under H2 (30psi) at 30°C for 5 h. The reaction mixture was filtered and the filtrate was concentrated to dryness. The crude was purified by prep-HPLC (Waters Xbridge Prep OBD C18150*40mm*10um column; 10-40 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 min gradient) to afford tert-butyl 6-[1,3-dihydroxy-1-(1H-imidazol-5-yl)propyl]-2-azaspiro[3.3] heptane-2-carboxylate (300 mg, 845 umol, 61%) as white solid. LCMS (ESI) m/z: 338.2 [M+H] ⁺ Step 6: tert-butyl 6-(7-hydroxy-5,6-dihydropyrrolo[1,2-c]imidazol-7-yl)-2-azasp iro[3.3]heptane-2- carboxylate. MsCl (160 mg, 1.40 mmol) was added dropwise to a cooled (0 °C) solution of tert-butyl 6-[1,3- dihydroxy-1-(1H-imidazol-5-yl)propyl]-2-azaspiro[3.3]heptane -2-carboxylate (300 mg, 889 umol) and DIPEA (229 mg, 1.78 mmol) in anhydrous THF (3 mL) while keeping the temperature of the solution below 10 °C. After stirring for 30 min. Water (3mL) was added and the resulting mixture was extracted with ethylacetate (3mL*2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was dissolved in MeCN (2 mL) and the solution was heated at 70 °C for 30 min. After the addition of MeOH (2 mL) and DIPEA (230 mg, 1.78 mmol), the mixture was heated at 70 °C for 6 h. The resultant mixture was concentrated in vacuo, diluted with water, and extracted with CH3Cl:i- PrOH(3:1) (3mL*3). The combined organic layers were washed with brine (3mL) and concentrated in vacuo to give the crude product tert-butyl 6-(7-hydroxy-5,6-dihydropyrrolo[1,2-c]imidazol-7-yl)-2- azaspiro[3.3]heptane-2-carboxylate (400 mg, 601 umol, 68%) as white solid. LCMS (ESI) m/z: 320.2 [M+H] ⁺ Step 7: 7-(2-azaspiro[3.3]heptan-6-yl)-5,6-dihydropyrrolo[1,2-c]imid azol-7-ol To a solution of tert-butyl 6-(7-hydroxy-5,6-dihydropyrrolo[1,2-c]imidazol-7-yl)-2- azaspiro[3.3]heptane-2-carboxylate (200 mg, 313 umol) in DCM (1.8 mL) was added TFA (924 mg, 8.10 mmol). The mixture was stirred at 20°C for 2 h and concentrated to dryness to give the crude product. The crude product was dissolved with MeOH(5mL),then was added AMbersep 900(OH),ion exchange resin(1g) to adjust the pH to 8. The mixture was filtered and the filtrate was concentrated to dryness to give the product 7-(2-azaspiro[3.3]heptan-6-yl)-5,6-dihydropyrrolo[1,2-c]imid azol-7-ol (100 mg, 228 umol, 73%) as yellow gum. LCMS (ESI) m/z: 220.2 [M+H] ⁺ Step 8: 7-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptan-6 -yl]-5,6-dihydropyrrolo[1,2-c]imidazol-7- ol. To a solution of 7-(2-azaspiro[3.3]heptan-6-yl)-5,6-dihydropyrrolo[1,2-c]imid azol-7-ol (90 mg, 205 umol) in DMF (1 mL) was added 5-fluoro-2-(trifluoromethyl)pyridine (34 mg, 205 umol) and TEA (62 mg, 616umol). The mixture was stirred at 100°C for 2h, the mixture was filtered and the filtrate was purified by prep-HPLC (Phenomenex Gemini-NX C1875*30mm*3um column; 20%-45% acetonitrile in an a 0.05% ammonium hydroxide and 10mM sodium bicarbonate solution in water, 8min gradient) to afford 7-[2-[6- (trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptan-6-yl]-5,6 -dihydropyrrolo[1,2-c]imidazol-7-ol (15 mg, 41 umol, 20%) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.84 (d, J = 2.2 Hz, 1H), 7.47 -7.44(d, J = 9.9 Hz, 2H), 6.89 (s, 1H), 6.70 (br d, J = 7.8 Hz, 1H), 4.25 - 4.17 (m, 1H), 4.03(m, 3H),3.95-3.87 (m, 2H), 2.68(m, 1H), 2.62-2.58(m, 2H), 2.42-2.40(m, 3H),2.39-2.23(m, 1H). LCMS (ESI for C18H19F3N4O) [M+H] ⁺ : 365.2 Synthesis of 1-(4-methoxy-3-pyridyl)-1-[2-[6-(trifluoromethyl)-3-pyridyl] -2-azaspiro[3.3]heptan-6- yl]propan-2-one oxime (Compound 322). To a solution of 1-(4-methoxy-3-pyridyl)-1-[2-[6-(trifluoromethyl)-3-pyridyl] -2-azaspiro[3.3]heptan- 6-yl]propan-2-one (80 mg, 197 umol) in MeOH (1 mL) was added NaOAc (49 mg, 592 umol) and hydroxylamine;hydrochloride (27 mg, 395 umol) at 20°C. The mixture was stirred for 12 h at 20°C. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (Phenomenex Gemini-NX C18 75*30mm*3um column; 25%-55% acetonitrile in an a 0.05% ammonium hydroxide and 10mM ammonium bicarbonate solution in water, 8min gradient). The product 1-(4-methoxy-3-pyridyl)-1-[2-[6- (trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptan-6-yl]prop an-2-one oxime (36 mg, 86 umol, 43%) was obtained as white solid. 1H NMR (400MHz, CHLOROFORM-d) δ 8.39 (d, J = 5.7 Hz, 1H), 8.29 (s, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 6.81 (d, J = 5.7 Hz, 1H), 6.64 (dd, J = 2.2, 8.6 Hz, 1H), 4.02 - 3.92 (m, 2H), 3.90 (s, 3H), 3.89 - 3.80 (m, 3H), 2.86 (br d, J = 10.5 Hz, 1H), 2.54 - 2.44 (m, 1H), 2.19 - 2.10 (m, 1H), 2.04 (dd, J = 8.3, 12.1 Hz, 1H), 1.82 (br dd, J = 8.4, 11.9 Hz, 1H), 1.71 (s, 3H) LCMS (ESI for C21H23F3N4O2) m/z: 421.1 [M+H]+ Synthesis of 6-[hydroxy-(4-methoxy-3-pyridyl)methyl]-2-[6-(trifluoromethy l)-3-pyridyl]-2- azaspiro[3.3]heptan-6-ol (Compound 323). Step 1: tert-butyl 6-hydroxy-6-[hydroxy-(4-methoxy-3-pyridyl)methyl]-2-azaspiro [3.3]heptane-2- carboxylate. To a solution of tert-butyl 6-[(4-methoxy-3-pyridyl)methylene]-2-azaspiro[3.3]heptane-2- carboxylate (100 mg, 316 umol) in H2O (1 mL) and t-BuOH (2 mL) was added NMO (41 mg, 348 umol), then OsO4 (40 mg, 158 umol) in portions at 0 ºC. Then the mixture was stirred at 25 ºC for 12 h. The reaction mixture was quenched by the addition saturated Na2SO3 (3 mL) at 0 ºC, then was stirred at 20 ºC for 2 h. Then the H2O phase was extracted with ethyl acetate (5 ml *3) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The mixture was purified by prep-HPLC (Phenomenex Gemini-NX C1875*30mm*3um column;10-40 % acetonitrile in an a 0.05% ammonia solution in water and in an a 10mM ammonium bicarbonate solution in water, 8 min gradient) to afford tert-butyl 6-hydroxy-6-[hydroxy-(4-methoxy-3- pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (20 mg, 54 umol, 17%) as a white solid. LCMS (ESI) m/z: 351.3 [M+H] ⁺ . Step 2: 6-[hydroxy-(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]hepta n-6-ol. To a solution of tert-butyl 6-hydroxy-6-[hydroxy-(4-methoxy-3-pyridyl)methyl]-2- azaspiro[3.3]heptane-2-carboxylate (20 mg, 57 umol) in DCM (0.5 mL) was add TFA (308 mg, 2.7 mmol) and the mixture was stirred at 20 ºC for 1 h. The reaction mixture was concentrated to obtain 6-[hydroxy- (4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]heptan-6-ol (17 mg, crude, TFA) was obtained as a yellow gum. Step 3: 6-[hydroxy-(4-methoxy-3-pyridyl)methyl]-2-[6-(trifluoromethy l)-3-pyridyl]-2-azaspiro[3.3]heptan-6- ol. To a solution of 6-[hydroxy-(4-methoxy-3-pyridyl)methyl]-2-azaspiro[3.3]hepta n-6-ol (27 mg, 108 umol) in DMF (0.5 mL) was added Et3N (33 mg, 324 umol) and 5-fluoro-2-(trifluoromethyl)pyridine (18 mg, 108 umol) and the mixture was stirred at 90 ºC for 2 h. The reaction mixture was concentrated in vacuum. The mixture was purified by prep-HPLC (Phenomenex Gemini-NX C1875*30mm*3um column;20-50 % acetonitrile in an a 0.05% ammonia solution in water and in an a 10mM ammonium bicarbonate solution in water, 8 min gradient) to obtain 6-[hydroxy-(4-methoxy-3-pyridyl)methyl]-2-[6-(trifluoromethy l)-3- pyridyl]-2-azaspiro[3.3]heptan-6-ol (7 mg, 16 umol, 15%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.67 - 8.55 (s, 1H), 8.51 - 8.39 (m, 1H), 7.87 - 7.78 (m, 1H), 7.50 - 7.40 (m, 1H), 6.89 - 6.79 (m, 1H), 6.72 - 6.62 (m, 1H), 5.08 - 5.00 (s, 1H), 4.06 - 3.97 (m, 2H), 3.94 (s, 3H), 3.82 (s, 2H), 3.42 - 2.80 (m, 2H), 2.77 - 2.64 (m, 1H), 2.60 - 2.49 (m, 1H), 2.45 - 2.34 (m, 1H), 2.24 (br d, J = 12.4 Hz, 1H). LCMS (ESI for C19H20F3N3O3) [M+H] ⁺ : 396.1.

Synthesis of 4-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptan-6 -yl]-2,3-dihydropyrano[3,2- c]pyridin-4-ol, (Compound 324). Step 1: tert-butyl 6-[(4-chloro-3-pyridyl)-hydroxy-methyl]-2-azaspiro[3.3]hepta ne-2-carboxylate. To a solution of 4-chloro-3-iodo-pyridine (5.02 g, 20.97 mmol) in THF (40 mL) was added i- PrMgCl-LiCl (1.3 M, 16.90 mL) at 0 ºC and the mixture was warmed up and stirred at 25 ºC for 1 h. To the resultant mixture then was added tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (4.5 g, 19.97 mmol) in THF (10 mL) and the mixture was stirred at 25 °C for 1 h. The mixture was poured into saturated NH4Cl (30mL) at 0 °C and extracted with ethyl acetate (20 mL x 3),washed with brine (10 mL), dried over Na2SO4. It was concentrated and the crude product was purified by flash column (ISCO 20 g silica, 0-80 % ethyl acetate in petroleum ether, gradient over 20 min) to obtain tert-butyl 6-[(4-chloro-3- pyridyl)-hydroxy-methyl]-2-azaspiro[3.3]heptane-2-carboxylat e (4.4 g, 11.95 mmol, 60%) as yellow oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.68 (br s, 1H), 8.41 (br s, 1H), 7.31 - 7.28 (m, 1H), 5.05 (d, J = 5.8 Hz, 1H), 3.95 - 3.82 (m, 4H), 2.67 - 2.50 (m, 1H), 2.47 - 2.22 (m, 1H), 2.19 - 2.08 (m, 1H), 2.05 (s, 2H) , 1.43 (s, 9H). Step 2: tert-butyl 6-(4-chloropyridine-3-carbonyl)-2-azaspiro[3.3]heptane-2-car boxylate. To a solution of tert-butyl 6-[(4-chloro-3-pyridyl)-hydroxy-methyl]-2-azaspiro[3.3]hepta ne-2- carboxylate (4.4 g, 12.99 mmol) in dichloromethane (50 mL) was added Des-Martin periodinane (11.02 g, 25.97 mmol) at 0 °C. The mixture was stirred at 25 °C for 3 h. Saturated aqueous NaHCO3 (10 mL) and saturated aqueous Na2SO3 (10 mL) were added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (15mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column (ISCO 20 g silica, 0-50 % ethyl acetate in petroleum ether, gradient over 20 min) to obtain tert-butyl 6-(4- chloropyridine-3-carbonyl)-2-azaspiro[3.3]heptane-2-carboxyl ate (3.2 g, 8.84 mmol, 68. %) as pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.69 (s, 1H), 8.58 (d, J = 5.3 Hz, 1H), 7.40 (d, J = 5.3 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 4.00 - 3.89 (m, 2H), 3.82 (br t, J = 8.3 Hz, 1H), 2.60 - 2.44 (m, 4H), 1.44 (s, 9H). Step 3: tert-butyl 6-[1-(4-chloro-3-pyridyl)-1-hydroxy-3-methoxy-3-oxo-propyl]- 2-azaspiro[3.3]heptane-2- carboxylate. To a solution of methyl acetate (1.32 g, 17.81 mmol) in THF (30 mL) was added drop wise lithium diisopropylamide (2 M, 8.91 mL) at -70 °C and stirred for 30 min. To the reaction mixture was then added tert-butyl 6-(4-chloropyridine-3-carbonyl)-2-azaspiro[3.3]heptane-2-car boxylate (3 g, 8.91 mmol) in THF (3 mL) and the entire reaction mixture was stirred at -70 °C for another 2 h and poured into to saturated NH4Cl (30mL) solution. The resulting mixture was extracted with EtOAc (20mL x 3), washed with brine (15 mL), dried over Na2SO4 and concentrated to obtain the crude product which was used directly to next step. The product tert-butyl 6-[1-(4-chloro-3-pyridyl)-1-hydroxy-3-methoxy-3-oxo-propyl]- 2- azaspiro[3.3]heptane-2-carboxylate (3.1 g, 7.54 mmol, 85%) was obtained as yellow oil. Step 4: tert-butyl 6-[1-(4-chloro-3-pyridyl)-1,3-dihydroxy-propyl]-2-azaspiro[3 .3]heptane-2-carboxylate. A solution of tert-butyl 6-[1-(4-chloro-3-pyridyl)-1-hydroxy-3-methoxy-3-oxo-propyl]- 2- azaspiro[3.3]heptane-2-carboxylate (3 g, 7.30 mmol) in THF (35 mL) was degassed with nitrogen three times and cooled to 0 °C. LiAlH4 (554.22 mg, 14.60 mmol) was added and the reaction mixture was warmed up to 25 °C and stirred for 2 h. The resultant mixture was cooled to 0°C, quenched with water(0.5 mL) and 15% aqueous NaOH(0.5 mL). The resulting mixture was filtered and the filtrate was concentrated to dryness to obtain the crude product which was purified by flash column (ISCO 20 g silica, 0-70 % ethyl acetate in petroleum ether, gradient over 20 min). The product tert-butyl 6-[1-(4-chloro-3- pyridyl)-1,3-dihydroxy-propyl]-2-azaspiro[3.3]heptane-2-carb oxylate (1.7 g, 4.22 mmol, 58%) was obtained as yellow gum. 1H NMR (400 MHz, CHLOROFORM-d) δ 9.05 (s, 1H), 8.26 (d, J = 5.3 Hz, 1H), 7.27 - 7.21 (m, 1H), 5.23 (s, 1H), 4.29 (br s, 1H), 3.93 - 3.74 (m, 5H), 3.48 - 3.36 (m, 1H), 3.05 (quin, J = 8.4 Hz, 1H), 2.57 - 2.44 (m, 2H), 2.20 - 1.95 (m, 2H), 1.86 (m, 1H), 1.56 (m, 1H), 1.45 - 1.39 (m, 9H). Step 5: tert-butyl 6-(4-hydroxy-2,3-dihydropyrano[3,2-c]pyridin-4-yl)-2-azaspir o[3.3]heptane-2- carboxylate. To a solution of tert-butyl 6-[1-(4-chloro-3-pyridyl)-1,3-dihydroxy-propyl]-2-azaspiro[3 .3]heptane- 2-carboxylate (800 mg, 2.09 mmol) in DMF (8 mL) under N2 was added NaH (124 mg, 3.10 mmol, 60% suspension) at 0 °C. The mixture was heated and stirred at 80°C for 15 h. The reaction mixture was poured to water (10mL) over an ice bath and was extracted with EtOAc (15 mL x 4). The organic phase was washed with brine (10mL), dried over Na2SO4 and concentrated. The crude was purified by prep- HPLC ( Waters Xbridge Prep OBD C18150*40mm*10um column; 20-50 % acetonitrile in an a 0.05% ammonia solution and 10mM ammonium bicarbonate in water, 8 min gradient) to obtain tert-butyl 6-(4- hydroxy-2,3-dihydropyrano[3,2-c]pyridin-4-yl)-2-azaspiro[3.3 ]heptane-2-carboxylate (95 mg, 274 umol, 13%) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.44 (s, 1H), 8.24 (d, J = 5.6 Hz, 1H), 6.73 (d, J = 5.6 Hz, 1H), 4.40 - 4.27 (m, 2H), 3.98 - 3.92 (m, 2H), 3.89 - 3.80 (m, 2H), 2.65 - 2.43 (m, 2H), 2.40 - 2.18 (m, 2H), 2.17 - 2.06 (m, 1H), 2.06 - 1.81 (m, 3H), 1.44 (s, 9H) Step 6: 4-(2-azaspiro[3.3]heptan-6-yl)-2,3-dihydropyrano[3,2-c]pyrid in-4-ol. To a solution of tert-butyl 6-(4-hydroxy-2,3-dihydropyrano[3,2-c]pyridin-4-yl)-2- azaspiro[3.3]heptane-2-carboxylate (70 mg, 202 umol) in dichloromethane (0.6 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol) dropwise at 0°C. The mixture was warmed up and stirred at 25 °C for 1 h. The resultant mixture was concentrated and the crude product thus obtained was dissolved with MeOH (3mL), followed by the addition of AMbersep 900(OH),ion exchange resin(500mg) to increase the pH to 8. The mixture was filtered and the filtrate was concentrated to dryness to give the product 4-(2- azaspiro[3.3]heptan-6-yl)-2,3-dihydropyrano[3,2-c]pyridin-4- ol (58 mg, 200 umol, 99%) as yellow gum. LCMS (ESI) m/z: 247.1 [M+H] ⁺ Step 7: 4-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptan-6 -yl]-2,3-dihydropyrano[3,2-c]pyridin-4-ol. To a solution of 4-(2-azaspiro[3.3]heptan-6-yl)-2,3-dihydropyrano[3,2-c]pyrid in-4-ol (57 mg, 230 umol) and 5-fluoro-2-(trifluoromethyl)pyridine (38 mg, 230 umol) in DMF (1 mL) was added triethylamine (46 mg, 460 umol). The resultant mixture was stirred at 80 °C for 3 h. The mixture was then filtered and the filtrate was concentrated. The crude product was purified by prep-HPLC (Phenomenex Gemini-NX 80*40mm*3um column; 20-50 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 min gradient) to obtain 4-[2-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptan-6 -yl]-2,3- dihydropyrano[3,2-c]pyridin-4-ol (46 mg, 118 umol, 51%) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.52 (br s, 1H), 8.26 (d, J = 5.9 Hz, 1H), 7.84 (d, J = 2.6 Hz, 1H), 7.50 - 7.28 (m, 1H), 6.80 (br t, J = 5.4 Hz, 1H), 6.69 (dd, J = 2.6, 8.6 Hz, 1H), 4.44-4.42 (m, 1H)，4.37-4.35 (m, 1), 4.35 ( s, 2H), 4.10 - 3.88 (m, 2H), 2.79 - 2.53 (m, 2H), 2.42 - 2.37 (m, 2H), 2.36 - 2.20 (m, 1H),2.10 - 1.82 (m, 3H). LCMS (ESI for C20H20F3N3O2 [M+H] ⁺ : 392.1. Synthesis of [2-[5-chloro-6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]h eptan-6-yl]-(4-methoxy-3- pyridyl)methanone (Compound 325) and 1-[2-[5-chloro-6-(trifluoromethyl)-3-pyridyl]-2- azaspiro[3.3]heptan-6-yl]-1-(4-methoxy-3-pyridyl)ethanol (Compound 326): Step 1: [2-[5-chloro-6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]h eptan-6-yl]-(4-methoxy-3- pyridyl)methanone (Compound 325). To a solution of [2-[5-chloro-6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]h eptan-6-yl]-(4-methoxy- 3-pyridyl)methanol (85 mg, 205 umol) in DCM (1 mL) was added Dess-Martin periodinane (174 mg, 411 umol) dropwise at 0°C and the mixture was warmed up and stirred at 25°C for 4 h.4 mL of saturated sodium carbonate and 4 mL sodium bisulfite was added to the reaction mixture and, it was extracted with EtOAc (2 mL* 3). The combined organic layers were washed with brine (3 mL) dried over Na2SO4 and filtered. The filtrate was concentrated to dryness to afford the crude product which was purified by flash column (ISCO 20 g silica, 90-100 % ethyl acetate in petroleum ether, gradient over 30 min) to give [2-[5- chloro-6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptan- 6-yl]-(4-methoxy-3-pyridyl)methanone (60 mg, 143 umol, 70%) as a white solid. 1H NMR (400MHz, CHLOROFORM-d) δ 8.81 (s, 1H), 8.61 (d, J = 5.9 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 6.92 (d, J = 6.0 Hz, 1H), 6.70 (d, J = 2.3 Hz, 1H), 4.06 (s, 2H), 3.99 (s, 5H), 3.91 - 3.77 (m, 1H), 2.68 - 2.49 (m, 4H) LCMS (ESI for C19H17ClF3N3O2 [M+H] ⁺ : 412.0. Step 2: preparation of 1-[2-[5-chloro-6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3 ]heptan-6-yl]-1-(4- methoxy-3-pyridyl)ethanol (Compound 326). To a solution of [2-[5-chloro-6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]h eptan-6-yl]-(4-methoxy- 3-pyridyl)methanone (50 mg, 121 umol) in THF (1 mL) was added bromo(methyl)magnesium (3 M, 81 uL) dropwise at 0°C .The resulting mixture was stirred at 25ºC for 2 h. The crude residue was purified by prep-HPLC (Phenomenex Gemini-NX 75*30mm*3um column; 50-80 % acetonitrile in an a 0.05% ammonia and 10mM ammonium bicarbonate solution in water, 8 min gradient) to obtain 1-[2-[5-chloro-6- (trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptan-6-yl]-1-( 4-methoxy-3-pyridyl)ethanol (50 mg, 116 umol, 95.43%) as a white solid. 1H NMR (400MHz, CHLOROFORM-d) δ 8.59 (s, 1H), 8.47 (br d, J = 5.8 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 6.96 (d, J = 5.9 Hz, 1H), 6.65 (s, 1H), 4.05 - 3.99 (m, 4H), 3.99 - 3.92 (m, 2H), 3.91 - 3.86 (m, 1H), 3.60 (br s, 1H), 2.90 (quin, J = 8.2 Hz, 1H), 2.51 (br dd, J = 8.2, 11.8 Hz, 1H), 2.35 - 2.26 (m, 1H), 2.21 - 2.15 (m, 1H), 2.08 - 1.99 (m, 1H), 1.96 - 1.71 (m, 3H) LCMS (ESI for C20H21ClF3N3O2 [M+H] ⁺ : 428.2. The following compounds were synthesized according to the protocol described for the compound 326.

Synthesis of 2-(1-imidazo[1,2-a]pyrazin-5-ylazetidin-3-yl)-1-(3-pyridyl)e thanol; (Compound 332). To a solution of 2-(azetidin-3-yl)-1-(3-pyridyl)ethanol (116 mg, 651 umol) in DMSO (3 mL) was added 5-chloroimidazo[1,2-a]pyrazine (100 mg, 651 umol) and DIPEA (168 mg, 1.30 mmol, 227 uL) and the resultant mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated and the crude product was purified by prep-HPLC (Phenomenex Gemini-NX 80*40mm*3um column; 1-20% acetonitrile in an a 0.05% ammonia and 10mM ammonium bicarbonate solution in water, 8 min gradient) to obtain 2- (1-imidazo[1,2-a]pyrazin-5-ylazetidin-3-yl)-1-(3-pyridyl)eth anol (35 mg, 118 umol, 18%) as a yellow gum. ¹ H NMR (400MHz, CHLOROFORM-d) δ 8.69 (s, 1H), 8.64 - 8.55 (m, 2H), 7.77 - 7.71 (m, 2H), 7.50 (s, 1H), 7.34 (dd, J = 4.9, 7.8 Hz, 1H), 7.08 (s, 1H), 4.88 (dd, J = 5.0, 7.6 Hz, 1H), 4.39 - 4.25 (m, 2H), 3.90 (t, J = 6.8 Hz, 1H), 3.81 (t, J = 6.8 Hz, 1H), 3.09 (td, J = 7.3, 14.3 Hz, 1H), 2.30 - 2.18 (m, 1H), 2.17 - 2.06 (m, 1H). LCMS (ESI H] ⁺ : 296.1. Synthesis of 2-(1-pyrazin-2-ylazetidin-3-yl)-1-(3-pyridyl)ethanol; (Compound 333). To a stirred solution of 2-(azetidin-3-yl)-1-(3-pyridyl)ethanol (150 mg, 842 umol) in DMSO (5 mL) was added 2-bromopyrazine (133.80 mg, 841.61 umol), pyrrolidine-2-carboxylic acid (39 mg, 337 umol) K2CO3 (349 mg, 2.52 mmol) and CuI (64.11 mg, 337 umol) and the mixture was stirred at 25 °C for 12 h under nitrogen atmosphere. The reaction mixture was then concentrated and the resultant crude product was purified by prep-HPLC (Phenomenex Luna C18200*40mm*10um column; 1-40% acetonitrile in an a 0.2% formic acid solution in water in water, 8 min gradient) to afford 2-(1-pyrazin-2-ylazetidin-3-yl)-1-(3- pyridyl)ethanol (22 mg, 82 umol, 9.79%) as a yellow oil. 1H NMR (400MHz, CHLOROFORM-d) δ 8.59 (br s, 2H), 8.00 (s, 1H), 7.83 (br s, 1H), 7.74 (br d, J = 7.5 Hz, 2H), 7.34 (br s, 1H), 4.83 (dd, J = 5.1, 7.9 Hz, 1H), 4.26 - 4.12 (m, 2H), 3.78 (dd, J = 5.8, 8.0 Hz, 1H), 3.72 (dd, J = 6.0, 8.2 Hz, 1H), 3.07 - 2.91 (m, 1H), 2.30 - 2.17 (m, 1H), 2.15 - 2.03 (m, 1H). LCMS (ESI for C14H16N4O [M+H] ⁺ : 257.1. The following compounds were synthesized according to the protocol described for Compound 333.

Synthesis of 2-methyl-1-(pyridin-3-yl)-2-(1-(6-(trifluoromethyl)pyridin-3 -yl)azetidin-3-yl)propan-1-ol (Compound 357): Step 1: preparation of tert-butyl 3-(1-cyano-1-methyl-ethyl)azetidine-1-carboxylate. To a solution of tert-butyl 3-(cyanomethyl)azetidine-1-carboxylate (500 mg, 2.55 mmol) in THF (5 mL) was added LiHMDS (1 M, 7.64 mL) at -70 °C. Then the mixture was stirred at -70 °C for 30 min. A solution of iodomethane (1.08 g, 7.64 mmol) in THF (1 mL) was added to the above solution and the mixture was stirred at 20 °C for 12 h. To the mixture was added H2O (3 mL) and extracted with EtOAc (15 mL*4). The organic layer was washed with brine (8 mL), dried over Na2SO4 and concentrated to give crude product. The crude product was purified by flash column (ISCO 10 g silica, 20-50 % ethyl acetate in petroleum ether, gradient over 20 min) to obtain tert-butyl 3-(1-cyano-1-methyl-ethyl)azetidine-1- carboxylate (0.48 g, 2.14 mmol, 84%) as a colorless oil. ¹ H NMR (400MHz, CHLOROFORM-d) δ 4.05 - 4.01 (m, 2H), 3.90-3.86 (m, 2H), 2.64 - 2.52 (m, 1H), 1.47 (s, 9H), 1.33 (s, 6H) Step 2: preparation of tert-butyl 3-(1,1-dimethyl-2-oxo-ethyl)azetidine-1-carboxylate. To a solution of tert-butyl 3-(1-cyano-1-methyl-ethyl)azetidine-1-carboxylate (430 mg, 1.92 mmol) in DCM (5 mL) was added DIBAL-H (1 M, 5.75 mL) at -70 °C. Then the mixture was stirred at -70 °C for 2 h. To the mixture was added H2O (3 mL) and extracted with EtOAc (10 mL*3). The organic layer was washed with brine (4 mL), dried over Na2SO4 and concentrated to give crude product. The crude product was purified by flash column (ISCO 10 g silica, 50-90 % ethyl acetate in petroleum ether, gradient over 20 min) to give tert-butyl 3-(1,1-dimethyl-2-oxo-ethyl)azetidine-1-carboxylate (170 mg, 748 umol, 39%) as a white solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ 9.42 (s, 1H), 3.89 (t, J=8.9 Hz, 2H), 3.70 - 3.59 (m, 2H), 2.72 - 2.60 (m, 1H), 1.36 (s, 9H), 1.03 (s, 6H) Step 3: preparation of tert-butyl 3-[2-hydroxy-1,1-dimethyl-2-(3-pyridyl)ethyl]azetidine-1-car boxylate. To a solution of 3-iodopyridine (235 mg, 1.14 mmol) in THF (3 mL) was added i-PrMgCl (2 M, 572 uL) at 0°C. Then the mixture was stirred at 20 °C for 30 min. Then tert-butyl 3-(1,1-dimethyl-2-oxo- ethyl)azetidine-1-carboxylate (130 mg, 572 umol) in THF (0.2 mL) was added to the above solution and the mixture was stirred at 20 °C for 2h. To the mixture was added H2O (3 mL) and extracted with EtOAc (15 mL*3). The organic layer was washed with brine (8 mL), dried over Na2SO4 and concentrated to give crude product. The crude product was purified by flash column (ISCO 4 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 20 min) to give tert-butyl 3-[2-hydroxy-1,1-dimethyl-2-(3- pyridyl)ethyl]azetidine-1-carboxylate (90 mg, 294 umol, 51%) as a colorless oil. Step 4: preparation of 2-(azetidin-3-yl)-2-methyl-1-(3-pyridyl)propan-1-ol. A mixture of tert-butyl 3-[2-hydroxy-1,1-dimethyl-2-(3-pyridyl)ethyl]azetidine-1-car boxylate (90 mg, 294 umol) in TFA (0.6 mL) and DCM (2 mL). Then the mixture was stirred at 20 °C for 1.5 h. The mixture was concentrated to give crude product. Then the crude product was then dissolved in MeOH(10 ml), basified by ion exchange resin, and the turbid liquid was filtered to remove the insoluble material, and the filtrate was concentrated in vacuo to give 2-(azetidin-3-yl)-2-methyl-1-(3-pyridyl)propan-1-ol (60 mg, 291 umol, 99%) as a colorless oil. LCMS (ESI) m/z: 207.4 [M+H]+. Step 5: preparation of 2-methyl-1-(pyridin-3-yl)-2-(1-(6-(trifluoromethyl)pyridin-3 -yl)azetidin-3-yl)propan-1- ol. To a solution of 2-(azetidin-3-yl)-2-methyl-1-(pyridin-3-yl)propan-1-ol (60 mg, 291 umol) in DMF (1 mL) was added 5-iodo-2-(trifluoromethyl)pyridine (72.03 mg, 436.29 umol) and Et3N (59 mg, 582 umol). Then the mixture was stirred at 80 °C for 12 h. The mixture was purified by prep-HPLC column: Phenomenex Gemini-NX 80*40mm*3um;mobile phase: [water(10Mm NH4HCO3)-ACN];B%: 25%-45%, 8min to give 2-methyl-1-(pyridin-3-yl)-2-(1-(6-(trifluoromethyl)pyridin-3 -yl)azetidin-3-yl)propan-1-ol (13 mg, 35 umol, 12%) as a pale yellow solid. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.64 - 8.52 (m, 2H), 7.85 (d, J=2.6 Hz, 1H), 7.71 (br d, J=7.8 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.33 (dd, J=4.8, 7.8 Hz, 1H), 6.69 (dd, J=2.4, 8.6 Hz, 1H), 4.54 (d, J=2.3 Hz, 1H), 3.97 (q, J=8.3 Hz, 2H), 3.85 - 3.73 (m, 2H), 3.12 - 2.99 (m, 1H), 0.97 (s, 6H) LCMS (ESI for C18H20F3N3O [M+H]+: 352.2 Synthesis of [2-(3-chloro-4-fluoro-phenyl)-3,3a,4,5,6,6a-hexahydro-1H-cyc lopenta[c]pyrrol-5-yl]-(3- pyridyl)methanol (trans-Isomer, Compound 358) and (cis-isomer, Compound 359): Step 1: preparation of tert-butyl 5-formyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-c arboxylate. To a solution of tert-butyl 5-(hydroxymethyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]py rrole-2- carboxylate (700 mg, 2.90 mmol) in DCM (15 mL) was added Dess-Martin periodinane (1.85 g, 4.35 mmol). Then the mixture was stirred at 20 °C for 2 h. The mixture was then diluted with DCM (20 mL), washed with sat. Na2SO3 (10 mL), sat. NaHCO3 (10 mL), brine (5 mL), dried over Na2SO4 and concentrated. The crude product was purified by flash column (ISCO 10 g silica, 30-50 % ethyl acetate in petroleum ether, gradient over 20 min) to afford tert-butyl 5-formyl-3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-2-carboxylate (650 mg, 2.72 mmol, 93%) as a colorless oil. ¹ H NMR (400MHz, CHLOROFORM-d) δ 9.66 (d, J=2.6 Hz, 1H), 3.61 - 3.45 (m, 2H), 3.25-3.15 (m, 2H), 2.97 - 2.83 (m, 1H), 2.77 - 2.63 (m, 2H), 2.22 - 2.10 (m, 2H), 1.79 - 1.68 (m, 2H), 1.48 (s, 9H) Step 2: preparation of tert-butyl 5-[hydroxy(3-pyridyl)methyl]-3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-2-carboxylate. To a solution of 3-iodopyridine (771 mg, 3.76 mmol) in THF (8 mL) was added i-PrMgCl (2 M, 1.88 mL) at 0 °C. Then the mixture was stirred at 0 °C for 30 min. Then tert-butyl 5-formyl-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (600 mg, 2.51 mmol) in THF (0.5 mL) was added to the above solution and the mixture was stirred at 20 °C for 2 h. The mixture was quenched with H2O (10 mL), extracted with EtOAc (20 mL*5). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated to give crude product. The crude product was purified by flash column (ISCO 10 g silica, 70-100 % ethyl acetate in petroleum ether, gradient over 20 min) to obtain tert-butyl 5-[hydroxy(3- pyridyl)methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrr ole-2-carboxylate (520 mg, 1.63 mmol, 65%) as a colorless oil. checked by HNMR ET7546-1893-P1A ¹ H NMR (400MHz, CHLOROFORM-d) δ 8.51 - 8.38 (m, 2H), 7.67 - 7.56 (m, 1H), 7.24 - 7.20 (m, 1H), 4.45 (dd, J=7.7, 16.3 Hz, 1H), 3.56 - 2.86 (m, 4H), 2.75 - 2.18 (m, 4H), 2.14 - 2.01 (m, 1H), 1.79 - 1.66 (m, 1H), 1.62 - 1.46 (m, 1H), 1.40 - 1.33 (m, 9H) Step 3: preparation of 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl(3-pyridy l)methanol. To a solution of tert-butyl 5-[hydroxy(3-pyridyl)methyl]-3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-2-carboxylate (500 mg, 1.57 mmol) in EtOAc (4 mL) was added HCl (2 mL). Then the mixture was stirred at 20 °C for 2 h and concentrated. Then the crude product was dissolved in MeOH(10 ml), basified by ion exchange resin, and the turbid liquid was filtered to remove the insoluble material, and the filtrate was concentrated in vacuo.1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5- yl(3-pyridyl)methanol (300 mg, crude) was obtained as a yellow oil. LCMS (ESI) m/z: 219.1 [M+H]+ Step 4: preparation of [2-(3-chloro-4-fluoro-phenyl)-3,3a,4,5,6,6a-hexahydro-1H-cyc lopenta[c]pyrrol-5-yl]- (3-pyridyl)methanol: (trans-Isomer, Compound 358) and (cis-Isomer, Compound 359): To a solution of 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl(3-pyridy l)methanol (200 mg, 916 umol) and 2-chloro-1-fluoro-4-iodo-benzene (282 mg, 1.10 mmol) in DMSO (3 mL) were added CuI (35 mg, 183 umol), DL-PROLINE (42mg, 366 umol) and K2CO3 (253 mg, 1.83 mmol). Then the mixture was stirred at 90 °C for 12 h. The mixture was filtered and the filtrate was purified by prep-HPLC column: 3_Phenomenex Luna C1875*30mm*3um;mobile phase: [water(0.2%FA)-ACN];B%: 20%-40%,9min; to obtain compound 358 and compound 359. Compound 358: ¹ H NMR (400MHz, CHLOROFORM-d) δ 8.58 (br s, 2H), 7.74 (br d, J=7.8 Hz, 1H), 7.33 (br s, 1H), 6.99 (t, J=8.9 Hz, 1H), 6.57 (dd, J=2.9, 6.1 Hz, 1H), 6.41 (td, J=3.4, 9.0 Hz, 1H), 4.56 (d, J=7.7 Hz, 1H), 3.46 - 3.31 (m, 2H), 3.05 - 2.84 (m, 4H), 2.55 - 2.40 (m, 1H), 1.91 - 1.82 (m, 2H), 1.69 - 1.53 (m, 1H), 1.38 (br dd, J=6.8, 11.7 Hz, 1H) LCMS (ESI for C19H20ClFN2O [M+H]+: 347.1 Compound 359: 1H NMR (400MHz, CHLOROFORM-d) δ = 8.51 (br d, J=8.3 Hz, 2H), 7.69 (br d, J=8.1 Hz, 1H), 7.33 - 7.25 (m, 1H), 6.96 (t, J=9.0 Hz, 1H), 6.57 (dd, J=3.0, 6.0 Hz, 1H), 6.40 (td, J=3.3, 8.8 Hz, 1H), 4.54 (d, J=7.5 Hz, 1H), 3.24 - 3.05 (m, 4H), 2.85 - 2.46 (m, 3H), 2.37 - 2.16 (m, 2H), 1.76 - 1.62 (m, 1H), 1.51 - 1.34 (m, 1H), 1.29 - 1.12 (m, 1H) LCMS (ESI for C19H20ClFN2O [M+H]+: 347.1. The following compounds were synthesized according to the protocol described for the Compound 99.

The following compound was synthesized according to the protocol described for the Compound 94: Synthesis of 2-(3-pyridylsulfonyl)-6-[6-(trifluoromethyl)-3-pyridyl]-2-az aspiro[3.3]heptane (Compound 351). Step 1: tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate. To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (1 g, 4.69 mmol) in toluene (20 mL) were added imidazole (958 mg, 14.07 mmol), iodine (1.79 g, 7.03 mmol, 1.42 mL) and PPh3 (2.46 g, 9.38 mmol, 2 eq). The mixture was stirred at 110 ºC for 1h, cooled and the mixture was extracted with ethyl acetate (20 mL *2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column (ISCO 40 g silica, 0-8% ethyl acetate in petroleum ether, gradient over 20 min) to obtain tert-butyl 6-iodo-2- azaspiro[3.3]heptane-2-carboxylate (1.3 g, 3.82 mmol) as a white solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 4.36 - 4.23 (m, 1H), 3.99 - 3.91 (m, 4H), 2.98 - 2.87 (m, 2H), 2.77 - 2.65 (m, 2H), 1.43 (s, 9H). Step 2: tert-butyl 6-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptane-2-c arboxylate. To a solution of tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (400 mg, 1.24 mmol) in i- PrOH (4 mL) was added (1R,2R)-2-aminocyclohexanol (21 mg, 186 umol) and NiI2 (58 mg, 186 umol) and then the mixture was stirred at 20 ºC for 0.5 h under N2. Then NaHMDS (1 M, 1.86 mL, 1.5 eq, in THF) was added, the mixture was stirred for 0.25 h under N2. A solution of [6-(trifluoromethyl)-3- pyridyl]boronic acid (236 mg, 1.24 mmol) in i-PrOH (2 mL) was added and the mixture was stirred at 120 ºC for 6 h. The reaction mixture was quenched by the addition H2O (3 mL) and extracted with ethyl acetate (20 mL *3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column (ISCO 10 g silica, 0-24% ethyl acetate in petroleum ether, gradient over 20 min) to obtain tert-butyl 6-[6-(trifluoromethyl)-3-pyridyl]-2- azaspiro[3.3]heptane-2-carboxylate (300 mg, 876 umol, 35%) was obtained as a white solid. LCMS (ESI) m/z: 287.2[M+H-56] ⁺ . Step 3: 6-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptane. To a solution of tert-butyl 6-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptane-2-c arboxylate (250 mg, 730 umol) in DCM (2 mL) was added TFA (1.54 g, 13.51 mmol). The mixture was stirred at 20 ºC for 2 h. The mixture was basified by AMBERSEP(R)900OH to pH＞7, was slow stirred at 2 h. Then the mixture was filtered and the filtrate was concentrated in vacuo to afford the desired product. The crude product 6-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptane (150 mg, 421 umol, 58%, TFA salt) was used into the next step without further purification. LCMS (ESI) m/z: 243.2[M+H] ⁺ . Step 4: 2-(3-pyridylsulfonyl)-6-[6-(trifluoromethyl)-3-pyridyl]-2-az aspiro[3.3]heptane. To a solution of 6-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptane (150 mg, 619 umol) in DCM (3 mL) was added Et3N (125 mg, 1.24 mmol), then was added pyridine-3-sulfonyl chloride (110 mg, 619 umol). The mixture was stirred at 15 ºC for 2 h. The reaction mixture was concentrated in vacuum and purified by prep-HPLC (Waters Xbridge Prep OBD C18150*40mm*10um column; 30-60% acetonitrile in a 10mM ammonium bicarbonate solution in water, 8 min gradient) to obtain 2-(3- pyridylsulfonyl)-6-[6-(trifluoromethyl)-3-pyridyl]-2-azaspir o[3.3]heptane (80 mg, 209 umol, 34%) as a pale yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 9.10 - 9.06 (m, 1H), 8.91 - 8.86 (m, 1H), 8.50 - 8.45 (m, 1H), 8.19 - 8.11 (m, 1H), 7.64 - 7.58 (m, 2H), 7.56 - 7.52 (m, 1H), 4.05 - 3.97 (s, 2H), 3.83 - 3.75 (s, 2H), 3.54 - 3.39 (m, 1H), 2.62 - 2.49 (m, 2H), 2.31 - 2.19 (m, 2H). LCMS (ESI) for C17H16F3N3O2S [M+H]+: 384.1. Synthesis of N-(1-(3,4-dichlorophenyl)azetidin-3-yl)-N-methylpyridine-3-s ulfonamide (Compound 352): Step 1: tert-butyl 3-(N-methylpyridine-3-sulfonamido)azetidine-1-carboxylate. To a solution of tert-butyl 3-(methylamino)azetidine-1-carboxylate (1 g, 5 mmol) and TEA (1 g, 13 mmol) in DCM (5 mL) was added pyridine-3-sulfonyl chloride (954 mg, 5 mmol) in DCM (5 mL) at 0 °C. The mixture was warmed up and stirred further at 25 °C for 1 h. The resultant mixture was extracted thrice with dichloromethane, washed with brine (30 mL) and dried over Na2SO4. The crude product tert- butyl 3-[methyl(3-pyridylsulfonyl)amino]azetidine-1-carboxylate (1.3 g, crude) was obtained as a pale yellow oil which was used in the next step without further purification. LCMS (ESI) m/z:328.1 [M+H] ⁺ Step 2: N-(azetidin-3-yl)-N-methylpyridine-3-sulfonamide. To a solution of tert-butyl 3-[methyl(3-pyridylsulfonyl)amino]azetidine-1-carboxylate (1 g, 4 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at 25 °C for 2 h and concentrated. The crude product N-(azetidin-3-yl)-N-methyl-pyridine-3-sulfonamide (600 mg, crude) was obtained as a pale yellow oil which was used in the next step without further purification. LCMS (ESI) m/z: 228.1 [M+H] ⁺ Step 3: N-(1-(3,4-dichlorophenyl)azetidin-3-yl)-N-methylpyridine-3-s ulfonamide. To a solution of N-(azetidin-3-yl)-N-methyl-pyridine-3-sulfonamide (300 mg, 1 mmol) in DMSO (5 mL) was added K2CO3 (365 mg, 3 mmol), DL-PROLINE (61 mg, 528 umol), CuI (101 mg, 528 umol) and 1,2-dichloro-4-iodo-benzene (360 mg, 1.32 mmol), the mixture was stirred at 90 °C for 5 h under N2. The reaction mixture was purified directly by prep-HPLC (Kromasil C18 (250*50mm*10 um column: 45-75 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 10 min gradient) to afford N-[1-(3,4- dichlorophenyl)azetidin-3-yl]-N-methyl-pyridine-3-sulfonamid e (220 mg, 590 umol, 45%) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ 8.98-8.93 (m, 2H), 8.24 (d, J = 8 Hz, 1H), 7.73-7.70 (m, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.61 (d, J = 2.8 Hz, 1H), 6.38 (dd, J = 2.8, 8.8 Hz, 1H), 4.75 - 4.70 (m, 1H), 4.01-3.95 (m, 2H), 3.76-3.73 (m, 2H), 2.87 (s, 3H) LCMS (ESI) for (C15H15Cl2N3O2S) [M+H] ⁺ : 372.0 The following compounds were synthesized according to the protocol reported for the synthesis of Compound 352. Synthesis of N-(3-pyridyl)-N-[4-(trifluoromethyl)phenyl]-2-[6-(trifluorom ethyl)-3-pyridyl]-2- azaspiro[3.3]heptan-6-amine (Compound 354). Step 1: tert-butyl 6-[4-(trifluoromethyl)anilino]-2-azaspiro[3.3]heptane-2-carb oxylate. To a solution of 4-(trifluoromethyl)aniline (500 mg, 3.10 mmol) in DCE (20 mL) were added tert- butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (656 mg, 3.10 mmol) and CH ₃ COOH (186 mg, 3.10 mmol). Then the mixture was stirred at 25°C for 0.5 h. NaBH(OAc)3 (1.97 g, 9.31 mmol, 3 eq) was then added to the above solution, the mixture was stirred at 25°C for another 4 h. The reaction mixture was quenched by addition of H ₂ O(20 mL), extracted with DCM(20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product tert-butyl 6-[4-(trifluoromethyl)anilino]-2-azaspiro[3.3]heptane-2-carb oxylate (1 g, 2.81 mmol, 90%) as a yellow gum. LCMS (ESI) m/z: 357.1 [M+H] ⁺ . Step 2: tert-butyl 6-[N-(3-pyridyl)-4-(trifluoromethyl)anilino]-2-azaspiro[3.3] heptane-2-carboxylate. To a solution of tert-butyl 6-[4-(trifluoromethyl)anilino]-2-azaspiro[3.3]heptane-2-carb oxylate (1 g, 2.81 mmol) in toluene (10 mL) were added 3-bromopyridine (443mg, 2.81 mmol), Pd(OAc)2 (63 mg, 281 umol), t-BuONa (809 mg, 8.42 mmol), Xantphos (325 mg, 561 umol). Then the mixture was stirred at 110 °C for 12 h under N ₂ atmosphere and concentrated. The resultant crude product was purified by flash column (ISCO 20 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 20 min) to afford tert- butyl 6-[N-(3-pyridyl)-4-(trifluoromethyl)anilino]-2-azaspiro[3.3] heptane-2-carboxylate (0.518 g, 834 umol, 30%) as a yellow gum. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.54 - 8.49 (m, 1H), 8.35 - 8.29 (m, 1H), 7.87 - 7.82 (m, 1H), 7.48 - 7.43 (m, 1H), 7.38 - 7.31 (m, 2H), 6.62 (br d, J = 8.8 Hz, 2H), 4.28 - 4.18 (m, 1H), 4.04 - 4.00 (m, 2H), 3.78 - 3.73 (m, 2H), 2.63 - 2.51 (m, 2H), 2.03 - 1.94 (m, 2H), 1.43 - 1.39 (m, 9H), LCMS (ESI) m/z: 434.1 [M+H] ⁺ . Step 3: N-(3-pyridyl)-N-[4-(trifluoromethyl)phenyl]-2-azaspiro[3.3]h eptan-6-amine. To a solution of tert-butyl 6-[N-(3-pyridyl)-4-(trifluoromethyl)anilino]-2-azaspiro[3.3] heptane-2- carboxylate (500 mg, 1.15 mmol) in DCM (5 mL) was added TFA (3.85 g, 33.77 mmol). Then the mixture was stirred at 25 °C for 1 h and concentrated to obtain the crude product. The compound N-(3-pyridyl)-N- [4-(trifluoromethyl)phenyl]-2-azaspiro[3.3]heptan-6-amine (240 mg, 720 umol, 62%) was obtained as a yellow gum. LCMS (ESI) m/z: 334.1 [M+H] ⁺ . Step 4: N-(3-pyridyl)-N-[4-(trifluoromethyl)phenyl]-2-[6-(trifluorom ethyl)-3-pyridyl]-2-azaspiro[3.3]heptan-6- amine. To a solution of N-(3-pyridyl)-N-[4-(trifluoromethyl)phenyl]-2-azaspiro[3.3]h eptan-6-amine (240 mg, 720 umol) in DMF (3 mL) was added Et3N (219 mg, 2.16 mmol) and 5-fluoro-2- (trifluoromethyl)pyridine (143 mg, 864 umol). The mixture was stirred at 80 °C for 2 hr. The crude product was purified by prep-HPLC (Waters Xbridge BEH C18100*30mm*10um column; 45-75 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 min gradient) to afford N-(3-pyridyl)-N-[4- (trifluoromethyl)phenyl]-2-[6-(trifluoromethyl)-3-pyridyl]-2 -azaspiro[3.3]heptan-6-amine (90 mg, 184 umol, 26%) as a white solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.54 – 8.53 (m, 1H), 8.35 (s, 1H), 7.82 (s, 1H), 7.48 - 7.44 (m, 3H), 7.37-7.27 (m, 2H),6.73-6.67 (m, 3H), 4.33 - 4.29 (m, 1H), 4.11 (s, 2H), 3.84 (s, 2H),2.70-2.65 (m, 2H),2.14-2.09 (m, 2H). LCMS (ESI) for (C24H20F6N4) [M+H] ⁺ : 479.2. The following compound was prepared according to the protocol described for the Compound 354.

Synthesis of 6-(3-chloro-4-fluoro-phenyl)-2-[2,2,2-trifluoro-1-(3-pyridyl )ethyl]-2,6- Step 1: tert-butyl 6-(3-chloro-4-fluoro-phenyl)-2,6-diazaspiro[3.3]heptane-2-ca rboxylate. To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate.oxalate salt (400 mg, 1.39 mmol) in dioxane (5 mL) was added t-BuONa (400 mg, 4.16 mmol), Pd2(dba)3 (64 mg, 69 umol), RuPhos (13 mg, 28 umol) and 2-chloro-1-fluoro-4-iodo-benzene (356 mg, 1.39 mmol) and then the mixture was stirred at 100 ºC for 20 min under N2.10 mL of water was added to the reaction mixture and it was extracted with Ethyl acetate (20 mL*3). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4 and concentrated. The crude product was purified by flash column (ISCO 10 g silica, 0-5 % ethyl acetate in petroleum ether, gradient over 20 min) to afford tert-butyl 6-(3-chloro-4-fluoro- phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (350 mg, 1.07 mmol, 77%) as a pale yellow solid.1H NMR (400MHz, CHLOROFORM-d) δ = 6.99 (t, J=8.9 Hz, 1H), 6.43 (dd, J=2.8, 6.0 Hz, 1H), 6.26 (td, J=3.3, 8.8 Hz, 1H), 4.09 (s, 4H), 3.93 (s, 4H), 1.46 (s, 9H) Step 2: 2-(3-chloro-4-fluoro-phenyl)-2,6-diazaspiro[3.3]heptane. To a solution of tert-butyl 6-(3-chloro-4-fluoro-phenyl)-2,6-diazaspiro[3.3]heptane-2-ca rboxylate (350 mg, 1.07 mmol) in DCM (4 mL) was added TFA (1.71 g, 14.99 mmol) at 0 ºC and then the mixture was stirred at 20 ºC for 2 h. The reaction mixture was concentrated to dryness to give the crude product. The crude product was used directly without purification. Yield: 570mg (TFA salt). Step 2: [2,2,2-trifluoro-1-(3-pyridyl)ethyl] trifluoromethanesulfonate. To a solution of 2,2,2-trifluoro-1-(3-pyridyl)ethanol (300 mg, 1.69 mmol) in DCM (6 mL) was added 2,6-dimethylpyridine (272 mg, 2.54 mmol) at 0 ºC and stirred for 5 min. Then Tf2O (717 mg, 2.54 mmol) was added to the above solution and the mixture was stirred at 0 °C for 30 min.10 mL of water was added to the reaction mixture and it was extracted with DCM(15 mL*2). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4 and concentrated. The crude product was used directly without purification. Yield: 500mg (pale yellow gum). Step 3: 6-(3-chloro-4-fluoro-phenyl)-2-[2,2,2-trifluoro-1-(3-pyridyl )ethyl]-2,6-diazaspiro[3.3]heptane. To a solution of 2-(3-chloro-4-fluoro-phenyl)-2,6-diazaspiro[3.3]heptane (100 mg, 441 umol) and [2,2,2-trifluoro-1-(3-pyridyl)ethyl] trifluoromethanesulfonate (409 mg, 1.32 mmol) in THF (3 mL) was added DIPEA (285 mg, 2.21 mmol). Then the mixture was stirred at 70 °C for 12h and concentrated. The crude was purified by prep-HPLC (Waters Xbridge Prep OBD C18150*4010u column; 45-70 % acetonitrile in an a 10mM ammonium bicarbonate solution in water, 8 min gradient) to afford 6-(3-chloro- 4-fluoro-phenyl)-2-[2,2,2-trifluoro-1-(3-pyridyl)ethyl]-2,6- diazaspiro[3.3]heptane (54 mg, 140 umol, 32%) as a pale yellow solid. 1H NMR (400MHz, CHLOROFORM-d) δ 8.62 (dd, J=1.6, 4.7 Hz, 1H), 8.59 (s, 1H), 7.74 (br d, J=7.9 Hz, 1H), 7.32 (dd, J=4.9, 8.0 Hz, 1H), 6.94 (t, J=8.9 Hz, 1H), 6.37 (dd, J=2.7, 6.0 Hz, 1H), 6.21 (td, J=3.2, 8.9 Hz, 1H), 3.87 (s, 4H), 3.78 (q, J=6.8 Hz, 1H), 3.46 - 3.35 (m, 4H). LCMS (ESI) for C18H16ClF4N3 [M+H]+: 386.0 Synthesis of enantiomer 1 (Compound 360) and enantiomer 2 (compound 361) of 4-(pyridin-3-yl(2- (6-(trifluoromethyl)pyridin-3-yl)-2-azaspiro[3.3]heptan-6-yl )methyl)morpholine. Step 1: pyridin-3-yl(2-(6-(trifluoromethyl)pyridin-3-yl)-2-azaspiro[ 3.3]heptan-6-yl)methyl methanesulfonate. To a solution of 1-tert-butyl 2-methyl 4-cyclopropyl-1H-pyrrole-1,2-dicarboxylate (60 mg, 0.17 mmol) in dichloromethane (15 mL) at 0°C, was added a solution of methanesulfonyl chloride (40 mg, 0.34 mmol) in dichloromethane (1 mL) slowly followed by N,N-Diisopropylethylamine (33 mg, 0.26 mmol). Then the reaction was stirred at 20°C for 5 h. The reaction was concentrated to afford pyridin-3-yl(2-(6- (trifluoromethyl)pyridin-3-yl)-2-azaspiro[3.3]heptan-6-yl)me thyl methanesulfonate (65 mg, 0.15 mmol, 89.5% yield) as yellow oil, which was used directly in the next step without further purification. LCMS (ESI) m/z: 428.1[M+H]+. Step 2: Synthesis of enantiomer 1 (Compound 360) and enantiomer 2 (compound 361) of 4-(pyridin-3- yl(2-(6-(trifluoromethyl)pyridin-3-yl)-2-azaspiro[3.3]heptan -6-yl)methyl)morpholine. A mixture of pyridin-3-yl(2-(6-(trifluoromethyl)pyridin-3-yl)-2-azaspiro[ 3.3]heptan-6-yl)methyl methanesulfonate (65 mg, 0.15 mmol), morpholine (excess, 0.5 mL) in Acetonitrile (5 mL) was stirred at 50°C for 5 hour. The reaction was concentrated. The residue was diluted with ethyl acetate/water (10 mL/10 mL), extracted with ethyl acetate (10 mL) twice. The combined organic phase was washed with brine (10 mL), dried over sodium sulate, filtered and concentrated. The residue was purified by Combi- Flash (Biotage, 20 g silica gel, eluted with 7N ammonia methanol:dichloromethane=1:10 in dichloromethane from 20% to 40%) to afford 40 mg of the racemic product (yield 63.8%) , which was separated by chiral-PREP-HPLC (Instrument: SFC-150 (Thar, Waters); Column: IG 20*250mm, 10um (Daicel) Column temperature: 35 °C; Mobile phase: carbon dioxide/methanol (0.2% Methanol Ammonia) = 40/60; Flow rate: 120 g/min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 7min; Sample solution: 40 mg dissolved in 20 ml Methanol;Injection volume: 4ml) to afford Enantiomer 1 (5.3 mg, 0.013 mmol) and Enantiomer 2 (3.4 mg, 0.008 mmol) as white solids. Enantiomer 1: ¹ H NMR (400 MHz, d-DMSO) δ 8.50-8.42 (m, 2H), 7.84 (d, J = 2.4 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.40-7.33 (m, 1H), 6.85 (dd, J=8.4 Hz, 2.4 Hz, 1H), 4.07-3.93 (m, 2H), 3.89-3.76 (m, 2H), 3.52 (brs, 4H), 3.33-3.25 (m, 2H), 2.85-2.68 (m, 1H), 2.39-2.07 (m, 5H), ,1.86- 1.74 (m, 1H), 1.68-1.56 (m, 1H). LCMS (ESI) m/z: 419.2[M+H]+; (Rt: 2.035min). Enantiomer 2: ¹ H NMR (400 MHz, d-DMSO) δ 8.51-8.42 (m, 2H), 7.84 (d, J = 2.4 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.40-7.33 (m, 1H), 6.84 (dd, J=8.4 Hz, 2.4 Hz, 1H), 4.08-3.93 (m, 2H), 3.88-3.75 (m, 2H), 3.52 (brs, 4H), 3.34-3.26 (m, 2H), 2.85-2.68 (m, 1H), 2.35-2.09 (m, 5H), ,1.85- 1.75 (m, 1H), 1.68-1.57 (m, 1H). LCMS (ESI) m/z: 419.2[M+H]+; (Rt: 2.998min). Synthesis of 4-(pyridin-3-yl(2-(6-(trifluoromethyl)pyridin-3-yl)-2-azaspi ro[3.3]heptan-6- yl)methyl)thiomorpholine 1,1-dioxide (compound 362): A mixture of pyridin-3-yl(2-(6-(trifluoromethyl)pyridin-3-yl)-2-azaspiro[ 3.3]heptan-6-yl)methyl methanesulfonate (150 mg, 0.35 mmol) , thiomorpholine 1,1-dioxide (47.4 mg, 0.35 mg) , N,N- diisopropylethylamine (90.63 mg, 0.70 mmol), Cesium carbonate (171.69 mg, 0.53 mmol) and Sodium iodide (79 mg, 0.53 mmol) in Acetonitrile (4 mL) was stirred at 80 ºC for 16h. The mixture was concentrated and purified by Prep-HPLC (BOSTON pHlex ODS 10um 21.2×250mm120A. The mobile phase was acetonitrile/0.1% Formic acid) to get 4-(pyridin-3-yl(2-(6-(trifluoromethyl)pyridin-3-yl)-2- azaspiro[3.3]heptan-6-yl)methyl)thiomorpholine 1,1-dioxide (16.2 mg, 0.035 mmol, 9.9%) as a white solid. ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.50 (s, 2H), 7.83-7.79 (m, 2H), 7.55 (d, J=8.8 Hz, 1H), 7.49-7.46 (m, 1H), 6.91-6.88 (m,1H), 4.08 (dd, J=7.6 Hz, 2H), 3.90 (dd, J=8.4 Hz, 2H), 3.71 (d, J=10.4 Hz, 1H), 3-.08- 2.89 (m, 9H), 2.61-2.59 (m, 1H), 2.34-2.29 (m, 1H), 2.01-2.05 (m, 1H), 1.82-1.77 (m, 1H). LCMS (ESI) m/z: 467.0[M+H] ⁺ . The following compounds were synthesized according to the protocol described for the Compound 362:

Inhibition of CYP51A1 by Compounds of the Invention Method: Recombinant human CYP51A1 (lanosterol-14a-demethylase) enzyme was co- expressed with CYP reductase in bacterial membranes and the fluorescent substrate BOMCC (a non- natural substrate that causes increases in fluorescence upon CYP51A1-dependent demethylation) was used to obtain 8-point dose concentration-response curves for each compound. Results: As shown in Table 4, the compounds of the invention inhibit CYP51A1. Table 4.

“+++” = ≤0.1 µM; “++” = >0.1 µM to ≤1 µM; “+” = >1 µM Inhibition of CYP51A1 modulates TDP-43 aggregation Introduction Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is an aggressive, debilitating disease in which affected patients succumb within two to five years after diagnosis. ALS presents with heterogeneous clinical features but has a common underlying pathology of motor neuron loss that limits the central nervous system’s ability to effectively regulate voluntary and involuntary muscle activity. Additionally, without neuronal trophic support muscles being to atrophy, further exacerbating motor deterioration. Cellular and tissue degeneration results in motor impairment such as fasciculations and weakening in the arms, legs and neck, difficulty swallowing, slurred speech and ultimately failure of the diaphragm muscles that control breathing. At the cellular level, 97% of all ALS cases have the common pathological feature of misfolded and aggregated TAR-DNA binding protein (TDP)-43 in spinal motor neuron inclusions. TDP-43 is a DNA/RNA binding protein involved in RNA splicing and is typically localized to the nucleus but can be translocated to the cytoplasm under conditions of cell stress. Nuclear clearing and cytoplasmic accumulation of misfolded and aggregated TDP-43 are hallmarks of degenerating motor neurons in ALS, but it remains unclear if mechanism of toxicity is due to aggregation-dependent loss of TDP-43 function or if the aggregates acquire toxic gain of function. Aggregates of TDP-43 accumulate in discrete cellular domains known as stress granules, which are also enriched with translationally inactive mRNAs. Stress granules are observed in multiple cellular types and are thought to be directly related to TDP-43- dependent toxicity in ALS and FTD. Dysfunction in DNA/RNA binding protein activity plays a crucial role in susceptible motor neurons in ALS, as familial cases have also been traced to mutations in the protein Fused in Sarcoma (FUS), a DNA/RNA binding protein that recently has been shown to be involved in gene silencing. Preclinical studies suggest that FUS mutations promote a toxic gain of function that may be causative in motor neuron degeneration. Mutations in the TDP-43 gene (TARDBP) have also been causally linked to familial forms of ALS. A common TDP-43 mutation is known as Q331K, in which glutamine (Q) 331 has been mutated to a lysine (K). This mutation results in a TDP-43 protein that is more aggregation prone and exhibits enhanced toxicity. A recent study has also demonstrated that the Q331K mutation can confer a toxic gain of function in a TDP-43 knock-in mouse, which exhibits cognitive deficits and histological abnormalities similar to that which occurs in frontotemporal dementia (FTD). FTD refers to a group of degenerative disorders that are characterized by atrophy in the frontal and temporal cortices due to progressive neuron loss. Due to the functional nature of the brain regions impacted in FTD, the most common symptoms involve noticeable alterations in personality, behavior and linguistic ability and can also present with loss of speech. The pathological basis of FTD appears to be multifactorial involving mutations in genes such as C9orf72, progranulin (GRN) and MAPT, but intracellular inclusions of aggregated TDP-43, FUS and tau have been observed. Although ALS and FTD may have different genetic and molecular triggers and occur in different cell types, similar protein misfolding and degenerative mechanisms may operate in multiple diseases. The toxic gain of function features of TDP-43 can be faithfully recapitulated in the simple model organism, budding yeast, where the protein also localizes to stress granules. Human disease mutations in TDP-43 enhance toxicity and yeast genetic screens have revealed key connections that are conserved to humans. The yeast model thus provides a robust cell-based screening platform for small molecules capable of ameliorating toxicity. To validate compounds from such phenotypic screens, it is imperative to test compounds in a mammalian neuronal context. In an effort to develop TDP-43-related mammalian models of neuron loss that occurs in ALS and FTD, primary cultures of rat cortical neurons were transfected with human wild type or Q331K mutant TDP-43. These cells were compared to cells which received an empty expression vector control. Validation studies have demonstrated that cells expressing either wild type or Q331K TDP-43 have are more susceptible to dying over time in culture. In the experiments described in this example, this model system is used to interrogate new therapeutic approaches to ameliorate TDP-43 toxicity. Results From the TDP-43 yeast model, a compound with known mode of action was identified that restored viability to TDP-43-expressing yeast (FIG.1A). Fluconazole is an antifungal known to inhibit Erg11, the yeast lanosterol 14-alpha demethylase (FIG.1B). Inhibition of Erg11 reduces ergosterol synthesis (yeast equivalent of cholesterol), while increasing lanosterol levels, the substrate of Erg11 (FIG. 1C). The human homolog of Erg11 is Cyp51A1, a member of the cytochrome P450 superfamily of enzymes but does not appear to have a role in detoxification of xenobiotics. CYP51A1 has also been known as lanosterol 14-alpha demethylase, which describes its function in removing the 14-alpha-methyl group from lanosterol to generate 4,4-dimethylcholesta-8(9),14,24-trien-3β-ol, which is a critical step in the cholesterol biosynthetic pathway. To evaluate the potential role of CYP51A1 in TDP-43 pathology, the aforementioned primary rat cortical neuron TDP-43 models were utilized to test the efficacy of published inhibitors (FIG.2). Rat cortical neurons transfected with wild type human TDP-43 exhibited a significant reduction in survival compared to neurons transfected with empty vector control, and this reduction in survival was partially alleviated by treatment with compound A (FIGS.3A and 3B). Compound A has the structure: A similar survival befit was conferred by compound A when applied to cells transfected with Q331K mutant TDP-43 (FIGS.4A and 4B). A similar effect in rescuing a survival deficit was observed for a structurally differentiated compound, compound B, when applied to cells transfected with wild-type TDP-43 (FIGS.5A and 5B). Compound B has the structure: These studies demonstrate that inhibition of Erg11 in yeast and inhibition of Cyp51A1 has a beneficial effect of rescuing cells from wild type and mutant TDP-43 toxicity and promotes cell survival. This is the first demonstration that inhibition of CYP51A1 is beneficial in treating and preventing TDP-43 pathological processes and represents a novel therapeutic approach for the treatment of ALS. Other Embodiments While the present invention has been described with reference to what are presently considered to be the preferred examples, it is to be understood that the invention is not limited to the disclosed examples. To the contrary, the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims. All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term. Other embodiments are in the claims.