WO2024149728A1 - Substituted (hetero)anilines and their use - Google Patents

Abstract

The present disclosure relates to substituted anilines and heteroanilines and their use as TRPV4 antagonists. In some embodiments, the disclosure provides a compound of Formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein ring A, R groups, X, Y, Z, m, p, q, and s are defined herein.

Description

SUBSTITUTED (HETERO)ANILINES AND THEIR USE CROSS-REFERENCE TO RELATED PATENT APPLICATION This specification claims the benefit of priority to U.S. Provisional Patent Application No. 63/479,275 (filed 10 January 2023). The entire text of the above-referenced patent application is incorporated by reference into this specification. FIELD [001] The present disclosure relates to substituted anilines and heteroanilines and their use as TRPV4 antagonists. In some embodiments, the disclosure provides a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein ring A, R groups, X, Y, Z, m, p, q, and s are defined herein. BACKGROUND [002] Transient Receptor Potential Vanilloid 4 (TRPV4) belongs to the Transient Receptor Potential (TRP) family that includes 28 transmembrane cation-permeable channels. TRPV4 consists of 871 amino acid residues in a tetrameric structure with 6 transmembrane α-helices (S1-S6) and a pore loop found between S5 and S6. The species differences are limited with approximately 95% identity human versus rat and mouse. TRPV4 has been shown to be activated by warm temperature (>27°C), lipid arachidonic acids and its epoxyeicosatrienoic acid metabolites, changes in extracellular osmolarity, low pH, inflammation, and natural and synthetic agonists (e.g., GSK1016790A). See, e.g., White et al., Physiol Rev 96:911-973 (2016). The apo cryo-EM structure of Xenopus tropicalis TRPV4 at 3.8-Å resolution has been published in Deng et al., Nat Struct Mol Biol 25:252-260 (2018). [003] TRPV4 overactivation is associated with numerous pathologies, including inflammation, respiratory diseases, metabolic diseases and disorders, dermatological diseases and disorders, skeletal diseases and disorders, and neuromuscular diseases and disorders. See, e.g., WO 2013/152109, WO 2014/209947, and WO 2017/177200; Rosenbaum et al., Int J Mol Sci 21(11):3837 (2020); and Lawhorn et al., Bioorganic Med Chem Lett 30(8):127022 (2020). For example, activation of TRPV4 in the lung has been shown to cause pulmonary edema (endothelial permeability), cough, contraction of smooth muscle cells, and release of adenosine triphosphate (ATP). Blocking of TRPV4 by small molecule antagonists has been shown to reduce eosinophilia in ovalbumin challenged rat and in addition reduce cough in TRPV4 agonist challenged Guinea pig (Wortley et al., Handb Exp Pharmacol 237:213-241 (2017)). In addition, TRPV4 antagonism has been suggested to suppress the metastasis of hepatocellular carcinoma (Cell Death and Disease (2023) 14:379), reduce invasiveness of colorectal cancer (BMC Cancer (2021) 21: 1264) and attenuate pathological cardiac hypertrophy by enhancing coronary angiogenesis (Hypertension. (2023) 80: 2345). Thus, compounds having selective TRPV4 antagonist activity may be beneficial for individuals with TRPV4-associated diseases or disorders. [004] To date, only one TRPV4 antagonist, GSK2798745, has advanced into clinical trials (see, e.g., NCT02497937). GSK2798745 was safe and well-tolerated in heart failure patients, but did not result in a significant effect on pulmonary gas diffusion (Stewart et al., Eur J Heart Fail 22:1641- 1645 (2020)). Subsequent studies indicate this may be due to a major circulating human metabolite of GSK2798745 being significantly less potent and limiting target engagement (Pero et al., ACS Med Chem Lett 12:1498−1502 (2021)). SUMMARY [005] The present disclosure provides substituted aniline and heteroaniline compounds and their use as TRPV4 antagonists. In some embodiments, the disclosure provides a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: ring A is a 5- to 11-membered N-heteroaryl or phenyl; each R¹, if present, is independently F, Cl, cyano, oxo, C3-C6 cycloalkyl, 3- to 6-membered heterocycle, C1-C5 alkyl, C1-C5 haloalkyl, phenyl, or combinations thereof, wherein the phenyl is optionally substituted with up to three substituents, wherein each substituent is independently selected from halo, cyano, C1-C5 alkyl, and C1-C3 alkoxy; R² is halo, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl, C3-C6 cycloalkoxy, C3-C6 halocycloalkoxy, or -OS(O)₂R⁴; wherein R⁴ is C1-C3 alkyl or C1-C3 haloalkyl; R^3a and each R^3b are independently selected from hydroxy, C1-C8 alkyl, C3-C6 cycloalkyl, a 5- to 6-membered heterocycle, -N(R⁵)(S(O)₂R⁶), -N(R⁵)C(O)OR⁶, and C1-C6 alkoxy, wherein: the C1-C8 alkyl is optionally substituted with up to three substituents selected from hydroxy, halo, oxo, carboxy, C1-C3 alkoxy, -S(O)₂R⁶, -S(O)₂NH₂, -C(O)OR₆, and -NR⁵R⁶; the 5- to 6-membered heterocycle is optionally substituted with up to three substituents selected from oxo and C1-C3 alkyl; the C3-C6 cycloalkyl is optionally substituted with up to three substituents selected from oxo and hydroxy; and each R⁵ and R⁶ is independent selected from C1-C3 alkyl and H; each R⁷ and R⁸, if present, is independently selected from H, halo, and C1-C3 alkyl, or together with the atom to which they are bound create a 3- to 6-membered carbocycle; X, Y, Z are each independently selected from CR⁹ and N; wherein each R⁹ is independently selected from H and halo; R^10a and ^R10b are independently selected from H and D; m is 0 or 1; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; and s is 0, 1, 2, or 3. In some embodiments, the compound described herein is a compound of Formula (I). In some embodiments the compound described herein is a pharmaceutically acceptable salt of a compound of Formula (I). [006] In some embodiments, ring A is phenyl. In some embodiments, p is 1, 2, or 3, and wherein each R¹ is independently cyano, C1-C5 alkyl, or C1-C5 haloalkyl. [007] In some embodiments, ring A is a 5- to 11-membered N-heteroaryl, wherein the N- heteroaryl comprises a single aromatic ring, or wherein the N-heteroaryl comprises two fused rings, wherein at least one ring comprises N and at least one ring is an aromatic ring. In some embodiments, ring A further comprises an oxygen. In some embodiments, ring A is a substituted or unsubstituted pyrrole, pyrazole, thiazole, pyridine, thienopyrrole, indole, benzoxazole, benzoxazine, or benzothiazepine. [008] In some embodiments, p is 0. In some embodiments, p is 1, 2, or 3, and wherein each R¹ is independently F, Cl, cyano, oxo, C1-C5 alkyl, C1-C5 haloalkyl, C3-C6 cycloalkyl, 3- to 6- membered heterocyclyl, or phenyl, wherein the C3-C6 cycloalkyl or the 3- to 6-membered heterocyclyl is optionally substituted with a halo, cyano, C1-C3 alkyl, or C1-C3 alkoxy. [009] In some embodiments, m is 0. In some embodiments, m is 1, and R⁷ and R⁸ are each independently H, halo, C1-C3 alkyl, or C1-C3 haloalkyl; or R⁷ and R⁸, together with the atom to which they are bound, create a 3-membered carbocycle. [010] In some embodiments, each of X, Y, and Z is CR⁹. In some embodiments, each R⁹ is H, and R² is halo, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl optionally substituted with one or more halo, C3-C6 cycloalkoxy optionally substituted with one or more halo, C1-C4 haloalkyl, C1-C4 haloalkoxy, or -OS(O)₂R⁴, wherein R⁴ is C1-C3 haloalkyl. In some embodiments, one R⁹ is halo, the remaining R⁹ are H, and R² is halo. [011] In some embodiments, each of X and Y is CR⁹ and Z is N; or wherein each of X and Z is CR⁹ and Y is N. In some embodiments, R² is C1-C4 haloalkyl or C1-C4 haloalkoxy. In some embodiments, R² is halo, trifluoromethyl, or difluoromethoxy. [012] In some embodiments, at least one of R^3a and R^3b comprises an oxygen. In some embodiments, at least one of R^3a and R^3b is hydroxy; C1-C8 alkyl substituted with at least one hydroxy, oxo, carboxy, C1-C3 alkoxy, -S(O)₂R⁶, -S(O)₂NH₂, or -C(O)OR₆; C3-C6 cycloalkyl substituted with up to three substituents selected from oxo and hydroxy; 5- to 6-membered O- heterocycle; 5- to 6-membered heterocycle substituted with at least one oxo; -N(R⁵)(S(O)₂R⁶); -N(R⁵)C(O)OR⁶; or C1-C6 alkoxy. [013] In some embodiments, s is 0, 1, or 3, and R^3a is C1-C8 alkyl substituted with hydroxy. [014] In some embodiments, s is 2, and R^3a is C1-C8 alkyl, C3-C6 cycloalkyl, or a 5- to 6- membered heterocycle. In some embodiments, R^3a is C1-C8 alkyl or C3-C6 cycloalkyl. In some embodiments, the C1-C8 alkyl or C3-C6 cycloalkyl is substituted with hydroxy, halo, C1-C3 alkoxy, -S(O)₂R⁶, -S(O)₂NH₂, -C(O)OR₆, -NR⁵R⁶, or combination thereof, wherein R⁵ and R⁶ are each independently H or C1-C3 alkyl. In some embodiments, R^3a is a 5- to 6-membered heterocycle comprising an N, S, O, or combination thereof. In some embodiments, the heterocycle is substituted with oxo or C1-C3 alkyl. [015] In some embodiments, q is 0. In some embodiments, q is 1, and R^3b is hydroxy, C1-C8 alkyl optionally substituted with one or more hydroxy, C1-C6 alkoxyl, or -N(R⁵)(S(O)₂R⁶), wherein R⁵ and R⁶ is independently H or C1-C3 alkyl. In some embodiments, q is 2, and each R^3b is independently hydroxy or C1-C8 alkyl, wherein the C1-C8 alkyl is optionally substituted with 1 to 3 hydroxy. [016] In some embodiments, the disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g. a compound of Formula (I)), wherein: ring A is a 5- membered N-heteroaryl; p is 1, 2, or 3; R¹ is phenyl optionally substituted with halo, m is 0; X, Y, Z are each CR⁹; R² is halo; s is 1 or 2; and R^3a is C1-C8 alkyl substituted with 1 to 3 hydroxy. In some embodiments, ring A is pyrazole. In some embodiments, each R⁹ is H. [017] In some embodiments, the disclosure provides a compound as found in Table 4, or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of Table 4. In some embodiments, the disclosure provides a pharmaceutically acceptable salt of a compound of Table 4. [018] In some embodiments, the disclosure provides a composition comprising a compound or pharmaceutically acceptable salt described herein (e.g. a compound described herein). In some embodiments, the composition further comprises a pharmaceutically acceptable excipient. [019] In some embodiments, the disclosure provides a method of inhibiting activity of Transient Receptor Potential Vanilloid 4 (TRPV4), comprising contacting TRPV4 with a compound or pharmaceutically acceptable salt described herein (e.g. a compound described herein) or a composition described herein. In some embodiments, the method is performed in vivo or in vitro. [020] In some embodiments, the disclosure provides a method of inhibiting activity of TRPV4 in a subject in need thereof, comprising administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt described herein (e.g. a compound described herein) or a composition described herein to the subject. [021] In some embodiments, the disclosure provides a method of treating, ameliorating, or preventing a TRPV4-associated disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt described herein (e.g. a compound described herein) or a composition described herein to the subject. [022] In some embodiments, the TRPV4-associated disease or disorder is inflammation, a respiratory disease or disorder, a metabolic disease or disorder, a dermatological disease or disorder, a skeletal disease or disorder, a neuromuscular disease disorder, or combination thereof. In some embodiments, the TRPV4-associated disease or disorder is pulmonary edema, systemic edema, hypertension, hyperalgesia, inflammation, brachyolmia, spondylometaphyseal dysplasia Kozlowski type, metatropic dysplasia, peripheral neuropathy, asthma, chronic cough, chronic obstructive pulmonary disease (COPD), overactive bladder, incontinence, acoustic cochlear injury, pancreatitis, epilepsy, arthritis, osteoarthritis, multiple sclerosis, stroke, central nervous system (CNS) autoimmune condition, traumatic brain injury, spinal cord injury, brain edema, CNS infection, neuro-psychiatric disorder, skeletal degenerative-inflammatory disorder, trigeminal pain, colitis, sclerosis, obesity, diabetes, or combination thereof. [023] In some embodiments, the TRPV4-associated disease or disorder is cancer. In some embodiments, the cancer is hepatocellular carcinoma or colorectal cancer. [024] In some embodiments, the TRPV4-associated disease or disorder is a cardiovascular disease or disorder. In some embodiments, the cardiovascular disease or disorder is hypertrophic cardiomyopathy. DETAILED DESCRIPTION [025] Unless otherwise defined herein, scientific and technical terms used in the present disclosure shall have the meanings that are commonly understood by one of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. [026] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. [027] The use of the term "or" in the claims is used to mean "and/or," unless explicitly indicated to refer only to alternatives or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and/or." [028] As used herein, the terms "comprising" (and any variant or form of comprising, such as "comprise" and "comprises"), "having" (and any variant or form of having, such as "have" and "has"), "including" (and any variant or form of including, such as "includes" and "include") or "contaiing" (and any variant or form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited, elements or method steps. [029] The use of the term "for example" and its corresponding abbreviation "e.g." means that the specific terms recited are representative examples and embodiments of the disclosure that are not intended to be limited to the specific examples referenced or cited unless explicitly stated otherwise. [030] As used herein, "about" can mean plus or minus 10% of the provided value. Where ranges are provided, they are inclusive of the boundary values. "About" can additionally or alternately mean either within 10% of the stated value, or within 5% of the stated value, or in some cases within 2.5% of the stated value; or, "about" can mean rounded to the nearest significant digit. [031] As used herein, "between" is a range inclusive of the ends of the range. For example, a number between x and y explicitly includes the numbers x and y and any numbers that fall within x and y. [032] The term "alkyl" means an acyclic alkyl moiety that is linear or branched, preferably containing one or more carbon atoms, e.g., about 1 to about 20 carbon atoms, or about 1 to about 10 carbon atoms, or about 1 to about 8 carbon atoms, about 1 to about 6 carbon atoms, or about 1 to about 4 carbon atoms, or about 2 to about 10 carbon atoms, or about 4 to about 8 carbon atoms. The alkyl moiety can be substituted with groups as described herein, e.g., hydroxy, halo, oxo, carboxy, alkoxy, sulfonyl, sulfamido, amino (e.g., primary, secondary, or tertiary), or any combination thereof. Alkyl includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, etc. It will be understood by one of ordinary skill in the art that unless otherwise specified, the chemical names throughout the present disclosure include all isomers thereof, e.g., "propyl" includes isopropyl and n-propyl, "butyl" includes isobutyl, tert-butyl, and sec-butyl, and the like. [033] The term "alkenyl" refers to an unsaturated, acyclic hydrocarbon moiety that is linear or branched and that contains at least one double bond, e.g., 1, 2, 3, 4, 5, or more than 5 double bonds, and preferably containing about 2 to about 20 carbon atoms, or about 1 to about 10 carbon atoms, or about 1 to about 5 carbon atoms, or about 2 to about 15 carbon atoms, or about 4 to about 10 carbon atoms. The alkenyl moiety can be optionally substituted with groups as described herein, e.g., hydroxy, halo, oxo, carboxy, alkoxy, sulfonyl, sulfamido, amino (e.g., primary, secondary, or tertiary), or any combination thereof. [034] The term "alkoxy" includes linear or branched oxy-containing moieties, each having an alkyl portion as described above, e.g., having about 1 to about 20 carbon atoms, or about 1 to about 10 carbon atoms, or about 1 to about 8 carbon atoms, about 1 to about 6 carbon atoms, or about 1 to about 4 carbon atoms, or about 2 to about 10 carbon atoms, or about 4 to about 8 carbon atoms. The term "alkoxyalkyl" includes alkyl moieties having one or more alkoxy moieties attached to the alkyl moiety. [035] The term "aryl" means a fully unsaturated ("aromatic") mono- or multi-ring structure, which may be 3 to 16 membered, or 4 to 14 membered, or 5 to 11 membered, or 6 to 10 membered, or 6 to 9 membered, or 6 to 8 membered, or 6 to 7 membered. Examples of such moieties include substituted or unsubstituted phenyl (or benzyl). As used herein, a ring "member" refers to an atom as part of the ring structure that is generally attached to at least two other ring members. The term "aryl" refers to an aromatic ring structure containing carbons as ring members. The term "heteroaryl" refers to an aromatic ring structure comprising carbon and at least one heteroatom, e.g., nitrogen, sulfur, and/or oxygen. As used herein, an "N-heteroaryl," "S-heteroaryl," or "O- heteroaryl" refer to a heteroaryl containing at least one nitrogen, sulfur, or oxygen, respectively, as a ring member. Exemplary heteroaryls include but are not limited to pyrrole, pyrazole, thiazole, pyridine, and benzothiazepine. [036] In some embodiments, the aryl or heteroaryl is a multi-ring structure ("polycyclic") containing two to four rings, wherein the rings are attached together in a pendent manner, fused, or form a bridged system. Exemplary polycyclic heteroaryls include but are not limited to indole, benzoxazole, benzoxazine, and thienopyrrole. It will be understood by one of ordinary skill in the art that a polycyclic aryl or heteroaryl needs only to contain one aromatic ring, while the remaining ring(s) may be aromatic or non-aromatic. For example, a polycyclic N-heteroaryl comprises at least one N-containing ring and at least one aromatic ring, wherein the N may be part of the aromatic ring or a non-aromatic ring. The aryls or heteroaryls described herein may have one or more substituents such as, but not limited to, halo, cyano, alkyl, alkoxy, oxo, hydroxy, or any combination thereof. In some embodiments, the aryl or heteroaryl described herein comprises 1, 2, 3, or more than 3 substituents. In some embodiments, one or more members of the aryl or heteroaryl each comprises a single substituent. In some embodiments, one or more members of the aryl or heteroaryl each comprises one or more substituents. In some embodiments, a member of the aryl or heteroaryl comprises more than one substituent. [037] The term "cyano" refers to a moiety in which a carbon atom is triple-bonded to a nitrogen atom (−C≡N), also known as a "nitrile" group. [038] The term "cycloalkyl" means a mono- or multi-ring structure that consists of carbon as ring members. A cycloalkyl may be 3 to 16 membered, or 4 to 14 membered, or 5 to 11 membered, or 6 to 10 membered, or 6 to 9 membered, or 6 to 8 membered, or 6 to 7 membered. A multi-ring cycloalkyl may include two to four rings, which may be attached in a pendent manner, fused, or form a bridged system. Illustrative examples of monocyclic, bicyclic, and tricyclic saturated cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[4.2.0]octyl, cyclononanyl, cyclodecanyl, decahydronapthalenyl, and tetradecahydroanthracenyl. Illustrative examples of monocyclic, bicyclic, and tricyclic partially saturated cycloalkyls include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[3.2.2]nonenyl, bicyclo[4.2.0]octenyl, cyclononenyl, cyclodecenyl, octahydronaphthalenyl, 1,2,3,4- tetrahydronaphthalenyl, and 1,2,3,4,4a,9,9a,10-octahydroanthracenyl. Examples of aromatic monocyclic, bicyclic, and tricyclic cycloalkyls, e.g., carboaryls, include phenyl, naphthalenyl, and anthracenyl. [039] The term "halo" means a moiety containing a halogen, i.e., fluorine, chlorine, bromine, or iodine. The term "haloalkyl" refers to an alkyl moiety in which one or more of the alkyl carbon atoms is substituted with halo group. In some embodiments, the haloalkyl is a monohaloalkyl, dihaloalkyl, or polyhaloalkyl. Examples of haloalkyls include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Perfluoroalkyl" means alkyl radicals having all hydrido radicals replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl. [040] The term "heterocycle" means a saturated or unsaturated mono- or multi-ring structure, wherein one or more ring members is a non-carbon atom, e.g., N, S, P, or O. The term "heterocycle" includes all possible isomeric forms of the heterocycles, e.g., pyrrolyl includes 1H-pyrrolyl and 2H- pyrrolyl. In some embodiments, a heterocycle described herein comprises at least one N, S, or O. Exemplary aromatic heterocycles (i.e., heteroaryls) are provided herein. [041] The term "substituted" means that any one or more hydrogen atoms is replaced with any suitable substituent, provided that the normal valency is not exceeded and the replacement results in a stable compound. Suitable substituents include but are not limited to alkyl, alkylaryl, aryl, heteroaryl, halo, hydroxyl, carboxylate, alkoxy, alkenyl, alkynyl, carbonyl (including alkylcarbonyl and arylcarbonyl), sulfonyl, amino, cyano, and oxo. [042] The term "inhibiting activity" refers to a reduction or blockade of activity of a target, e.g., Transient Receptor Potential Vanilloid 4 (TRPV4), relative to the activity in an untreated or control sample, and does not require total elimination of an activity. [043] In some embodiments, the disclosure provides a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein ring A, the R groups, X, Y, and Z, and m, p, q, and s are as described herein. In some embodiments the disclosure provides a compound of Formula (I). In some embodiments the disclosure provides a pharmaceutically acceptable salt of a compound of Formula (I). [044] In some embodiments, ring A is a 3- to 16-membered ring, or a 4- to 14-membered ring, or a 5- to 11-membered ring. In some embodiments, ring A is a 5, 6, 7, 8, 9, 10, or 11-membered ring. In some embodiments, ring A comprises an aromatic ring. In some embodiments, ring A comprises a multi-ring structure, wherein at least one ring is aromatic. [045] In some embodiments, ring A is phenyl. In some embodiments, the phenyl is unsubstituted. In some embodiments, the phenyl comprises 1 to 10, or 1 to 8, or 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3 substituents. In some embodiments, the phenyl comprises one, two, or three substituents. In some embodiments, the phenyl comprises more than one substituted carbons, wherein each substituted carbon comprises one or more substituents. In some embodiments, the phenyl comprises more than one substituted carbons, wherein each carbon independently comprises one, two, or three substituents. [046] In some embodiments, ring A is phenyl, and p is 1, 2, or 3, i.e., the phenyl is substituted with one, two, or three R¹ substituents, wherein the one, two, or three R¹ substituents are on one or more carbons of the phenyl. In some embodiments, each R¹ is independently F, Cl, cyano, oxo, C3-C6 cycloalkyl, 3- to 6-membered heterocycle, C1-C5 alkyl, C1-C5 haloalkyl, or phenyl, or combinations thereof. In some embodiments, R¹ comprises phenyl, and the phenyl is unsubstituted or substituted with up to three substituents, wherein each substituent is independently selected from halo, cyano, C1-C5 alkyl, and C1-C3 alkoxy. In some embodiments, each R¹ is independently cyano, C1-C5 alkyl, or C1-C5 haloalkyl. In some embodiments, the phenyl is substituted with one R¹ substituent, wherein the R¹ is methyl. In some embodiments, the phenyl is substituted with two R¹ substituents, wherein one R¹ is methyl and one R¹ is cyano or halo, e.g., fluoro or chloro. In some embodiments, the phenyl is substituted with two R¹ substituents, wherein one R¹ is methyl and one R¹ is cyano. In some embodiments, the phenyl is substituted with two R¹ substituents, wherein one R¹ is methyl and one R¹ is fluoro. In some embodiments, the phenyl is substituted with three R¹ substituents, wherein one of the R¹ is cyano, and two of the R¹ are halo, e.g., independently fluoro or chloro. In some embodiments, the phenyl is substituted with three R¹ substituents, wherein one of the R¹ is cyano, and two of the R¹ are fluoro. [047] In some embodiments, ring A is a heteroaryl. In some embodiments, ring A is a single-ring heteroaryl. In some embodiments, ring A is a polycyclic heteroaryl. In some embodiments, ring A is N-heteroaryl. In some embodiments, the N-heteroaryl is a single-ring N-heteroaryl or a polycyclic N-heteroaryl. In some embodiments, the polycyclic N-heteroaryl ring comprises two fused rings, wherein at least one ring comprises N and at least one ring is an aromatic ring. In some embodiments, the N is in the aromatic ring of the polycyclic N-heteroaryl. In some embodiments, the N is in a non-aromatic ring of the polycyclic N-heteroaryl. In some embodiments, the N- heteroaryl further comprises an oxygen. In some embodiments, the N-heteroaryl is polycyclic, and the oxygen is in the same ring as the nitrogen of the N-heteroaryl. In some embodiments, the N- heteroaryl is polycyclic, and the oxygen is in a different ring as the nitrogen of the N-heteroaryl. [048] In some embodiments, the N-heteroaryl is unsubstituted. In some embodiments, the N- heteroaryl is substituted with 1 to 10, or 1 to 8, or 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3 substituents. In some embodiments, the N-heteroaryl is substituted with one, two, or three substituents. In some embodiments, the N-heteroaryl comprises a substituted member, wherein the substituted member comprises one, two, or three substituents. In some embodiments, the N-heteroaryl comprises more than one substituted members, wherein each substituted member comprises one or more substituents. In some embodiments, the N-heteroaryl comprises more than one substituted members, wherein each member independently comprises one, two, or three substituents. [049] In some embodiments, ring A is N-heteroaryl, and p is 0, i.e., the N-heteroaryl is unsubstituted. In some embodiments, ring A is N-heteroaryl, and p is 1, 2, or 3, i.e., the N- heteroaryl is substituted with one, two, or three R¹ substituents, wherein the one, two, or three R¹ substituents are on one or more members of the N-heteroaryl. In some embodiments, each R¹ is independently F, Cl, cyano, oxo, C3-C6 cycloalkyl, 3- to 6-membered heterocycle, C1-C5 alkyl, C1-C5 haloalkyl, or phenyl, or combinations thereof. In some embodiments, R¹ comprises phenyl, and the phenyl is unsubstituted or substituted with up to three substituents, wherein each substituent is independently selected from halo, cyano, C1-C5 alkyl, and C1-C3 alkoxy.

[050] In some embodiments, the N-heteroaryl comprises a substituted or unsubstituted pyrrole, pyrazole, thiazole, pyridine, thienopyrrole, indole, benzoxazole, benzoxazine, or benzothiazepine. In some embodiments, the thienopyrrole is thieno[3,2]pyrrole or thieno[3,4]pyrrole. In some embodiments, the benzoxazine is 2H- 1,3 -benzoxazine, 2H-1,4-benzoxazine, 4H-1,4-benzoxazine, 4H-l,3-benzoxazine, 4H-3,1 -benzoxazine, or 1H-2,1-benzoxazine. Structures of these N-heteroaryls are as follows:

[051] In some embodiments, the N-heteroaryl is an unsubstituted pyrrole, pyrazole, thiazole, pyridine, thienopyrrole, indole, benzoxazole, benzoxazine, or benzothiazepine. In some embodiments, the N-heteroaryl comprises any of the combinations according to Table 1: Table 1. Substituted N-heteroaryls.

[052] In some embodiments, the N-heteroaryl comprises a pyrrole substituted with one, two, or three C1-C5 alkyl, e.g., one, two, or three methyl. In some embodiments, the N-heteroaryl comprises a thiazole substituted with one, two, or three C1-C5 alkyl, e.g., one, two, or three methyl. In some embodiments, the N-heteroaryl comprises an unsubstituted pyridine. In some embodiments, the N-heteroaryl comprises a pyridine substituted with one, two, or three halo, e.g., one, two, or three chloro. In some embodiments, the N-heteroaryl comprises an unsubstituted thieno[3,2]pyrrole or unsubstituted thieno[3,4]pyrrole. In some embodiments, the N-heteroaryl comprises an indole substituted with one, two, or three halo and/or one, two, or three C1-C5 alkyl, e.g., a fluoro and a methyl. In some embodiments, the N-heteroaryl comprises an unsubstituted benzoxazole. In some embodiments, the N-heteroaryl comprises a 1,4-benzoxazine, e.g., 2H-1,4-benzoxazine or 4H-1,4- benzoxazine, substituted with one, two, or three halo, e.g., one, two, or three fluoro. In some embodiments, the N-heteroaryl comprises a benzothiazepine substituted with one, two, or three oxo. [053] In some embodiments, the N-heteroaryl comprises a substituted pyrazole. In some embodiments, a nitrogen of the pyrazole is substituted. In some embodiments, a carbon of the pyrazole is substituted. In some embodiments, the pyrazole is substituted at a nitrogen and a carbon. In some embodiments, the pyrazole comprises a nitrogen substituted with phenyl. In some embodiments, the phenyl is unsubstituted. In some embodiments, the phenyl is substituted with one or more substituents selected from halo, cyano, C1-C5 alkyl, and C1-C3 alkoxy. In some embodiments, the phenyl is substituted with one, two, or three halo, e.g., fluoro. In some embodiments, the phenyl is substituted with one, two, or three cyano. In some embodiments, the phenyl is substituted with one, two, or three C1-C3 alkoxy, e.g., methoxy. [054] In some embodiments, the pyrazole comprises (i) a nitrogen substituted with fluorophenyl and (ii) a carbon substituted with cyano; C1-C5 alkyl, e.g., methyl; C1-C5 haloalkyl, e.g., fluoromethyl, difluoromethyl, or trifluoromethyl; or a 3- to 6-membered heterocyclyl. In some embodiments, the 3- to 6-membered heterocyclyl is oxiranyl, aziridinyl, oxetanyl, furanyl, oxolanyl, oxazolidinyl, thiophenyl, pyrrolyl, pyrrolidinyl, pyranyl, pyridinyl, piperidinyl, imiazolyl, thiazolyl, thiazolidinyl, dioxanyl, morpholinyl, or pyrimidinyl. In some embodiments, the 3- to 6-membered heterocyclyl is oxetanyl. In some embodiments, the 3- to 6-membered heterocyclyl is unsubstituted. In some embodiments, the 3- to 6-membered heterocyclyl is substituted with halo (e.g., fluoro or chloro), cyano, C1-C3 alkyl, or C1-C3 alkoxy. [055] In some embodiments, the pyrazole comprises (i) a nitrogen substituted with difluorophenyl, cyanophenyl, or methoxyphenyl and (ii) a carbon substituted with difluorophenyl and (ii) a carbon substituted with C1-C5 alkyl, e.g., methyl. In some embodiments, the C1-C5 alkyl is substituted with halo (e.g., fluoro or chloro), cyano, C1-C3 alkyl, or C1-C3 alkoxy. [056] In some embodiments, the m of Formula (I) is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1, and R⁷ and R⁸ are each independently H, halo, C1-C3 alkyl, or C1-C3 haloalkyl; or R⁷ and R⁸, together with the atom to which they are bound, create a 3-membered carbocycle. In some embodiments, m is 1, and R⁷ and R⁸ are each H. In some embodiments, m is 1, and R⁷ and R⁸ are each C1-C3 alkyl, e.g., methyl, ethyl, isopropyl, or n-propyl. In some embodiments, m is 1, and R⁷ and R⁸ are each C1-C3 haloalkyl, e.g., fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, chloromethyl, dichloropropyl, trichloropropyl, fluorobutyl, difluorobutyl, trifluorobutyl, chlorobutyl, dichlorobutyl, or trichlorobutyl. In some embodiments, m is 1, and R⁷ and R⁸, together with the carbon atom to which they are bound, form a C3-C8 cycloalkyl, or C3-C6 cycloalkyl. In some embodiments, m is 1, and R⁷ and R⁸, together with the carbon atom to which they are bound, form a cyclopropyl. [057] In some embodiments, the X, Y, and Z of Formula (I) are each independently selected from CR⁹ and N. In some embodiments, R⁹ is H. In some embodiments, R⁹ is halo, e.g., fluoro or chloro. In some embodiments, each of X, Y, and Z is CH. In some embodiments, each of X, Y, and Z is CF. In some embodiments, each of X, Y, and Z is N. In some embodiments, X is N, and Y and Z are each CR⁹, e.g., CH. In some embodiments, Y is N, and X and Z are each CR⁹, e.g., CH. In some embodiments, Z is N, and X and Y are each CR⁹, e.g., CH. In some embodiments, X is CF, and Y and Z are each CH. In some embodiments, Y is CF, and X and Z are each CH. In some embodiments, Z is CF, and X and Y are each CH. In some embodiments, X is CR⁹, e.g., CH, and Y and Z are each N. In some embodiments, Y is CR⁹, e.g., CH, and X and Z are each N. In some embodiments, Z is CR⁹, e.g., CH, and X and Y are each N. [058] In some embodiments, each of X, Y, and Z of Formula (I) is CH, and R² of Formula (I) is halo, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or -OS(O)₂R⁴. In some embodiments, the C3-C6 cycloalkyl or C3-C6 cycloalkoxy is substituted with one or more halo. In some embodiments, R⁴ is C1-C3 alkyl. In some embodiments, R⁴ is C1- C3 haloalkyl. In some embodiments, the halo is F or Cl. [059] In some embodiments, each of X, Y, and Z is CH, and R² is: (i) halo, e.g., fluoro or chloro; (ii) C1-C4 alkyl, e.g., methyl, ethyl, isopropyl, n-propyl, isobutyl, sec-butyl, or tert-butyl; (iii) C1-C4 alkoxy, e.g., methoxy, ethoxy, isopropoxy, n-propoxy, isobutoxy, sec-butoxy, or tert- butoxy; (iv) C3-C6 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (v) C3-C6 cycloalkyl substituted with one or more halo, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl substituted with fluoro or chloro; (vi) C3-C6 cycloalkoxy, e.g., cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy; (vii) C3-C6 cycloalkoxy substituted with one or more halo, e.g., cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy, substituted with fluoro or chloro; (viii) C1-C4 haloalkyl, e.g., fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, chloropropyl, dichloropropyl, trichloropropyl, fluorobutyl, difluorobutyl, trifluorobutyl, chlorobutyl, dichlorobutyl, or trichlorobutyl; (ix) C1-C4 haloalkoxy, e.g., fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, chloroethoxy, dichloroethoxy, trichloroethoxy, fluoropropoxy, difluoropropoxy, trifluoropropoxy, chloromethoxy, dichloropropoxy, trichloropropoxy, fluorobutoxy, difluorobutoxy, trifluorobutoxy, chlorobutoxy, dichlorobutoxy, or trichlorobutoxy; or (x) -OS(O)₂R⁴, wherein R⁴ is C1-C3 alkyl (e.g., methyl, ethyl, isopropyl, or n-propyl), or wherein R⁴ is C1-C3 haloalkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, chloropropyl, dichloropropyl, or trichloropropyl). In some embodiments, R² is -OS(O)2CF₂. [060] In some embodiments, X, Y, and Z are each CR⁹, wherein one R⁹ is halo (e.g., F) and the remaining R⁹ are H, and R² is halo. In some embodiments, X is CF, Y and Z are each CH, and R² is fluoro or chloro. In some embodiments, Y is CF, X and Z are each CH, and R² is fluoro or chloro. In some embodiments, Z is CF, X and Y are each CH, and R² is fluoro or chloro. [061] In some embodiments, Y is N, X and Z are each CH, and R² is halo, C1-C4 haloalkyl, or C1-C4 haloalkoxy. In some embodiments, Z is N, X and Y are each CH, and R² is halo, C1-C4 haloalkyl, or C1-C4 haloalkoxy. In some embodiments, R² is fluoro. In some embodiments, R² is fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, R² is fluoromethoxy, difluoromethoxy, or trifluoromethoxy. [062] In some embodiments, R^10a and ^R10b are independently selected from H and D. In some embodiments, R^10a and R^10b are each H. In some embodiments, R^10a and R^10b are each D. In some embodiments, one of R^10a and R^10b is H, and the other is D. [063] In some embodiments, R^3a is hydroxy, C1-C8 alkyl, C3-C6 cycloalkyl, a 5- to 6-membered heterocycle, -N(R⁵)(S(O)₂R⁶), -N(R⁵)C(O)OR⁶, or C1-C6 alkoxy. In some embodiments, the C1-C8 alkyl is substituted with up to three substituents selected from hydroxy, halo, oxo, carboxy, C1-C3 alkoxy, -S(O)₂R⁶, -S(O)₂NH₂, -C(O)OR₆, and -NR⁵R⁶. In some embodiments, the heterocycle is substituted with up to three substituents selected from oxo and C1-C3 alkyl. In some embodiments, the cycloalkyl is substituted with up to three substituents selected from oxo and hydroxy. In some embodiments, R⁵ is selected from C1-C3 alkyl and H. In some embodiments, R⁶ is selected from C1-C3 alkyl and H. [064] In some embodiments, R^3b is not present, i.e., q is 0. In some embodiments, at least one R^3b is present, i.e., q is at least 1. In some embodiments, each R^3b _, when present, is hydroxy, C1-C8 alkyl, C3-C6 cycloalkyl, a 5- to 6-membered heterocycle, -N(R⁵)(S(O)₂R⁶), -N(R⁵)C(O)OR⁶, or C1- C6 alkoxy. In some embodiments, the C1-C8 alkyl is substituted with up to three substituents selected from hydroxy, halo, oxo, carboxy, C1-C3 alkoxy, -S(O)₂R⁶, -S(O)₂NH₂, -C(O)OR₆, and -NR⁵R⁶. In some embodiments, the heterocycle is substituted with up to three substituents selected from oxo and C1-C3 alkyl. In some embodiments, the cycloalkyl is substituted with up to three substituents selected from oxo and hydroxy. In some embodiments, R⁵ is selected from C1-C3 alkyl and H. In some embodiments, R⁶ is selected from C1-C3 alkyl and H. [065] In some embodiments, s is 0, and R^3a is hydroxy, C1-C8 alkyl, C3-C6 cycloalkyl, a 5- to 6- membered heterocycle, -N(R⁵)(S(O)₂R⁶), -N(R⁵)C(O)OR⁶, or C1-C6 alkoxy as described herein. In some embodiments, s is 1, and R^3a is C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is substituted with up to three substituents selected from hydroxy, halo, oxo, carboxy, C1-C3 alkoxy, -S(O)₂R⁶, -S(O)₂NH₂, -C(O)OR₆, and -NR⁵R⁶ as described herein. In some embodiments, the C1-C8 alkyl is substituted with hydroxy. In some embodiments, R^3a is hydroxypropyl. In some embodiments, q is 0. In some embodiments, q is 1, 2, or 3, and each R^3b is independently hydroxy, C1-C8 alkyl, C3-C6 cycloalkyl, a 5- to 6-membered heterocycle, -N(R⁵)(S(O)₂R⁶), or -N(R⁵)C(O)OR⁶, or C1-C6 alkoxy as described herein. [066] In some embodiments, s is 1, q is 0, and R^3a is hydroxy, C1-C8 alkyl, C3-C6 cycloalkyl, a 5- to 6-membered heterocycle, -N(R⁵)(S(O)₂R⁶), -N(R⁵)C(O)OR⁶, or C1-C6 alkoxy. In some embodiments, the C1-C8 alkyl is substituted with up to three substituents selected from hydroxy, halo, oxo, carboxy, C1-C3 alkoxy, -S(O)₂R⁶, -S(O)₂NH₂, -C(O)OR₆, and -NR⁵R⁶. In some embodiments, the heterocycle is substituted with up to three substituents selected from oxo and C1- C3 alkyl. In some embodiments, the cycloalkyl is substituted with up to three substituents selected from oxo and hydroxy. In some embodiments, R⁵ is selected from C1-C3 alkyl and H. In some embodiments, R⁶ is selected from C1-C3 alkyl and H. [067] In some embodiments, s is 1, q is 0, and R^3a is C1-C8 alkyl as described herein, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl. In some embodiments, the C1-C8 alkyl is substituted with one or more hydroxy. In some embodiments, the C1-C8 alkyl is substituted with one or more halo, e.g., fluoro or chloro. In some embodiments, the C1-C8 alkyl is substituted with C1-C3 alkoxy, e.g., methoxy, ethoxy, or propoxy. In some embodiments, the C1-C8 alkyl is substituted with -NH₂. In some embodiments, the C1-C8 alkyl is substituted with -NHR⁶, wherein R⁶ is C1-C3 alkyl. In some embodiments, the C1-C8 alkyl is substituted with -NR⁵R⁶, wherein each of R⁵ and R⁶ is C1-C3 alkyl. In some embodiments, the C1-C8 alkyl is substituted with -S(O)₂H. In some embodiments, the C1-C8 alkyl is substituted with -S(O)₂R⁶, wherein R⁶ is C1-C3 alkyl. In some embodiments, the C1-C8 alkyl is substituted with -S(O)₂NH₂. In some embodiments, the C1- C8 alkyl is substituted with -C(O)OR₆, wherein the R⁶ is H or C1-C3 alkyl. [068] In some embodiments, s is 1. In some embodiments, R^3a is hydroxymethyl or dihydroxymethyl. In some embodiments, R^3a is hydroxyethyl or dihydroxyethyl. In some embodiments, R^3a is hydroxypropyl or dihydroxypropyl. In some embodiments, R^3a is hydroxybutyl or dihydroxybutyl. In some embodiments, R^3a is ethyl substituted with hydroxy and amino, methylamino, or dimethylamino. In some embodiments, R^3a is propyl substituted with hydroxy and amino, methylamino, or dimethylamino. In some embodiments, R^3a is butyl substituted with hydroxy and amino, methylamino, or dimethylamino. In some embodiments, R^3a is ethyl substituted with hydroxy and fluoro or difluoro. In some embodiments, R^3a is propyl substituted with hydroxy and fluoro or difluoro. In some embodiments, R^3a is butyl substituted with hydroxy and fluoro or difluoro. In some embodiments, R^3a is ethyl substituted with hydroxy and methoxy, ethoxy, or propoxy. In some embodiments, R^3a is propyl substituted with hydroxy and methoxy, ethoxy, or propoxy. In some embodiments, R^3a is butyl substituted with hydroxy and methoxy, ethoxy, or propoxy. In some embodiments, R^3a is ethyl substituted with hydroxy and sulfonyl, methylsulfonyl, ethylsulfonyl, or propylsulfonyl. In some embodiments, R^3a is propyl substituted with hydroxy and sulfonyl, methylsulfonyl, ethylsulfonyl, or propylsulfonyl. In some embodiments, R^3a is butyl substituted with hydroxy and sulfonyl, methylsulfonyl, ethylsulfonyl, or propylsulfonyl. In some embodiments, R^3a is methyl, ethyl, propyl, or butyl substituted with sulfamoyl. In some embodiments, R^3a is hydroxyethoanoic acid, hydroxypropanoic acid, or hydroxybutanoic acid. In some embodiments, R^3a is hydroxyethoanoate, hydroxypropanoate, or hydroxybutanoate. [069] In some embodiments, s is 1, q is 0, and R^3a is a 5- to 6-membered heterocycle as described herein. Exemplary heterocyles are described herein. In some embodiments, R^3a is a 5-membered heterocycle. In some embodiments, the heterocycle comprises nitrogen, sulfur, oxygen, or a combination thereof. In some embodiments, the heterocycle is substituted with one or more C1-C3 alkyl, e.g., methyl, ethyl, isopropyl, or n-propyl. In some embodiments, the heterocycle is substituted with one or more oxo. In some embodiments, R^3a is oxazolidinyl substituted with methyl. In some embodiments, R^3a is oxazolidinyl substituted with oxo. In some embodiments, R^3a is oxazolidinyl substituted with two methyls and one oxo. In some embodiments, R^3a is thiazolidinyl substituted with two oxos. In some embodiments, R^3a is dioxolanyl substituted with methyl. [070] In some embodiments, s is 1, q is 0, and R^3a is a C3-C6 cycloalkyl as described herein, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl is substituted with one or more hydroxy. In some embodiments, R^3a is hydroxycyclobutyl. [071] In some embodiments, s is 2, q is 0, and R^3a is C1-C8 alkyl as described herein, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl. In some embodiments, the C1-C8 alkyl is unsubstituted. In some embodiments, R^3a is methyl. [072] In some embodiments, s is 2, q is 0, and R^3a is C1-C8 alkyl as described herein, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl, wherein the C1-C8 alkyl is substituted with one or more hydroxy. In some embodiments, R^3a is hydroxymethyl, dihydroxymethyl, hydroxyethyl, dihydroxyethyl, hydroxypropyl, dihydroxypropyl, hydroxybutyl, or dihydroxybutyl. In some embodiments, R^3a is hydroxymethyl. In some embodiments, R^3a is hydroxypropyl. [073] In some embodiments, s is 2, q is 0, and R^3a is a C3-C6 cycloalkyl as described herein, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl is substituted with one or more hydroxy. In some embodiments, R^3a is hydroxycyclopropyl. [074] In some embodiments, s is 3, q is 0, and R^3a is C1-C8 alkyl as described herein, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl. In some embodiments, the C1-C8 alkyl is substituted with one or more hydroxy. In some embodiments, R^3a is hydroxymethyl, dihydroxymethyl, hydroxyethyl, dihydroxyethyl, hydroxypropyl, dihydroxypropyl, hydroxybutyl, or dihydroxybutyl. In some embodiments, R^3a is hydroxypropyl. [075] In some embodiments, s is 1; q is 1; and each of R^3a and R^3b is hydroxy, C1-C8 alkyl, C3-C6 cycloalkyl, a 5- to 6-membered heterocycle, -N(R⁵)(S(O)₂R⁶), -N(R⁵)C(O)OR⁶, or C1-C6 alkoxy. In some embodiments, the C1-C8 alkyl is substituted with up to three substituents selected from hydroxy, halo, oxo, carboxy, C1-C3 alkoxy, -S(O)₂R⁶, -S(O)₂NH₂, -C(O)OR₆, and -NR⁵R⁶. In some embodiments, the heterocycle is substituted with up to three substituents selected from oxo and C1- C3 alkyl. In some embodiments, the cycloalkyl is substituted with up to three substituents selected from oxo and hydroxy. In some embodiments, R⁵ is selected from C1-C3 alkyl and H. In some embodiments, R⁶ is selected from C1-C3 alkyl and H. [076] In some embodiments, s is 1; q is 1; and each of R^3a and R^3b is C1-C8 alkyl as described herein, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl, wherein the C1-C8 alkyl of R^3a is unsubstituted, and the C1-C8 alkyl of R^3b is substituted. In some embodiments, the C1-C8 alkyl of R^3b is substituted with one or more hydroxy. In some embodiments, R^3a is methyl. In some embodiments, R^3b is hydroxymethyl, dihydroxymethyl, hydroxyethyl, dihydroxyethyl, hydroxypropyl, dihydroxypropyl, hydroxybutyl, or dihydroxybutyl. In some embodiments, R^3a is methyl, and R^3b is hydroxymethyl, dihydroxymethyl, hydroxyethyl, dihydroxyethyl, hydroxypropyl, dihydroxypropyl, hydroxybutyl, or dihydroxybutyl. In some embodiments, R^3a is methyl, and R^3b is hydroxyethyl. [077] In some embodiments, s is 1; q is 1; R^3a is C1-C8 alkyl as described herein, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; and R^3b is hydroxy. In some embodiments, the C1-C8 alkyl of R^3a is substituted with one or more hydroxy. In some embodiments, R^3a is hydroxymethyl or dihydroxymethyl, and R^3b is hydroxy. In some embodiments, R^3a is hydroxyethyl or dihydroxyethyl, and R^3b is hydroxy. In some embodiments, R^3a is hydroxypropyl or dihydroxypropyl, and R^3b is hydroxy. In some embodiments, R^3a is hydroxybutyl or dihydroxybutyl, and R^3b is hydroxy. [078] In some embodiments, s is 1; q is 1; and each of R^3a and R^3b is C1-C8 alkyl as described herein, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl, wherein the C1-C8 alkyl of R^3a and the C1-C8 alkyl of R^3b are each substituted. In some embodiments, the C1-C8 alkyl of R^3a and the C1-C8 alkyl of R^3b are each substituted with one or more hydroxy. In some embodiments, R^3a and R^3b comprise any of the combinations of Table 2. In some embodiments, each of R^3a and R^3b is hydroxymethyl. In some embodiments, each of R^3a and R^3b is hydroxypropyl.

Table 2. R^3a and R^3b Combinations.

[079] In some embodiments, s is 1; q is 1; and each of R^3a and R^3b is C1-C8 alkyl as described herein, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl, wherein the C1-C8 alkyl of R^3a is substituted, and the C1-C8 alkyl of R^3b is unsubstituted. In some embodiments, the C1-C8 alkyl of R^3a is substituted with one or more hydroxy. In some embodiments, R^3a is hydroxymethyl, dihydroxymethyl, hydroxyethyl, dihydroxyethyl, hydroxypropyl, dihydroxypropyl, hydroxybutyl, or dihydroxybutyl. In some embodiments, R^3b is methyl. In some embodiments, R^3a is hydroxypropyl, and R^3b is methyl, ethyl, propyl, or butyl. In some embodiments, R^3a is hydroxypropyl, and R^3b is methyl. [080] In some embodiments, s is 1; q is 1; R^3a is C1-C8 alkyl as described herein, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; and R^3b is C1-C6 alkoxy as described herein, e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy. In some embodiments, the C1-C8 alkyl of R^3a is substituted, and the alkoxy of R^3b is unsubstituted. In some embodiments, the C1-C8 alkyl of R^3a is substituted with one or more hydroxy. In some embodiments, R^3a is hydroxymethyl, dihydroxymethyl, hydroxyethyl, dihydroxyethyl, hydroxypropyl, dihydroxypropyl, hydroxybutyl, or dihydroxybutyl. In some embodiments, R^3a is hydroxymethyl, dihydroxymethyl, hydroxyethyl, dihydroxy ethyl, hydroxypropyl, dihydroxypropyl, hydroxybutyl, or dihydroxybutyl, and R^3b is methoxy. In some embodiments, R^3a is hydroxypropyl, and R^3b is methoxy. In some embodiments, R^3a and R^3b comprise any of the combinations of Table 3.

Table 3. R^3a and R^3b Combinations.

[081] In some embodiments, s is 1; q is 1; R^3a is C1-C8 alkyl as described herein, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; and R^3b is -N(R⁵)(S(O)2R⁶), wherein the C1-C8 alkyl of R^3a is substituted, and R⁵ and R⁶ are each independently H or C1-C3 alkyl. In some embodiments, the C1-C8 alkyl of R^3a is substituted with one or more hydroxy. In some embodiments, R^3a is hydroxymethyl, dihydroxymethyl, hydroxyethyl, dihydroxyethyl, hydroxypropyl, dihydroxypropyl, hydroxybutyl, or dihydroxybutyl. In some embodiments, R^3b is - NHS(O)₂CH₃, -N(CH₃)S(O)₂CH3, -N(CH₂CH₃)S(O)₂CH₃, or -N(CH₂CH₂CH₃)S(O)₂CH₃. In some embodiments, R^3a is hydroxypropyl, and R^3b is -NHS(O)₂CH₃. In some embodiments, R^3a is hydroxypropyl, and R^3b is -N(CH₃)S(O)₂CH₃. [082] In some embodiments, s is 1, q is 2, R^3a and a first R^3b are each C1-C8 alkyl as described herein, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; and a second R^3b is hydroxy. In some embodiments, one of both of the C1-C8 alkyl of R^3a and the C1-C8 alkyl of the first R^3b is substituted with one or more hydroxy. In some embodiments, R^3a is hydroxymethyl, dihydroxymethyl, hydroxyethyl, dihydroxyethyl, hydroxypropyl, dihydroxypropyl, hydroxybutyl, or dihydroxybutyl; the first R^3b is hydroxymethyl, dihydroxymethyl, hydroxyethyl, dihydroxyethyl, hydroxypropyl, dihydroxypropyl, hydroxybutyl, or dihydroxybutyl; and the second R^3b is hydroxy. In some embodiments, R^3a is hydroxypropyl, the first R^3b is hydroxypropyl, and the second R^3b is hydroxy. [083] In some embodiments, s is 2, q is 2, R^3a and a first R^3b are each C1-C8 alkyl as described herein, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; and a second R^3b is hydroxy. In some embodiments, the C1-C8 alkyl of R^3a and the C1-C8 alkyl of the first R^3b is unsubstituted. In some embodiments, R^3a is methyl, ethyl, propyl, or butyl; the first R^3b is methyl, ethyl, propyl, or butyl; and the second R^3b is hydroxy. In some embodiments, R^3a is methyl, the first R^3b is methyl, and the second R^3b is hydroxy. [084] In some embodiments, the disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g. a compound of Formula (I)), wherein ring A is a 5- to 11-membered N-heteroaryl; p is 0, 1, 2, or 3; each R¹, if present, is independently F, Cl, cyano, oxo, C3-C6 cycloalkyl, 3- to 6-membered heterocycle, C1-C5 alkyl, C1-C5 haloalkyl, phenyl, or combinations thereof as described herein; m is 0 or 1; each R⁷ and R⁸, if present, is independently selected from H, halo, and C1-C3 alkyl; X, Y, Z are each independently selected from CR⁹ and N, wherein each R⁹ is independently selected from H and halo; R² is halo, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl, C3-C6 cycloalkoxy, C3-C6 halocycloalkoxy, or -OS(O)₂R⁴, wherein R⁴ is C1-C3 alkyl or C1-C3 haloalkyl; R^10a and ^R10b are independently selected from H and D; s is 0, 1, 2, or 3; q is 0, 1, 2, or 3; and R^3a and each R^3b, if present, are independently selected from hydroxy, C1-C8 alkyl, C3-C6 cycloalkyl, a 5- to 6-membered heterocycle, -N(R⁵)(S(O)₂R⁶), -N(R⁵)C(O)OR⁶, and C1-C6 alkoxy as described herein. [085] In some embodiments, the disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g. a compound of Formula (I)), wherein ring A is a 5- to 6-membered N-heteroaryl; p is 1, 2, or 3; each R¹, if present, is independently F or Cl; m is 0 or 1; each R⁷ and R⁸, if present, is independently selected from H, halo, and C1-C3 alkyl; X, Y, Z are each CR⁹, wherein each R⁹ is independently selected from H and halo; R² is halo, C1-C4 alkyl, C3- C6 cycloalkyl, C2-C5 alkenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl, C3-C6 cycloalkoxy, C3-C6 halocycloalkoxy, or -OS(O)₂R⁴, wherein R⁴ is C1-C3 alkyl or C1-C3 haloalkyl; R^10a and ^R10b are independently selected from H and D; s is 1 or 2; q is 0, 1, 2, or 3; and R^3a and each R^3b, if present, are independently selected from hydroxy, C1-C8 alkyl, C3-C6 cycloalkyl, a 5- to 6- membered heterocycle, -N(R⁵)(S(O)₂R⁶), -N(R⁵)C(O)OR⁶, and C1-C6 alkoxy as described herein. In some embodiments, ring A is a 5-membered N-heteroaryl. In some embodiments, ring A is pyrazole. In some embodiments, p is 1. In some embodiments, R¹ is F or Cl. In some embodiments, R¹ is F. In some embodiments, R¹ is Cl. In some embodiments, m is 0. In some embodiments, m is 1, and R⁷ and R⁸ are each independently H, F, Cl, or C1-C3 alkyl. In some embodiments, X, Y, and Z are each CR⁹, wherein R⁹ is H. In some embodiments, X, Y, and Z are each CR⁹, wherein at least one R⁹ is H and at least one R⁹ is halo, e.g., F or Cl. In some embodiments, R² is halo. In some embodiments, R² is F. In some embodiments, R² is Cl. In some embodiments, R^10a and R^10b are each H. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, R^3a is C1-C8 alkyl. In some embodiments, R^3a is C1-C8 alkyl substituted with up to three substituents selected from hydroxy, halo, oxo, carboxy, and C1-C3 alkoxy. In some embodiments, R^3a is C1-C8 alkyl substituted with one to three hydroxy. In some embodiments, R^3a is dihydroxypropyl. In some embodiments, R^3a is 1,2-dihydroxypropan-2-yl. [086] In some embodiments, the disclosure provides a compound as shown in Table 4, or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of Table 4. In some embodiments, the disclosure provides a pharmaceutically acceptable salt of a compound of Table 4.

³2 OO O O ²⁰¹² _60-W O -^PC

_T

³3 FN N O O F F O 2⁰¹² _60-W O -^P

^C _T

³6 2⁰¹² _60-W O -^P

^C _T

³8 FN N O C O 2⁰¹² _60-W O -^P

^C _T ³9 FN N O C O O 2⁰¹² _60-W O -^P

^C _T ⁴0 O O ²⁰¹² _60-W O -^P

^C _T

[087] The present specification is intended to include all isotopes of atoms occurring in the present compounds. Isotopes will be understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include 13C and 14C. Isotopes of nitrogen include 15N. Optionally, isotopes may be present in positions as specified in formulae described herein.

[088] The compounds described herein may contain one or more chiral centres. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e. as individual enantiomers, diastereoisomers, or as a stereoisomerically enriched mixture. All such stereoisomer (and enriched) mixtures are included within the scope of the embodiments, unless otherwise stated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.

[089] Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name is intended to embrace all possible stereoisomers and diastereoisomers of the compound depicted. For example, a compound containing a chiral carbon atom (a stereocentre) is intended to embrace both the (R) enantiomer and the (S) enantiomer, as well as mixtures of the enantiomers, including racemic mixtures; and a compound containing two chiral carbons is intended to embrace all enantiomers and diastereoisomers including (R,R), (S,S), (R,S) and (S,R). In compounds depicted herein, graphical representation of stereocentres such as

and 'or' may be used to describe the configuration of the stereochemical centres present in the structure. In general, the label '&' at a stereocentre means the configuration at that stereocentre is a mixture of both (R) and (S); and a label 'or' means the configuration at that stereocentre is either (S) or (R). In general, for structures where all of the stereocentres are designated as '&', the structure is named with a “rac-” prefix. For structures where all of the stereocentres are designated as 'or', the structure is named with a “rel-” prefix. In general, compounds are named using the descriptors (RS) and (SR) to denote general '&' centres for chemical structures with multiple chiral centres where only some are designated as '&', and the descriptors (R*) and (S*) are used to denote the general 'or' centres for chemical structures with multiple chiral centres where only some are designated as 'or'. In general, the descriptors (r) and (s) are used to describe the absolute configuration of any pseudoasymmetric centres in the structures depicted herein. [090] The compound described herein may exist in various forms, for example as conformers, rotamers and tautomers. In cases where compounds may exist in tautomeric forms (e.g. keto/enol, amide/iminol), whether existing in equilibrium or predominantly in one form, depiction of one tautomer is intended to encompass the other tautomer.

[091] The compounds described herein may exist in salt form or in non-salt form (i.e., as a free base), and the present disclosure covers both salt forms and non-salt forms. In some embodiments, a compound described herein is in a salt form, for example a pharmaceutically acceptable salt of a compound of Formula (I). In some embodiments, a compound described herein is in a non-salt form, for example, a compound of Formula (I).

The term “pharmaceutically acceptable” is used to specify that an object (for example a salt, dosage form or excipient) is suitable for use in patients. An example list of pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, editors, Weinheim/Zurich:Wiley-VCH/VHCA, 2002. A suitable pharmaceutically acceptable salt of a compound described herein is, for example, an acid-addition salt or a base-addition salt. An acid addition salt of a compound described herein may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person. A base-addition salt of a compound described herein may be formed by bringing the compound into contact with a suitable inorganic or organic base under conditions known to the skilled person. A further suitable pharmaceutically acceptable salt is, for example, a salt formed within a patient’s body after administration of a compound described herein to the patient.

[092] In some embodiments, a compound provided herein, e.g., the compound of Formula (I) or pharmaceutically acceptable salt thereof as described herein or any of the compounds of Table 4, or pharmaceutically acceptable salts thereof, is included in a composition. In some embodiments, the disclosure provides a composition configured to be administered to a subject in need thereof. In some embodiments, the composition comprises the compound of Formula (I) as described herein. In some embodiments, the composition comprises a compound as found in Table 4. In some embodiments, the composition comprises a pharmaceutically acceptable salt of the compound of Formula (I) as described herein. In some embodiments, the composition comprises a pharmaceutically acceptable salt of the compound of Table 4.

[093] In some embodiments, the composition provided herein is capable of being adapted for administration via any suitable route by selection of appropriate excipients and dosage of the compound effective for the treatment intended, e.g., a Transient Receptor Potential Vanilloid 4 (TRPV4)-associated disease or disorder. For example, compositions described herein can be prepared in a form suitable for administration orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly, or rectally. In some embodiments, the composition is a solid or a liquid, or both, and is further formulated with the compound as a unit-dose composition.

[094] In some embodiments, the composition comprises a compound of the present disclosure, e.g., a compound of Formula (I) as described herein and/or as found in Table 4, or a pharmaceutically acceptable salt thereof, and further comprises one or more pharmaceutically acceptable excipients. Exemplary pharmaceutically acceptable excipients are known to one of ordinary skill in the art and include but are not limited to diluents, disintegrants, binding agents and adhesives, wetting agents, lubricants, anti-adherents, surfactants, humectants, plasticizers, crystallization inhibitors, bulk filling agents, solubilizers, bioavailability enhancers, pH adjusting agents, colorants, and flavorants.

[095] In some embodiments, the disclosure provides a method of inhibiting activity of TRPV4, comprising contacting TRPV4 with a compound of the present disclosure, e.g., a compound of Formula (I) as described herein and/or as found in Table 4, or a pharmaceutically acceptable salt thereof, or with a composition comprising the compound as described herein.

[096] In some embodiments, the disclosure provides a compound of the present disclosure, e.g., a compound of Formula (I) as described herein and/or as found in Table 4, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of the present disclosure, for use in therapy.

[097] In some embodiments, the disclosure provides a method of treating, ameliorating, or preventing a TRPV4-associated disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of the present disclosure, e.g., a compound of Formula (I) as described herein and/or as found in Table 4, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound, as described herein. In some embodiments, the subject is a mammalian subject. In some embodiments, the subject is a human subject. In some embodiments, the subject is an animal subject, e.g., mouse, rat, rabbit, pig, or non-human primate (NHP) such as monkey.

[098] In some embodiments, the disclosure provides a compound of the present disclosure, e.g., a compound of Formula (I) as described herein and/or as found in Table 4, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound, as described herein, for use in a method of treating, ameliorating, or preventing a TRPV4- associated disease or disorder. [099] In some embodiments, the disclosure provides the use of a compound of the present disclosure, e.g., a compound of Formula (I) as described herein and/or as found in Table 4, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound, as described herein, in the manufacture of a medicament for treating, ameliorating, or preventing a TRPV4-associated disease or disorder.

[0100] In some embodiments of the methods and uses, the compound of the present disclosure is a compound of Formula (I) as described herein and/or as found in Table 4. In some embodiments, the compound of the present disclosure is a pharmaceutically acceptable salt of a compound of Formula (I) as described herein and/or as found in Table 4.

[0101] In some embodiments, the TRPV4-associated disease or disorder is inflammation, a respiratory disease or disorder, a metabolic disease or disorder, a dermatological disease or disorder, a skeletal disease or disorder, a neuromuscular disease disorder, or combination thereof. In some embodiments, the TRPV4-associated disease or disorder is pulmonary edema, systemic edema, hypertension, hyperalgesia, inflammation, brachyolmia, spondylometaphyseal dysplasia Kozlowski type, metatropic dysplasia, peripheral neuropathy, asthma, chronic cough, chronic obstructive pulmonary disease (COPD), overactive bladder, incontinence, acoustic cochlear injury, pancreatitis, epilepsy, arthritis, osteoarthritis, multiple sclerosis, stroke, central nervous system (CNS) autoimmune condition, traumatic brain injury, spinal cord injury, brain edema, CNS infection, neuro-psychiatric disorder, skeletal degenerative-inflammatory disorder, trigeminal pain, colitis, sclerosis, obesity, diabetes, or combination thereof. TRPV4-associated diseases and disorders are further discussed in, e.g., WO 2013/152109, WO 2014/209947, and WO 2017/177200.

[0102] In some embodiments, the TRPV4-associated disease or disorder is cancer. In some embodiments, the cancer is hepatocellular carcinoma or colorectal cancer.

[0103] In some embodiments, the TRPV4-associated disease or disorder is a cardiovascular disease or disorder. In some embodiments, the cardiovascular disease or disorder is hypertrophic cardiomyopathy. This may also be referred to as pathological cardiac hypertrophy.

[0104] The compounds described herein may be prepared according to procedures exemplified by the specific examples provided herein. Moreover, by utilising the procedures described herein and variants thereof, one of ordinary skill in the art can readily prepare additional compounds that fall within the scope of the present claims. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0105] The compounds exemplified herein may also be isolated in the form of their pharmaceutically acceptable salts, such as those described herein.

[0106] It may be necessary to protect reactive functional groups in intermediates used in the preparation of compounds described herein to avoid their unwanted participation in a reaction leading to the formation of the compounds. Conventional protecting groups, for example those described by P. G. M. Wuts in “Greene’s Protective Groups in Organic Synthesis”, Fifth Edition., John Wiley & Sons Inc., 2014, may be used.

[0107] The present disclosure is not intended to be limited to the illustrative embodiments described in this specification, and may be variously modified. In addition, it is to be appreciated that various features of the disclosure that are, for clarity reasons, described in the context of separate embodiments, also may be combined to form a single embodiment. Conversely, various features of the disclosure that are, for brevity reasons, described in the context of a single embodiment, also may be combined to form sub-combinations thereof.

[0108] The entire contents of all publications, patents, and patent applications referenced herein are hereby incorporated herein by reference.

EXAMPLES

[0109] The specific examples included herein are for illustrative purposes only and are not to be considered as limiting to this disclosure. These examples provide guidance to the skilled person in the art to prepare and use the compounds, compositions, and methods of the present disclosure. Moreover, the compounds, compositions, and methods provided herein have been described in relation to certain embodiments thereof, and many details have been set forth for purposes of illustration. It will be apparent to those skilled in the art that the disclosure is susceptible to additional embodiments and that certain of the details described herein may be varied without departing from the basic principles of the disclosure.

[0110] In the following Examples, chemical shifts are expressed as parts per million (ppm) units. Coupling constants (J), where accounted for, are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double triplet), m, (multiplet), br (broad). Column chromatography was performed on silica gel unless otherwise stated. The naming program used is ACD/Chem Sketch 2020.2.0. Vibrational circular dichroism was used for some examples to indicate absolute configuration.

[0111] Table 5 shows a list of intermediates used in the following Examples.

Table 5. Intermediates

[0112] Preparation of Intermediates 1-92 is described below. Intermediate 1: (3R,4r,5S)-1-{[4-amino-2-(trifluoromethyl)phenyl]methyl}-3,5- dimethylpiperidin-4-ol

[0113] Step 1: [4-amino-2-(trifluoromethyl)phenyl][(3R,4r,5S)-4-hydroxy-3,5- dimethylpiperidin-1-yl]methanone

[0114] 4-amino-2-(trifluoromethyl)benzoic acid (771 mg, 3.76 mmol), (3R,4r,5S)-3,5- dimethylpiperidin-4-ol, prepared as described in WO2001085728, (500 mg, 3.87 mmol) and HBTU (1453 mg, 3.83 mmol) were dissolved in acetonitrile (10 mL). TEA (1.047 mL, 7.51 mmol) was added and the reaction stirred at room temperature for 1 h. (A precipitate started to form after 10 min). The reaction was put on an ice bath to drive precipitation. The solid was filtered off, washed with a small amount of acetonitrile and dried in vacuo to give the title compound as a colourless solid (707 mg, 60% isolated yield): ¹H-NMR (500 MHz, DMSO-d₆) δ 0.75 (d, 3H), 0.95 (d, 3H), 1.17 – 1.46 (m, 2H), 2.32 (q, 1H), 2.60 – 2.75 (m, 2H), 3.21 (dd, 1H), 4.32 – 4.45 (m, 1H), 4.71 (dd, 1H), 5.76 (s, 2H), 6.78 (t, 1H), 6.87 (d, 1H), 6.99 (dd, 1H); m/z (ES⁺) 317.3 [M+H]⁺. [0115] Step 2: (3R,4r,5S)-1-{[4-amino-2-(trifluoromethyl)phenyl]methyl}-3,5- dimethylpiperidin-4-ol (Intermediate 1) [0116] [4-amino-2-(trifluoromethyl)phenyl][(3R,4r,5S)-4-hydroxy-3,5-dimethylpiperidin-1- yl]methanone (707 mg, 2.24 mmol) was dissolved in THF (20 mL). Borane dimethyl sulfide complex (0.849 mL, 8.94 mmol) was added dropwise (gas evolved) and the reaction heated to 80°C for 2 h. The reaction was allowed to cool to room temperature, quenched by slow addition of MeOH (gas evolved) and allowed to stir for 3 days (to break the borane complex). The reaction mixture was concentrated in vacuo. The residue was dissolved in MeOH (5 mL) and acidified with 4 M HCl in dioxane. The solution was loaded onto a 10 g SCX-2 ion exchange column, preconditioned with MeOH. The column was washed with MeOH (70 mL), water (40 mL) and MeOH (50 mL). The product was eluted with 2M NH3 in MeOH (50 mL) and evaporated in vacuo to yield the title compound as a colourless oil (607 mg, 90% isolated yield): ¹H-NMR (500 MHz, DMSO-d₆) δ 0.83 (d, 6H), 1.38 – 1.52 (m, 2H), 1.55 – 1.63 (m, 2H), 2.39 – 2.47 (m, 1H), 2.61 – 2.71 (m, 2H), 3.33 (s, 2H), 4.43 (d, 1H), 5.42 (s, 2H), 6.75 (dd, 1H), 6.84 (d, 1H), 7.29 (d, 1H); ¹⁹F-NMR (470 MHz, DMSO-d6) δ -57.84; m/z (ES⁺) 303.2 [M+H]⁺. Intermediate 2: (3R,4r,5S)-1-{[4-amino-2-(difluoromethoxy)phenyl]methyl}-3,5- dimethylpiperidin-4-ol

[0117] Step 1: 2-(hydroxymethyl)-5-nitrophenol [0118] To 2-hydroxy-4-nitrobenzoic acid (5 g, 27.30 mmol) in THF (50 mL), cooled to 0 °C, was added slowly over 5 min Borane dimethyl sulfide complex (10.36 ml, 109.22 mmol). Once the addition was complete, the reaction was warmed to room temperature and stirred for 22 h. The reaction was quenched by slow addition of methanol (15 mL) and left stirring for 2 h before being concentrated. Flash column chromatography of the residue using EtOAc in heptane (50- 75%, stepwise gradient elution) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (4.30 g, 93 %): ¹H NMR (500 MHz, DMSO) δ 10.46 (s, 1H), 7.70 (dd, 1H), 7.58 (d, 1H), 7.55 – 7.58 (m, 1H), 5.31 (s, 1H), 4.55 (s, 2H). [0119] Step 2: 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-nitrophenol

[0120] To 2-(hydroxymethyl)-5-nitrophenol (3300 mg, 19.51 mmol) in DCM (50 mL) was added 1H-imidazole (1461 mg, 21.46 mmol) followed by tert-butylchlorodimethylsilane (3235 mg, 21.46 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with DCM (10 mL) and washed with saturated NH4Cl (15 mL) and brine (15 mL). The organic layer was dried (MgSO4), filtered and concentrated. Column chromatography of the residue using EtOAc in heptane (15-50 %, stepwise gradient elution) followed by concentration of the appropriate fractions gave the title compound as a yellow oil which crystallized upon standing. [0121] The crude product was purified by column chromatography on silica gel (heptane:EtOAC – 1:0 to 85:15) to afford 2-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitrophenol (4.56 g, 82 %, 25 % di-protection as judged by NMR) as a yellow oil which crystallized upon standing: ¹H NMR (500 MHz, DMSO) δ 10.62 (s, 1H), 7.73 (dd, 1H), 7.59 (d, 1H), 7.53 (dt, 1H), 4.73 (d, 2H), 0.92 (s, 9H), 0.10 (s, 6H). [0122] Step 3: tert-butyl{[2-(difluoromethoxy)-4-nitrophenyl]methoxy}dimethylsilane

[0123] To 2-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitrophenol (4.5 g, 15.88 mmol) in mixture of acetonitrile (24 mL) and water (24.00 mL), cooled to 0 °C, was added potassium hydroxide (8.91 g, 158.79 mmol) followed by diethyl (bromodifluoromethyl)phosphonate (5.64 ml, 31.76 mmol). After 15 min, the reaction was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2x 30 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford tert-butyl((2-(difluoromethoxy)-4- nitrobenzyl)oxy)dimethylsilane (4.95 g, 94 %, NMR purity: 90%) as a yellow oil: 1H NMR (500 MHz, DMSO) δ 8.19 (dd, 1H), 8.01 (d, 1H), 7.77 (dt, 1H), 7.45 (t, 1H), 4.82 (d, 2H), 0.92 (s, 9H), 0.12 (s, 6H). [0124] Step 4: [2-(difluoromethoxy)-4-nitrophenyl]methanol

[0125] To tert-butyl((2-(difluoromethoxy)-4-nitrobenzyl)oxy)dimethylsilane (2.5 g, 7.50 mmol). The resulting solution was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure and the resulting oil was diluted with EtOAc (15 mL), washed with sat. aq. NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over MgSO₄, filtered and concentrated under reduced pressure to give a clear oil, R_f = 0.29 (heptane:EtOAc – 3:1). The crude product was purified by flash column chromatography on silica gel (heptane:EtOAc – 1:0 to 3:1) to yield [2-(difluoromethoxy)-4-nitrophenyl]methanol (1.33 g, 6.07 mmol, 81 %) as a white solid: ¹H NMR (500 MHz, DMSO) δ 8.17 (dd, 1H), 7.99 (d, 1H), 7.81 (dd, 1H), 7.42 (t, 1H), 5.60 (t, 1H), 4.63 (d, 2H). [0126] Step 5: 1-(chloromethyl)-2-(difluoromethoxy)-4-nitrobenzene

[0127] To (2-(difluoromethoxy)-4-nitrophenyl)methanol (1300 mg, 5.93 mmol), cooled to 0 °C, was added slowly sulfurous dichloride (865 µl, 11.86 mmol) followed by N,N- dimethylformamide (43.4 mg, 0.59 mmol). Once the addition was complete the reaction was allowed to warm to room temperature and stirred at this temperature for 14 h. The reaction mixture was then diluted with EtOAc (50 mL), washed with sat. aq. NaHCO₃ (2 x 25 mL) and brine (30 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give a brown oil, Rf = 0.32 (heptane:EtOAC – 8:2). The crude product was purified by column chromatography on silica gel (heptane:EtOAC – 1:0 to 8:2) to afford the title compound (1.300 g, 92 %) as an orange liquid: ¹H NMR (500 MHz, DMSO) δ 8.15 (dd, 1H), 8.07 (d, 1H), 7.88 (d, 1H), 7.52 (t, 1H), 4.85 (s, 2H). [0128] Step 6: (3R,4r,5S)-1-{[2-(difluoromethoxy)-4-nitrophenyl]methyl}-3,5- dimethylpiperidin-4-ol

[0129] To (3R,4r,5S)-3,5-dimethylpiperidin-4-ol, prepared as described in WO2001085728, (884 mg, 6.84 mmol) in acetonitrile (30 mL) was added potassium carbonate (2269 mg, 16.42 mmol) followed by 1-(chloromethyl)-2-(difluoromethoxy)-4-nitrobenzene (1300 mg, 5.47 mmol). The resulting reaction mixture was stirred at 50 °C for 14 h. LCMS of the reaction mixture at this point indicated formation of the desired product at Rt = 0.64 min and ES⁺ m/z 331.3 [M+H]⁺. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried over MgSO₄, filtered and concentrated under reduced pressure to afford a yellow oil, Rf = 0.32 (heptane:EtOAC – 1:1). The crude product was purified by column chromatography on silica gel (heptane:EtOAC – 1:0 to 1:1) to afford the title compound (1.350 g, 74.7 %) as a yellow solid: 1H NMR (500 MHz, DMSO) δ 8.14 (dd, 1H), 7.99 (d, 1H), 7.76 (d, 1H), 7.37 (t, 1H), 4.51 (d, 1H), 3.54 (s, 2H), 2.66 – 2.75 (m, 2H), 2.45 (td, 1H), 1.73 (t, 2H), 1.44 – 1.57 (m, 2H), 0.85 (d, 6H). [0130] Step 7: (3R,4r,5S)-1-{[4-amino-2-(difluoromethoxy)phenyl]methyl}-3,5- dimethylpiperidin-4-ol (Intermediate 2) [0131] To (3R,4r,5S)-1-(2-(difluoromethoxy)-4-nitrobenzyl)-3,5-dimethylpiperidin-4-ol (2600 mg, 7.87 mmol) and water (16 mL) was added iron (4395 mg, 78.71 mmol), followed by ammonia hydrochloride (2105 mg, 39.35 mmol) . The resulting solution was stirred at 80 °C for 45 min. LCMS of the reaction mixture at this point indicated completion of the reaction with formation of the desired product at R_t = 0.35 min and ES⁺ m/z 301.30 [M+H]⁺. The reaction mixture was filtered over a pad of Dicalite and concentrated under reduce pressure to give a yellow oil. The resulting oil was dissolved in EtOAc (40 mL), washed with sat. aq. NaHCO3 (20 mL) and brine (120 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow oil, Rf = 0.25 (DCM:MeOH – 95:5). The crude product was purified by flash column chromatography on silica gel (DCM:MeOH – 1:0 to 95:5) to give the title compound (1.53 g, 5.09 mmol, 64.7 %) as a yellow glassy solid: ¹H NMR (500 MHz, DMSO) δ 6.78 – 7.13 (m, 1H), 6.95 (d, 1H), 6.40 (dd, 1H), 6.34 (d, 1H), 5.29 (s, 2H), 4.42 (d, 1H), 3.21 (s, 2H), 2.65 – 2.71 (m, 2H), 2.40 (td, 1H), 1.57 (t, 2H), 1.40 (tdd, 2H), 0.83 (d, 6H). Intermediate 3: 1-(3,4-difluorophenyl)-3-methyl-1H-pyrazole-4-carboxylic acid [ 3,4-difluorophenyl)-3-methyl-1H-pyrazole-4-carboxylate

[0133] Ethyl 3-methyl-1H-pyrazole-4-carboxylate (200 mg, 1.30 mmol), diacetoxycopper (259 mg, 1.43 mmol) and pyridine (0.250 mL) were stirred in DMF (5 mL) at room temperature (dark blue mix) for 20 h. Then, the solids were filtered off and washed with EtOAc (25 mL). The combined organic layers was washed with 0.1 M HCl (aq.) (2x25 mL), brine (20 mL), dried with a phase separator and concentrated. The residue was purified on a Biotage® Sfär HC D column using a gradient of 0-20 % EtOAc in heptane over 15 CV. The product fractions were collected and concentrated to give the title compound as a white solid (0.027 g, 7.82 %): ¹H NMR (500 MHz, CDCl3) δ 1.36 (t, 3H), 2.53 (s, 3H), 4.31 (q, 2H), 7.19 – 7.28 (m, 1H), 7.35 – 7.42 (m, 1H), 7.54 – 7.62 (m, 1H), 8.27 (s, 1H). m/z (ES⁺) [M+H]⁺ = 267.3. [0134] Step 2: 1-(3,4-difluorophenyl)-3-methyl-1H-pyrazole-4-carboxylic acid, Intermediate 3 [0135] Ethyl 1-(3,4-difluorophenyl)-3-methyl-1H-pyrazole-4-carboxylate (27 mg, 0.10 mmol) was dissolved in THF (1 mL), aq.3.8 M NaOH (133 µl, 0.51 mmol) and water (0.5 mL) was added followed by MeOH until homogenous solution. The reaction was stirred at room temperature for 8 h, then diluted with water 5 mL and acidified with 3.8 M HCl. The product was extracted with EtOAc (3x5 mL). The combined organic layers were dried with a phase separator and concentrated to give the title compound as a white solid (0.023 g, 95 %): ¹H NMR (500 MHz, DMSO) δ 2.43 (s, 3H), 7.55 – 7.64 (m, 1H), 7.74 – 7.81 (m, 1H), 8 – 8.08 (m, 1H), 8.96 (d, 1H), 12.59 (bs, 1H). Intermediate 4: 1-(3-cyanophenyl)-3-methyl-1H-pyrazole-4-carboxylic acid

[0136] Step 1: ethyl 1-(3-cyanophenyl)-3-methyl-1H-pyrazole-4-carboxylate

[0137] A mixture of ethyl 3-methyl-1H-pyrazole-4-carboxylate (0.25 g, 1.62 mmol), copper(I) iodide (0.093 g, 0.49 mmol) and potassium carbonate (0.493 g, 3.57 mmol) in toluene (2 mL) was degassed with nitrogen, then 3-iodobenzonitrile (0.446 g, 1.95 mmol), N1,N2- dimethylethane-1,2-diamine (0.086 g, 0.97 mmol) was added together and the mixture was degassed for another 2 minutes. The resulting mixture was sealed and stirred at 110 °C overnight. The reaction mixture then cooled to rt, taken up in EtOAc 30 mL, and washed subsequently with 2M NH3 (aq.20 mL), Brine (10 mL), dried (sodium sulfate), filtered and concentrated. The residue was dissolved in minimal volume of dichloromethane, applied onto a silica column, pre-conditioned with H:E 7:1. The product was eluted with 7.1 to 5:1 to 4:1. Appropriate fractions where concentrated to provide the title compound as a white solid (0.19 g, 46 %).¹H NMR (500 MHz, DMSO) δ 1.31 (t, J = 7.1 Hz, 3H), 2.45 (s, 3H), 4.26 (q, J = 7.1 Hz, 2H), 7.71 (t, J = 8.0 Hz, 1H), 7.81 (dt, J = 1.1, 7.7 Hz, 1H), 8.25 (ddd, J = 1.0, 2.3, 8.3 Hz, 1H), 8.38 – 8.44 (m, 1H), 9.12 (s, 1H). [0138] Step 2: 1-(3-cyanophenyl)-3-methyl-1H-pyrazole-4-carboxylic acid (Intermediate 4) [0139] To a solution of ethyl 1-(3-cyanophenyl)-3-methyl-1H-pyrazole-4-carboxylate (0.19 g, 0.74 mmol) in 1:1 THF-MeOH (6 mL) was added aq.1M NaOH (3 ml, 3.0 mmol) and the obtained solution was stirred at 50 °C for 45 minutes. Then organic solvent was evaporated in vacuo and the remaining mixture was diluted with water (25 mL) and neutralized with 1M HCl (4 mL) upon which the product precipitated as a white solid. The solid was extracted into EtOAc (2 x 20 mL), washed with brine (10 mL), dried (sodium sulfate), filtered and concentrated. The residue was used without further purification in the next step, off-white solid (0.12 g, 71 %, purity 87%): ¹H NMR (500 MHz, DMSO) δ 2.44 (s, 3H), 7.71 (t, J = 8.0 Hz, 1H), 7.80 (dt, J = 1.2, 7.7 Hz, 1H), 8.24 (ddd, J = 1.0, 2.3, 8.3 Hz, 1H), 8.36 – 8.43 (m, 1H), 9.05 (s, 1H), 12.57 (s, 1H). Intermediate 5: 1-(2,4-difluorophenyl)-3-methyl-1H-pyrazole-4-carboxylic acid

[0140] Intermediate 5 was prepared similar as described for Intermediate 4, using 2,4-difluoro- 1-iodobenzene and ethyl 3-methyl-1H-pyrazole-4-carboxylate as starting materials. The title compound was obtained as an off-white solid: ¹H NMR (500 MHz, DMSO) δ 2.42 (s, 3H), 7.21 – 7.33 (appt, 1H), 7.58 (ddd, J = 2.7, 9.0, 11.6 Hz, 1H), 7.82 (dt, J = 6.0, 9.0 Hz, 1H), 8.52 (d, J = 2.1 Hz, 1H), 12.52 (s, 1H). Intermediate 6: 1-(3,5-difluorophenyl)-3-methyl-1H-pyrazole-4-carboxylic acid

[0141] Intermediate 6 was prepared similar as described for Intermediate 4, using 1,3-difluoro- 5-iodobenzene and ethyl 3-methyl-1H-pyrazole-4-carboxylate as starting materials. The title compound was obtained as an off-white solid: ¹H NMR (500 MHz, DMSO) δ 2.42 (s, 3H), 7.23 (appt, 1H), 7.65 – 7.75 (appd, 2H), 9.04 (s, 1H), 12.62 (s, 1H). Intermediate 7: 1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carboxylic acid

[0142] Intermediate 7 was prepared similar as described for Intermediate 4, using 1-iodo-4- methoxybenzene and ethyl 3-methyl-1H-pyrazole-4-carboxylate as starting materials. The title compound was obtained as a pale solid: ¹H NMR (500 MHz, DMSO) δ 2.41 (s, 3H), 3.79 (s, 3H), 7 – 7.07 (m, 2H), 7.74 – 7.81 (m, 2H), 8.76 (s, 1H), 12.38 (s, 1H). Intermediate 8: 3-cyano-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid

[0143] Step 1: ethyl 3-cyano-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylate

[0144] Ethyl 3-cyano-1H-pyrazole-4-carboxylate (300 mg, 1.82 mmol), (4-fluorophenyl)boronic acid (280 mg, 2.00 mmol), copper (II) acetate (363 mg, 2.00 mmol) and Molecular Sieves 4 Å (300 mg) were stirred in pyridine (10 mL) at 80 °C for 18 h. The reaction mixture was partitioned in EtOAc (50 mL) and aq. saturated NaHCO₃ (50 mL). The aqueous layer was extracted with EtOAc (2x50 mL) and the combined organic layers were washed with brine (50 mL), dried with a phase separator and concentrated. The product was triturated from EtOAc, filtrated and dried in vacuo to give the title compound as a white solid (0.200 g, 42 %): ¹H NMR (500 MHz, DMSO) δ 1.33 (t, 3H), 4.35 (q, 2H), 7.4 – 7.49 (m, 2H), 7.98 – 8.06 (m, 2H), 9.35 (s, 1H).19F NMR (470 MHz, DMSO) δ -112.67. [0145] Step 2: 3-cyano-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid (Intermediate 8) [0146] Ester hydrolysis of Ethyl 3-cyano-1H-pyrazole-4-carboxylate (0.2 g, 0.77 mmol) was performed similar as described for intermediate 1, giving the title compound as a pale solid (0.169 g, 95 %, containing 10 % of the undesired regioisomer): ¹H NMR (500 MHz, DMSO) δ 7.41 – 7.48 (m, 2H), 7.98 – 8.03 (m, 2H), 9.27 (s, 1H), 13.54 (s, 1H). Intermediate 9: 1-(4-fluorophenyl)-3-(oxetan-3-yl)-1H-pyrazole-4-carboxylic acid

[0147] Step 1: ethyl 3-bromo-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylate

[0148] A mixture of ethyl 3-bromo-1H-pyrazole-4-carboxylate (1 g, 4.57 mmol), (4- fluorophenyl)boronic acid (0.703 g, 5.02 mmol), Copper(II) acetate (0.745 g, 4.1 mmol), molecular sieves 4Å (1 g, 4.57 mmol) in pyridine (20 mL) was heated with stirring at 80 °C for 60 minutes. The reaction mixture was allowed to cool, then diluted with EtOAc (20 mL) and filtered through celite. The filtrate was concentrated and the residue was taken up in EtOAc (50 mL), washed with aq.1.5M H2SO4 (40 mL), aq.2M NH3 (aq., 40 mL), Brine (20 mL), then dried (sodium sulfate), filtered and concentrated. The residue was dissolved in minimal amount of DCM, and was applied onto a silica gel column, pre-conditioned with H:E 4:1. The column was eluted with ethyl acetate in hexane (stepwise elution, 4:1 to 2:1), appropriate fractions were pooled and concentrated to give the title compound as a white solid (1.04 g, 73 %): ¹H NMR (500 MHz, DMSO) δ 1.31 (t, J = 7.1 Hz, 3H), 4.28 (q, J = 7.1 Hz, 2H), 7.34 – 7.42 (m, 2H), 7.91 – 7.99 (m, 2H), 9.10 (s, 1H). [0149] Step 2: ethyl 1-(4-fluorophenyl)-3-(oxetan-3-yl)-1H-pyrazole-4-carboxylate

[0150] A vial containing NiCl2*glyme (8.77 mg) and 4,4’-di-tert-butyl-2,2’-bipyridine (10.7 mg) under nitrogen was added dimethoxyethane (10 mL), then nitrogen was bubbled through the solution for 5 minutes with stirring which gave a slight yellowish solution. [0151] To a separate vial containing ethyl 3-bromo-1-(4-fluorophenyl)-1H-pyrazole-4- carboxylate (0.25 g, 0.80 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (8.96 mg, 7.98 µmol), sodium carbonate (0.169 g, 1.60 mmol), 3-bromooxetane (0.328 g, 2.40 mmol) and 1,1,1,3,3,3- hexamethyl-2-(trimethylsilyl)trisilane (0.199 g, 0.80 mmol) under nitrogen was added dimethoxyethane (10 mL) and the obtained stirred suspension was bubbled with nitrogen for a few minutes.1 mL of the NiCl2*glyme solution above was added under nitrogen to the vial containing the reagents, then placed in a reactor and subsequently irradiated with a 34W Blue LED-lamp under stirring and fan cooling for 8 h. The reaction mixture was diluted in a small amount of DCM, then applied to a silica gel column, pre-conditioned with H:E 7:1. Stepwise gradient elution with ethyl acetate in hexane (7:1 to 4:1) followed by concentration of appropriate fractions gave the title compound as a white solid (0.14 g, 60%): ¹H NMR (500 MHz, DMSO) δ 1.29 (t, J = 7.1 Hz, 3H), 4.23 (q, J = 7.1 Hz, 2H), 4.60 (ddd, J = 7.0, 8.4, 15.4 Hz, 1H), 4.84 (dd, J = 5.8, 6.9 Hz, 2H), 4.92 (dd, J = 5.7, 8.5 Hz, 2H), 7.33 – 7.43 (m, 2H), 7.92 – 8.03 (m, 2H), 9.04 (s, 1H). [0152] Step 3: 1-(4-fluorophenyl)-3-(oxetan-3-yl)-1H-pyrazole-4-carboxylic acid (Intermediate 9) [0153] Ester hydrolysis of ethyl 1-(4-fluorophenyl)-3-(oxetan-3-yl)-1H-pyrazole-4-carboxylate (0.07 g, 0.24 mmol) was performed similar as described for Intermediate 4 giving the title compound as a white solid (0.061 g, 96 %): ¹H NMR (500 MHz, DMSO) δ 7.41 – 7.48 (m, 2H), 7.98 – 8.03 (m, 2H), 9.27 (s, 1H), 13.54 (s, 1H). Intermediate 10: 3-(difluoromethyl)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid

[0154] Step 1: ethyl 3-(difluoromethyl)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylate

[0155] Prepared as similar as described for Intermediate 4 from methyl 3-(difluoromethyl)-1H- pyrazole-4-carboxylate (317 mg, 1.80 mmol) and 1-fluoro-4-iodobenzene (249 µl, 2.16 mmol) giving the title compound as a pale solid methyl 3 (0.089 g, 18.30 %): ¹H NMR (500 MHz, DMSO) δ 3.84 (s, 3H), 7.2 – 7.47 (m, 3H), 7.95 – 8.03 (m, 2H), 9.21 (d, 1H).19F NMR (470 MHz, DMSO) δ -115.77, -114.01. [0156] Step 2: 3-(difluoromethyl)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid, (Intermediate 10) [0157] Ester hydrolysis of ethyl 3-(difluoromethyl)-1-(4-fluorophenyl)-1H-pyrazole-4- carboxylate (0.089 g, 0.31 mmol) was performed similar as described for Intermediate 4 giving the title compound as a white solid (0.082 g, quantitative yield): ¹H NMR (500 MHz, DMSO) δ 7.17 – 7.51 (m, 3H), 7.93 – 8.01 (m, 2H), 9.09 (d, 1H), 13.14 (s, 1H). Intermediate 11: 3-cyclopropyl-1-(oxetan-3-yl)-1H-pyrazole-4-carboxylic acid

[0158] Step 1: ethyl 3-cyclopropyl-1-(oxetan-3-yl)-1H-pyrazole-4-carboxylate

[0159] A mixture of ethyl 3-cyclopropyl-1H-pyrazole-4-carboxylate (1.16 g, 6.44 mmol), 3- bromooxetane (0.970 g, 7.08 mmol) and cesium carbonate (6.29 g, 19.31 mmol) in DMF (9 mL) was stirred at 100 °C overnight. The reaction mixture was allowed to cool to rt, then partitioned between EtOAc (70 mL) and water (70 mL). The water layer was extracted once with EtOAC (70 mL), and the combined organic layers were washed with successively with water (3 x 40 mL), brine (40mL), dried (sodium sulfate), filtered and concentrated. Column chromatography with EtOAc in hexane (5:1 to 2:1, stepwise gradient elution) gave the title compound as colorless oil (0.9 g, 59 %, containing 5% of the undesired regioisomer): 1H NMR (500 MHz, DMSO) δ 8.30 (s, 1H), 5.44 – 5.54 (m, 1H), 4.78 – 4.87 (m, 4H), 4.21 (q, 2H), 2.45 – 2.49 (m, 1H), 1.26 (t, 3H), 0.92 (ddt, 2H), 0.85 (qt, 2H). [0160] Step 2: 3-cyclopropyl-1-(oxetan-3-yl)-1H-pyrazole-4-carboxylic acid (Intermediate 11) [0161] Ester hydrolysis of ethyl 3-cyclopropyl-1-(oxetan-3-yl)-1H-pyrazole-4-carboxylate ((0.90 g, 3.81 mmol) was performed similar as described for Intermediate 4 giving the title compound as a white solid (0.725 g, 91 %): 1H NMR (500 MHz, DMSO) δ 12.23 (s, 1H), 8.22 (s, 1H), 5.41 – 5.55 (m, 1H), 4.77 – 4.89 (m, 4H), 2.51 – 2.56 (m, 1H), 0.90 (ddt, 2H), 0.84 (tq, 2H). Intermediate 12: 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid

[0162] Step 1: ethyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate

[0163] A mixture of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (1 g, 4.16 mmol), methyl 2-(4-fluorophenyl)hydrazine-1-carboxylate (0.767 g, 4.16 mmol) in dichloroethane (10 mL) stirred at 80 °C overnight. To the reaction mixture was added 0.15 mL of TFA, and the reaction was put back to stirring with heating for 30 minutes, which showed 20% conversion from intermediate to product. Trifluoroacetic acid was then added (0.45 mL in total) followed by additional stirring at 80 °C until product formation was complete (3 h). The reaction mixture was then allowed to cool, diluted with EtOAc (100 mL) and washed successively with aq.0.2M NaOH (60 mL), water (50 mL) and brine (20 mL). The organic layer was then dried (sodium sulfate), filtered and concentrated. Column chromatography of the residue (dissolved in dichloromethane, 15 mL) using EtOAc in hexane (10-12.5 %, stepwise gradient elution) followed by concentration of the appropriate fractions gave the title compound as a tan solid (0.75 g, 60%): ¹H NMR (500 MHz, DMSO) δ 9.29 (d, 1H), 7.95 – 8.03 (m, 2H), 7.38 – 7.47 (m, 2H), 4.31 (q, 2H), 1.31 (t, 3H). [0164] Step 2: 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, (Intermediate 12) [0165] Ester hydrolysis of ethyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4- carboxylate (0.75 g, 2.48 mmol) was performed similar as described for Intermediate 4 giving the title compound as a brownish solid (0.65 g, 96 %): ¹H NMR (500 MHz, DMSO) δ 13.22 (s, 1H), 9.20 (d, 1H), 7.95 – 8.01 (m, 2H), 7.38 – 7.46 (m, 2H). Intermediate 13: 1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carboxylic acid

[0166] Step 1: ethyl 1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carboxylate

[0167] Ethyl 3-methyl-1H-pyrazole-4-carboxylate (5.00 g, 32.43 mmol), copper(I) iodide (1.85 g, 9.73 mmol) and potassium carbonate (9.86 g, 71.35 mmol) were combined in toluene (15 mL) and the mixture was degassed with nitrogen for 2 minutes.1-Fluoro-4-iodobenzene (7.92 g, 35.68 mmol) and N1,N2-dimethylethane-1,2-diamine (1.72 g, 19.46 mmol) were added and the mixture was degassed with nitrogen for a further 2 minutes before the vessel was sealed with a lid and stirred at 110°C for 4 hours. The reaction mixture was allowed to cool and was diluted with EtOAc (150 mL). The mixture was washed with dilute aqueous ammonium hydroxide (2 x 80 mL), water (100 mL) and brine (30 mL) before drying over Na₂SO₄. After filtration and concentration to dryness under reduced pressure, purification was achieved by flash column chromatography through a 220g silica cartridge, pre-conditioned with 5% EtOAc in heptane. Elution with a stepped gradient elution (5% EtOAc in heptane (480 mL), then 10% EtOAc in heptane (480 mL)) afforded ethyl 1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carboxylate as an off-white solid (4.75 g, 59% isolated yield): ¹H-NMR (500 MHz, DMSO-d6) δ 1.30 (t, 3H), 2.43 (s, 3H), 4.25 (q, 2H), 7.29 – 7.38 (m, 2H), 7.89 – 7.96 (m, 2H), 8.94 (s, 1H); LCMS m/z (ES⁺) 249.2 [M+H]⁺. [0168] Step 2: 1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carboxylic acid (Intermediate 13) [0169] 1.0M NaOH(aq) (30 mL, 30.00 mmol) was added to a solution of ethyl 1-(4- fluorophenyl)-3-methyl-1H-pyrazole-4-carboxylate (2.80 g, 11.28 mmol) in 1:1 THF/MeOH (40 mL) and the solution was stirred at 50°C for 60 minutes. The reaction was concentrated under reduced pressure to remove the bulk of the organic solvents, then the remaining aqueous solution was diluted with water (30 mL) and 1.0M HCl_(aq) (35 mL) which precipitated the product, and the product was extracted into EtOAc (2 x 75 mL). The combined extractions were washed with brine (20 mL) then dried over Na2SO4. Filtration and concentration afforded 1-(4- fluorophenyl)-3-methyl-1H-pyrazole-4-carboxylic acid as a colourless solid (2.44 g, 98% isolated yield): ¹H-NMR (500 MHz, DMSO-d6) δ 2.42 (s, 3H), 7.28 – 7.39 (m, 2H), 7.83 – 7.95 (m, 2H), 8.87 (s, 1H), 12.47 (s, 1H); LCMS m/z (ES-) 219.2 [M-H]-. Intermediate 14: N-[4-(chloromethyl)-3-(difluoromethoxy)phenyl]-4-cyano-2- methylbenzamide

[0170] Step 1: 2-(hydroxymethyl)-5-nitrophenol

[0171] Borane dimethyl sulfide complex (15.54 ml, 163.83 mmol) was slowly added by syringe pump (1 mL/min) to a chilled solution (ca.0°C) of 2-hydroxy-4-nitrobenzoic acid (15 g, 81.91 mmol) in THF (200 mL). Once the addition was complete, the reaction was warmed to room temperature and stirred for 40 h. The reaction was quenched by slow addition of methanol (50 mL) and left stirring for 2 h before being concentrated under reduced pressure to afford a crude yellow oil. Trituration with diethyl ether and hexane gave 2-(hydroxymethyl)-5-nitrophenol to ca.90% purity, as a dark yellow solid (13.00 g, 85% yield). The compound was used without further purification: ¹H-NMR (500 MHz, DMSO-d₆) δ 4.54 (s, 2H), 7.56 (d, 1H), 7.58 (d, 1H), 7.70 (dd, 1H), 10.46 (s, 1H), benzylic OH unassigned; LCMS m/z (ES-) 168.0 [M-H]-. [0172] Step 2: 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-nitrophenol

[0173] tert-Butylchlorodimethylsilane (6.92 g, 45.94 mmol) was added to a mixture of 2- (hydroxymethyl)-5-nitrophenol (7.40 g, 43.75 mmol) and 1H-imidazole (2.98 g, 43.75 mmol) in DCM (200 mL) and the resulting reaction mixture was stirred at room temperature overnight. The reaction was diluted with DCM (100 mL) and washed with sat. NH₄Cl_(aq) (150 mL) and brine (15 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Partial purification by column chromatography on silica gel (gradient elution 0 to 15% EtOAc in heptane) gave 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-nitrophenol to 80% purity, as a yellow oil which crystallized on standing (10.55 g, 68%): ¹H-NMR (500 MHz, DMSO-d6) δ 0.10 (s, 6H), 0.92 (s, 9H), 4.73 (d, 2H), 7.53 (dt, 1H), 7.59 (d, 1H), 7.73 (dd, 1H), 10.61 (s, 1H); LCMS m/z (ES-) 282.3 [M-H]-. [0174] Step 3: tert-butyl{[2-(difluoromethoxy)-4-nitrophenyl]methoxy}dimethylsilane

[0175] Diethyl (bromodifluoromethyl)phosphonate (1.25 mL, 7.06 mmol) was added by syringe pump (2 mL/min) to a chilled mixture (ca.0 °C) of 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)- 5-nitrophenol (1 g, 3.53 mmol) and potassium hydroxide (1.98 g, 35.29 mmol) in 1:1 acetonitrile/water (30 mL). After 15 min, the reaction was allowed to warm to room temperature and stirred for 1 h before the mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO₄, filtered and concentrated under reduced pressure, to afford tert-butyl{[2- (difluoromethoxy)-4-nitrophenyl]methoxy}dimethylsilane as a yellow oil (1.13 g, 96% yield): ¹H-NMR (500 MHz, DMSO-d6) δ 0.12 (s, 6H), 0.92 (s, 9H), 4.82 (d, 2H), 7.44 (t, 1H), 7.77 (dt, 1H), 8.01 (d, 1H), 8.18 (dd, 1H); LCMS m/z (ES-) 332.0 [M-H]-. [0176] Step 4: 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(difluoromethoxy)aniline

[0177] Iron (10.05 g, 179.96 mmol), followed by ammonia hydrochloride (4.81 g, 89.98 mmol), was added to a mixture of tert-butyl{[2-(difluoromethoxy)-4- nitrophenyl]methoxy}dimethylsilane (6.00 g, 18.00 mmol) in 25% water in ethanol (80 mL). The resulting solution was stirred at 80°C for 1 h before filtration of the mixture through a pad of Dicalite and concentration under reduce pressure. The resulting oil was dissolved in EtOAc (45 mL), washed with aq. sat. NaHCO₃ (30 mL) and brine (30 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (gradient elution, 0 to 25% EtOAc in heptane) gave 4-({[tert- butyl(dimethyl)silyl]oxy}methyl)-3-(difluoromethoxy)aniline as a yellow oil (4.23 g, 77% isolated yield):¹H-NMR (500 MHz, DMSO-d6) δ 0.04 (s, 6H), 0.86 (s, 9H), 4.51 (s, 2H), 5.32 (s, 2H), 6.34 (dd, 1H), 6.40 (dd, 1H), 6.99 (t, 1H), 7.05 (d, 1H). [0178] Step 5: N-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(difluoromethoxy)phenyl]-4- cyano-2-methylbenzamide

[0179] Oxalyl dichloride (4.18 mL, 49.4 mmol) was added to a suspension of 4-cyano-2- methylbenzoic acid (1.91 g, 11.9 mmol) in dichloromethane (65 mL), followed by slow addition of N,N-dimethylformamide (7.23 mg, 0.10 mmol). The resulting solution was stirred at room temperature for 1 h and then concentrated to dryness under reduced pressure. The resulting residue was dissolved in 2-methyl tetrahydrofuran (25 mL) and added slowly to a mixture of 4- ({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(difluoromethoxy)aniline (3.00 g, 9.89 mmol) and triethylamine (4.13 mL, 29.66 mmol) in 2-methyltetrahydrofuran (65 mL). Once the addition was complete, the reaction was left stirring at room temperature for 22 h before the mixture was diluted with EtOAc (50 mL) and washed with sat. NaHCO3(aq) (50 mL) and brine (50 mL). The organic layer was dried over MgSO₄, filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (gradient elution: 0 to 20% EtOAc in heptane) gave N-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(difluoromethoxy)phenyl]-4- cyano-2-methylbenzamide as a pale yellow solid (4.03 g, 91% isolated yield): ¹H-NMR (500 MHz, DMSO-d6) δ 0.09 (s, 6H), 0.90 (s, 9H), 2.40 (s, 3H), 4.68 (s, 2H), 7.14 (t, 1H), 7.44 (d, 1H), 7.54 (dd, 1H), 7.65 (d, 1H), 7.73 (d, 1H), 7.77 – 7.82 (m, 1H), 7.84 (d, 1H), 10.66 (s, 1H); LCMS m/z (ES-) 445.4 [M-H]-. [0180] Step 6: 4-cyano-N-[3-(difluoromethoxy)-4-(hydroxymethyl)phenyl]-2-methylbenzamide

[0181] 4-Methylbenzenesulfonic acid hydrate (8.52 g, 44.79 mmol) was added to N-[4-({[tert- butyl(dimethyl)silyl]oxy}methyl)-3-(difluoromethoxy)phenyl]-4-cyano-2-methylbenzamide (4.0 g, 8.96 mmol) in MeOH (100 mL). The resulting solution was stirred at room temperature for 1 h before the reaction mixture was diluted with EtOAc (100 mL) and washed with sat. NaHCO_3(aq) (2 x 50 mL) and brine (50 mL). The organic layer was dried over MgSO₄, filtered and concentrated under reduced pressure to give crude 4-cyano-N-[3-(difluoromethoxy)-4- (hydroxymethyl)phenyl]-2-methylbenzamide as a pale yellow solid (3.45 g, quantitative yield), which was used without further purification: ¹H-NMR (500 MHz, DMSO-d6) δ 2.40 (s, 3H), 4.50 (d, 2H), 5.19 (t, 1H), 7.11 (t, 1H), 7.47 (d, 1H), 7.54 (dd, 1H), 7.65 (d, 1H), 7.69 (d, 1H), 7.77 – 7.82 (m, 1H), 7.84 (d, 1H), 10.63 (s, 1H); LCMS m/z (ES-) 331.2 [M-H]-. [0182] Step 7: N-[4-(chloromethyl)-3-(difluoromethoxy)phenyl]-4-cyano-2-methylbenzamide (Intermediate 14) [0183] Sulfurous dichloride (1.32 mL, 18.1 mmol), followed by N,N-dimethylformamide (70 µl, 0.90 mmol) was slowly added to a chilled mixture (ca.0°C) of 4-cyano-N-[3-(difluoromethoxy)- 4-(hydroxymethyl)phenyl]-2-methylbenzamide (3.00 g, 9.0 mmol) in acetonitrile (60 mL). Once the addition was complete, the reaction was allowed to warm to room temperature and stirred at this temperature for 8 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with sat. NaHCO3(aq) (2 x 25 mL) and brine (30 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (gradient elution, 0 to 40% EtOAc in heptane) gave N-[4-(chloromethyl)-3- (difluoromethoxy)phenyl]-4-cyano-2-methylbenzamide as a yellow solid (2.94 g, 93% isolated yield): ¹H-NMR (500 MHz, DMSO-d6) δ 2.41 (s, 3H), 4.73 (s, 2H), 7.23 (t, 1H), 7.52 – 7.56 (m, 2H), 7.66 (d, 1H), 7.78 (s, 1H), 7.79 – 7.82 (m, 1H), 7.84 – 7.87 (m, 1H), 10.76 (s, 1H); SFC- MS m/z (ES-) 351.0 [M(³⁵Cl)-H]-, 353.0 [M(³⁷Cl)-H]-. Intermediate 15: 2-[(3RS)-azepan-3-yl]propan-2-ol

[0184] Step 1: 1-benzyl 3-methyl (3RS)-azepane-1,3-dicarboxylate

[0185] To a stirred solution of azepane-3-carboxylic acid hydrochloride (1.25 g, 6.96 mmol, CAS RN 2007916-48-3) in 1M NaOH (20.88 mL, 20.88 mmol) at 0 °C was added dropwise a solution of benzyl chloroformate (1.088 mL, 7.66 mmol) in THF (5 mL) over 5 minutes, then stirred at rt for 2.5 h. The reaction mixture was then diluted with water (20 mL), washed with EtOAc (20 mL). The aqueous phase was then acidified with 25 mL aq.1M HCl, which gave a precipitate which was extracted into EtOAc (2 x 25 mL). The combined organic layers was washed with brine (25 mL), dried (sodium sulfate) and concentrated which gave a residue which solidified upon standing. The residue was dissolved in DMF (6 mL), added carbonate (0.934 g, 6.76 mmol) and iodomethane (0.421 mL, 6.76 mmol) and the resulting suspension was stirred at rt overnight. The reaction mixture was then diluted with EtOAc (40 mL), washed with water (3 x 20 mL), dried (sodium sulfate), filtered and concentrated. Column chromatography of the residue (dissolved in a minimal volume of dichloromethane) using EtOAc in hexane (17-25 % stepwise gradient elution) followed by concentration of the appropriate fractions gave the title compound as a colorless oil (1 g): ¹H NMR (500 MHz, CDCl3) 1.4 – 1.52 (1H, m), 1.56 – 1.94 (5H, m), 2.69 – 2.87 (1H, m), 3.19 (1H, ddt), 3.28 (1H, ddd), 3.65 (3H, d), 3.75 (1H, dd), 4.03 (1H, ddd), 5.09 – 5.19 (2H, m), 7.28 – 7.39 (5H, m). [0186] Step 2: 2-[(3RS)-azepan-3-yl]propan-2-ol (Intermediate 15) [0187] To a stirred solution of 1-benzyl 3-methyl azepane-1,3-dicarboxylate (0.92 g, 3.16 mmol) in THF (20 mL) was dropwise added 3M MeMgBr in Et2O (3.16 mL, 9.47 mmol) over a few minutes, then cooling was removed and the resulting reaction mixture was stirred overnight. The reaction mixture was then quenched by the addition of aq sat NH4Cl (20 mL) and partitioned between EtOAc (40 mL) and water (30 mL). The water layer was extracted with EtOAc (20 mL) and the combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated. To the residue dissolved in methanol (20 mL) was added Pd/C (10 %, 0.08 g) then hydrogenated at 4 bars overnight. The reaction mixture was then filtered and concentrated to provide the title compound which was used in the next step without further purification (0.49 g): ¹H NMR (500 MHz, MeOD) 1.14 (3H, s), 1.19 (3H, s), 1.35 – 1.46 (1H, m), 1.48 – 1.6 (1H, m), 1.64 – 1.78 (2H, m), 1.86 (2H, tdt), 1.92 – 1.99 (1H, m), 2.82 (1H, dd), 2.9 – 3.06 (2H, m), 3.26 – 3.3 (1H, m). Intermediate 16: (2S)-2-[(3S)-piperidin-3-yl]propane-1,2-diol

[0188] Step 1: 1-benzyl 3-ethyl (3S)-piperidine-1,3-dicarboxylate

[0189] To a solution of ethyl (S)-piperidine-3-carboxylate (50 g, 318.04 mmol) in water (497 mL) and THF (497 mL) was added sodium bicarbonate (53.4 g, 636.08 mmol) and N- (Benzyloxycarbonyloxy)succinimide (95 g, 381.65 mmol) in portions at 0 °C. The resulting reaction mixture was left to slowly reach room temperature and stirred for 16 h. The reaction mixture was then diluted with EtOAc (1 L) and water (500 mL). After extraction, the organic phase was further washed with water (2x200 mL) and brine (200 mL). The organic layer was dried over MgSO₄, filtered and concentrated under reduced pressure to give 105 g of crude. This crude was purified by prep-HPLC: Column: DCPakA, 250x50 mm, 5 microm, 2% IPA in CO2 120 bar, 400 mL/min to obtain the title compound (79 g, 85 %): ¹H NMR (500 MHz, DMSOd6, 25°C) δ 1.15 (3H, d), 1.39 (1H, d), 1.63 (2H, dtd), 1.90 (1H, s), 2.47 (1H, s), 2.93–3.27 (2H, m), 3.6–3.8 (1H, m), 3.94 (1H, d), 4.05 (2H, d), 5.07 (2H, d), 7.28–7.41 (5H, m). [0190] Step 2: (3S)-1-[(benzyloxy)carbonyl]piperidine-3-carboxylic acid

[0191] To a solution of 1-benzyl 3-ethyl (S)-piperidine-1,3-dicarboxylate (79 g, 271.15 mmol) in THF (1356 ml) and water (226 ml) was added dropwise a solution of lithium hydroxide monohydrate (12.52 g, 298.27 mmol) in water (226 ml) during 10 min at 0 °C. Cooling was removed and after stirring 3 hours at rt, the reaction mixture was quenched by the addition of 5M aqueous HCl solution to reach pH ~4. The mixture was then extracted with EtOAc (1.5 L) and the organic phase was washed with water (2x300 mL) and brine (400 mL). After drying over anhydrous MgSO4 and filtration, the organic phase was evaporated to obtain (S)-1- ((benzyloxy)carbonyl)piperidine-3-carboxylic acid (71.0 g, 99 %): ¹H NMR (500 MHz, DMSO, 25°C) δ 1.3–1.42 (1H, m), 1.49–1.57 (1H, m), 1.58–1.68 (1H, m), 1.86–1.96 (1H, m), 2.29–2.41 (1H, m), 2.8–3.2 (2H, m), 3.68–3.86 (1H, m), 3.91–4.09 (1H, m), 5.07 (2H, s), 7.28–7.41 (5H, m), 12.42 (1H, s). This material was used in the next step without further purification. [0192] Step 3: benzyl (3S)-3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate

[0193] To a solution of (S)-1-((benzyloxy)carbonyl)piperidine-3-carboxylic acid (71 g, 269.66 mmol) in dichloromethane (1269 ml) was added at 0 °C N,O-dimethylhydroxylamine hydrochloride (28.9 g, 296.63 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3- tetramethylisouronium hexafluorophosphate(V) (113 g, 296.63 mmol). Then, triethylamine (79 ml, 566.29 mmol) was added over a period of 10 minutes. The mixture was stirred 1.5 h at 0 °C followed by 1.5 h at room temperature. The reaction mixture was then quenched by the addition of water (300 mL) followed by a vigorous stirring for 10 minutes. After further dilution with water (400 mL) and phases separation, the organic phase was washed with water (2x400 mL) and brine (400 mL). The organic phase was dried over MgSO₄, filtered and evaporated to obtain 135 g of crude. This crude was divided in three parts and purified by flash chromatography (Biotage, 340 g column KP-Sil, 10% EtOAc in heptane (1CV) to 80% (8CV)) to yield the title compound (72.0 g, 87 %, contains 5 wt-% tetramethyl urea): ¹H NMR (500 MHz, DMSO, 25°C) δ 1.34–1.46 (1H, m), 1.48–1.6 (1H, m), 1.63–1.73 (1H, m), 1.79–1.85 (1H, m), 2.72–2.98 (3H, m), 3.07 (3H, s), 3.53–3.74 (3H, m), 3.89–3.96 (1H, m), 3.96–4.05 (1H, m), 5.05 (1H, d), 5.10 (1H, d), 7.28–7.41 (5H, m). [0194] Step 4: benzyl (3S)-3-acetylpiperidine-1-carboxylate

[0195] To a solution of benzyl (S)-3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (72 g, 235.02 mmol) in dry THF (689 ml) at -10 °C was added dropwise a 3M solution methylmagnesium bromide in Et2O (94 ml, 282.02 mmol) over 40 minutes. The reaction mixture was left to slowly reach room temperature. Then, after 1 hour, the reaction mixture was cooled to 0 °C and quenched by the careful addition of 5% aqueous HCl solution until the reaction mixture reached pH ~4. The mixture was diluted with TBME (1 L) and water (200 mL) and extracted. The organic phase was further washed with water (200 mL) and brine (200 mL). The organic phase was dried over MgSO4, filtered and evaporated to obtain crude title compound that was used in the next step without further purification (58.6 g, 95 %): ¹H NMR (500 MHz, CDCl3, 25°C) δ 1.42–1.6 (2H, m), 1.69–1.81 (1H, m), 1.95–2.04 (1H, m), 2.17 (3H, s), 2.43–2.61 (1H, m), 2.82–2.91 (1H, m), 2.94–3.06 (1H, m), 3.92–4.08 (1H, m), 4.12–4.31 (1H, m), 5.11 (1H, d), 5.15 (1H, d), 7.28–7.4 (5H, m). [0196] Step 5: benzyl (3R)-3-(prop-1-en-2-yl)piperidine-1-carboxylate

201260-WO-PCT [0197] In a 5 L reactor equipped with mechanical stirring was added dry THF (2069 ml) and methyltriphenylphosphonium bromide (112 g, 314.00 mmol). The suspension was cooled to 10 °C followed by dropwise addition of 1.6M in hexanes of BuLi (182 ml, 291.57 mmol), while maintaining the internal temperature between 11-14 °C. After 50 minutes stirring the internal temperature reached 6 °C and a solution of benzyl (S)-3-acetylpiperidine-1-carboxylate (58.61 g, 224.28 mmol) in dry THF (552 ml) was added over a period of 1 hour while maintaining the internal temperature at ≤8 °C. After an additional 1 hour, the reaction mixture was carefully quenched by the addition of saturated NH4Cl solution (1 L) followed by TBME (1 L). After vigorous stirring for 10 minutes, the water phase was separated and the organic phase washed with brine (1 L). The organic phase was dried over MgSO4, filtered and evaporated to obtain a crude solid. This solid was suspended in diethyl ether (400 mL). The white solid of triphenylphosphine oxide was filtered off and washed with diethyl ether (3x50 mL). The filtrate was evaporated to ~1/2V and the resulting solution kept at 5 °C for 60 hours. The formed crystals of triphenylphosphine oxide were filtered off and washed with diethyl ether (3x50 mL). The filtrate was evaporated to obtain 68.6 g of crude. This crude was divided in two equal parts and purified by flash chromatography (Biotage, KP-SIL 340 g, 5% EtOAc in Heptane (2CV) then to 30% (6 CV)). The same column was used in the second purification after washing it with 100% EtOAc and equilibration to 5% EtOAc. The fractions containing product of each purifications were combined and evaporated to yield the title compound (48.2 g, 83 %): ¹H NMR (500 MHz, CDCl3, 25°C) δ 1.3–1.4 (1H, m), 1.43–1.55 (1H, m), 1.66–1.79 (4H, m), 1.85–1.94 (1H, m), 1.99–2.1 (1H, m), 2.52–2.67 (1H, m), 2.67–2.78 (1H, m), 4.07–4.36 (2H, m), 4.72 (1H, s), 4.79 (1H, s), 5.14 (2H, s), 7.28–7.39 (5H, m). [0198] A separate batch (63 g) prepared under less controlled conditions resulted in a product having partial racemization and was resolved by preparative chiral chromatography (Column: (R, R)-WHELK-O®1-Kromasil, 5*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: IPA(0.5% 2M NH3-MeOH)–HPLC; Flow rate: 200 mL/min; Gradient: isocratic 25% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 9.5; RT2(min): 10.60; Sample Solvent: MeOH–HPLC; Injection Volume: 9.9 mL; Number Of Runs: 71). Concentration of the appropriate fractions gave benzyl (3R)-3-(prop-1-en-2-yl)piperidine-1- carboxylate (50.9 g, 82 %) and benzyl (3R)-3-(prop-1-en-2-yl)piperidine-1-carboxylate (0.7 g, 1.1%). [0199] Step 6: benzyl (3S)-3-[(2RS)-1,2-dihydroxypropan-2-yl]piperidine-1-carboxylate 86

[0200] To a stirred solution of benzyl (R)-3-(prop-1-en-2-yl)piperidine-1-carboxylate (24.12 g, 93.00 mmol) in THF (698 ml) and water (233 ml) was added at room temperature 4- methylmorpholine-4-oxide (11.98 g, 102.30 mmol) and potassium dioxidodioxoosmium dihydrate (1.713 g, 4.65 mmol). After 23 hours, additional 4-methylmorpholine-4-oxide was added (1.1 g, 0.1 equiv.) and stirring was continued for 24 h. The reaction mixture was then diluted with EtOAc (1 L) and washed with saturated NH4Cl solution (3x400 mL) and brine (400 mL). The organic phase was dried over MgSO4, filtered and evaporated to obtain 27.61 g of crude. This crude was purified by flash chromatography (Biotage, 340 g silica gel KP-SIL, 50% EtOAc (2CV), 50 to 100% EtOAc (10 CV) in Heptane) to yield the title compound as a mixture of diastereomers (22.25 g, 82 %): ¹H NMR (500 MHz, DMSOd6, 25°C) δ 0.9–1.02 (3H, m), 1.08–1.32 (2H, m), 1.4–1.83 (3H, m), 2.5–2.7 (2H, m), 3.1–3.26 (2H, m), 3.93–3.99 (1H, m), 4.07 (1H, s), 4.1–4.23 (1H, m), 4.46–4.52 (1H, m), 4.99–5.09 (2H, m), 7.25–7.38 (5H, m). [0201] Step 7: benzyl (3S)-3-[(2S)-1,2-dihydroxypropan-2-yl]piperidine-1-carboxylate and benzyl (3S)-3-[(2R)-1,2-dihydroxypropan-2-yl]piperidine-1-carboxylate

[0202] 44.5 g of a mixture of diastereoisomers were separated (Column: Chiralpak® IA, 250x50 mm, 5 micron, 17% EtOH/DEA 100/20 mM in CO2, 120 bar) to obtain the major product, benzyl (3S)-3-[(2S)-1,2-dihydroxypropan-2-yl]piperidine-1-carboxylate (23.62 g, 52 %): ¹H NMR (500 MHz, DMSOd6, 25°C) δ 0.93 (3H, s), 1.11–1.2 (1H, m), 1.2–1.31 (1H, m), 1.44– 1.55 (1H, m), 1.59–1.66 (1H, m), 1.7–1.76 (1H, m), 2.5–2.72 (2H, m), 3.21 (2H, d), 3.94–4.01 (1H, m), 4.08 (1H, s), 4.17–4.23 (1H, m), 4.49 (1H, t), 5.03 (1H, d), 5.06 (1H, d), 7.25–7.38 (5H, m), Chiral HPLC: 99.5% d.e.; and the minor product benzyl (3S)-3-[(2R)-1,2- dihydroxypropan-2-yl]piperidine-1-carboxylate (16.74 g, 38 %): ¹H NMR (500 MHz, DMSOd6, 25 °C) δ 0.99 (3H, s), 1.18–1.3 (2H, m), 1.4–1.51 (1H, m), 1.6–1.67 (1H, m), 1.77–1.82 (1H, m), 2.5–2.68 (2H, m), 3.1–3.17 (1H, m), 3.23–3.29 (1H, m), 3.93–4 (1H, m), 4.08 (1H, s), 4.1– 4.18 (1H, m), 4.50 (1H, t), 5.04 (2H, s), 7.25–7.38 (5H, m). Chiral HPLC: 91.9% d.e. Absolute stereochemistry determined by vibrational circular dichroism (VCD). [0203] Step 8: (2S)-2-[(3S)-piperidin-3-yl]propane-1,2-diol (Intermediate 16) [0204] To palladium on carbon (0.508 g, 0.24 mmol) placed in autoclave reactor and in MeOH (5 mL) was added a solution of benzyl (S)-3-((S)-1,2-dihydroxypropan-2-yl)piperidine-1- carboxylate (5 g, 17.04 mmol) in MeOH (48.7 mL) The mixture was sealed in the reactor, purged with N2 five times, with H2 five times and left over the weekend stirring at room temperature under 2 bars of H2. After 68 hours and once the mixture was purged with N2, the suspension was filtered through a pad of celite. The solid in the filter was washed with MeOH (3x50 mL) and the resulting filtrate evaporated to yield (S)-2-((S)-piperidin-3-yl)propane-1,2- diol (2.75 g, Quantitative yield).¹H NMR (500 MHz, D2O) 1.10 (3H, s), 1.23 – 1.35 (1H, m), 1.49 – 1.62 (1H, m), 1.79 – 1.89 (3H, m), 2.58 – 2.7 (2H, m), 3.13 – 3.19 (1H, m), 3.27 – 3.33 (1H, m), 3.45 (1H, d), 3.55 (1H, d).3 H’s exchanged with D. Intermediate 17: (2R)-2-[(3S)-piperidin-3-yl]propane-1,2-diol

[0205] To palladium on carbon (5%) (0.272 g, 0.13 mmol) in MeOH (5.0 mL) was added a solution of benzyl (S)-3-((R)-1,2-dihydroxypropan-2-yl)piperidine-1-carboxylate, the minor product of step 7, intermediate 16 (1.5 g, 5.11 mmol) in MeOH (20 mL). The reaction mixture was sealed in an autoclave vessel and flushed and degassed with nitrogen followed by hydrogen (4 times). The reaction mixture was stirred at room temperature overnight (18 h) under 2 bar of hydrogen. The reaction mixture was filtered over a pad of celite under a flow of nitrogen to remove the residual palladium and concentrated under reduced pressure to afford the title compound (0.930 g, quantitative yield) as a colourless oil: ¹H NMR (400 MHz, MeOD) δ 3.37 – 3.46 (m, 2H), 3.16 (dt, 1H), 3 – 3.07 (m, 1H), 2.52 – 2.6 (m, 1H), 2.50 (d, 1H), 1.9 – 1.98 (m, 1H), 1.68 – 1.83 (m, 2H), 1.52 (qt, 1H), 1.34 (qd, 1H), 1.10 (s, 3H) Intermediate 18: 1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carboxamide

[0206] Oxalyl dichloride (2.20 mL, 25.6 mmol) was added to a suspension of intermediate 13 (2.45 g, 11.1 mmol) in dichloromethane (50 mL), followed by a few drops of N,N-DMF to initiate the reaction. After 40 minutes, the reaction (now a solution) was concentrated under reduced pressure. The residue was dissolved in dichloromethane (30 mL) and the solution was added to a chilled solution (ca.0°C) of 4.0M ammonia in methanol (40 mL, 160.0 mmol). The reaction was concentrated to dryness under reduced pressure; the crude material was slurried in EtOAc (120 mL) and the solution was washed with water (50 mL) and brine (30 mL). The organic phase was dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure, to afford the title compound as a colourless solid (2.35 g, 96% isolated yield; contains ca.5% of methyl ester): ¹H-NMR (500 MHz, DMSO-d6) δ 2.41 (s, 3H), 7.07 (s, 1H), 7.32 – 7.43 (m, 3H), 7.69 – 7.8 (m, 2H), 8.81 (s, 1H); LCMS m/z (ES⁺) 220.1 [M+H]⁺. Intermediate 19: N-(3-chloro-4-formylphenyl)-1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4- carboxamide

[0207] In a 500 mL round-bottomed flask was added Intermediate 18 (16.2 g, 73.90 mmol), 4- bromo-2-chlorobenzaldehyde (16.30 g, 74.27 mmol), cesium carbonate (48.2 g, 147.80 mmol), Xantphos Pd G3 (2.102 g, 2.22 mmol), (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) (0.428 g, 0.74 mmol) and a magnetic stirrer bar.1,4-dioxane (320 mL) was added and the suspension was degassed with nitrogen, then the flask was sealed and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into water (300 mL), stirred for 10 minutes followed by reducing organic solvents in vacuo. Then the mixture was diluted with another 200 mL of water, and the precipitated solid was isolated by filtration, washed carefully with water, then dried in a steam of air, giving 28.3 g (quantitative yield) of the crude product as a yellow solid of sufficient quality to be used in the next steps: ¹H NMR (400 MHz, DMSO) 2.48 (3H, s), 7.38 – 7.46 (2H, m), 7.77 (1H, dd), 7.81 – 7.86 (2H, m), 7.90 (1H, d), 8.10 (1H, d), 9.07 (1H, s), 10.23 (1H, s), 10.35 (1H, s). Intermediate 20: N-[3-chloro-4-(chloromethyl)phenyl]-1-(4-fluorophenyl)-3-methyl-1H- pyrazole-4-carboxamide.

[0208] Step 1: N-[3-chloro-4-(hydroxymethyl)phenyl]-1-(4-fluorophenyl)-3-methyl-1H- pyrazole-4-carboxamide

[0209] To N-(3-chloro-4-formylphenyl)-1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4- carboxamide, intermediate 17 (17 g, 47.52 mmol) in THF (400 mL), cooled to 20 °C, was added sodium tetrahydroborate (1.888 g, 49.89 mmol). The resulting reaction mixture was stirred for 120 min, then quenched by slow addition of sat. aq. ammonium chloride (100 mL). Water (100 mL) and EtOAc (250 mL) was added and the layers separated. The aqueous layer was extracted with EtOAc (100 mL), the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 17.5 g of a brownish solid. This material was triturated with DCM (100 mL), filtered and washed with DCM (25 mL) and dried in a stream of air, to give a grey-white solid (13 g, 36 mmol, 76 %) used in the next step without further purification: ¹H NMR (500 MHz, DMSO) 2.47 (3H, s), 4.53 (2H, d), 5.31 (1H, t), 7.36 – 7.45 (2H, m), 7.50 (1H, d), 7.60 (1H, dd), 7.78 – 7.86 (2H, m), 7.88 (1H, d), 9.02 (1H, s), 9.95 (1H, s). [0210] Step 2: N-[3-chloro-4-(chloromethyl)phenyl]-1-(4-fluorophenyl)-3-methyl-1H-pyrazole- 4-carboxamide (Intermediate 20) [0211] To N-(3-chloro-4-(hydroxymethyl)phenyl)-1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4- carboxamide (6 g, 16.68 mmol) in acetonitrile (400 mL), cooled to 0 °C, was added slowly sulfurous dichloride (2.433 mL, 33.35 mmol) followed by N,N-dimethylformamide (0.122 g, 1.67 mmol). Once the addition was complete the reaction was allowed to warm to room temperature and stirred at this temperature for 2 h. The heterogenous reaction mixture was partly concentrated under reduced pressure (volume of solvent reduced to 100 mL), then cooled in an ice bath for 1 h increasing precipitation of the product. The solid was collected by filtration, washed with cold acetonitrile (50 mL) and dried under reduced pressure to afford the title compound (4.8 g, 12.69 mmol, 76 %) as a beige solid pure enough for the next step: ¹H NMR (500 MHz, DMSO, 25°C) δ 2.47 (3H, s), 4.81 (2H, s), 7.37–7.44 (2H, m), 7.57 (1H, d), 7.71 (1H, dd), 7.8–7.87 (2H, m), 8.05 (1H, d), 9.26 (1H, s), 10.28 (1H, s). Intermediate 21: (2S)-2-[(3R)-piperidin-3-yl]propane-1,2-diol

[0212] Step 1: benzyl (3R)-3-[(2RS)-1,2-dihydroxypropan-2-yl]piperidine-1-carboxylate

[0213] Potassium osmate(VI) dihydrate 51.0-52.0% Os (3.55 g, 9.64 mmol) was added to NMO (9.03 g, 77.12 mmol) and benzyl (S)-3-(prop-1-en-2-yl)piperidine-1-carboxylate, obtained as described in step 5, intermediate 16 (5 g, 19.28 mmol) in t-BuOH (30 mL) and THF (90 mL). The resulting mixture was stirred at RT for 14 hours. LCMS was ok. The reaction mixture was then added to a solution of aq. sat Na2S2O3 (30 ml) and 100 ml water. The aqueous layer was extracted with EtOAc 2 x 100 ml, the combined organic layers were washed successively with aq. saturated NaHCO3 (1 x 50 ml), brine (30 ml), then dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using EtOAc in petroleum ether (0 to 15% gradient elution) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (5.40 g, 95 %): ¹H NMR (400 MHz, MeOD, 24 °C) δ 1.13 (s, 3H), 1.31–1.47 (m, 2H), 1.57–1.68 (m, 1H), 1.7–1.78 (m, 1H), 1.94 (dd, J = 9.2, 6.1 Hz, 1H), 2.68 (s, 2H), 3.36– 3.47 (m, 2H), 4.12 (d, J = 13.2 Hz, 1H), 4.28 (s, 1H), 5.11 (s, 2H), 7.25–7.39 (m, 5H). [0214] Step 2: benzyl (3R)-3-[(2S)-1,2-dihydroxypropan-2-yl]piperidine-1-carboxylate and benzyl (3R)-3-[(2R)-1,2-dihydroxypropan-2-yl]piperidine-1-carboxylate

[0215] The diastereomeric pair Benzyl (3R)-3-[(2RS)-1,2-dihydroxypropan-2-yl]piperidine-1- carboxylate (5.4 g) was resolved by preparative chiral-HPLC (Column: CHIRALPAK IG, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MEOH(0.1% 2M NH3-MEOH); Flow rate: 100 mL/min; Gradient: isocratic 45% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 3.18; RT2(min): 5.32; Sample Solvent: MeOH—Preparative; Injection Volume: 2.5 mL; Number Of Runs: 14). Appropriate fractions were concentrated to afford the benzyl (3R)-3-[(2S)-1,2-dihydroxypropan-2-yl]piperidine-1-carboxylate as a purple oil (2.0 g, 37 %, isomer 1): ¹H NMR (300 MHz, MeOD) δ 1.13 (s, 3H), 1.32–1.47 (m, 2H), 1.56–1.79 (m, 2H), 1.85–2 (m, 1H), 2.67 (s, 2H), 3.36–3.49 (m, 2H), 4.08–4.17 (m, 1H), 4.28 (d, J = 12.8 Hz, 1H), 5.1 (s,2H),7.24–7.45 (m, 5H) and benzyl (3R)-3-[(2R)-1,2-dihydroxypropan-2- yl]piperidine-1-carboxylate (1.69 g, 31 %, isomer 2): 1H NMR (300 MHz, MeOD) δ 1.07 (s, 3H), 1.21–1.51 (m, 2H), 1.6–1.77 (m, 2H), 1.8–1.9 (m, 1H), 2.69 (s, 2H), 3.34–3.48 (m, 2H), 4.12 (d, 1H), 4.37 (d, J = 12.3 Hz, 1H), 5.11 (d, J = 2.0 Hz, 2H), 7.25–7.43 (m, 5H). [0216] Step 3: (2S)-2-[(3R)-piperidin-3-yl]propane-1,2-diol (Intermediate 21) [0217] To palladium on carbon (10%) (0.091 g, 0.04 mmol) in MeOH (5.0 mL) was added a solution of benzyl (R)-3-((R*)-1,2-dihydroxypropan-2-yl)piperidine-1-carboxylate (0.5 g, 1.70 mmol) in MeOH (10 mL). The reaction mixture was sealed in an autoclave vessel and flushed and degassed with nitrogen followed by hydrogen (4 times). The reaction mixture was stirred at room temperature for 4 h under 2 bar of hydrogen, then filtered over a pad of celite under a flow of nitrogen to remove the residual palladium and concentrated to afford the title compound as a colorless oil (0.350 g, containing residual MeOH): 1H NMR (500 MHz, MeOD, 25°C) δ 1.09 (3H, s), 1.32 (1H, qd), 1.50 (1H, qt), 1.67–1.8 (2H, m), 1.9–1.98 (1H, m), 2.42–2.55 (2H, m), 3.00 (1H, dt), 3.12 (1H, dt), 3.38 (1H, d), 3.43 (1H, d). Intermediate 22: (2R)-2-[(3R)-piperidin-3-yl]propane-1,2-diol

[0218] Benzyl (3R)-3-[(2R)-1,2-dihydroxypropan-2-yl]piperidine-1-carboxylate from step 2, intermediate 20 (0.5 g, 1,70 mmol) was treated as described in step 3 for intermediate 20. This afforded the title compound as a colorless oil (0.320 g, containing residual MeOH): ¹H NMR (500 MHz, MeOD, 25°C) δ 1.06 (3H, s), 1.26 (1H, qd), 1.51 (1H, qt), 1.69–1.78 (2H, m), 1.79– 1.86 (1H, m), 2.47–2.57 (2H, m), 2.96–3.03 (1H, m), 3.17–3.24 (1H, m), 3.37 (1H, d), 3.43 (1H, d). Intermediate 23: (2S)-1-(dimethylamino)-2-[(3S)-piperidin-3-yl]propan-2-ol

[0219] Step 1: benzyl (3S)-3-[(2S)-2-hydroxy-1-oxopropan-2-yl]piperidine-1-carboxylate

[0220] To a solution of benzyl (S)-3-((S)-1,2-dihydroxypropan-2-yl)piperidine-1-carboxylate from intermediate 16, step 7 (1.357 g, 4.63 mmol) in DCM (38.8 ml) was added 0.5 M aqueous solution of KBr (0.925 ml, 0.46 mmol), 1 M aqueous solution of sodium bicarbonate (13.88 ml, 13.88 mmol), 0.1 M solution in DCM of TEMPO (0.925 ml, 0.09 mmol) at 0 °C, 1.8 M aqueous solution of sodium hypochlorite (3.34 ml, 6.01 mmol) over a period of 5 minutes. After 40 minutes, the reaction mixture was quenched by the addition of saturated Na2S2O3 solution (5 mL). After stirring for 1 minute, the reaction mixture was diluted with TBME (100 mL) and water (20 mL). After decantation, the organic phase was further washed with water (20 mL) and brine (20 mL). Once filtered through a phase separator and concentration, crude title compound was obtained (1.339 g, 99 %): ¹H NMR (500 MHz, DMSOd6, 25°C) δ 1.07 (3H, s), 1.14–1.24 (1H, m), 1.24–1.38 (1H, m), 1.61–1.72 (3H, m), 2.57–2.76 (2H, m), 3.95–4.05 (2H, m), 5.01– 5.11 (2H, m), 5.48 (1H, s), 7.28–7.41 (5H, m), 9.51 (1H, s). Purity >95%. [0221] Step 2: benzyl (3S)-3-[(2S)-1-(dimethylamino)-2-hydroxypropan-2-yl]piperidine-1- carboxylate

[0222] To a solution of benzyl (S)-3-((S)-2-hydroxy-1-oxopropan-2-yl)piperidine-1-carboxylate (100 mg, 0.34 mmol) in 1,2-dichloroethane (3.2 mL) was added acetic acid (30 µl, 0.51 mmol) and dimethylamine 2M in THF (0.21 mL, 0.43 mmol). After 20 minutes, sodium triacetoxyborohydride (145 mg, 0.69 mmol) was added. After 20 hours, the reaction mixture was diluted with DCM (20 mL) and water (5 mL). The pH of the aqueous phase was adjusted to 9-10 by adding aq.5% Na2CO3 solution. After separation, the aqueous phase was further extracted with DCM (5 mL). The combined organic phase was washed with brine (10 mL), filtered through a phase separator and evaporated to obtain 111 mg of the crude title compound (containing approximately 10% of the starting material): ¹H NMR (500 MHz, DMSO-d6, 25 °C) δ 0.98 (3H, s), 1.1–1.21 (1H, m), 1.22–1.34 (1H, m), 1.48–1.6 (1H, m), 1.61–1.76 (2H, m), 2.21 (6H, s), 2.55–2.69 (2H, m), 3.95–4.03 (1H, m), 4.11 (1H, s), 4.2–4.28 (1H, m), 5.06 (2H, s), 7.27–7.4 (5H, m). [0223] Step 3: (2S)-1-(dimethylamino)-2-[(3S)-piperidin-3-yl]propan-2-ol (Intermediate 23). [0224] To 10% palladium on carbon (4.88 mg, 4.59 µmol) placed in autoclave reactor and in MeOH (0.5 mL) was added a solution of benzyl (S)-3-((S)-1-(dimethylamino)-2-hydroxypropan- 2-yl)piperidine-1-carboxylate (105 mg, 0.33 mmol) in MeOH (2.7 mL) The mixture was sealed in the reactor, purged with N2 five times, with H2 five times and left at room temperature under 2 bars of hydrogen for 18 h. After the mixture was purged with N2, the suspension was filtered through a glass fiber filter. The obtained solid was washed with MeOH (3x1 mL) and the resulting filtrate concentrated to yield the crude title compound which was used without further purification in the next step (65.0 mg, quantitative yield): ¹H NMR (500 MHz, D2O, 25°C) δ 1.14 (3H, s), 1.21–1.33 (1H, m), 1.48–1.61 (1H, m), 1.69–1.78 (1H, m), 1.78–1.87 (2H, m), 2.29 (6H, s), 2.47 (2H, s), 2.51–2.66 (2H, m), 3.1–3.16 (1H, m), 3.25–3.31 (1H, m). Intermediate 24: (2S)-1-(methylamino)-2-[(3S)-piperidin-3-yl]propan-2-ol

[0225] To a solution of benzyl (S)-3-((S)-2-hydroxy-1-oxopropan-2-yl)piperidine-1- carboxylate, from step 1, Intermediate 23 (200 mg, 0.69 mmol) in 1,2-dichloroethane (6.3 mL) was added acetic acid (59 µl, 1.03 mmol) and methanamine 2M in THF (0.48 mL, 0.96 mmol). After 20 minutes, sodium triacetoxyborohydride (291 mg, 1.37 mmol) was added. After 19 hours, the reaction mixture was diluted with DCM (20 mL) and water (5 mL). The pH of the aqueous phase was adjusted to 9-10 by addition of 5% Na2CO3 solution. The aqueous phase was further extracted with DCM (10 mL). The combined organic phase was washed with brine (10 mL), filtered through a phase separator and evaporated to obtain crude benzyl (S)-3-((S)-2- hydroxy-1-(methylamino)propan-2-yl)piperidine-1-carboxylate (213 mg, Quantitative yield). An aliquot (70 mg, 0.23 mmol) of this material was hydrogenated similar as described for intermediate 23, step 3, providing the crude title compound which was used without further purification (41 mg, quantitative yield): ¹H NMR (500 MHz, D2O, 25°C) δ 1.14 (3H, d), 1.2– 1.33 (1H, m), 1.45–1.59 (1H, m), 1.65–1.76 (1H, m), 1.77–1.85 (2H, m), 2.36 (3H, s), 2.49–2.73 (4H, m), 3.04–3.11 (1H, m), 3.19–3.25 (1H, m). Intermediate 25: (5S)-3,5-dimethyl-5-[(3S)-piperidin-3-yl]-1,3-oxazolidin-2-one

[0226] To a solution of Intermediate 24 (110 mg, 0.36 mmol), in dry THF (1.2 mL) was added di(1H-imidazol-1-yl)methanone (64.0 mg, 0.39 mmol). [0227] After 2 hours, the reaction mixture was concentrated to obtain crude benzyl (3S)-3-[(5S)- 3,5-dimethyl-2-oxo-1,3-oxazolidin-5-yl]piperidine-1-carboxylate. This material (119 mg, 0.36 mmol) was further hydrogenated similar as described for intermediate 23, step 3, providing the crude title compound which was used without further purification (71 mg, quantitative yield): ¹H NMR (500 MHz, DMSO, 25°C) δ 1.02–1.14 (1H, m), 1.25 (3H, s), 1.27–1.36 (1H, m), 1.54– 1.63 (2H, m), 1.64–1.71 (1H, m), 2.16–2.26 (1H, m), 2.3–2.39 (1H, m), 2.72 (3H, s), 2.83–2.89 (1H, m), 2.89–2.97 (1H, m), 3.13 (1H, d), 3.34 (1H, s), 3.41 (1H, d). Intermediate 26: (2S)-1-amino-2-[(3S)-piperidin-3-yl]propan-2-ol

[0228] Step 1: benzyl (3S)-3-[(2S)-1-(benzylamino)-2-hydroxypropan-2-yl]piperidine-1- carboxylate

[0229] To a solution of benzyl (S)-3-((S)-2-hydroxy-1-oxopropan-2-yl)piperidine-1- carboxylate, intermediate 23, step 1 (200 mg, 0.69 mmol) in 1,2-dichloroethane (6701 µl) was added acetic acid (59 µl, 1.03 mmol) and benzylamine (105 µl, 0.96 mmol). After 20 minutes, sodium triacetoxyborohydride (291 mg, 1.37 mmol) was added. After 19 hours, the reaction mixture was diluted with DCM (20 mL) and water (5 mL). The pH of the aqueous phase was adjusted to 9-10 by addition of 5% Na2CO3 solution. The aqueous phase was further extracted with DCM (10 mL). The combined organic phase was washed with brine (10 mL), filtered through a phase separator and evaporated to obtain the title compound which was used without further purification (283 mg, quantitative yield): ¹H NMR (500 MHz, DMSOd6, 25°C) δ 0.98 (3H, s), 1.07–1.16 (1H, m), 1.22–1.34 (1H, m), 1.54–1.68 (3H, m), 1.96 (1H, s), 2.37 (1H, d), 2.43 (1H, d), 2.52–2.73 (2H, m), 3.65–3.74 (2H, m), 3.96–4.02 (1H, m), 4.2–4.27 (2H, m), 5.01– 5.11 (2H, m), 7.17–7.24 (1H, m), 7.26–7.38 (9H, m). Purity >95% [0230] Step 2: (2S)-1-amino-2-[(3S)-piperidin-3-yl]propan-2-ol (Intermediate 26) [0231] To 10% palladium on carbon (18.36 mg, 0.02 mmol) placed in a 10 mL vial was added MeOH (0.5 mL). To this mixture was added a solution of benzyl (S)-3-((S)-1-(benzylamino)-2- hydroxypropan-2-yl)piperidine-1-carboxylate (110 mg, 0.29 mmol) in MeOH (3 mL). The vial was placed in an autoclave and once sealed, it was purged with N2 five times, with H2 five times and left to react at room temperature under 4 bars of H2. After 72 hours and once the mixture was puregeyd with N2, the suspension was filtered through a glass fiber filter. The solid in the filter was washed with MeOH (3x1 mL) and the resulting filtrate evaporated to yield the title compound which was used in the next step without further purification (42.0 mg, 92 %): ¹H NMR (500 MHz, DMSOd6, 25°C) δ 0.89 (3H, s), 0.98–1.1 (1H, m), 1.23–1.37 (1H, m), 1.38– 1.48 (1H, m), 1.52–1.6 (1H, m), 1.61–1.67 (1H, m), 2.2–2.38 (4H, m), 2.43 (1H, d), 2.78–2.92 (1H, m), 3–3.06 (1H, m). Intermediate 27: (2S,3RS)-2-[(3S)-piperidin-3-yl]butane-2,3-diol

[0232] Step 1: bnzl (3S)-3-[(2S,3RS)-2,3-dihydroxybutan-2-yl]piperidine-1-carboxylate

[0233] Crude benzyl (S)-3-((S)-2-hydroxy-1-oxopropan-2-yl)piperidine-1-carboxylate, prepared as described for step 1, intermediate 23 (12.52 g, 42.98 mmol) was dissolved in THF (100 mL) and slowly added via dropping funnel to a chilled solution of 3.0 M methylmagnesium bromide in diethyl ether (43.0 mL, 128.94 mmol) in THF (400 mL) on a salt/ice bath. The colourless solution was stirred for two hours on the salt/ice bath, then left to stir overnight. The reaction mixture was then quenched by the careful addition of 1.0 M HCl_(aq) (200 mL). The bulk of the THF was removed under reduced pressure; and the residue was diluted with water (500 mL) and extracted with dichloromethane (2 x 250 mL). The combined organic layers were passed through a phase separator before concentrating to dryness. The residue was loaded as a solution in DCM (40 mL) onto a Biotage® Sfär Silica HC D 100 g/20 µm column, preconditioned with heptane, and purified by gradient elution (100% heptane (1CV), 0 to 25% EtOAc in heptane (1CV), 25 to 100% EtOAc in heptane (20CV)) via automated flash column chromatography (Biotage Selekt). Pure fractions were combined and concentrated to dryness under reduced pressure, to afford the title compound as a colourless gum (4.65 g, 35.2 %): ¹H NMR (500 MHz, DMSOd6, 25°C) δ 0.86–0.97 (3H, m), 0.97–1.07 (3H, m), 1.18–1.33 (2H, m), 1.44–1.69 (2H, 97 m), 1.7–1.84 (1H, m), 2.51–2.75 (2H, m), 3.47–3.57 (1H, m), 3.81–3.95 (1H, m), 3.95–4.01 (1H, m), 4.15–4.37 (2H, m), 5.06 (2H, s), 7.27–7.4 (5H, m). Mixture of two diastereoisomers. [0234] Step 2: (2S,3RS)-2-[(3S)-piperidin-3-yl]butane-2,3-diol (Intermediate 27) [0235] To 10% palladium on carbon (36.4 mg, 0.03 mmol) placed in a vial inside an autoclave reactor and in MeOH (1 mL) was added a solution of benzyl (3S)-3-[(2S,3RS)-2,3- dihydroxybutan-2-yl]piperidine-1-carboxylate (210 mg, 0.68 mmol) in MeOH (6 mL). The mixture was sealed in the reactor, purged with N₂ five times, with H₂ five times and left to react at room temperature under 2 bars of H2. After 16 hours and once the mixture purged with N2, the suspension was filtered through a glass fiber filter. The solid in the filter was washed with MeOH (3x2 mL) and the resulting filtrate evaporated to yield the title compound which was used without further purification (123 mg, quantitative yield %): ¹H NMR (500 MHz, D2O, 25°C) δ 1.15–1.34 (6H, m), 1.35–1.49 (1H, m), 1.64 (1H, dtt), 1.75–2.06 (2H, m), 2.56–2.76 (2H, m), 2.98–3.14 (1H, m), 3.17–3.23 (1H, m), 3.31–3.4 (1H, m), 3.87–3.99 (1H, m). Intermediate 28: N-[4-(chloromethyl)-3-(difluoromethoxy)phenyl]-1-(4-fluorophenyl)-3- methyl-1H-pyrazole-4-carboxamide

[0236] Step 1: 4-bromo-2-(difluoromethoxy)benzaldehyde

[0237] 4-Bromo-2-hydroxybenzaldehyde (5 g, 24.87 mmol) and potassium hydroxide (9.77 g, 174.11 mmol) were combined in 1:1 acetonitrile/water (50 mL) and the mixture was chilled on an ice-water bath. Diethyl (bromodifluoromethyl)phosphonate (7.08 mL, 39.80 mmol) was added dropwise over 10 minutes and the mixture was stirred for a further 10 minutes before allowing to warm up to room temperature and stirring for 1 hour. The mixture was diluted with water and extracted with EtOAc (3 x 60 mL). The combined extractions were washed with brine, dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. Purification by flash column chromatography over silica (gradient elution, 5 to 12.5% EtOAc in heptane) gave 4-bromo-2-(difluoromethoxy)benzaldehyde as a yellow solid (3.7 g, 59% isolated yield): ¹H-NMR (500 MHz, DMSO-d₆) δ 7.44 (t, 1H), 7.63 – 7.70 (m, 2H), 7.77 (d, 1H), 10.22 (s, 1H). [0238] Step 2: N-[3-(difluoromethoxy)-4-formylphenyl]-1-(4-fluorophenyl)-3-methyl-1H- pyrazole-4-carboxamide

[0239] Intermediate 18 (2.40 g, 10.40 mmol), 4-bromo-2-(difluoromethoxy)benzaldehyde (2.61 g, 10.40 mmol), cesium carbonate (6.78 g, 20.80 mmol), Xantphos Pd G3 (395 mg, 0.42 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (60 mg, 0.10 mmol) in 1,4-dioxane (60mL) was degassed with nitrogen then the mixture was heated with stirring at 80°C for 90 minutes. The reaction mixture was then partitioned between EtOAc (120 mL) and water (50 mL). The aqueous phase was extracted with EtOAc (2 x 20 mL) and the combined organic phases were washed with water (50 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated. Slurrying the resulting residue in dichloromethane (20 mL) afforded a solid. Isolation by filtration, washing with a small amount of DCM (10-15 mL), and drying in air, gave the title compound as a yellow solid (3.20 g, 79% isolated yield): ¹H-NMR (500 MHz, DMSO- d6) δ 2.49 (s, 3H), 7.34 (t, 1H), 7.39 – 7.44 (m, 2H), 7.70 (dd, 1H), 7.82 – 7.85 (m, 2H), 7.87 (d, 1H), 7.93 (s, 1H), 9.09 (s, 1H), 10.17 (s, 1H), 10.40 (s, 1H); LCMS m/z (ES⁺) 390.1 [M+H]⁺. [0240] Step 3: N-[3-(difluoromethoxy)-4-(hydroxymethyl)phenyl]-1-(4-fluorophenyl)-3-methyl- 1H-pyrazole-4-carboxamide

[0241] Sodium tetrahydroborate (87 mg, 2.29 mmol) was added a chilled solution (ca.0°C) of N-[3-(difluoromethoxy)-4-formylphenyl]-1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4- carboxamide (850 mg, 2.18 mmol) in THF (20 mL). The resulting reaction mixture was stirred for 4 h, then was quenched by slow addition of acetone (0.5 mL) and sat. NH4Cl(aq) (10 mL). EtOAc (15 mL) was added and the layers separated. The aqueous layer was extracted with EtOAc (15 mL), the combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated. Purification by flash column chromatography on silica gel (gradient elution 0 to 50% EtOAc in heptane) to give N-[3-(difluoromethoxy)-4-(hydroxymethyl)phenyl]- 1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carboxamide as a pale orange solid (700 mg, 82% isolated yield): ¹H-NMR (500 MHz, DMSO-d6) δ 2.47 (s, 3H), 4.50 (d, 2H), 5.16 (t, 1H), 7.12 (t, 1H), 7.37 – 7.44 (m, 2H), 7.46 (d, 1H), 7.55 (dd, 1H), 7.67 (d, 1H), 7.79 – 7.88 (m, 2H), 9.02 (s, 1H), 9.96 (s, 1H); LCMS m/z (ES⁺) 392.3 [M+H]⁺. [0242] Step 4: N-[4-(chloromethyl)-3-(difluoromethoxy)phenyl]-1-(4-fluorophenyl)-3-methyl- 1H-pyrazole-4-carboxamide (Intermediate 28) [0243] Sulfurous dichloride (270 µL, 3.71 mmol), followed by N,N-dimethylformamide (15 µL, 0.19 mmol) was added to a chilled mixture (ca.0°C) of N-[3-(difluoromethoxy)-4- (hydroxymethyl)phenyl]-1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carboxamide (725 mg, 1.85 mmol) in acetonitrile (30 mL). Once the addition was complete, the reaction was allowed to warm to room temperature and stirred at this temperature for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with sat. NaHCO3(aq) (2 x 25 mL) and brine (30 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (gradient elution, 0 to 40% EtOAc in heptane) gave N-[4-(chloromethyl)-3-(difluoromethoxy)phenyl]-1-(4-fluorophenyl)-3-methyl- 1H-pyrazole-4-carboxamide as a colourless solid (640 mg, 84% isolated yield): ¹H-NMR (500 MHz, DMSO-d6) δ 2.47 (s, 3H), 4.73 (s, 2H), 7.24 (t, 1H), 7.39 – 7.44 (m, 2H), 7.52 (d, 1H), 7.56 (dd, 1H), 7.76 – 7.78 (m, 1H), 7.81 – 7.86 (m, 2H), 9.03 (s, 1H), 10.08 (s, 1H); SFC-MS m/z (ES⁺) 410.2 [M(³⁵Cl)+H]⁺, 412.2 [M(³⁷Cl)+H]⁺. Intermediate 29: (1RS)-1-[(3S)-piperidin-3-yl]ethane-1,2-diol

[0244] Step 1: benzyl (3R)-3-ethenylpiperidine-1-carboxylate

[0245] To a suspension of methyltriphenylphosphonium bromide (860 mg, 2.41 mmol) in dry THF (15.86 mL) and at 0 °C was added slowly 1.6M in hexanes of BuLi (1396 µl, 2.23 mmol). After 10 minutes, the yellow cloudy solution of the ylide was slowly added over a solution of benzyl (3S)-3-formylpiperidine-1-carboxylate (425 mg, 1.72 mmol, CAS RN 405063-39-0) in dry THF (4.2 mL) at 0 °C. After 20 minutes at 0 °C, the reaction mixture was quenched by the addition of aq. saturated NH4Cl solution (20 mL), water (10 mL) and TBME (70 mL). The organic phase was washed with brine (20 mL), dried (MgSO4), filtered and concentrated. Flash chromatography of the residue (Biotage; Column: Silica gel 10 g; Gradient: 10 to 30% EtOAc in Heptane) followed by concentration of the appropriate fractions gave the title compound (0.211 g, 50.0 %): 1H NMR (500 MHz, CDCl3) δ 1.2 – 1.35 (m, 1H), 1.44 – 1.56 (m, 1H), 1.63 – 1.77 (m, 1H), 1.82 – 1.91 (m, 1H), 2.09 – 2.24 (m, 1H), 2.53 – 2.75 (m, 1H), 2.76 – 2.85 (m, 1H), 3.98 – 4.21 (m, 2H), 5.02 (d, 1H), 5.07 (d, 1H), 5.1 – 5.2 (m, 2H), 5.65 – 5.76 (m, 1H), 7.27 – 7.39 (m, 5H). [0246] Step 2: benzyl (3S)-3-[(1RS)-1,2-dihydroxyethyl]piperidine-1-carboxylate

[0247] To a solution of benzyl (R)-3-vinylpiperidine-1-carboxylate (196 mg, 0.80 mmol) in THF (8.33 mL) and water (2.78 mL) was added at room temperature 4-methylmorpholine 4- oxide (140 mg, 1.20 mmol) and 4% wt. solution in water of osmium(VIII) oxide (313 µl, 0.04 mmol). After 24 hours, the reaction mixture was diluted with EtOAc (60 mL) and washed successively with aq. saturated NaHCO3 (20 mL), brine (20 mL), then dried (MgSO4), filtered and concentrated. Flash chromatography of the residue (Biotage, Column: 5 g silica gel, Gradient: 60 to 100% EtOAc in Heptane) followed by concentration of the appropriate fractions gave the title compound (0.197 g, 88 %): ¹H NMR (500 MHz, DMSOd6) δ 1.18 – 1.36 (m, 2H), 1.42 – 1.57 (m, 1H), 1.59 – 1.78 (m, 2H), 2.57 – 2.83 (m, 2H), 3.16 – 3.31 (m, 2H), 3.33 – 3.45 201260-WO-PCT (m, 1H), 3.84 – 4.21 (m, 2H), 4.43 – 4.49 (m, 1H), 4.49 – 4.54 (m, 1H), 5.01 – 5.11 (m, 2H), 7.27 – 7.4 (m, 5H). Mixture of two diastereoisomers. [0248] Step 3: (1RS)-1-[(3S)-piperidin-3-yl]ethane-1,2-diol (Intermediate 29) [0249] To palladium on carbon (37.0 mg, 0.02 mmol) placed in autoclave reactor and in MeOH (1 mL) was added a solution of benzyl (R)-3-((RS)-1,2-dihydroxyethyl)piperidine-1-carboxylate (194 mg, 0.69 mmol) in MeOH (11 mL). The mixture was sealed in the reactor, purged with N2 five times, with H2 five times and left over the night stirring at room temperature under 2 bars of H2. After 20 hours and once the mixture was purged with N2, the suspension was filtered using a glass fiber filter. The solid in the filter was washed with MeOH (3x2 mL) and the resulting filtrate was concentrated to provide the title compound (0.102 g, quantitative yield): ¹H NMR (500 MHz, DMSO) δ 1.1 – 1.22 (m, 1H), 1.25 – 1.4 (m, 1H), 1.45 – 1.78 (m, 3H), 2.25 – 2.45 (m, 2H), 2.78 – 3.08 (m, 2H), 3.15 – 3.41 (m, 4H), 4.38 (s, 2H). Intermediate 30: 2-[(3RS)-piperidin-3-yl]propane-1,3-diol

[0250] Step 1: benzyl (3RS)-3-(1,3-dihydroxypropan-2-yl)piperidine-1-carbo 51] To a stirred suspension of sodium tetrahydroborate 49 mL) and at 0 °C was added portion w Oise 2 N-(1- &((benzy Oxylate

[02 O ( lH2 o O83 xH mg, 7.47 mmol) in dry THF (5. 1y)carbonyl)piperidin-3-yl)malonic acid (500 mg, 1.56 mmol, CAS RN 2384904-41-8). After 5 minutes, a solution of diiodine (790 mg, 3.11 mmol) in dry THF (3.66 mL) was added dropwise in a ~1 hour period. The mixture was left to slowly reach room temperature then refluxed for 19 hours. The mixture was then allowed to reach rt, then carefully quenched by the addition of MeOH (2 mL) and concentrated. The residue was added aq.20% KOH (4 mL), stirred at room temperature for 40 min, then diluted with water (10 mL), extracted with DCM (5x20 mL). The combined organic layers were washed with brine (10 mL), filtered using a phase separator and concentrated. The residue was purified by flash chromatography (Biotage, silica gel 10 g, 60 to 100% EtOAc in Heptane followed by 0 to 10% MeOH in EtOAc) to yield the title compound (0.149 g, 32.6 %): ¹H NMR (500 MHz, DMSOd6) δ 1.19 – 1.39 (m, 3H), 1.48 – 1.67 (m, 2H), 1.69 – 1.8 (m, 1H), 2.56 – 2.88 (m, 2H), 3.36 – 3.5 (m, 4H), 3.86 – 4.02 (m, 2H), 4.36 (dt, 2H), 5.06 (s, 2H), 7.27 – 7.4 (m, 5H). 102 201260-WO-PCT [0252] Step 2: 2-[(3RS)-piperidin-3-yl]propane-1,3-diol (Intermediate 30) [0253] Benzyl (3RS)-3-(1,3-dihydroxypropan-2-yl)piperidine-1-carboxylate (140 mg, 0.48 mmol) was hydrogenated similar as described for intermediate 29, step 3 to yield the title compound which was used without further purification (0.075 g, 99 %): 1H NMR (500 MHz, DMSOd6+D2O) δ 1.04 – 1.16 (m, 1H), 1.2 – 1.38 (m, 2H), 1.46 – 1.57 (m, 2H), 1.65 – 1.72 (m, 1H), 2.26 (dd, 1H), 2.31 – 2.4 (m, 1H), 2.75 – 2.82 (m, 1H), 2.82 – 2.91 (m, 1H), 3.33 – 3.47 (m, 4H). Intermediate 31: (2RS)-1-methoxy-2-[(3S)-piperidin-3-yl]propan-2-ol

[0254] Step 1: benzyl (3S)-3-[(2RS)-2-methyloxiran-2-yl]piperidine-1-carboxylate

[0255] Sodium bicarbonate (5.60 g, 66.63 mmol) in water (4 ml) was added to benzyl (3R)-3- (prop-1-en-2-yl)piperidine-1-carboxylate, step 5, intermediate 16 (864 mg, 3.33 mmol), and mCPBA (1.15 g, 6.66 mmol) in DCM (8mL) at rt. The resulting mixture was stirred at rt for 15 hours. The reaction mixture was then diluted with DCM (50 mL), and washed sequentially with water (2 x 50 mL) and saturated brine (2 x 50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica chromatography, elution gradient 10 to 20% EtOAc in petroleum ether. Pure fractions were concentrated to dryness to afford the title compound as a yellow gum (545 mg, 59 %). [0256] Step 2: benzyl (3S)-3-[(2RS)-2-hydroxy-1-methoxypropan-2-yl]piperidine-1-carboxylate

[0257] Sodium methoxide (801 mg, 4.45 mmol) was added to benzyl (3S)-3-[(2RS)-2- methyloxiran-2-yl]piperidine-1-carboxylate (245 mg, 0.89 mmol) in MeOH (5 mL) at rt. The resulting mixture was stirred at 40 °C for 15 hours. Then diluted with EtOAc (20 mL) washed with water (2x20 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford the title compound which was used in the next step without further purification (244 mg). [0258] Step 3: (2RS)-1-methoxy-2-[(3S)-piperidin-3-yl]propan-2-ol 103 201260-WO-PCT [0259] Benzyl (3S)-3-[(2RS)-2-hydroxy-1-methoxypropan-2-yl]piperidine-1-carboxylate (300mg, 0.98 mmol) was hydrogenated similar as described for intermediate 29, step 3 to yield the title compound which was used without further purification (200 mg). Intermediate 32: (2S)-2-hydroxy-2-[(3S)-piperidin-3-yl]propanoic acid

[0260] Step 1: (2S)-2-{(3S)-1-[(benzyloxy)carbonyl]piperidin-3-yl}-2-hydroxypropanoic acid

[0261] To a solution of benzyl (3S)-3-[(2S)-1,2-dihydroxypropan-2-yl]piperidine-1-carboxylate, major isomer from step 7, Intermediate 16 (300 mg, 1.02 mmol) in DCM (20.14 mL) was added sodium bicarbonate (258 mg, 3.07 mmol). Once cooled at 0 °C, 3-oxo-1l5- benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate (520 mg, 1.23 mmol) was added. The reaction was slowly left to reach room temperature over the night. After 20 hours and once cooled again at 0 °C, additional DMP (156 mg.0.3 eq.) was added. After additional 4 hours, the reaction mixture was quenched with saturated Na₂S₂O₃ (10 mL) and saturated NaHCO₃ (10 mL). After stirring for 5 minutes, the mixture was further diluted with water (10 mL) and TBME (50 mL). After separation, the organic layer was washed with saturated NaHCO3 (10 mL), water (10 mL) and brine (10 mL). The organic layer was filtered through a phase separator and concentrated providing 291 mg of crude aldehyde, as judged by NMR. To this crude was added tert-butanol (8.3 mL), water (1.7 mL), sodium dihydrogen phosphate dihydrate (319 mg, 2.05 mmol) and 2- methylbut-2-ene (433 µl, 4.09 mmol). Once cooled to 0 °C, it was added sodium chlorite (231 mg, 2.05 mmol). The mixture was left to reach room temperature and then stirred for 40 minutes. The reaction mixture was diluted with EtOAc (40 mL) and washed with water/brine 1:1 (10 mL) and brine (10 mL). The organic layer was filtered through a phase separator and concentrated. This residue was purified by flash chromatography (Biotage, 10 g silica gel, 70% 1%AcOH/EtOAc in heptane (1CV) to 100% (5CV) to yield the title compound (0.148 g, 47 %): ¹H NMR (500 MHz, DMSOd6) 1.19 – 1.39 (5H, m), 1.56 – 1.73 (2H, m), 1.79 – 1.85 (1H, m), 2.53 – 2.8 (2H, m), 3.97 (2H, t), 4.95 (1H, s), 5.06 (2H, s), 7.25 – 7.43 (5H, m), 12.21 (1H, s). [0262] Step 2: (2S)-2-hydroxy-2-[(3S)-piperidin-3-yl]propanoic acid (Intermediate 32) [0263] (2S)-2-{(3S)-1-[(benzyloxy)carbonyl]piperidin-3-yl}-2-hydroxypropanoic acid (139 mg, 0.45 mmol) was hydrogenated similar as described for intermediate 29, step 3 to afford the title 104 201260-WO-PCT compound which was used without further purification in the next step (75 mg, 96%): ¹H NMR (500 MHz, D2O) 1.34 (3H, s), 1.35 – 1.42 (1H, m), 1.65 – 1.78 (1H, m), 1.99 – 2.12 (3H, m), 2.83 – 2.93 (2H, m), 3.15 – 3.21 (1H, m), 3.34 – 3.4 (1H, m). Intermediate 33: 1-[(3RS)-piperidin-3-yl]cyclobutan-1-ol

[0264] Step 1: (3RS)-1-benzyl-3-(1-hydroxycyclobutyl)piperidin-2-one

[0265] To a stirred solution of 1-benzylpiperidin-2-one (1 g, 5.28 mmol) in dry THF (20 mL) at -76 °C was added 2 M Lithium diisopropylamide in THF (2.91 ml, 5.81 mmol) over 1 min and the mixture was stirred at -76 degrees for 1 hour. Then a solution of cyclobutanone (0.370 g, 5.28 mmol) and Borontrifluoride etherate (0.750 g, 5.28 mmol) in dry THF (2 mL) was added over 2 minutes. The resulting solution was stirred at -76 °C another 3 hours, then allowed to reach rt. The reaction mixture was quenched by the addition of saturated NH₄Cl (20 mL), then partitioned between EtOAc (20 mL) and water (20 mL). The water layer was extracted once with EtOAc (10 mL) and the combined organic layers were washed with brine, dried (sodium sulfate) and concentrated. Column chromatography of the residue (dissolved in DCM) using EtOAc in heptane (1:2) followed by concentration of appropriate fractions gave the title compound as a slight brownish syrup (0.47 g, 34 %): ¹H NMR (500 MHz, DMSO) 1.53 (1H, dtt), 1.58 – 1.71 (2H, m), 1.71 – 1.81 (1H, m), 1.81 – 1.95 (3H, m), 1.96 – 2.05 (1H, m), 2.11 (1H, dddd), 2.43 – 2.49 (1H, m), 2.52 – 2.62 (1H, m), 3.09 – 3.22 (2H, m), 4.43 (1H, d), 4.58 (1H, d), 5.16 (1H, s), 7.24 (3H, td), 7.28 – 7.35 (2H, m). [0266] Step 2: 1-[(3RS)-1-benzylpiperidin-3-yl]cyclobutan-1-ol

[0267] In a 25 mL vial was dissolved (3RS)-1-benzyl-3-(1-hydroxycyclobutyl)piperidin-2-one (0.45 g, 1.74 mmol) in THF (10 mL) and to the stirred solution was added dropwise Borane dimethyl sulfide complex (0.658 ml, 6.94 mmol) over 1-2 minutes. After complete addition, the bubbling settled and the vial was sealed and heated at 75^oC for 2 hours. Then, the crude reaction mixture was carefully added to stirred MeOH (40 mL) and the resulting solution was stirred for another 2 hours, after which the mixture was concentrated. The residual oil was applied onto an 105 201260-WO-PCT acidified SCX-2 cartridge (10 g), and the cartridge was washed subsequently with water (50 mL), MeOH (50 mL) and then washed out from the cartridge with methanolic 2 M Ammonia (50 mL). Concentration of the ammonia solution gave the title compound as a colorless syrup, which was used directly in the next step (0.35 g, 82 %): ¹H NMR (500 MHz, DMSO) 1.04 – 1.16 (1H, m), 1.42 (2H, tdd), 1.56 (1H, tt), 1.65 (3H, ddt), 1.74 – 1.87 (4H, m), 1.92 – 1.99 (1H, m), 2.03 (1H, ddt), 2.72 (1H, d), 2.78 – 2.85 (1H, m), 3.38 – 3.51 (2H, m), 4.71 (1H, s), 7.2 – 7.27 (1H, m), 7.27 – 7.36 (4H, m). [0268] Step 3: 1-[(3RS)-piperidin-3-yl]cyclobutan-1-ol (Intermediate 27) [0269] In a 30 mL vial was added a solution of 1-[(3RS)-1-benzylpiperidin-3-yl]cyclobutan-1-ol (0.35 g, 1.43 mmol) in MeOH (15 mL) and Pd(OH)220% on carbon (0.05 g, 0.07 mmol) and the vial was fitted into a steel autoclave. The mixture was stirred under 4 atm of hydrogen overnight. Then, the crude mixture was filtered through celite, and the clear colorless filtrate was concentrated to give the title compound as a clear oil (0.22g, 99 %): ¹H NMR (500 MHz, MeOD) 1.32 (1H, qd), 1.44 – 1.67 (3H, m), 1.77 (1H, dp), 1.85 (2H, dtd), 1.9 – 2.07 (2H, m), 2.18 (2H, dddd), 2.4 – 2.54 (2H, m), 2.95 – 3.03 (1H, m), 3.07 (1H, dt). Intermediate 34: (2RS)-2-fluoro-2-[(3S)-piperidin-3-yl]propan-1-ol

[0270] Step 1: benzyl (3S)-3-{(2R)-2-hydroxy-1-[(methanesulfonyl)oxy]propan-2-yl}piperidine- 1-carboxylate

[0271] Methanesulfonyl chloride (120 µl, 1.53 mmol) was added to a solution of benzyl (3S)-3- [(2R)-1,2-dihydroxypropan-2-yl]piperidine-1-carboxylate, prepared as described for intermediate 16, step 7 (300 mg, 1.02 mmol) in DIPEA (536 µl, 3.07 mmol) and DCM (3 mL) at 0°C under nitrogen. The resulting mixture was stirred at 0 °C for 3 hours. The reaction mixture was then quenched with water (5 mL), extracted with EtOAc (2 x 50 mL), the organic layer was dried over Na2SO4, filtered and evaporated to afford yellow oil. The crude product was purified by flash silica chromatography, elution gradient 50 to 60% EtOAc in petroleum ether. Appropriate fractions were concentrated to dryness to afford the title compound as a colourless oil which was used in the next step (200 mg, 53 %). 106 201260-WO-PCT [0272] Step 2: benzyl (3S)-3-[(2R)-2-methyloxiran-2-yl]piperidine-1-carboxylate

[0273] Sodium hydride (25.8 mg, 1.08 mmol) was added to benzyl (3S)-3-{(2R)-2-hydroxy-1- [(methanesulfonyl)oxy]propan-2-yl}piperidine-1-carboxylate (200 mg, 0.54 mmol) in THF (4 mL) at 0°C under nitrogen. The resulting mixture was stirred at 0 °C for 2 hours. The reaction mixture was then quenched with water (50 mL), extracted with EtOAc (2 x 50 mL), the organic layer was dried over Na2SO4, filtered and evaporated to afford the crude title compound as a yellow oil which was used in the next step without further purification (170 mg). [0274] Step 3: benzyl (3S)-3-[(2RS)-2-fluoro-1-hydroxypropan-2-yl]piperidine-1-carboxylate

[0275] Triethylamine trihydrofluoride (2mL, 0.62 mmol) was added to benzyl (3S)-3-[(2R)-2- methyloxiran-2-yl]piperidine-1-carboxylate (170 mg, 0.62 mmol). The resulting mixture was stirred at 100 °C for 4 hours under nitrogen. The reaction mixture was quenched with saturated NaHCO3 (5 mL), extracted with EtOAc (2 x 25 mL), the organic layer was dried over Na2SO4, filtered and evaporated to afford yellow oil. [0276] The residue was purified by preparative TLC (EtOAc: petroleum ether = 1: 1), to afford the title compound as a colourless oil (0.100 g, 55 %): 1H NMR (300 MHz, DMSO, 26°C) δ 1.08–1.2 (3H, m), 1.21–1.4 (2H, m), 1.6–1.91 (3H, m), 2.68 (2H, s), 3.37 (1H, d), 3.45 (1H, dd), 3.86–4.2 (2H, m), 4.95 (1H, t), 5.06 (2H, s), 7.33 (5H, qd). [0277] Step 4: (2RS)-2-fluoro-2-[(3S)-piperidin-3-yl]propan-1-ol [0278] benzyl (3S)-3-[(2RS)-2-fluoro-1-hydroxypropan-2-yl]piperidine-1-carboxylate was hydrogenated similar as described for Intermediate 29, step 3 to yield the title compound which was used without further purification (40 mg). Intermediate 35: (2R)-1-fluoro-2-[(3S)-piperidin-3-yl]propan-2-ol

[0279] Step 1: benzyl (3S)-3-[(2R)-1-fluoro-2-hydroxypropan-2-yl]piperidine-1-carboxylate 107

[0280] Potassium fluoride hydrate (820 mg, 8.72 mmol) was added to benzyl (3S)-3-[(2R)-2- methyloxiran-2-yl]piperidine-1-carboxylate, prepared as described in step 2, Intermediate 34 (120 mg, 0.44 mmol) in DMSO (4 mL) at rt. The resulting mixture was stirred at 100 °C for 10 hours. The reaction mixture was then diluted with EtOAc (25 mL), and washed sequentially with water (3 x 20 mL) and brine (2 x 20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (EtOAc: petroleum ether = 2: 1), to afford the title compound as a colourless oil (0.060 g, 46.6 %): ¹H NMR (300 MHz, DMSO, 22°C) δ 1.20 (3H, s), 1.22–1.32 (2H, m), 1.38 (2H, ddt), 1.66 (1H, dt), 1.72–1.83 (1H, m), 2.55– 2.8 (3H, m), 3.89–4.04 (2H, m), 5.07 (2H, s), 7.35 (5H, qd). [0281] Step 2: (2R)-1-fluoro-2-[(3S)-piperidin-3-yl]propan-2-ol (Intermediate 29) [0282] benzyl (3S)-3-[(2R)-1-fluoro-2-hydroxypropan-2-yl]piperidine-1-carboxylate was hydrogenated similar as described for intermediate 29, step 3 to yield the title compound which was used without further purification (15 mg). Intermediate 36: (2RS)-1-(methanesulfonyl)-2-[(3S)-piperidin-3-yl]propan-2-ol

[0283] Step 1: benzyl (3S)-3-[(2RS)-2-hydroxy-1-(methylsulfanyl)propan-2-yl]piperidine-1- carboxylate

[0284] Sodium methanethiolate (153 mg, 2.18 mmol) was added to benzyl benzyl (3S)-3- [(2RS)-2-methyloxiran-2-yl]piperidine-1-carboxylate, prepared as described in intermediate 30, step 1 (300 mg, 1.09 mmol) in t-BuOH (1 mL) at rt. The resulting mixture was stirred at 50 °C for 2 hours, then the reaction mixture was diluted with EtOAc (20 mL), washed with water (2 x 15 mL) and saturated brine (2 x 15 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude title compound which was used in the next without further purification (284 mg). [0285] Step 2: benzyl (3S)-3-[(2RS)-2-hydroxy-1-(methanesulfonyl)p carboxylate

[0286] mCPBA (320 mg, 1.85 mmol) was added to (3S)-3-[(2RS)-2-hydroxy-1- (methylsulfanyl)propan-2-yl]piperidine-1-carboxylate (200 mg, 0.62 mmol) in DCM (5 mL) at rt. The resulting mixture was stirred at rt for 3 hours. The reaction mixture was diluted with DCM (20 mL), and washed sequentially with water (2 x 20 mL) and brine (2 x 20 mL). The organic layer was dried (Na₂SO₄), filtered and concentrated to afford the title compound which was used without further purification in the next step (200 mg). [0287] Step 3: (2RS)-1-(methanesulfonyl)-2-[(3S)-piperidin-3-yl]propan-2-ol (Intermediate 30) [0288] benzyl (3S)-3-[(2RS)-2-hydroxy-1-(methanesulfonyl)propan-2-yl]piperidine-1- carboxylate (200 mg, 0.56 mmol) was hydrogenated similar as described for Intermediate 29, step 3 to yield the title compound which was used without further purification (114 mg). Intermediate 37: 3-[(3S)-piperidin-3-yl]-1,3-oxazolidin-2-one

[0289] Prepared starting from CAS RN 625471-18-3 followed by reaction with oxirane, then the obtained amino alcohol was treated with carbonyl diimidazole and finally N-Boc deprotection under acidic conditions. Intermediate 38: 2-[(3S)-piperidin-3-yl]-1λ⁶,2-thiazolidine-1,1-dione

[0290] Prepared starting from CAS RN 625471-18-3 followed by reaction with 3- chloropropane-1-sulfonyl chloride followed by ring closure under basic conditions and finally N-Boc-deprotection under acidic conditions. Intermediate 39: rac-(3R,4R)-3-(2-hydroxypropan-2-yl)piperidin-4-ol

[0291] Step 1: methyl rac-(3R,4R)-1-benzyl-4-hydroxypiperidine-3-carboxylate

[0292] Sodium cyanoborohydride (1.271 g, 20.22 mmol) was added to methyl (3RS)-1-benzyl- 4-oxopiperidine-3-carboxylate (5 g, 20.22 mmol) and AcOH (5mL) in MeOH (50 mL) under nitrogen. The resulting mixture was stirred at rt for 14 hours. The reaction mixture was diluted with EtOAc (100 mL), and washed with water (3 x 100 mL), then dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using methanol in DCM (0-2 %, stepwise gradient elution) followed by concentration of the appropriate fractions gave title compound as a yellow oil (2.50 g, 50 %, 85 % purity): LCMS m/z (ES⁺) 250 [M+H]⁺. [0293] Step 2: methyl rac-(3R,4R)-1-benzyl-4-{[tert-butyl(dimethyl)silyl]oxy}piperidine-3- carboxylate

[0294] t-Butyldimethylsilyl chloride (266 mg, 1.76 mmol) was added to 1H-imidazole (109 mg, 1.60 mmol) DMAP (19.60 mg, 0.16 mmol) and methyl rac-(3R,4R)-1-benzyl-4- hydroxypiperidine-3-carboxylate (400 mg, 1.60 mmol) in DCM (5 mL) at 0°C under nitrogen. The resulting mixture was stirred at rt for 4 hours. The reaction mixture was then diluted with DCM (10 mL), washed sequentially with 1N HCl (1 x 10 mL), aq. saturated NaHCO3 (1 x 10 mL), brine (1 x 10 mL), dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using methanol in DCM (0-1 %, stepwise gradient elution) followed by concentration of the appropriate fractions gave the title compound as a colourless oil (0.150 g, 25.7 %): ¹H NMR (400 MHz, DMSO-d6) δ 7.34 – 7.21 (m, 5H), 3.80 (td, J = 9.7, 4.5 Hz, 1H), 3.55 (s, 3H), 3.53 – 3.43 (m, 2H), 2.83 – 2.70 (m, 2H), 2.44 (ddd, J = 10.6, 9.2, 3.7 Hz, 1H), 2.11 (dd, J = 12.0, 9.6 Hz, 2H), 1.81 (dd, J = 12.9, 4.0 Hz, 1H), 1.46 (dtd, J = 14.0, 11.7, 4.0 Hz, 1H), 0.81 (s, 9H). [0295] Step 3: 2-[rac-(3R,4R)-1-benzyl-4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-3- yl]propan-2-ol

[0296] Methylmagnesium bromide (3.0 M in diethyl ether, 5.50 ml, 16.50 mmol) was added to methyl rac-(3R,4R)-1-benzyl-4-{[tert-butyl(dimethyl)silyl]oxy}piperidine-3-carboxylate (1.0 g, 2.75 mmol) in THF (10 mL) at -78°C over a period of 5 minutes under nitrogen. The resulting mixture was stirred at rt for 1 hour. The reaction mixture was then quenched with saturated NH4Cl (10 mL), extracted with EtOAc (10 x 2 mL), and the organic layer was dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using methanol in DCM (0-5 %, stepwise gradient elution) followed by concentration of the appropriate fractions gave the title compound as a colourless oil (0.700 g, 70 %): 1H NMR (400 MHz, DMSO-d6) δ 7.35 – 7.18 (m, 5H), 4.84 (s, 1H), 3.87 (td, J = 7.5, 3.8 Hz, 1H), 3.48 (d, J = 13.1 Hz, 1H), 3.37 (d, J = 13.1 Hz, 1H), 2.83 – 2.77 (m, 1H), 2.60 – 2.53 (m, 1H), 2.15 (q, J = 11.2, 10.7 Hz, 2H), 1.94 (ddd, J = 12.9, 6.8, 3.5 Hz, 1H), 1.48 (ddt, J = 14.8, 8.5, 4.1 Hz, 2H), 1.11 (s, 3H), 1.03 (s, 3H), 0.86 (s, 9H), 0.07 (s, 6H). [0297] Step 4: rac-(3R,4R)-1-benzyl-3-(2-hydroxypropan-2-yl)piperidin-4-ol

[0298] 1 M Tetrabutylammonium fluoride in THF (2.3 mL, 2.3 mmol) was added to 2-[rac- (3R,4R)-1-benzyl-4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-3-yl]propan-2-ol (650 mg, 1.79 mmol) in THF (7 mL) at 0°C under nitrogen. The resulting mixture was stirred at rt for 1 hours. The reaction mixture was then diluted with EtOAc (10 mL), washed sequentially with water (3 x 15 mL), brine (3 x 15 mL), then dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using methanol in DCM (0-5%, stepwise gradient elution) followed by concentration of the appropriate fractions gave the title compound as a colorless oil (0.360 g, 81 %). [0299] Step 5: rac-(3R,4R)-3-(2-hydroxypropan-2-yl)piperidin-4-ol (Intermediate 33) [0300] Palladium on carbon (10 wt. %, 90 mg) and rac-(3R,4R)-1-benzyl-3-(2-hydroxypropan- 2-yl)piperidin-4-ol (700 mg, 2.81 mmol) in EtOH (7 mL) was stirred under 1 atm of hydrogen at rt for 14 hours. The mixture was then filtered through a Celite pad and the obtained solution was concentrated to give the title compound as a yellow oil which was used in the following step without further purification (0.410 g, 92 %): ¹H NMR (400 MHz, DMSO-d6) δ 5.42 (brs, 1H), 201260-WO-PCT 3.56 (dt, 1H), 2.85 (dt, 2H), 2.36 (app t, 1H), 2.02 (app t, 1H), 1.72 (dd, 1H), 1.38 – 1.21 (m, 2H), 1.08 (2 s, 6H). Intermediate 40: [(3R,5S)-piperidine-3,5-diyl]dimethanol

[0301] Step 1: 1-benzyl 3,5-dimethyl (3R,5S)-piperidine-1,3,5-tricarboxylate

[0302] To a stirred solution of dimethyl piperidine-3,5-dicarboxylate (4.4 g, 21.87 mmol 45:55 cis/trans mixture), prepared similar as described in ACS Med. Chem. Lett.2014, 5, 7, 787–792, and DIPEA (7.62 ml, 43.73 mmol) in dichloromethane (50 mL) at 0 °C was added benzyl chloroformate (3.38 ml, 22.96 mmol) over 2 minutes, then stirred at rt for 3 h. The reaction mixture was then diluted with dichloromethane (50 mL), washed subsequently with aq.1M HCl (1 x 60 mL), water (1 x 20 mL) and brine (1 x 20 mL), then dried (sodium sulfate), filtered and concentrated. The residue was redissolved in dichloromethane and purified by flash column chromatography (Biotage pre-packed cartridge) by gradient elution (hexane-EtOAc 9:1 to 3:1). Pure fractions of the first eluting product were pooled and concentrated to provide the title compound as a white crystalline solid (3.1 g, 42 %): ¹H NMR (500 MHz, MeOD) δ 7.28 – 7.39 (m, 5H), 5.14 (d, 2H), 4.34 (dd, 2H), 3.69 (s, 6H), 2.84 (s, 2H), 2.56 (tt, 2H), 2.39 (ddq, 1H), 1.69 (dt, 1H). Pure fractions of the second eluting product was treated similar as above which gave 1-benzyl 3,5-dimethyl rac-(3R,5R)-piperidine-1,3,5-tricarboxylate as a colorless oil containing 9% of the title compound (3.0 g, 41%): 1H NMR (500 MHz, MeOD) δ 7.27 – 7.4 (m, 5H), 5.05 – 5.16 (m, 2H), 3.81 (s, 2H), 3.5 – 3.72 (m, 8H), 2.83 (tt, 2H), 2.09 (d, 2H). [0303] Step 2: benzyl (3R,5S)-3,5-bis(hydroxymethyl)piperidine-1-carboxylate

[0304] To a stirred solution of 1-benzyl 3,5-dimethyl (3R,5S)-piperidine-1,3,5-tricarboxylate (2.66 g, 7.93 mmol) in dry THF (50 mL) was added a solution of 2M lithium borohydride in THF (15.86 ml, 31.73 mmol) over 2 minutes at rt. The reaction mixture was stirred at 55 °C for 112 201260-WO-PCT 2.5 h, then allowed to cool and added dropwise to a vigorously stirred mixture of aq. saturated sodium hydrogen carbonate (100 mL) and EtOAc (100 mL) at 0 °C. This mixture was diluted with additional EtOAc (50 mL) and water. The water layer was extracted once with EtOAc (100 mL), and the combined organic layers was further washed with aq. saturated sodium hydrogen carbonate (50 mL), brine (20 mL), then dried (sodium sulfate), filtered and concentrated to provide the crude title compound as yellowish oil with trace amounts of EtOAc which was used without further purification in the next step. (2.3 g, quantitative): ¹H NMR (500 MHz, CDCl3) 0.95 (1H, q), 1.79 (2H, dq), 1.86 – 1.95 (1H, m), 2.48 (2H, t), 3.55 (4H, qd), 4.33 (2H, d), 5.16 (2H, s), 7.3 – 7.42 (5H, m). [0305] Step 3: [(3R,5S)-piperidine-3,5-diyl]dimethanol (Intermediate 34) [0306] A mixture of benzyl (3R,5S)-3,5-bis(hydroxymethyl)piperidine-1-carboxylate (2.3 g, 8.23 mmol) and palladium on carbon (5 wt-%, 0.3 g) was hydrogenated at 4 bar overnight, then filtered through celite and concentrated to afford the title compound as a colorless syrup (1.2 g, quantitative): ¹H NMR (500 MHz, MeOD) 0.88 (1H, q), 1.74 – 1.89 (3H, m), 2.34 (2H, t), 3.2 – 3.27 (2H, m), 3.40 (2H, dd), 3.48 (2H, dd). Intermediate 41: 2,2’-[(3R,5S)-piperidine-3,5-diyl]di(propan-2-ol)

[0307] Step 1: benzyl (3R,5S)-3,5-bis(2-hydroxypropan-2-yl)piperidine-1-carboxylate

[0308] 3 M Methylmagnesium bromide in 2-Me-THF (20.87 ml, 62.62 mmol) was added to a solution of 1-benzyl 3,5-dimethyl piperidine-1,3,5-tricarboxylate, prepared similar as described in ACS Med. Chem. Lett.2014, 5, 7, 787–792 (3 g, 8.95 mmol) in THF (15 mL) at 0 °C. The resulting mixture was stirred at 0 °C for another 2.5 hours, then poured into aq. saturated ammonium chloride (50 ml).The aqueous layer was extracted with DCM (2 x 40 ml) and the combined organic layers were washed with water (1 x 25 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water. Fractions containing product concentrated to dryness to afford a yellow 113 oil. The yellow oil was further purified by preparative chiral-HPLC on a CHIRALPAK® IG, 5*25 cm, 10 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2M NH3-MeOH); Flow rate: 200 mL/min; Gradient: isocratic 35% B; Column Temperature (℃): 35; Back Pressure (bar): 100; Wave Length: 220 nm; Sample Solvent: MeOH. Concentration of the first eluting isomer gave the title compound as a yellow oil (1.100 g, 55 %): ¹H NMR (300 MHz, Methanol- d4) δ 7.40 – 7.25 (m, 5H), 5.12 (s, 2H), 4.32 (d, J = 12.8 Hz, 2H), 3.35 (s, 1H), 2.53 (s, 2H), 2.05 (d, J = 12.5 Hz, 1H), 1.44 (t, J = 12.2, 7.4, 4.3 Hz, 2H), 1.18 (s, 12H). Concentration of the second eluting isomers gave benzyl rac-(3R,5R)-3,5-bis(2-hydroxypropan-2-yl)piperidine-1- carboxylate as a yellow oil (0.530 g, 26.5 %): 1H NMR (300 MHz, Methanol-d4) δ 7.42 – 7.25 (m, 5H), 5.12 (s, 2H), 3.72 (dd, J = 13.0, 4.9 Hz, 2H), 3.35 (s, 1H), 3.26 (s, 1H), 1.94 – 1.78 (m, 2H), 1.69 (t, J = 7.3 Hz, 2H), 1.18 (s, 12H). [0309] Step 2: 2,2’-[(3R,5S)-piperidine-3,5-diyl]di(propan-2-ol) (Intermediate 35) [0310] Benzyl (3R,5S)-3,5-bis(2-hydroxypropan-2-yl)piperidine-1-carboxylate (1.05 g, 3.13 mmol) was hydrogenated similar as described in step 3, intermediate 40 to provide the title compound as a colorless oil which was used without further purification in the next step (0.56 g, 89 %): ¹H NMR (400 MHz, DMSO-d6) δ 4.02 (s, 2H) 2.96 (d, J = 11.7 Hz, 2H), 2.06 (t, J = 11.5 Hz, 2H), 1.88 (d, J = 11.5, 2.5 Hz, 1H), 1.32 – 1.20 (m, 2H), 1.02 (s, 12H), 0.89 – 0.75 (m, 1H). Intermediate 42: 2,2’-[rel-(3R,5R)-piperidine-3,5-diyl]di(propan-2-ol), isomer 1

[0311] Step 1: benzyl rel-(3R,5R)-3,5-bis(2-hydroxypropan-2-yl)piperidine-1-carboxylate, isomer 1

[0312] The second eluting isomers of step 1, isomer 41, benzyl rac-(3R,5R)-3,5-bis(2- hydroxypropan-2-yl)piperidine-1-carboxylate (0.53 g, 1.58 mmol) was further purified by preparative chiral-HPLC under similar conditions as described above. Concentration of the fractions containing the first eluting isomer gave the title compound as a yellow oil (192 mg, 36 %). Concentration of the fractions containing the second eluting isomer gave benzyl rel- 114 (3R,5R)-3,5-bis(2-hydroxypropan-2-yl)piperidine-1-carboxylate, isomer 2, as a yellow oil (278 mg, 52 %). [0313] Step 2: 2,2’-[rel-(3R,5R)-piperidine-3,5-diyl]di(propan-2-ol) (Intermediate 41, isomer 1) [0314] Benzyl rel-(3R,5R)-3,5-bis(2-hydroxypropan-2-yl)piperidine-1-carboxylate, isomer 1 (170 mg, 0.51 mmol) was hydrogenated similar as described in step 3, intermediate 40 to provide the title compound as a colorless oil which was used without further purification in the next step (0.100 mg, 98 %): ¹H NMR (400 MHz, DMSO-d6) δ4.78-4.58 (s,2H) , 2.78 (d, J = 4.9 Hz, 4H), 1.69 – 1.63 (m, 2H), 1.61 (d, J = 5.7 Hz, 2H), 1.08 (d, J = 15.1 Hz, 12H). Intermediate 43: 2,2’-[rel-(3R,5R)-piperidine-3,5-diyl]di(propan-2-ol), isomer 2

[0315] Benzyl rel-(3R,5R)-3,5-bis(2-hydroxypropan-2-yl)piperidine-1-carboxylate, isomer 2 (260 mg, 0.78 mmol) from step 2, Intermediate 38 was hydrogenated similar as described in step 3, Intermediate 40 to provide the title compound as a colorless oil which was used without further purification in the next step (0.154 mg, 99 %): ¹H NMR (400 MHz, DMSO-d6) δ4.7-4.5 (s, 2H) 2.77 (d, J = 4.9 Hz, 4H), 1.71 – 1.52 (m, 4H), 1.08 (d, 12H). Intermediate 44: 2-[rac-(3R,5S)-5-methoxypiperidin-3-yl]propan-2-ol

[0316] Step 1: benzyl rac-(3R,5S)-3-(2-hydroxypropan-2-yl)-5-methoxypiperidine-1- carboxylate

[0317] To a solution of methyl 5-methoxypiperidine-3-carboxylate (556 mg, 3.21 mmol, CAS RN 113826-40-7) and triethylamine (1313 µl, 9.63 mmol) in DCM (20 mL) was added benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (960 mg, 3.85 mmol). The reaction was stirred at room temperature for 19 h. The organic layer was washed successively with 0.1 M HCl (20 mL), water (20 mL), brine (20 mL), dried with a phase separator and concentrated. The residue was 115 201260-WO-PCT purified by silica gel flash chromatography using a 25 g Biotage® Sfär HC D column using a gradient of 5 – 50 % EtOAc in heptane over 12 CV. Appropriate fractions were concentrated to provide 1-benzyl 3-methyl 5-methoxypiperidine-1,3-dicarboxylate (0.727 g, 73.7 %) as a colorless oil. [0318] The material from above in THF (10 mL) at 0 °C was added 3 M methylmagnesium bromide in diethyl ether (2.36 ml, 7.10 mmol), then cooling was removed and the reaction mixture was stirred at rt overnight. The reaction was then quenched by addition of 10 % NH₄Cl (aq) (20 mL) and extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (20 mL), dried with a phase separator and evaporated in vacuo. The residue was purified by silica gel flash chromatography on a 25 g Biotage® Sfär HC D column using a gradient of 5-60 % EtOAc in heptane over 12 CV. The product was detected at 257 nm, collected and concentrated to give the title compound as a colorless oil (0.274 g, 38 %): 1H NMR (500 MHz, DMSO) δ 0.94 – 1.09 (m, 7H), 1.32 – 1.42 (m, 1H), 2.14 (d, 1H), 2.27 – 2.48 (m, 2H), 3.04 – 3.14 (m, 1H), 3.28 (s, 3H), 4.08 – 4.17 (m, 1H), 4.17 – 4.27 (m, 1H), 4.33 (s, 1H), 5.07 (s, 2H), 7.27 – 7.41 (m, 5H). [0319] Step 2: 2-[rac-(3R,5S)-5-methoxypiperidin-3-yl]propan-2-ol (Intermediate 44) [0320] A mixture of benzyl rac-(3R,5S)-3-(2-hydroxypropan-2-yl)-5-methoxypiperidine-1- carboxylate (274 mg, 0.89 mmol) and Pd-C (5-wt %, 95 mg, 0.04 mmol) in MeOH (5 mL) was hydrogenated in a Buchi hydrogenator at 2 bar and room temperature for 17 h. The catalyst was filtered off and washed with MeOH. The filtrate was concentrated to give the title compound as a colorless oil (0.151 g, 98 %): ¹H NMR (500 MHz, MeOD) δ 1.04 (td, 1H), 1.16 (s, 6H), 1.5 – 1.6 (m, 1H), 2.15 – 2.23 (m, 1H), 2.23 – 2.34 (m, 2H), 3.05 – 3.12 (m, 1H), 3.19 – 3.29 (m, 2H), 3.38 (s, 3H). Apparent one set of signals. Intermediate 45: N-[rac-(3R,5S)-5-(2-hydroxypropan-2-yl)piperidin-3-yl]-N- methylmethanesulfonamide

[0321] Step 1: 1-tert-butyl 3-methyl rac-(3R,5S)-5-[(methanesulfonyl)amino]piperidine-1,3- dicarboxylate 116

[0322] To a solution of 1-tert-butyl 3-methyl rac-(3R,5S)-5-aminopiperidine-1,3-dicarboxylate, prepared similar as described in ACS Med. Chem. Lett.2016, 7, 933−938 (500 mg, 1.94 mmol), pyridine (470 µl, 5.81 mmol) in dichloromethane (5 mL) at 0 °C was added dropwise during 1 minute methanesulfonyl chloride (226 µl, 2.90 mmol) under nitrogen. The resulting solution was allowed to reach rt and stirred for 4 h. The reaction mixture was then concentrated, diluted with DCM (50 mL), washed sequentially with water (3 x 50 mL), brine (2 x 50 mL), dried (sodium sulfate), filtered and concentrated. The residue containing the crude title compound (630 mg) which was used in the next step without further purification.¹H NMR (300 MHz, DMSO-d6) δ 3.98 (d, J = 7.5 Hz, 2H), 3.50 (s, 4H), 2.83 (s, 3H), 2.28 (s, 5H), 1.27 (s, 9H). [0323] Step 2: 1-benzyl 3-methyl rac-(3R,5S)-5-[(methanesulfonyl)amino]piperidine-1,3- dicarboxylate

[0324] A solution of 1-tert-butyl 3-methyl rac-(3R,5S)-5-[(methanesulfonyl)amino]piperidine- 1,3-dicarboxylate from above (580 mg, 1.72 mmol) in 4.0 M HCl in 1,4-dioxane (6 mL, 24.00 mmol) was stirred at rt for 2 hours, then concentrated. To the residue was added 3:1 THF-water (6 mL), sodium hydrogen carbonate (427 mg, 5.08 mmol) and benzyl chloroformate (435 µl, 3.05 mmol) was added over 1 minute and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated, diluted with EtOAc (50 mL), washed sequentially with water (3 x 50 mL), brine (1 x 50 mL), dried (sodium sulfate) filtered and concentrated. The residue was purified by flash C18-flash chromatography, elution gradient 0 to 70% MeCN in water. Pure fractions were concentrated to dryness to afford the title compound as a colourless oil (0.450 g, 73 %): 1H NMR (400 MHz, DMSO-d6) δ 7.42 – 7.26 (m, 5H), 5.09 (d, J = 3.1 Hz, 2H), 4.12 (dq, J = 30.3, 5.1 Hz, 2H), 3.63 (s, 3H), 3.17 (d, J = 5.2 Hz, 2H), 2.94 (s, 3H), 2.65 (s, 1H), 2.22 (d, J = 12.8 Hz, 1H), 1.44 (q, J = 12.1 Hz, 1H). LCMS m/z (ES⁺) 371 [M+H]⁺. 201260-WO-PCT [0325] Step 3: 1-benzyl 3-methyl rac-(3R,5S)-5-[(methanesulfonyl)(methyl)amino]piperidine- 1,3-dicarboxylate

[0326] To a solution of 1-benzyl 3-methyl rac-(3R,5S)-5-[(methanesulfonyl)amino]piperidine- 1,3-dicarboxylate (170 mg, 0.46 mmol) and methyl iodide (143 µl, 2.29 mmol) in DMF (3 mL) at 0 C under nitrogen was added NaH (corresponding to 2.29 mmol) and the resulting reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was then quenched with water (50 mL), extracted with EtOAc (2 x 50 mL) and the organic layers were dried (sodium sulfate) filtered and concentrated. The crude product was combined with previous test reactions, then purified by flash C18-flash chromatography, elution gradient 0 to 60% EtOAc in water. Pure fractions were concentrated to dryness to afford the title compound as a colourless oil (0.280 g). ¹H NMR (400 MHz, DMSO-d6) δ 7.42 – 7.29 (m, 5H), 5.16 – 5.03 (m, 2H), 4.17 (d, J = 11.5 Hz, 1H), 3.93 (d, J = 12.6 Hz, 1H), 3.52 (s, 0H), 3.31 (s, 2H), 2.93 (s, 3H), 2.92 – 2.88 (m, 1H), 2.75 (d, J = 2.7 Hz, 3H), 2.05 (d, J = 12.9 Hz, 1H), 1.83 (q, J = 12.0 Hz, 1H). LCMS m/z (ES⁺) 385 [M+H]⁺. [0327] Step 4: benzyl rac-(3R,5S)-3-(2-hydroxypropan-2-yl)-5- [(methanesulfonyl)(methyl)amino]piperidine-1-carboxylate

[0328] Methyl magnesium bromide (572 µl, 1.72 mmol) was added dropwise to a solution of 1- benzyl 3-methyl rac-(3R,5S)-5-[(methanesulfonyl)(methyl)amino]piperidine-1,3-dicarboxylate (110 mg, 0.29 mmol) and Lanthanum(III) chloride bis(lithium chloride) complex solution 0.6 M in THF (1431 µl, 0.86 mmol) in THF (3 mL) under nitrogen at 0°C over a period of 5 minutes. The resulting mixture was stirred at 0 °C for 1 hour, then combined with an equal parallel batch, quenched with aq. saturated ammonium chloride (25 mL) and extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried (sodium sulfate) filtered and concentrated. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water. Pure fractions were concentrated to dryness to afford the title compound as a white solid (0.18 g).¹H NMR (300 MHz, DMSO-d6) δ 7.34 (d, J = 4.6 Hz, 5H), 5.07 (s, 2H), 118 201260-WO-PCT 4.10 (d, J = 12.8 Hz, 1H), 3.92 (d, J = 12.6 Hz, 3H), 2.88 (d, J = 4.8 Hz, 3H), 2.72 (d, J = 3.7 Hz, 3H), 1.80 (s, 1H), 1.49 (t, J = 10.5 Hz, 2H), 1.06 (d, J = 4.0 Hz, 6H). LCMS m/z (ES⁺) 385 [M+H]⁺. [0329] Step 5: N-[rac-(3R,5S)-5-(2-hydroxypropan-2-yl)piperidin-3-yl]-N- methylmethanesulfonamide (Intermediate 41) [0330] The product from step 4 above (0.18 g) was hydrogenated similar as described in step 3, Intermediate 40 to provide the title compound which was used without further purification in the next step (0.10 g). LCMS m/z (ES⁺) 251 [M+H]⁺. Intermediate 46: [rel-(3R,5R)-piperidine-3,5-diyl]dimethanol, isomer 1

[0331] Step 1: benzyl rel-(3R,5R)-3,5-bis(hydroxymethyl)piperidine-1-carboxylate, isomer 1

[0332] To a stirred solution of 1-benzyl 3,5-dimethyl rac-(3R,5R)-piperidine-1,3,5- tricarboxylate from step 1, intermediate 40 (1.5 g, 4.47 mmol) in THF (25 mL) at rt was added dropwise a 2 M solution of lithium borohydride in THF (8.95 ml, 17.89 mmol) over 2 minutes. The reaction mixture was stirred 10 minutes at rt and additional 3 h at 55 °C. The reaction mixture was then allowed to reach rt and added dropwise to a vigorously stirred and cooled (0 °C) 1:1 mixture of aq. saturated sodium hydrogen carbonate and EtOAc (140 mL). The mixture was stirred another 10 min, then diluted with additional 1:1 water-EtOAc (100 mL). The water layer was extracted with EtOAc (100 mL) and the combined organic layers were washed with aq. saturated sodium hydrogen carbonate (50 mL), brine (20 mL), then dried (sodium sulfate), filtered and concentrated. The residue (1.2 g) was purified by chiral chromatography on a Lux C2 column (5 μM, 250 x 30 mm) using isocratic condition of 15% EtOH/DEA 100/20 mM in CO2, 125 bar with a flow of 140 mL/min at 40 °C, detection at 210 nm. This gave the title compound as the first eluting isomer (469 mg, 37 %): ee = 99.9 % (Analytical conditions: Lux C2 column (3 μM, 150 x 4.6 mm) using isocratic condition of 20% EtOH/DEA 100/20mM in CO2, 120 bar with a flow of 3.5 mL/min at 40 °C). Specific rotation: [a]D²⁰ = +10.9 (c = 1.0 g/100 mL, chloroform).¹H NMR (500 MHz, DMSO) 1.43 (2H, s), 1.71 (2H, dq), 3.12 (1H, s), 3.21 – 3.33 (5H, m), 3.50 (2H, s), 4.52 (2H, t), 5.02 – 5.12 (2H, m), 7.28 – 7.42 (5H, m). Second 119 eluting isomer (462 mg, 37 %): ee = 97.4 (analytical conditions as above). Specific rotation: [a]D²⁰ = - 11.8 (c = 0.5 g/100 mL, chloroform).1H NMR (500 MHz, DMSO) 1.43 (2H, q), 1.71 (2H, hept), 3.12 (1H, s), 3.26 (5H, qd), 3.51 (2H, s), 4.52 (2H, t), 5.02 – 5.12 (2H, m), 7.29 – 7.42 (5H, m). [0333] Step 2: [rel-(3R,5R)-piperidine-3,5-diyl]dimethanol (Intermediate 46, isomer 1) [0334] Benzyl rel-(3R,5R)-3,5-bis(hydroxymethyl)piperidine-1-carboxylate, isomer 1 (0.46 g, 1.65 mmol) was hydrogenated similar as described in step 3, intermediate 40 to provide the title compound as a colorless syrup (0.24 g, quantitative): 1H NMR (500 MHz, MeOD) 1.66 (2H, t), 2.05 (2H, hd), 2.95 (2H, dd), 3.14 (2H, dd), 3.56 (2H, dd), 3.62 (2H, dd). Intermediate 47: [rel-(3R,5R)-piperidine-3,5-diyl]dimethanol, isomer 2

[0335] The second eluting isomer from step 1, Intermediate 42, benzyl rel-(3R,5R)-3,5- bis(hydroxymethyl)piperidine-1-carboxylate, isomer 2 (0.46 g, 1.65 mmol) was hydrogenated similar as described in step 3, Intermediate 40 to provide the title compound as a colorless syrup (0.24 g, quantitative): ¹H NMR (500 MHz, MeOD) 1.59 (2H, t), 1.90 (2H, qd), 2.78 (2H, dd), 3.00 (2H, dd), 3.48 – 3.58 (4H, m). Intermediate 48: rac-(3R,5S)-3,5-bis(2-hydroxypropan-2-yl)piperidin-4-ol

[0336] Step 1: dimethyl rac-(3R,5S)-1-benzyl-4-hydroxypiperidine-3,5-dicarboxylate

[0337] Benzyl bromide (20.08 g, 117.39 mmol) was added to a mixture of potassium carbonate (32.4 g, 234.78 mmol) and dimethyl 4-hydroxypiperidine-3,5-dicarboxylate, prepared similar as described in ACS Med. Chem. Lett.2014, 5, 787−792 (17 g, 78.26 mmol) in DMF (100 mL) at 25°C under nitrogen. The resulting mixture was stirred at 60 °C for 12 hours, then allowed to reach rt, diluted with water (300 mL) and extracted with EtOAc (3 x 200 mL). The combined 120 201260-WO-PCT organic layers were washed with water (2 x 200 mL) and brine (1 x 200 ml), then dried (sodium sulfate), filtered and concentrated. The crude product was purified by flash C18-chromatography (100mL/min), elution gradient 0 to 70% water (0.05%TFA) in MeCN within 30 mins. Pure fractions were evaporated to dryness to afford the title compound as a yellow oil (17.00 g, 71 %) which contained a 86/14 cis/trans ratio as indicated by LC-MS with ELSD detection (Analytical conditions: Poroshell HPH-C18 (2.7 μM, 50 x 3.0 mm) using a 3 minute gradient of 10-90 % acetonitrile in water/6.5mM NH4HCO3+Ammonium Hydroxide (pH=10)). [0338] Step 2: rac-(3R,5S)-1-benzyl-3,5-bis(2-hydroxypropan-2-yl)piperidin-4-ol

[0339] Dimethyl rac-(3R,5S)-1-benzyl-4-hydroxypiperidine-3,5-dicarboxylate (1.8 g, 5.86 mmol) in a solution of THF (15 mL) was added to a solution of 3M methylmagnesium bromide in diethylether (15.62 ml, 46.85 mmol) in THF (15 mL) at 0°C over a period of 10 seconds under nitrogen. The resulting solution was stirred at 25 °C for 12 hours. The reaction mixture was then quenched with water (10 mL), extracted with EtOAc (3 x 20mL), the organic layers were combined, dried (sodium sulfate), filtered and concentrated. The residue was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were concentrated to afford the title compound as a yellow oil (0.720 g, 40.0 %): ¹H NMR (400 MHz, DMSO-d6) δ 7.34-7.21 (m, 5H), 4.76 (d, J = 2.2 Hz, 1H), 4.43 (s, 2H), 3.59 (m, 2H), 2.77 – 2.63 (m, 2H), 2.32–2.13 (m, 2H), 1.37 (dd, 2H), 1.16 (s, 6H), 1.08 (s, 6H). [0340] Step 3: rac-(3R,5S)-3,5-bis(2-hydroxypropan-2-yl)piperidin-4-ol (Intermediate 48) [0341] Pd-C (10 wt-%, 485 mg, 0.46 mmol) and rac-(3R,5S)-1-benzyl-3,5-bis(2- hydroxypropan-2-yl)piperidin-4-ol (700 mg, 2.28 mmol) in EtOH (20 mL) was stirred under an atmosphere of hydrogen at 30 psi and 25 °C for 12 hours. The reaction mixture was filtered through silica to afford the title compound as a yellow oil which was used in the next step without further purification (0.440 g, 89 %, purity ~80%). Intermediate 49: N-(3-fluoro-4-formylphenyl)-1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4- carboxamide 121

[0342] Intermediate 18 (300 mg, 1.37 mmol), 4-bromo-2-fluorobenzaldehyde (278 mg, 1.37 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (7.92 mg, 0.01 mmol) and cesium carbonate (892 mg, 2.74 mmol) were loaded into a microwave vial. The vial was placed under nitrogen and 1,4-dioxane (12 mL) added. The resulting mixture was degassed with nitrogen for 5 min before addition of XantPhos Pd G3 (51.9 mg, 0.05 mmol). The resulting reaction mixture was sealed and stirred at 80 °C for 5 h. The reaction mixture was then portioned between EtOAc (40 mL) and water (15 mL). The aqueous layer was extracted with EtOAc (2 x 40 mL) and the combined organic layers were washed with brine (40 mL), dried (MgSO4), filtered and concentrated. The residue was triturated in DCM to give the title compound as a yellow solid (0.392 g, 84 %): ¹H NMR (500 MHz, DMSO) δ 2.48 (3H, s), 7.38 – 7.46 (2H, m), 7.58 (1H, dd), 7.81 – 7.92 (4H, m), 9.07 (1H, s), 10.12 (1H, s), 10.40 (1H, s). Intermediate 50: N-[6-(chloromethyl)-5-(difluoromethoxy)pyridin-3-yl]-1-(4- fluorophenyl)-3-methyl-1H-pyrazole-4-carboxamide

[0343] Step 1: 5-bromo-3-(difluoromethoxy)-2-methylpyridine

[0344] Potassium hydroxide (18.80 g, 335.06 mmol) in water (30 mL) was added to 5-bromo-2- methylpyridin-3-ol (6.3 g, 33.5 mmol) in acetonitrile (30 mL) at 5°C, then diethyl (bromodifluoromethyl)phosphonate (1789 670 mmol) was added and the resulting mixture 201260-WO-PCT was stirred at 20 °C for 2 hours. The reaction mixture was quenched with water (20mL), extracted with EtOAc (3 x 30mL), the organic layers were combined, dried (sodium sulfate), filtered and concentrated. The residue was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were to afford the title compound as a yellow oil (3.00 g, 38 %): ¹H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.89 (s, 1H), 7.31 (t, J = 73.2, 1H), 2.38 (s, 3H). [0345] Step 2: [5-bromo-3-(difluoromethoxy)pyridin-2-yl]methyl acetate

[0346] m-CPBA (6.52 g, 37.81 mmol) was added to 5-bromo-3-(difluoromethoxy)-2- methylpyridine (7.5 g, 31.51 mmol) in DCM (50mL) at 25°C. The resulting solution was stirred at 25 °C for 3 hours. The reaction mixture was poured into aq. sat Na2CO3 and extracted with DCM (2 x 50 mL). The combined organic layers were combined and washed with water (2 x 40 ml), dried (sodium sulfate), filtered and concentrated. The residual yellow solid was heated in stirred acetic anhydride (50mL) at 120 °C for 1 h. The reaction mixture was then diluted with water (200 ml), extracted with EtOAc (3 x80 ml) and the combined organic layers were washed with water (2 x 50 mL), dried (sodium sulfate), filtered and concentrated. The residue was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were concentrated to dryness to afford the title compound as a yellow oil (5.85 g, 71.7 %): ¹H NMR (300 MHz, Methanol-d4) δ 8.51 (s, 1H), 7.92 – 7.89 (m, 1H), 7.00 (t, J = 72.6 Hz, 1H), 5.21 (s, 2H), 2.09 (s, 3H). [0347] Step 3: N-[5-(difluoromethoxy)-6-(hydroxymethyl)pyridin-3-yl]-1-(4-fluorophenyl)-3- methyl-1H-pyrazole-4-carboxamide

[0348] BrettPhos Palladacycle G3 (0.344 g, 0.38 mmol) and dicyclohexyl(2’,4’,6’-triisopropyl- 3,6-dimethoxy-[1,1’-biphenyl]-2-yl)phosphane (0.272 g, 0.51 mmol) were added to [5-bromo-3- 123 201260-WO-PCT (difluoromethoxy)pyridin-2-yl]methyl acetate (1 g, 2.53 mmol), Intermediate 18 (0.389 g, 1.77 mmol) and sodium 2-methylpropan-2-olate (0.487 g, 5.07 mmol) in 1,4-dioxane (30 mL) under nitrogen. The resulting mixture was stirred at 90 °C for 14 h, then concentrated. The residue was purified by C18-flash chromatography, elution gradient 0 to 100% MeCN in water (with 0.1% FA ). Pure fractions were concentrated to afford the title compound as a yellow solid (0.380 g, 38 %): ¹H NMR (300 MHz, Methanol-d4) δ 8.71 (d, 2H), 8.24 (s, 1H), 7.77 (dd, 2H), 7.28 (t, 2H), 6.94 (t, J = 73.3 Hz, 1H), 4.72 (s, 2H), 2.55 (s, 3H). [0349] Step 4: N-[6-(chloromethyl)-5-(difluoromethoxy)pyridin-3-yl]-1-(4-fluorophenyl)-3- methyl-1H-pyrazole-4-carboxamide (Intermediate 50) [0350] Thionyl chloride (172 µl, 2.36 mmol) was added to DMF (14.60 µl, 0.19 mmol) and N- [5-(difluoromethoxy)-6-(hydroxymethyl)pyridin-3-yl]-1-(4-fluorophenyl)-3-methyl-1H- pyrazole-4-carboxamide (370 mg, 0.94 mmol) in MeCN (10 mL) under nitrogen. The resulting mixture was stirred at rt for 1 hour, then concentrated. The resulting mixture was partitioned between aqueous saturated sodium hydrogen carbonate (50 ml) and EtOAc (50 mL). The aqueous layer was extracted once with EtOAc (50 mL) and the combined organic layers were washed with water (2 x 25 mL), then dried (sodium sulfate), filtered and concentrated to obtain the title compound as a yellow solid which was used without further purification (0.451 g, ~87 % purity). Intermediate 51: N-[6-(chloromethyl)-5-(trifluoromethyl)pyridin-3-yl]-1-(4-fluorophenyl)- 3-methyl-1H-pyrazole-4-carboxamide

[0351] Step 1: 5-bromo-2-methyl-3-(trifluoromethyl)pyridine 1-oxide

[0352] m-CPBA (4.31 g, 25.00 mmol) was added to 5-bromo-2-methyl-3- (trifluoromethyl)pyridine (5 g, 20.83 mmol) in DCM (50 mL) at 24°C under nitrogen. The 124 201260-WO-PCT resulting solution was stirred at 25 °C for 2 hours. The reaction mixture was then poured into aq. sat Na2CO3 and extracted with DCM (2 x 50 mL). The combined organic layers were combined and washed with water (2 x 40 ml), dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using EtOAc in petroleum ether (0-30%, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (5.00 g, 94 %): ¹H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 1.7 Hz, 1H), 7.88 (dd, J = 3.1, 1.8 Hz, 1H), 2.39 (d, J = 1.6 Hz, 3H). [0353] Step 2: [5-bromo-3-(trifluoromethyl)pyridin-2-yl]methyl acetate

[0354] 5-bromo-2-methyl-3-(trifluoromethyl)pyridine 1-oxide (5.6 g, 21.9 mmol) was added to acetic anhydride (100 mL) at 25°C under nitrogen and the resulting solution was then at 140 °C for 2 hours. The reaction mixture was then quenched with water (200 mL), extracted with EtOAc (3 x 100mL), the organic layer was dried over Na₂SO₄, filtered and concentrated. Flash chromatography of the residue using EtOAc in petroleum ether (0-30%, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (5.00 g, 77 %): ¹H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 2.1 Hz, 1H), 8.52 (d, J = 2.2 Hz, 1H), 5.25 (d, J = 1.2 Hz, 2H), 2.08 (s, 3H). [0355] Step 3: 1-(4-fluorophenyl)-N-[6-(hydroxymethyl)-5-(trifluoromethyl)pyridin-3-yl]-3- methyl-1H-pyrazole-4-carboxamide

[0356] Brett{hos Pd G3 (60.8 mg, 0.07 mmol) was added to BrettPhos (36.0 mg, 0.07 mmol), Ethyl bromodifluoroacetate t-butoxide (64.5 mg, 0.67 mmol), [5-bromo-3- (trifluoromethyl)pyridin-2-yl]methyl acetate (100 mg, 0.34 mmol) and Intermediate 18 (73.5 mg, 0.34 mmol) in 1,4-dioxane (4 mL) at RT under nitrogen. The resulting mixture was stirred at 90 °C for 16 hours. The reaction mixture was then filtered through silica and concentrated. Flash C18-flash chromatography of the residue with acetonitrile in water (30-60%, gradient 125 201260-WO-PCT elution) followed by concentration of appropriate fractions gave the title compound as a yellow solid (80 mg, 60.5 %): ¹H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.11 – 9.05 (m, 2H), 8.55 (d, J = 2.4 Hz, 1H), 7.88 – 7.81 (m, 2H), 7.43 (t, J = 8.8 Hz, 2H), 4.66 (s, 2H). [0357] Step 4: N-[6-(chloromethyl)-5-(trifluoromethyl)pyridin-3-yl]-1-(4-fluorophenyl)-3- methyl-1H-pyrazole-4-carboxamide (Intermediate 51) [0358] DMF (19.64 µl, 0.25 mmol) was added to a solution of SOCl2 (370 µl, 5.07 mmol) and 1-(4-fluorophenyl)-N-[6-(hydroxymethyl)-5-(trifluoromethyl)pyridin-3-yl]-3-methyl-1H- pyrazole-4-carboxamide (500 mg, 1.27 mmol) in MeCN (1 mL) at 0 °C under nitrogen. The resulting mixture was stirred at rt for 2 hours, then diluted with EtOAc (10 mL), washed successively with water (2 x 10 mL), brine (10 mL), dried (sodium sulfate) filtered and concentrated to afford the title compound which was used in the next step without further purification. Intermediate 52: N-[3-(cyclopropyloxy)-4-formylphenyl]-1-(4-fluorophenyl)-3-methyl-1H- pyrazole-4-carboxamide

[0359] Step 1: [4-bromo-2-(cyclopropyloxy)phenyl]methanol

[0360] 2.5 M lithium aluminum hydride solution in THF (1.24 mL, 3.1 mmol) was added to a solution of methyl 4-bromo-2-cyclopropoxybenzoate, prepared similar as described in WO2018210988 (1.4 g, 5.16 mmol) in THF (15 mL) at 0°C under nitrogen. The resulting solution was stirred at 25 °C for 2 hours. The reaction mixture was then quenched with 2M NaOH (5 mL) and water (3 mL), extracted with EtOAc (3 x 15 mL). The combined organic layers were dried (sodium sulfate), filtered and concentrated. [0361] Flash column chromatography using EtOAc in petroleum ether (0 to 50%, gradient elution) followed by concertation of the appropriate fractions gave the title compound as a white 126 201260-WO-PCT solid (1.0 g, 80 %): ¹H NMR (400 MHz, DMSO-d6) δ 7.49 – 7.27 (m, 2H), 7.15 (dd, J = 8.1, 1.9 Hz, 1H), 5.06 (t, J = 5.6 Hz, 1H), 4.35 (d, J = 5.6 Hz, 2H), 3.90 (tt, J = 6.1, 3.0 Hz, 1H), 1.01 – 0.76 (m, 2H), 0.66 (q, J = 3.5, 3.1 Hz, 2H). [0362] Step 2, 4-bromo-2-(cyclopropyloxy)benzaldehyde

[0363] Manganese(IV) oxide (215 mg, 2.47 mmol) was added to (4-bromo-2- cyclopropoxyphenyl)methanol (200 mg, 0.82 mmol) in acetonitrile (8 mL) at 25°C under nitrogen. The resulting solution was stirred at 80°C for 3 hours, then filtered through silica to afford the title compound which was used without further purification in the next step (0.170 g, 86 %): ¹H NMR (400 MHz, DMSO-d6) δ 10.20 (d, J = 0.8 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.32 (ddd, J = 8.2, 1.8, 0.8 Hz, 1H), 4.13 (tt, J = 6.1, 3.0 Hz, 1H), 0.94 – 0.75 (m, 4H). [0364] Step 3: N-[3-(cyclopropyloxy)-4-formylphenyl]-1-(4-fluorophenyl)-3-methyl-1H- pyrazole-4-carboxamide (Intermediate 52) [0365] Methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2’-amino-1,1’- biphenyl]palladium(II) (236 mg, 0.25 mmol) was added to Cs2CO3 (405 mg, 1.24 mmol), 4- bromo-2-cyclopropoxybenzaldehyde (300 mg, 1.24 mmol) and Intermediate 18 (300 mg, 1.37 mmol) in 1,4-dioxane (8 mL) at 25 °C under nitrogen. The resulting solution was stirred at 90 °C for 12 hours, then filtered through silica. [0366] The reaction mixture was filtered through silica and the residue was purified by flash C18-flash chromatography with acetonitrile in 0.05 % TFA in water (0-80 %, gradient elution). Pure fractions were concentrated to dryness to afford the title compound as a brown solid (0.245 g, 52 %): ¹H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 10.15 (s, 1H), 9.08 (s, 1H), 8.04 (d, J = 1.9 Hz, 1H), 7.85 (ddt, J = 8.4, 6.1, 2.9 Hz, 2H), 7.69 (d, J = 8.6 Hz, 1H), 7.43 – 7.39 (m, 3H), 4.03 – 3.95 (m, 1H), 0.89 – 0.79 (m, 4H). Intermediate 53: N-(3-ethoxy-4-formylphenyl)-1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4- carboxamide 127 [0367] Step 1, 4-bromo-2-ethoxybenzaldehyde

[0368] 4-bromo-2-hydroxybenzaldehyde (2 g, 9.95 mmol) was added to iodoethane (3.10 g, 19.90 mmol), K2CO3 (2.75 g, 19.90 mmol) in DMF (20 mL) at 17°C over a period of 1 minute under nitrogen. The resulting solution was stirred at RT for 13 hours. [0369] The reaction mixture was then diluted with EtOAc (75 mL), washed sequentially with water (2 X 50 mL), brine (50 mL), dried (sodium sulfate), filtered and concentrated. [0370] Flash C18-flash chromatography of the residue using acetonitrile in water (0-70 %, gradient elution) followed by concentration of appropriate fractions gave the title compound as a yellow solid (2.100 g, 92 %): ¹H NMR (300 MHz, DMSO-d6) δ 10.28 (d, J = 0.8 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 1.7 Hz, 1H), 7.23 (ddd, J = 8.3, 1.7, 0.8 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H). [0371] Step 2: N-(3-ethoxy-4-formylphenyl)-1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4- carboxamide (Intermediate 53) [0372] Intermediate 18 (287 mg, 1.31 mmol) was added to 4-bromo-2-ethoxybenzaldehyde (250 mg, 1.09 mmol), Cs2CO3 (711 mg, 2.18 mmol) and Xant{hos Palladacycle Gen.3 (207 mg, 0.22 mmol) in 1,4-dioxane (3 mL) at 17 °C over a period of 1 minute under nitrogen. The resulting solution was stirred at 90 °C for 2 hours, then filtered through Celite and concentrated. Flash C18-flash chromatography of the residue using acetonitrile in water (0-50 %, gradient elution) followed by concentration of appropriate fractions gave the title compound as a yellow solid (0.268 g, 67 %): ¹H NMR (300 MHz, DMSO-d6) δ 10.31 – 10.16 (m, 5H), 9.07 (s, 2H), 7.88 – 7.76 (m, 4H), 7.76 – 7.57 (m, 4H), 7.45 – 7.26 (m, 7H), 7.30 – 7.18 (m, 1H), 4.23 – 4.02 (m, 5H), 2.46 (s, 6H), 2.43 – 2.32 (m, 1H), 1.39 (dt, J = 13.3, 6.9 Hz, 7H), 1.26 – 1.15 (m, 1H). Intermediate 54: N-(3-{[(1RS)-2,2-difluorocyclopropyl]oxy}-4-formylphenyl)-1-(4- fluorophenyl)-3-methyl-1H-pyrazole-4-carboxamide 128

[0373] Step 1: methyl 4-bromo-2-{[(1RS)-2,2-difluorocyclopropyl]oxy}benzoate

[0374] Trifluoromethyltrimethylsilane (2.49 g, 17.50 mmol) was added to sodium iodide (1.05 g, 7.00 mmol), methyl 4-bromo-2-(vinyloxy)benzoate, prepared similar as described in WO2018210988 (1.80 g, 7.00 mmol) in THF (20 mL) at 25 °C under nitrogen. The resulting solution was stirred at 70 °C for 5 hours. The reaction mixture was then quenched with water (20 mL), extracted with EtOAc (3 x 50 mL), the combined organic layers were dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using EtOAc in petroleum ether (0 to 20%, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (1.40 g, 65 %): ¹H NMR (300 MHz, DMSO- d6) δ 7.65 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.35 (dd, J = 8.3, 1.8 Hz, 1H), 4.72 (dddd, J = 9.8, 8.8, 4.8, 2.7 Hz, 1H), 3.77 (s, 3H), 2.18 – 2.00 (m, 1H), 1.78 (ddt, J = 16.9, 10.0, 5.0 Hz, 1H). [0375] Step 2: (4-bromo-2-{[(1RS)-2,2-difluorocyclopropyl]oxy}phenyl)methanol

[0376] Lithium hydroxide (0.797 g, 33.28 mmol) was added to methyl 4-bromo-2-(2,2- difluorocyclopropoxy)benzoate (1.46 g, 4.75 mmol) in THF (12 mL) and water (3 mL) at 0°C over a period of 1 minute under nitrogen. The resulting mixture was stirred at rt for 2 hours, then acidified using aq.2M HCl and the resulting precipitate was filtered off, washed with petroleum ether and dried in vacuum. The residue was combined with a parallel batch, total 1.34 g, 4.57 mmol and Borane-tetrahydrofuran complex (13.72 ml, 13.72 mmol) was added under nitrogen. The resulting mixture was stirred at rt for 2 hours then quenched with MeOH (10 mL). The 201260-WO-PCT reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (3 x 50 mL), brine (3 x 50 mL), dried (sodium sulfate), filtered and concentrated. Flash chromatography using EtOAc in petroleum ether (0-20 %, gradient elution) followed by concentration of appropriate fractions gave the title compound as a yellow solid (1.100 g, 86 %): ¹H NMR (400 MHz, DMSO-d6) δ 7.39 – 7.33 (m, 1H), 7.31 – 7.23 (m, 2H), 5.16 (s, 1H), 4.64 (dddd, J = 9.9, 8.8, 4.8, 2.5 Hz, 1H), 4.37 (s, 2H), 2.19 – 2.04 (m, 1H), 1.77 (ddt, J = 17.1, 9.9, 4.9 Hz, 1H). [0377] Step 3: 4-bromo-2-{[(1RS)-2,2-difluorocyclopropyl]oxy}benzaldehyde

[0378] Manganese(IV) oxide (1.682 g, 19.35 mmol) was added to (4-bromo-2-(2,2- difluorocyclopropoxy)phenyl)methanol (1.08 g, 3.87 mmol) in MeCN (11 mL) under nitrogen. The resulting mixture was stirred at 80 °C for 2 hours, then allowed to cool to rt and filtered through celite. The residue (1.04 g) was used directly in the next step without further purification. [0379] Step 4: N-(3-{[(1RS)-2,2-difluorocyclopropyl]oxy}-4-formylphenyl)-1-(4-fluorophenyl)- 3-methyl-1H-pyrazole-4-carboxamide (Intermediate 54) [0380] Cs2CO3 (941 mg, 2.89 mmol) was added to methanesulfonato[9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene][2’-amino-1,1’-biphenyl]palladium(II) (274 mg, 0.29 mmol), 4-bromo-2-{[(1RS)-2,2-difluorocyclopropyl]oxy}benzaldehyde (400mg, 1.44 mmol) and Intermediate 18 (348 mg, 1.59 mmol) in 1,4-dioxane (5mL) at 25°C under nitrogen. The resulting solution was stirred at 90 °C for 12 hours, then filtered through silica and concentrated. Flash C18 chromatography using acetonitrile in 0.05% TFA in water (0-80 %, gradient elution) followed by concentration of the appropriate fractions gave the title compound as an orange solid (0.230 g, 38 %): ¹H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 10.20 (d, J = 0.7 Hz, 1H), 9.07 (s, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.89 – 7.83 (m, 2H), 7.75 (d, J = 8.6 Hz, 1H), 7.47 – 7.39 (m, 3H), 4.73 – 4.65 (m, 1H), 2.48 (s, 3H), 2.16 (dq, J = 16.6, 9.1 Hz, 1H), 2.00 (ddt, J = 15.0, 9.8, 4.8 Hz, 1H). Intermediate 55: 1-(4-fluorophenyl)-N-(4-formyl-3-methoxyphenyl)-3-methyl-1H-pyrazole- 4-carboxamide 130

[0381] 1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carboxamide, prepared as described in step 3, intermediate 9 (300 mg, 1.37 mmol), 4-bromo-2-methoxybenzaldehyde (294 mg, 1.37 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (7.92 mg, 0.01 mmol) and cesium carbonate (892 mg, 2.74 mmol) were loaded into a microwave vial. The vial was placed under nitrogen and 1,4-dioxane (12 mL) added. The resulting mixture was degassed with nitrogen for 5 min before addition of XantPhos Pd G3 (51.9 mg, 0.05 mmol). The resulting reaction mixture was sealed and stirred at 80 °C for 5 h. The reaction mixture was then portioned between EtOAc (40 mL) and water (15 mL). The aqueous layer was extracted with EtOAc (2 x 40 mL) and the combined organic layers were washed with brine (40 mL), dried (magnesium sulfate) filtered and concentrated. The residue was triturated in DCM to give the title compound as a pale off- white solid (0.372 g, 77 %): ¹H NMR (500 MHz, DMSO) 2.48 (3H, s), 3.92 (3H, s), 7.36 – 7.46 (3H, m), 7.70 (1H, d), 7.76 (1H, d), 7.81 – 7.89 (2H, m), 9.13 (1H, s), 10.22 – 10.27 (2H, m). Intermediate 56: 1-(4-fluorophenyl)-N-(4-formyl-3-methylphenyl)-3-methyl-1H-pyrazole- 4-carboxamide

[0382] Intermediate 18 (293 mg, 1.34 mmol), 4-bromo-2-methylbenzaldehyde (271 mg, 1.36 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (7.73 mg, 0.01 mmol) and cesium carbonate (871 mg, 2.67 mmol) were suspended in 1,4-dioxane (15 mL). The resulting mixture was degassed with nitrogen for 5 min. XantPhos Pd G3 (50.7 mg, 0.05 mmol) was added, the resulting reaction mixture was degassed and backfilled with nitrogen x 3 and stirred at 90 °C for 15 h. The reaction mixture was then allowed to cool to room temperature and diluted with EtOAc (20 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic l shed with brine (15 mL), dried (magnesium 201260-WO-PCT sulfate), filtered and concentrated. The residue was concentrated from DCM to give a pale solid. The solid was triturated in DCM to give the title compound as a light beige solid (0.282 g, 62 %): ¹H NMR (500 MHz, DMSO) 2.48 (3H, s), 2.62 (3H, s), 7.37 – 7.45 (2H, m), 7.70 (1H, d), 7.77 (1H, dd), 7.8 – 7.87 (3H, m), 9.07 (1H, s), 10.09 – 10.14 (2H, m). Intermediate 57: 5-{[1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carbonyl]amino}-2- formylphenyl difluoromethanesulfonate

[0383] Step 1: 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-nitrophenol

[0384] t-butylchlorodimethylsilane (11.47 g, 76.09 mmol) was added to 2-(hydroxymethyl)-5- nitrophenol (9.9 g, 58.53 mmol) and imidazole (7.97 g, 117.07 mmol) in DCM (100 mL) at 0°C. The resulting mixture was stirred at rt for 15 hours. The reaction mixture was then diluted with DCM (200 mL), washed sequentially with water (250 mL), brine (250 mL) then dried (sodium sulfate) filtered and concentrated. Flash chromatography of the residue using EtOAc in petroleum ether (0-5 %, gradient elution) followed by concentration of the appropriate fractions gave the title ompound as a pale yellow solid (6.60 g, 40 %): ¹H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 7.72 (dd, J = 8.3, 2.3 Hz, 1H), 7.60 (d, J = 2.3 Hz, 1H), 7.56 – 7.49 (m, 1H), 4.76 – 4.71 (m, 2H), 0.92 (d, J = 5.8 Hz, 1H), 0.92 (s, 9H), 0.10 (s, 6H). [0385] Step 2: 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-nitrophenyl difluoromethanesulfonate

[0386] 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-nitrophenol (1.00 g, 3.53 mmol) was added to TEA (0.984 ml, 7.06 mmol) and difluoromethanesulfonyl chloride (0.797 g, 5.29 mmol) in 132 201260-WO-PCT DCM (12 mL) at 17°C over a period of 1 minute under nitrogen. The resulting solution was stirred at RT for 8 hours. The reaction mixture was then diluted with DCM (50 mL), washed sequentially with brine (2 x 50 mL), water (50 mL), dried (sodium sulfate), filtered and concentrated. Flash C18-flash chromatography of the residue using acetonitrile in water (0-100 %, gradient elution) followed by concentration of appropriate fractions gave the title compound as a colourless oil (1.180 g, 84 %): ¹H NMR (400 MHz, DMSO-d6) δ 8.36 (dd, J = 8.5, 2.3 Hz, 1H), 8.21 (d, J = 2.2 Hz, 1H), 7.92 – 7.84 (m, 2H), 4.90 (d, J = 1.0 Hz, 2H), 0.92 (d, J = 5.9 Hz, 1H), 0.92 (s, 9H), 0.12 (s, 6H), 0.15 – 0.08 (m, 1H). [0387] Step 3: 5-amino-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl difluoromethanesulfonate

[0388] 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-nitrophenyl difluoromethanesulfonate (2.50 g, 6.29 mmol) was added to ammonium chloride (1.346 g, 25.16 mmol) and iron (1.405 g, 25.16 mmol) in EtOH (20 mL) and water (5 mL) at 17°C over a period of 1 minute, then stirred at 70 °C for 8 hours. The mixture was then allowed to reach rt and filtered through Celite and the obtained solution was concentrated. Flash chromatography of the residue using EtOAc in petroleum ether (0-60 %, gradient elution) followed by concentration of appropriate fractions gave the title compound as a colourless oil (1.230 g, 53.2 %): ¹H NMR (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.15 (d, J = 8.3 Hz, 1H), 6.58 (dd, J = 8.3, 2.2 Hz, 1H), 6.52 (d, J = 2.1 Hz, 1H), 5.56 (s, 2H), 4.58 (s, 2H), 0.88 (d, J = 5.8 Hz, 1H), 0.88 (s, 9H), 0.05 (s, 6H). [0389] Step 4: 1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carbonyl chloride

[0390] Intermediate 18 (3 g, 13.62 mmol) was added to oxalyl chloride (6.92 g, 54.50 mmol) and DMF (0.199 g, 2.72 mmol) in DCM (40 mL) at 0 °C over a period of 1 minute under nitrogen. The resulting solution was stirred at 40 °C for 2 hours, then concentrated. The residue containing the title compound was used without further purification directly in the next step. 133 201260-WO-PCT [0391] Step 5: 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-{[1-(4-fluorophenyl)-3-methyl-1H- pyrazole-4-carbonyl]amino}phenyl difluoromethanesulfonate

[0392] 1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carbonyl chloride (1.95 g, 8.16 mmol) was added to 5-amino-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl difluoromethanesulfonate (1.00 g, 2.72 mmol) and TEA (0.759 ml, 5.44 mmol) in DCM (12 mL) at 17 °C over a period of 1 minute under nitrogen. The resulting solution was stirred at rt for 5 hours then diluted with DCM (25 mL), washed sequentially with water (50 mL), brine (50 mL), water (50 mL), then dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using EtOAc in petroleum ether (0-70 %, gradient elution) followed by concentration of appropriate fractions gave the title compound as a colourless solid (1.20 g, 77 %): ¹H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.03 (s, 1H), 8.01 – 7.85 (m, 2H), 7.88 – 7.80 (m, 2H), 7.80 – 7.68 (m, 2H), 7.55 (d, J = 8.5 Hz, 1H), 7.47 – 7.36 (m, 3H), 4.75 (s, 2H), 2.48 (s, 4H), 0.91 (s, 9H), 0.94 – 0.83 (m, 1H), 0.10 (s, 6H). [0393] Step 6: 5-{[1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carbonyl]amino}-2- (hydroxymethyl)phenyl difluoromethanesulfonate

[0394] 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-{[1-(4-fluorophenyl)-3-methyl-1H- pyrazole-4-carbonyl]amino}phenyl difluoromethanesulfonate (500 mg, 0.88 mmol) was added to TBAF (1317 µl, 1.32 mmol) in THF (8 mL) at 17°C over a period of 1 minute under nitrogen. The resulting solution was stirred at RT for 3 hours, then concentrated. 134 201260-WO-PCT [0395] Flash chromatography of the residue using EtOAc in petroleum ether (0-80 %, gradient elution) followed by concentration of appropriate fractions gave the title compound as a colourless solid (0.220 g, 55 %):¹H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 2H), 9.03 (s, 2H), 7.95 – 7.78 (m, 7H), 7.75 (s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.72 – 7.60 (m, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 2.3 Hz, 1H), 7.43 – 7.29 (m, 4H), 5.38 (t, J = 5.6 Hz, 2H), 4.55 (d, J = 5.6 Hz, 4H), 4.26 (t, J = 7.1 Hz, 1H), 3.17 (d, J = 5.3 Hz, 0H), 2.45 (d, J = 20.3 Hz, 9H), 2.20 – 2.08 (m, 1H), 1.23 (s, 2H), 0.95 – 0.81 (m, 1H). [0396] Step 7: 5-{[1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carbonyl]amino}-2- formylphenyl difluoromethanesulfonate (Intermediate 57) [0397] 5-{[1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carbonyl]amino}-2- (hydroxymethyl)phenyl difluoromethanesulfonate (200 mg, 0.44 mmol) was added to Manganese(IV) oxide (573 mg, 6.59 mmol) in DCM (3 mL) at 17°C over a period of 1 minute under nitrogen. The resulting solution was stirred at RT for 3 hours, then filtered through celite and concentrated. The residue containing the title compound was used directly in the next step without further purification (0.08 g, 40%): ¹H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 3H), 10.07 (s, 3H), 9.08 (s, 3H), 8.07 (d, J = 1.9 Hz, 3H), 8.00 (d, J = 8.6 Hz, 3H), 7.96 (d, J = 3.4 Hz, 1H), 7.93 – 7.80 (m, 12H), 7.71 (s, 1H), 7.47 – 7.37 (m, 7H), 5.75 (s, 1H), 2.89 (s, 1H), 2.73 (s, 1H), 2.49 (s, 8H), 2.00 (q, J = 7.1 Hz, 1H), 1.46 (d, J = 8.0 Hz, 1H), 1.24 (d, J = 3.1 Hz, 5H), 0.85 (t, J = 6.6 Hz, 1H). Intermediate 58: N-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(trifluoromethyl)phenyl]- 1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carboxamide

[0398] Step 1: 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(trifluoromethyl)aniline

135 201260-WO-PCT [0399] (4-Amino-2-(trifluoromethyl)phenyl)methanol (5.75 g, 30.08 mmol, CAS RN 900254- 46-8)) and 1H-imidazole (4.10 g, 60.16 mmol) were combined in DCM (150 mL) and the solution was chilled on an ice/water bath.1.0 M tert-butylchlorodimethylsilane in DCM (39.1 mL, 39.10 mmol) was added and the reaction was stirred for 18 hours, slowly coming to room temperature. Aq.8% NaHCO3 (50 mL) was added and the mixture was stirred vigorously. The organic phase was isolated by passing through a phase separator and concentrated to dryness under reduced pressure. Purification by normal phase flash column chromatography (Puriflash® 120g/25µm silica column, preconditioned with heptane. Elution with heptane (400 mL), then 5% EtOAc in heptane) afforded the title compound as a pale orange oil (7.40 g, 81% isolated yield): ¹H NMR (400 MHz, DMSO-d6) δ 0.05 (s, 6H), 0.88 (s, 9H), 4.64 (s, 2H), 5.50 (s, 2H), 6.78 (dd, 1H), 6.87 (d, 1H), 7.28 (d, 1H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ -58.82; LCMS m/z (ES⁺) 306.2 [M+H]⁺. [0400] Step 2: N-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(trifluoromethyl)phenyl]-1-(4- fluorophenyl)-3-methyl-1H-pyrazole-4-carboxamide

[0401] DIPEA (2.06 mL,11.8 mmol) was added to HATU (449 mg, 1.18 mmol) and Intermediate 18 (200 mg, 0.91 mmol) in DMF (5 mL). After 10 min of stirring, 4-({[tert- butyl(dimethyl)silyl]oxy}methyl)-3-(trifluoromethyl)aniline (416 mg, 1.36 mmol) was added and the reaction mixture was stirred another 4 h at 40 °C. The reaction mixture was then diluted with EtOAc (50 mL), washed successively with aq. saturated sodium hydrogen carbonate (20 mL), brine (20 mL), then dried (sodium sulfate), filtered and concentrated. Flash C18-flash chromatography of the residue using acetonitrile in water (0-100 %, gradient elution) followed by concentration of appropriate fractions gave the title compound as a white solid (200 mg, 43.4 %): ¹H NMR (300 MHz, DMSO, 22°C) δ 0.10 (6H, s), 0.91 (9H, s), 2.48 (3H, s), 4.81 (2H, s), 7.37–7.46 (2H, m), 7.69 (1H, d), 7.79–7.87 (2H, m), 7.96–8.01 (1H, m), 8.14 (1H, d), 9.04 (1H, s), 10.14 (1H, s). [0402] Step 2: N-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(trifluoromethyl)phenyl]-1-(4- fluorophenyl)-3-methyl-1H-pyrazole-4-carboxamide (Intermediate 58) 136 201260-WO-PCT [0403] Thionyl chloride (0.10 mL, 1.4 mmol) was added to N-[4-({[tert- butyl(dimethyl)silyl]oxy}methyl)-3-(trifluoromethyl)phenyl]-1-(4-fluorophenyl)-3-methyl-1H- pyrazole-4-carboxamide (180 mg, 0.35 mmol) and catalytic volume of DMF (0.014 mL, 0.18 mmol) in MeCN (2 mL). The resulting mixture was stirred at rt for 2 h, then quenched with saturated NaHCO3 (75 mL). The water layer was extracted with EtOAc (2 x 50 mL) and the combined organic layers were dried (sodium sulfate), filtered and concentrated to afford the title compound as a white solid which was used in the next step without further purification (140 mg, 96 %): ¹H NMR (300 MHz, DMSO, 22°C) δ 2.48 (3H, s), 4.85 (2H, s), 7.36–7.46 (2H, m), 7.72 (1H, d), 7.79–7.88 (2H, m), 8.03 (1H, dd), 8.20 (1H, d), 9.07 (1H, s), 10.25 (1H, s). Intermediate 59: N-(3-cyclopropyl-4-formylphenyl)-1-(4-fluorophenyl)-3-methyl-1H- pyrazole-4-carboxamide

[0404] Step 1: 4-bromo-2-cyclopropylbenzoic acid

[0405] Diacetoxypalladium (0.457 g, 2.03 mmol) was added to a solution of 4-bromo-2- iodobenzoic acid (13.3 g, 40.68 mmol), cyclopropylboronic acid (4.19 g, 48.82 mmol), potassium phosphate (30.2 g, 142.39 mmol) and tricyclohexylphosphonium tetrafluoroborate (1.648 g, 4.48 mmol) in 4:1 toluene-water (200 mL) under nitrogen. The resulting reaction mixture is stirred at 100 °C overnight. The reaction mixture was then allowed to cool to rt and poured in water and extracted with EtOAc. The aqueous phase is acidified to pH 2 with 1 M HCl, and extracted with EtOAc twice. The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated. The remaining residue was purified by column chromatography on silica gel (0-30% EtOAc in Heptanes) to yield the title compound as a beige solid (6.11 g, 62.3 %): ¹H NMR (500 MHz, CDCl3) 0.7 – 0.78 (2H, m), 1.03 – 1.12 (2H, m), 2.74 – 2.84 (1H, m), 7.18 (1H, d), 7.38 (1H, dd), 7.85 (1H, d). [0406] Step 2: (4-bromo-2-cyclopropylphenyl)methanol 137

[0407] Borane dimethyl sulfide complex solution (4.81 ml, 50.69 mmol) was added dropwise to a solution of 4-bromo-2-cyclopropylbenzoic acid (6.11 g, 25.34 mmol) at room temperature and stirred overnight. The reaction mixture was quenched with 1M HCl, diluted with CH2Cl2 and passed through a phase separator. The organic phase was concentrated and column chromatography of the residue using EtOAc in heptane (0-50%, stepwise gradient elution) followed by concentration of the appropriate fractions gave the title compound which crystallized upon standing (5.39 g, 94 %, light yellow solid): ¹H NMR (500 MHz, CDCl3) 0.65 – 0.71 (2H, m), 0.93 – 1.03 (2H, m), 1.93 – 2.02 (1H, m), 4.83 (2H, s), 7.13 (1H, d), 7.21 – 7.28 (1H, m), 7.32 (1H, dd). [0408] Step 3: 4-bromo-2-cyclopropylbenzaldehyde

[0409] DMSO (1.062 mL, 14.96 mmol) was slowly added to a cold solution (-78°C, acetone/cardice) of oxalyl dichloride (0.636 mL, 7.41 mmol) in dichloromethane (40 mL). After stirring for 5 minutes, (4-bromo-2-cyclopropylphenyl)methanol (1.02 g, 4.49 mmol) was added as a solution in dichloromethane (10 mL), and a thick suspension formed. After stirring for a further 15 minutes, triethylamine (4.16 mL, 29.91 mmol) was added and the thick colorless suspension was allowed to slowly warm to rt overnight. The reaction was quenched with water (50 mL) and acidified with aq.1.0M HCl (50 mL). The organic phase was isolated by passing through a phase separator, then concentrated which gave a colorless oil, which slowly crystallised to give a mixture of solid and colourless oil. The residue was purified by automated flash column chromatography (Biotage Selekt) via a Biotage® Sfär Silica HC D 25 g/20 µm column, preconditioned with heptane. The product was isolated by isocratic elution with heptane (2CV) followed by gradient elution 0 to 20% EtOAc in heptane over 15CV, to afford colorless oil (770 mg, 76%): ¹H NMR (500 MHz, CDCl3, 25°C) δ 0.77–0.83 (2H, m), 1.07–1.16 (2H, m), 2.55–2.64 (1H, m), 7.27 (1H, d), 7.46 (1H, dd), 7.67 (1H, d), 10.54 (1H, s). [0410] Step 4: N-(3-cyclopropyl-4-formylphenyl)-1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4- carboxamide (Intermediate 59) 201260-WO-PCT [0411] A 10-20 mL Biotage microwave vial was charged with Intermediate 18 (0.219 g, 1.00 mmol), cesium carbonate (0.652 g, 2.00 mmol), XantPhos Pd G3 (0.028 g, 0.03 mmol) and (9,9- dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (5.79 mg, 10.00 µmol) and capped. The vial was flushed with nitrogen by 3 x cycle of evacuation and nitrogen, before dioxane (5 mL) that had previously been purged with bubbling N2 for 30 minutes was added. The pale yellow mixture was stirred at room temperature for 15 minutes; the mixture was now dark orange. A solution of 4-bromo-2-cyclopropylbenzaldehyde (0.248 g, 1.10 mmol) in dioxane (5 mL, purged with N2) was added and the orange mixture was stirred at 80°C overnight. The reaction mixture was then allowed to reach rt, diluted with EtOAc (25 mL) and washed consecutively with water (2 x 10 mL) and brine (5 mL) before passing through a phase separator and concentrating to dryness. Automated flash column chromatography (Biotage Selekt) via a Biotage® Sfär Silica HC D 25 g/20 µm column, preconditioned with heptane and gradient elution with 0 to 50% EtOAc in heptane (15CV) afforded the title compound as colourless solid (182 mg, 50 %).¹H NMR (500 MHz, CDCl3, 25°C) δ 0.75–0.82 (2H, m), 1.02–1.12 (2H, m), 2.62 (4H, s), 7.1–7.17 (2H, m), 7.46 (1H, d), 7.49 (1H, dd), 7.56–7.64 (2H, m), 7.79 (1H, d), 7.90 (1H, s), 8.31 (1H, s), 10.48 (1H, s). Intermediate 60: N-(3-ethyl-4-formylphenyl)-1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4- carboxamide

[0412] Intermediate 18 (226 mg, 1.03 mmol) was added to 4-bromo-2-ethylbenzaldehyde (220 mg, 1.03 mmol),Cs2CO3 (673 mg, 2.07 mmol) and XantPhos Palladacycle Gen.3 (147 mg, 0.15 mmol) in 1,4-dioxane (3 mL) at 25°C under nitrogen. The resulting solution was stirred at 90 °C for 2 hours, then allowed to reach rt and filtered through celite and concentrated. The residue was redissolved in EtOAc (50 mL), washed successively with water (2 x 25 mL), saturated brine (25 mL), dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using EtOAc in petroleum ether (0-50 %, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a white solid (250 mg, 69 %): ¹H NMR (400 MHz, DMSO, 23°C) δ 1.21 (3H, t), 3.03 (2H, q), 7.38–7.46 (2H, m), 7.83 (4H, ddd), 9.08 (1H, s), 10.12 (2H, d). 139 201260-WO-PCT Intermediate 61: N-(2,3-difluoro-4-formylphenyl)-1-(4-fluorophenyl)-3-methyl-1H- pyrazole-4-carboxamide

[0413] Cesium carbonate (147 mg, 0.45 mmol) was added to Intermediate 18 (59.5 mg, 0.27 mmol), 4-bromo-2,3-difluorobenzaldehyde (50 mg, 0.23 mmol) and XantPhos (26.2 mg, 0.05 mmol) in 1,4-dioxane (1 mL) under nitrogen. The resulting mixture was stirred at 80 °C for 3 hours, then allowed to reach rt and filtered through celite and concentrated. The residue was redissolved in EtOAc (50 mL), washed successively with water (2 x 25 mL), saturated brine (25 mL), dried (sodium sulfate), filtered and concentrated. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 80% MeCN in water. Pure fractions were evaporated to dryness to afford N-(2,3-difluoro-4-formylphenyl)-1-(4-fluorophenyl)-3-methyl- 1H-pyrazole-4-carboxamide (50.0 mg, 61.5 %) as a brown solid.¹H NMR (400 MHz, DMSO, 23°C) δ 2.47 (s, 3H), 7.41 (d, J = 8.8 Hz, 2H), 7.68 (ddd, J = 8.9, 7.1, 1.9 Hz, 1H), 7.84 (dd, J = 9.0, 4.5 Hz, 2H), 7.90 (ddd, J = 8.5, 6.4, 1.7 Hz, 1H), 9.16 (s, 1H), 10.12 (s, 2H). Intermediate 62: N-(3-chloro-5-fluoro-4-formylphenyl)-1-(4-fluorophenyl)-3-methyl-1H- pyrazole-4-carboxamide

[0414] Prepared similar as described for Intermediate 61 from 4-bromo-2-chloro-6- fluorobenzaldehyde and Intermediate 18. Intermediate 63: N-(2,5-difluoro-4-formylphenyl)-1-(4-fluorophenyl)-3-methyl-1H- pyrazole-4-carboxamide 140

[0415] Prepared similar as described for Intermediate 61 from 4-bromo-2,5- difluorobenzaldehyde (300 mg, 1.36 mmol) and Intermediate 18 (357 mg, 1.63 mmol) to provide the title compound as a yellow solid (300 mg, 62 %): ¹H NMR (400 MHz, DMSO, 23 °C) δ 2.48 (s, 3H), 7.38–7.43 (m, 2H), 7.71 (dd, J = 10.5, 6.3 Hz, 1H), 7.81–7.87 (m, 2H), 8.14 (dd, J = 12.5, 5.9 Hz, 1H), 9.20 (s, 1H), 9.98 (s, 1H), 10.11 (d, J = 2.4 Hz, 1H). Intermediate 64: N-(5-chloro-2-fluoro-4-formylphenyl)-1-(4-fluorophenyl)-3-methyl-1H- pyrazole-4-carboxamide

[0416] Prepared similar as described for Intermediate 61 from 4-bromo-2-chloro-5- fluorobenzaldehyde (300 mg, 1.26 mmol, CAS RN 1214386-29-4) and Intermediate 18 (332 mg, 1.52 mmol) to provide the title compound as a brown solid (250 mg, 53 %): ¹H NMR (400 MHz, DMSO, 23 °C) δ 2.48 (s, 3H), 7.42 (d, J = 8.6 Hz, 3H), 7.84 (d, J = 4.4 Hz, 2H), 8.34 (d, J = 6.6 Hz, 1H), 9.19 (s, 1H), 10.00 (s, 1H), 10.21 (d, J = 2.8 Hz, 1H). Intermediate 65: N-(3,5-difluoro-4-formylphenyl)-1-(4-fluorophenyl)-3-methyl-1H- pyrazole-4-carboxamide

201260-WO-PCT [0417] Prepared similar as described for Intermediate 61 from 4-bromo-2,6- difluorobenzaldehyde (300 mg, 1.36 mmol) and Intermediate 18 (357 mg, 1.63 mmol) to provide the title compound as a brown solid (290 mg, 60 %): ¹H NMR (400 MHz, DMSO, 23 °C) δ 2.47 (s, 3H), 7.42 (dd, J = 9.7, 7.9 Hz, 2H), 7.55 (d, J = 11.8 Hz, 2H), 7.81–7.87 (m, 2H), 9.04 (s, 1H), 10.11 (s, 1H), 10.53 (s, 1H). Intermediate 66: N-[3-chloro-4-(chloromethyl)-2-fluorophenyl]-1-(4-fluorophenyl)-3- methyl-1H-pyrazole-4-carboxamide

[0418] Step 1: N-[3-chloro-2-fluoro-4-(hydroxymethyl)phenyl]-1-(4-fluorophenyl)-3-methyl- 1H-pyrazole-4-carboxamide

[0419] XantPhos (145 mg, 0.25 mmol) was added to XantPhos PD G3 (123 mg, 0.13 mmol), Cs2CO3 (1225 mg, 3.76 mmol) and Intermediate 18 (330 mg, 1.50 mmol), (4-bromo-2-chloro- 3-fluorophenyl)methanol (300mg, 1.25 mmol, CAS RN 1891698-71-7) in 1,4-dioxane (2 mL). The resulting mixture was stirred at 80 °C for 12 hours, then allowed to cool to rt, filtered through Celite and concentrated. Flash C18-flash chromatography of the residue using acetonitrile in water (0 to 100%, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a white solid (70 mg, 15 %): ¹H NMR (300 MHz, DMSO- d6) δ 9.81 (s, 1H), 9.07 (s, 1H), 7.92 – 7.79 (m, 2H), 7.79 – 7.61 (m, 1H), 7.51 – 7.29 (m, 3H), 4.57 (d, 2H), 2.47 (s, 3H). [0420] Step 2: N-[3-chloro-4-(chloromethyl)-2-fluorophenyl]-1-(4-fluorophenyl)-3-methyl-1H- pyrazole-4-carboxamide (Intermediate 66) 142 201260-WO-PCT [0421] Thionyl chloride (0.052 mL, 0.71 mmol) was added to DMF (0.922 µl, 0.01 mmol), N- [3-chloro-2-fluoro-4-(hydroxymethyl)phenyl]-1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4- carboxamide (90 mg, 0.24 mmol) and in MeCN (2 mL). The resulting mixture was stirred at rt for 30 minutes. The reaction mixture was concentrated and diluted with EtOAc (10 mL), and washed sequentially with water (2 x 5 mL), brine (5 mL), then dried (sodium sulfate), filtered and concentrated and used as such directly in the next step without further purification. Intermediate 67: rac-(3R,4S)-3-(2-hydroxypropan-2-yl)piperidine-3,4-diol

[0422] Step 1: tert-butyl 5-(2-hydroxypropan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0423] To a solution of 1-(tert-butyl) 3-ethyl 5,6-dihydropyridine-1,3(2H)-dicarboxylate (1.04 g, 4.07 mmol, CAS RN 126114-09-8) in THF (20 mL) at 0 °C was dropwise added 3M methylmagnesium bromide in diethyl ether (4.07 ml, 12.22 mmol) then allowed to reach rt and stirred for 24 h. The reaction was then quenched by addition of aq.10 % NH4Cl (20 mL) and extracted with EtOAc (2x30 mL). The combined organic layers were washed with brine (30 mL), dried with a phase separator and concentrated to give the crude title compound as a pale oil which was used in the next step without further purification (0.872 g, 89 %): ¹H NMR (500 MHz, DMSO) δ 1.20 (s, 6H), 1.40 (s, 9H), 2 – 2.09 (m, 2H), 3.29 – 3.35 (m, 2H), 3.88 (s, 2H), 4.56 (s, 1H), 5.66 – 5.72 (m, 1H). [0424] Step 2: tert-butyl rac-(3R,4S)-3,4-dihydroxy-3-(2-hydroxypropan-2-yl)piperidine-1- carboxylate

[0425] tert-butyl 5-(2-hydroxypropan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (744 mg, 3.08 mmol) was dissolved in THF (20 mL) and water (6.67 mL).4-methylmorpholine 4-oxide (542 mg, 4.62 mmol) and potassium dioxidodioxoosmium dihydrate (56.8 mg, 0.15 mmol) were added and the reaction stirred at room temperature for 18 h. The reaction mixture was then diluted with EtOAc (30 mL), washed with aq. sat NaHCO3 (30 mL), brine (30 mL), dried with a phase separator and concentrated. Flash chromatography of the residue (25 g Biotage® Sfär HC D column using a gradient of 20-100 % EtOAc in heptane over 12 CV followed by 100 % 143 201260-WO-PCT EtOAc over 10 CV, detection using ELSD) followed by concentration of the appropriate fractions gave the title compound as a colourless film (0.280 g, 33 %): ¹H NMR (500 MHz, DMSO) δ 1.10 (s, 3H), 1.21 (s, 3H), 1.37 (s, 9H), 1.42 – 1.5 (m, 1H), 1.6 – 1.75 (m, 1H), 2.54 – 2.78 (m, 2H), 3.61 – 3.74 (m, 1H), 3.74 – 3.91 (m, 3H), 4.68 (s, 1H), 5.01 (d, 1H). [0426] Step 3: rac-(3R,4S)-3-(2-hydroxypropan-2-yl)piperidine-3,4-diol (Intermediate 67) [0427] tert-butyl rac-(3R,4S)-3,4-dihydroxy-3-(2-hydroxypropan-2-yl)piperidine-1-carboxylate (280 mg, 1.02 mmol) was dissolved in HCl, 4 M in dioxane (3 mL, 12.00 mmol) and stirred at room temperature for 2 h and was then concentrated in vacuo to give the title compound as a semi solid which was used in the next step without further purification (0.215 g, quantitative yield): ¹H NMR (500 MHz, DMSO) δ 1.13 (s, 3H), 1.25 (s, 3H), 1.67 – 1.73 (m, 1H), 1.83 – 1.95 (m, 1H), 2.77 – 2.9 (m, 2H), 3 – 3.11 (m, 2H), 3.89 (dd, 1H), 4.58 – 5.54 (m, 3H), 7.9 – 8.09 (m, 1H), 9.15 (d, 1H). Intermediate 68: N-[4-(chloromethyl)-3-(difluoromethoxy)phenyl]-1-(4-cyanophenyl)-3- methyl-1H-pyrazole-4-carboxamide

[0428] Step 1: ethyl 1-(4-cyanophenyl)-3-methyl-1H-pyrazole-4-carboxylate

[0429] Ethyl 3-methyl-1H-pyrazole-4-carboxylate (10 g, 64.86 mmol) and cesium carbonate (31.7 g, 97.30 mmol) were added to 4-fluorobenzonitrile (10.61 g, 87.57 mmol) in acetonitrile (300 mL). The mixture was heated at mild reflux for 18 hours. The reaction mixture was allowed to cool to room temperature and diluted with water (100 mL). The cesium carbonate dissolved while the product slowly crystallised. The reaction was stirred at room temperature for 144 201260-WO-PCT 2 hours before refrigerating overnight. The precipitate was isolated by filtration and washed with a 1:1 mixture of acetonitrile:water (70 mL) before drying under reduced pressure at room temperature afforded ethyl 1-(4-cyanophenyl)-3-methyl-1H-pyrazole-4-carboxylate as a colourless solid (10.41 g, 63% isolated yield): ¹H NMR (500 MHz, DMSO-d₆) δ 1.31 (t, 3H), 2.45 (s, 3H), 4.26 (q, 2H), 7.95 – 8.02 (m, 2H), 8.09 – 8.16 (m, 2H), 9.15 (s, 1H); LCMS m/z (ES⁺) 256.2 [M+H]⁺. [0430] Step 2: 1-(4-cyanophenyl)-3-methyl-1H-pyrazole-4-carboxylic acid

[0431] Potassium trimethylsilanolate (1.675 g, 11.75 mmol) was added to a solution of ethyl 1- (4-cyanophenyl)-3-methyl-1H-pyrazole-4-carboxylate (1 g, 3.92 mmol) in THF (25 mL). The mixture was stirred at room temperature for 18 hours. The reaction was quenched slowly by addition of 4 M hydrogen chloride in 1,4-dioxane (3.43 mL, 13.71 mmol). The reaction was stirred for 30 min, then concentrated. The residue was suspended in a 1:1 mixture of acetonitrile:water (40 mL) at rt, stirred for 1 hour and then cooled down on ice/water for 30 min. The suspended solid was isolated by filtration, washed with cold MeCN:water (1:1) (10 mL) and dried at room temperature under reduced pressure to afford the title compound as a colourless solid (770 mg, 87%): ¹H NMR (500 MHz, DMSO-d₆) δ 2.44 (s, 3H), 7.94 – 8.03 (m, 2H), 8.08 – 8.14 (m, 2H), 9.09 (s, 1H), 12.65 (s, 1H); LCMS m/z (ES⁺) 228.1 [M+H]⁺. [0432] Step 3: 1-(4-cyanophenyl)-3-methyl-1H-pyrazole-4-carboxamide

[0433] Oxalyl dichloride (1.755 mL, 20.75 mmol) was added to a suspension of 1-(4- cyanophenyl)-3-methyl-1H-pyrazole-4-carboxylic acid (1.62 g, 6.92 mmol) in dichloromethane (120 mL). A single drop of N,N-dimethylformamide was added and the resulting solution was stirred at room temperature for 4.5 hours before the reaction was concentrated. The residue was dissolved in dichloromethane (120 mL) and slowly added to a chilled solution of 7N ammonia in 145 201260-WO-PCT MeOH (14.82 ml, 103.74 mmol) over 15 minutes. Once the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 20 hours while a precipitate formed. Water (50 mL) was added to the suspension and, after stirring for 30 minutes, the solid was isolated by filtration, washed with DCM and dried under reduced pressure at 50°C, to afford the title compound as a near colourless solid (1.460 g, 93%) : ¹H NMR (500 MHz, DMSO-d6) 2.43 (s, 3H), 7.18 (s, 1H), 7.44 (s, 1H), 7.89 – 7.96 (m, 2H), 7.97 – 8.04 (m, 2H), 9.00 (s, 1H). [0434] Step 4: 1-(4-cyanophenyl)-N-[3-(difluoromethoxy)-4-formylphenyl]-3-methyl-1H- pyrazole-4-carboxamide

[0435] Nitrogen was bubbled through a suspension of 1-(4-cyanophenyl)-3-methyl-1H- pyrazole-4-carboxamide (4.02 g, 17.77 mmol), 4-bromo-2-(difluoromethoxy)benzaldehyde (4.91 g, 19.55 mmol, prepared as described in step 1 for Intermediate 28), (9,9-dimethyl-9H- xanthene-4,5-diyl)bis(diphenylphosphane) (0.206 g, 0.36 mmol) and cesium carbonate (11.58 g, 35.54 mmol) in 1,4-dioxane (400 mL) for 5 minutes before XantPhos Pd G3 (674 mg, 0.71 mmol) was added. The reaction mixture was stirred at mild reflux under an atmosphere of nitrogen for 17 hours. The reaction mixture was allowed to cool to room temperature before partitioning between EtOAc (300 mL) and water (300 mL). After separation, the aqueous layer was extracted with EtOAc (2 x 400 mL). The organic layers were combined and washed with brine (400 mL) before passing through a phase separator and concentrated. The residue was triturated with DCM, filtered and dried at room temperature under reduced pressure, to afford the title compound as a pale yellow solid (5.38 g, 76% isolated yield): ¹H NMR (500 MHz, DMSO-d6) δ 7.34 (t, 1H), 7.71 (dd, 1H), 7.87 (d, 1H), 7.91 – 7.95 (m, 1H), 7.97 – 8.08 (m, 4H), 9.27 – 9.36 (m, 1H), 10.16 (s, 1H), 10.47 – 10.56 (m, 1H), CH3 unassigned, under residual DMSO peak; LCMS m/z (ES⁺) 397.2 [M+H]⁺. [0436] Step 5: 1-(4-cyanophenyl)-N-[3-(difluoromethoxy)-4-(hydroxymethyl)phenyl]-3-methyl- 1H-pyrazole-4-carboxamide 146

[0437] Sodium tetrahydroborate (666 mg, 17.62 mmol) was added portionwise to 1-(4- cyanophenyl)-N-[3-(difluoromethoxy)-4-formylphenyl]-3-methyl-1H-pyrazole-4-carboxamide (6.65 g, 16.78 mmol) in THF (250 mL) at 0°C (ice/water bath). Once the addition was complete, the stirred reaction mixture was allowed to warm to room temperature. After 90 minutes, the reaction was cooled with an ice/water bath and quenched by slow addition of 10% aqueous NH4Cl (400 mL). The mixture was extracted with EtOAc (2 x 400 mL). The combined extractions were washed with brine (400 mL) before passing through a phase separator. Concentration to dryness under reduced pressure gave 1-(4-cyanophenyl)-N-[3- (difluoromethoxy)-4-(hydroxymethyl) phenyl]-3-methyl-1H-pyrazole-4-carboxamide as a near colourless solid (6.70 g, quantitative yield): ¹H NMR (500 MHz, DMSO-d₆) δ 2.48 (s, 3H), 4.50 (d, 2H), 5.17 (t, 1H), 7.12 (t, 1H), 7.47 (d, 1H), 7.55 (dd, 1H), 7.67 (d, 1H), 7.97 – 8.07 (m, 4H), 9.20 (s, 1H), 10.06 (s, 1H); LCMS m/z (ES⁺) 399.3 [M+H]⁺. [0438] Step 6: N-[4-(chloromethyl)-3-(difluoromethoxy)phenyl]-1-(4-cyanophenyl)-3-methyl- 1H-pyrazole-4-carboxamide (Intermediate 68) [0439] Thionyl chloride (2.45 mL, 33.54 mmol) and N,N-dimethylformamide (130 µL, 1.68 mmol) were added consecutively to 1-(4-cyanophenyl)-N-[3-(difluoromethoxy)-4- (hydroxymethyl)phenyl]-3-methyl-1H-pyrazole-4-carboxamide (6.68 g, 16.77 mmol) in acetonitrile (400 mL) at 0°C (ice/water bath). Once the addition was complete the stirred reaction was allowed to warm to room temperature and stirred for 4 hours, to give a suspension. The precipitate was isolated by filtration, washed with acetonitrile and dried at room temperature under reduced pressure, to afford the title compound as an off-white solid (5.91 g, 85% isolated yield): ¹H NMR (500 MHz, DMSO-d6) δ 2.49 (s, 3H), 4.73 (s, 2H), 7.24 (t, 1H), 7.51 – 7.6 (m, 2H), 7.78 (s, 1H), 7.97 – 8.08 (m, 4H), 9.24 (s, 1H), 10.20 (s, 1H); LCMS m/z (ES⁺) 417.2 [M+H]⁺. Intermediate 69: 2-[(3S,6S)-6-methylpiperidin-3-yl]propan-2-ol

[0440] Step 1: 1-benzyl 3-methyl (3S,6S)-6-methylpiperidine-1,3-dicarboxylate

[0441] To a solution of methyl (3S,6S)-6-methylpiperidine-3-carboxylate (480 mg, 3.05 mmol, CAS RN 1009376-90-2) and triethylamine (1249 µl, 9.16 mmol) in DCM (20 mL) was added benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (913 mg, 3.66 mmol) and the reaction was stirred at rt for 19 h. The rection mixture was then washed with 0.1 M HCl (20 mL), water (20 mL), brine (20 mL), dried with a phase separator and concentrated. The residue was purified by silica gel flash chromatography using a 25 g Biotage® Sfär HC D column using a gradient of 5 – 50 % EtOAc in heptane over 12 CV. The product was collected using 257 nm. Appropriate fractions were concentrated to give the title compound as a colorless oil (0.537 g, 60.4 %).¹H NMR (500 MHz, CDCl3) 1.17 (3H, d), 1.35 – 1.43 (1H, m), 1.76 – 1.95 (2H, m), 2 – 2.08 (1H, m), 2.60 (1H, s), 3.13 (1H, dd), 3.61 (3H, s), 4.41 – 4.53 (2H, m), 5.08 (1H, d), 5.18 (1H, d), 7.28 – 7.39 (5H, m). [0442] Step 2: benzyl (2S,5S)-5-(2-hydroxypropan-2-yl)-2-methylpiperidine-1-carboxylate

[0443] To a solution of 1-benzyl 3-methyl (3S,6S)-6-methylpiperidine-1,3-dicarboxylate (537 mg, 1.84 mmol) in THF (10 mL) at 0 ° was added dropwise 3M methylmagnesium bromide in diethyl ether (1.84 µl, 5.53 mmol) was added dropwise, the ice bath was then removed and the reaction stirred at room temperature for 18 h. The reaction was quenched by addition of 10 % NH₄Cl (aq) (20 mL) and extracted with EtOAc (2x20 mL). The combined organic phases were washed with brine (20 mL), dried with a phase separator and evaporated in vacuo. The residue was purified by silica gel flash chromatography on a 25 g Biotage® Sfär HC D column using a gradient of 5-60 % EtOAc in heptane over 12 CV. The product was detected at 257 nm (very weak UV activity). Appropriate fractions were concentrated to give the title compound as a colorless oil (0.328 g, 61 %): ¹H NMR (500 MHz, DMSO) 0.98 (3H, s), 1.02 (3H, s), 1.10 (4H, d), 1.18 – 1.29 (1H, m), 1.56 – 1.7 (2H, m), 1.76 – 1.85 (1H, m), 3.13 (1H, dd), 3.73 (1H, dd), 3.76 – 3.86 (1H, m), 4.12 (1H, s), 5 – 5.1 (2H, m), 7.27 – 7.39 (5H, m). [0444] Step 3: 2-[(3S,6S)-6-methylpiperidin3yl]propan-2-ol (Intermediate 69) 201260-WO-PCT [0445] Benzyl (2S,5S)-5-(2-hydroxypropan-2-yl)-2-methylpiperidine-1-carboxylate (328 mg, 1.13 mmol) was dissolved in MeOH (5 mL) and Pd-C (120 mg, 0.06 mmol) was added. The reaction was hydrogenated in a Buchi hydrogenator at 2 bar and room temperature for 17 h. The catalyst was filtered off and washed with MeOH. The filtrate concentrated to give the title compound as a colorless oil which solidified upon standing (0.155 g, 88 %): ¹H NMR (500 MHz, DMSO) 0.91 – 0.98 (4H, m), 1.01 (6H, d), 1.03 – 1.14 (1H, m), 1.21 – 1.32 (1H, m), 1.56 – 1.64 (1H, m), 1.7 – 1.79 (1H, m), 2.27 (1H, t), 2.38 – 2.48 (1H, m), 2.99 – 3.06 (1H, m), 4.05 (1H, s). Intermediate 70: 2-[(2R,3S)-2-methylpiperidin-3-yl]propan-2-ol

[0446] Step 1: 1-benzyl 3-methyl (2R,3S)-2-methylpiperidine-1,3-dicarboxylate

[0447] Sulfurous dichloride (250 µl, 3.43 mmol) was added dropwise to a solution of (2R,3S)-1- ((benzyloxy)carbonyl)-2-methylpiperidine-3-carboxylic acid (475 mg, 1.71 mmol, CAS RN 2301169-13-9) in DCM (10 mL) at 0 °C, then stirred at room temperature for 2.5 h. The reaction was then cooled again to 0 °C, MeOH (2 mL) was added and the reaction stirred at room temperature for 1 h. The reaction mixture was then diluted with EtOAc (20 mL), washed with aq. sat. NaHCO3 (20 mL). The aqueous phase was extracted with EtOAc (2x20 mL) and the combined organic layers were washed with brine (20 mL), dried with a phase separator and concentrated. The residue was purified by silica gel flash chromatography on a 10 g Biotage® Sfär HC D column using a gradient of 0-50 % EtOAc in heptane over 15 CV. The product peak was collected and concentrated to give the title compound as a colorless oil (0.441 g, 88 %): ¹H NMR (500 MHz, CDCl3) 1.25 (3H, d), 1.49 – 1.58 (1H, m), 1.58 – 1.72 (1H, m), 1.74 – 1.85 (1H, m), 2.04 – 2.11 (1H, m), 2.42 – 2.46 (1H, m), 2.85 – 2.95 (1H, m), 3.63 (3H, s), 4.03 (1H, d), 4.93 – 5.01 (1H, m), 5.11 (1H, d), 5.17 (1H, d), 7.28 – 7.39 (5H, m). [0448] Step 2: benzyl (2R,3S)-3-(2-hydroxypropan-2-yl)-2-methylpiperidine-1-carboxylate

[0449] 1-benzyl 3-methyl (2R,3S)-2-methylpiperidine-1,3-dicarboxylate (0.441 g, 1.51 mmol) was treated similar as described in step 2 for Intermediate 69 to give the title compound as a 149 201260-WO-PCT colorless oil (0.320 g, 73 %): ¹H NMR (500 MHz, DMSO) 1.01 (3H, s), 1.06 (3H, s), 1.13 (3H, d), 1.26 – 1.41 (2H, m), 1.41 – 1.52 (1H, m), 1.57 – 1.74 (2H, m), 2.9 – 3.13 (1H, m), 3.66 – 3.75 (1H, m), 4.17 (1H, s), 4.42 – 4.55 (1H, m), 5.06 (2H, s), 7.26 – 7.39 (5H, m). [0450] Step 3: 2-[(2R,3S)-2-methylpiperidin-3-yl]propan-2-ol (Intermediate 70) [0451] Benzyl (2R,3S)-3-(2-hydroxypropan-2-yl)-2-methylpiperidine-1-carboxylate (0.320 g, 1.10 mmol) was treated similar as described in step 3 for Intermediate 69 to give the title compound as a colorless oil (0.167 g, 97 %): ¹H NMR (500 MHz, DMSO) 1.01 – 1.25 (11H, m), 1.29 – 1.42 (1H, m), 1.58 – 1.67 (1H, m), 1.71 – 1.78 (1H, m), 2.48 – 2.57 (1H, m), 2.61 – 2.72 (1H, m), 2.86 – 2.94 (1H, m), 3.16 – 3.46 (1H, m). Intermediate 71: 2-[(3S,6R)-6-methylpiperidin-3-yl]propan-2-ol

[0452] Step 1: 1-benzyl 3-methyl (3S,6R)-6-methylpiperidine-1,3-dicarboxylate

[0453] (3S,6R)-1-((benzyloxy)carbonyl)-6-methylpiperidine-3-carboxylic acid (478 mg, 1.72 mmol, CAS RN 1227916-29-1) was treated similar as described in step 1 for Intermediate 70 to give the title compound as a colorless oil (0.446 g, 89 %): ¹H NMR (500 MHz, CDCl3) 1.17 (3H, d), 1.51 – 1.63 (1H, m), 1.63 – 1.83 (2H, m), 1.88 – 1.96 (1H, m), 2.37 – 2.48 (1H, m), 2.93 – 3.06 (1H, m), 3.69 (3H, s), 4.15 – 4.39 (1H, m), 4.41 – 4.57 (1H, m), 5.14 (2H, s), 7.28 – 7.4 (5H, m). [0454] Step 2: benzyl (2R,5S)-5-(2-hydroxypropan-2-yl)-2-methylpiperidine-1-carboxylate

[0455] 1-benzyl 3-methyl (3S,6R)-6-methylpiperidine-1,3-dicarboxylate (446 mg, 1.53 mmol) was treated similar as described in step 2 for Intermediate 69 to give the title compound as a colorless oil (0.380 g, 85 %): ¹H NMR (500 MHz, DMSO) 1.01 – 1.09 (9H, m), 1.22 – 1.32 (1H, m), 1.32 – 1.43 (1H, m), 1.5 – 1.6 (3H, m), 2.56 – 2.74 (1H, m), 4.05 (1H, d), 4.25 (1H, s), 4.26 – 4.35 (1H, m), 5.02 – 5.11 (2H, m), 7.27 – 7.4 (5H, m). [0456] Step 3: 2-[(3S,6R)-6-methylpiperidin-3-yl]propan-2-ol (Intermediate 71) 150 201260-WO-PCT [0457] Benzyl (2R,5S)-5-(2-hydroxypropan-2-yl)-2-methylpiperidine-1-carboxylate (380 mg, 1.30 mmol) was treated similar as described in step 3 for Intermediate 69 to give the title compound as a colorless oil which was used without further purification (0.243 g, 90 % purity according to NMR): ¹H NMR (500 MHz, DMSO) 1.01 – 1.08 (6H, m), 1.09 (3H, s), 1.31 – 1.39 (1H, m), 1.47 – 1.65 (4H, m), 2.80 (1H, dd), 2.84 – 2.93 (1H, m), 2.96 – 3.1 (1H, m), 3.32 (1H, bs), 5.59 (1H, bs). Intermediate 72: 2-[(3S)-1-{[4-amino-2-(difluoromethoxy)phenyl]methyl}piperidin-3- yl]propan-2-ol

[0458] Step 1: 2-[(3S)-1-{[2-(difluoromethoxy)-4-nitrophenyl]methyl}piperidin-3-yl]propan-2- ol

[0459] To (S)-2-(piperidin-3-yl)propan-2-ol (324 mg, 2.26 mmol, CAS RN 1173880-33-5) in acetonitrile (30 mL) was added potassium carbonate (750 mg, 5.43 mmol) followed by 1- (chloromethyl)-2-(difluoromethoxy)-4-nitrobenzene (430 mg, 1.81 mmol, from step 5, intermediate 2). The resulting reaction mixture was stirred at 50 °C for 18 h, then allowed to reach rt, diluted with EtOAc (50 mL), washed successively with water (20 mL), brine (20 mL), dried (MgSO4), filtered and concentrated. Column chromatography of the residue using EtOAc in heptane (0-50 %, stepwise gradient elution) gave the title compound as a yellow oil (0.510 g, 82 %): ¹H NMR (500 MHz, DMSO) δ 8.14 (dd, 1H), 8.00 (d, 1H), 7.76 (d, 1H), 7.38 (t, 1H), 4.09 (s, 1H), 3.57 (s, 2H), 2.96 (dt, 1H), 2.75 (d, 1H), 1.87 (td, 1H), 1.75 (q, 2H), 1.64 (dt, 1H), 1.38 – 1.52 (m, 2H), 0.89 – 1.05 (m, 7H). [0460] Step 2: 2-[(3S)-1-{[4-amino-2-(difluoromethoxy)phenyl]methyl}piperidin-3-yl]propan- 2-ol (Intermediate 72) [0461] To 2-[(3S)-1-{[2-(difluoromethoxy)-4-nitrophenyl]methyl}piperidin-3-yl]propan-2-ol (500 mg, 1.45 mmol) in a mixture of ethanol (12 mL) and water (4 mL) was added iron (811 mg, 14.52 mmol), followed by ammonia hydrochloride (388 mg, 7.26 mmol). The resulting solution was stirred at 80 °C for 1 h. The reaction mixture was then filtered through a pad of 151 201260-WO-PCT Dicalite and concentrated. The residue was dissolved in EtOAc (40 mL), washed successively with aq. sat. NaHCO3 (20 mL), brine (120 mL), dried (MgSO4), filtered and concentrated. Flash column chromatography of the residue using methanol in dichloromethane (0-15%, stepwise gradient elution) gave the title compound as a colourless oil (0.424 g, 93 %): ¹H NMR (500 MHz, DMSO) δ 6.76 – 7.17 (m, 2H), 6.40 (dd, 1H), 6.35 (d, 1H), 5.11 – 5.42 (m, 2H), 4.08 (s, 1H), 3.27 (s, 2H), 2.95 (s, 1H), 2.67 – 2.8 (m, 1H), 1.52 – 1.84 (m, 4H), 1.28 – 1.48 (m, 2H), 0.88 – 1.07 (m, 7H). Intermediate 73: 3-cyclopropyl-1-(2,2-difluoroethyl)-N-[3-(difluoromethoxy)-4- formylphenyl]-1H-pyrazole-4-carboxamide

[0462] Step 1: ethyl 3-cyclopropyl-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxylate

[0463] Cesium carbonate (5.88 g, 18.03 mmol) was added to a stirred solution of ethyl 5- cyclopropyl-1H-pyrazole-4-carboxylate (2.50 g, 13.87 mmol) in acetonitrile (15 mL) in a 10 – 20 mL Biotage microwave vial. After stirring for five minutes, 1,1-difluoro-2-iodoethane (3.66 mL, 41.62 mmol) was added, the vial was capped and the reaction was stirred at 60°C over the weekend. The crude reaction mixture was partitioned between EtOAc (100 mL) and water (50 mL). The organic phase was washed with water (50 mL) and brine (10 mL) before passing through a phase separator and concentrating. The residue was purified by automated flash column chromatography (Biotage Selekt) via a Biotage® Sfär Silica HC D 50 g/20 µm column, preconditioned with heptane. The product was isolated by elution with heptane (2 CV) gradient to 10% EtOAc in heptane (3 CV) and isocratic 10% EtOAc in heptane. Fractions were combined and concentrated to dryness under reduced pressure, to afford a 10:1 mixture of the title compound and its regioisomer ethyl 5-cyclopropyl-1-(2,2-difluoroethyl)-1H-pyrazole-4- carboxylate as a colourless syrup (2.85 g, 84 %): ¹H NMR δ 0.89–0.98 (4H, m), 1.34 (3H, t), 152 201260-WO-PCT 2.52 (1H, tt), 4.25–4.37 (4H, m), 6.05 (1H, tt), 7.84 (1H, s).19F NMR (470 MHz, CDCl3) δ - 122.73 (-122.33 minor isomer). [0464] Step 2: 3-cyclopropyl-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxylic acid

[0465] Aq.3.8M sodium hydroxide (8.27 mL, 31.43 mmol) was added portionwise to a colourless solution of ethyl 3-cyclopropyl-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxylate (3.07 g, 12.57 mmol) in methanol (20 mL). The bright yellow hazy mixture was then stirred at 50°C; within an hour the reaction appeared as a clear pale yellow solution, which was stirred at 50°C overnight. The reaction was poured into ice/water (100 mL) and acidified by slow addition of ca.2 mL 37% hydrochloric acid. The resulting colourless precipitate was extracted into EtOAc (2 x 75 mL). The combined extractions were washed with water (50 mL) and brine (10 mL) before passing through a phase separator and concentrating to obtain a 10:1 mixture of the title compound and its regioisomer as a colourless solid (2.33 g, 86%): ¹H-NMR δ 0.75–0.92 (4H, m), 2.46–2.49 (1H, m), 4.54 (2H, td), 6.31 (1H, tt), 8.15 (1H, s), 12.30 (1H, s).19F NMR (470 MHz, DMSO) δ -121.95(minor), -122.92(major). [0466] Step 3: 3-cyclopropyl-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxamide

[0467] N-ethyl-N-isopropylpropan-2-amine (3.22 mL, 18.50 mmol) was added to a suspension of 3-cyclopropyl-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxylic acid (1.000 g, 4.63 mmol) in acetonitrile (30 mL), to afford a colourless solution. HATU (695 mg, 1.83 mmol) was added and the reaction stirred for ten minutes, to give a dark brown solution. Ammonium chloride (619 mg, 11.56 mmol) was added and the reaction was stirred at room temperature overnight. The resulting suspension was poured into aq. sat. NaHCO3 (200 mL) and the product was extracted into EtOAc (50 mL). The organic layer was washed with water (20 mL) and brine (5 mL) before passing through a phase separator and the resulting orange solution was concentrated. The residue was purified by automated flash column chromatography (Biotage Selekt) via a Biotage® Sfär Silica HC D 25 g/20 µm column, preconditioned with heptane. The product was isolated by elution with isocratic heptane (1CV) followed by gradient elution to 50% EtOAc in 153 201260-WO-PCT heptane over 2CV, then 75% EtOAc over 10CV. The product spots were combined and concentrated to dryness under reduced pressure. The resulting solid was triturated with DCM (10 mL) and isolated by filtration, to afford the title compound, with only trace amounts of the regioisomer, as a colourless powdered solid (540 mg, 54%): ¹H-NMR δ 0.61–0.68 (2H, m), 0.69–0.77 (2H, m), 2.47–2.55 (1H, m), 4.41 (2H, td), 6.18 (1H, t), 6.83 (1H, s), 7.27 (1H, s), 8.00 (1H, s).19F NMR (470 MHz, DMSO) δ -122.75. [0468] Step 4: 3-cyclopropyl-1-(2,2-difluoroethyl)-N-[3-(difluoromethoxy)-4-formylphenyl]- 1H-pyrazole-4-carboxamide (Intermediate 73) [0469] A 10-20 mL Biotage microwave vial was charged with 3-cyclopropyl-1-(2,2- difluoroethyl)-1H-pyrazole-4-carboxamide (0.215 g, 1.00 mmol), 4-bromo-2- (difluoromethoxy)benzaldehyde (0.251 g, 1.00 mmol), cesium carbonate (0.652 g, 2.00 mmol), XantPhos Pd G3 (0.028 g, 0.03 mmol) and (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) (5.79 mg, 10.00 µmol) and capped. The vial was flushed with N2 by 3 x cycle of evacuation and N₂, before dioxane (10 mL) that had previously been purged with bubbling N2 for 30 minutes was added. The reaction was stirred at 80°C overnight. The reaction was diluted with EtOAc (25 mL) and washed with water (2 x 25 mL) and brine (5 mL). The organic layer was passed through an ISOLUTE® Si-TMT 500 mg /6 mL cartridge to remove Pd residues and a phase separator before concentrating. The residue was purified by automated flash column chromatography (Biotage Selekt) via a Biotage® Sfär Silica HC D 25 g/20 µm column, preconditioned with heptane. The product was isolated by gradient elution 0 to 75% EtOAc in heptane over 30CV, to afford the title compound as a colourless solid (310 mg, 80 %): ¹H NMR (500 MHz, DMSO, 25°C) δ 0.79–0.84 (2H, m), 0.88–0.94 (2H, m), 2.56–2.65 (1H, m), 4.62 (2H, td), 6.36 (1H, tt), 7.33 (1H, t), 7.71 (1H, dd), 7.84 (1H, d), 7.92 (1H, d), 8.43 (1H, s), 10.15 (1H, s), 10.33 (1H, s).19F NMR (470 MHz, DMSO) δ -81.76, -122.76. Intermediate 74: 3-cyclopropyl-N-[3-(difluoromethoxy)-4-formylphenyl]-1- (trifluoromethyl)-1H-pyrazole-4-carboxamide – mixture of regioisomers

[0470] Step 1: ethyl 1-[bromo(difluoro)methyl]-3-cyclopropyl-1H-pyrazole-4-carboxylate 154

[0471] NaH (2.66 g, 110.98 mmol) was added to ethyl 3-cyclopropyl-1H-pyrazole-4- carboxylate (10 g, 55.49 mmol, CAS RN 1246471-38-4) in DMF (80 mL) cooled to 0°C. The resulting mixture was stirred at 0 °C for 30 minutes, then dibromodifluoromethane (58.2 g, 277.46 mmol) was added to the mixture. The resulting mixture was stirred at 0 °C for overnight. The reaction mixture was combined with two parallel reaction mixtures starting from ethyl 3- cyclopropyl-1H-pyrazole-4-carboxylate (1 g and 10 g), then reaction mixture was diluted with EtOAc (750 mL), and washed sequentially with water (3 x 400 mL), brine (3 x 400 mL), dried (sodium sulfate), filtered and concentrated. Flash C18-flash chromatography of the residue using acetonitrile in water (0 to 80 %, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a mixture with its regioisomer ethyl 1- [bromo(difluoro)methyl]-5-cyclopropyl-1H-pyrazole-4-carboxylate as a yellow oil (18.20 g, 87 %): ¹H NMR (400 MHz, DMSO, 24°C) δ 0.90 (ddt, J = 17.9, 6.8, 4.3 Hz, 2H), 0.97–1.05 (m, 1H), 1.08–1.14 (m, 1H), 1.29 (td, J = 7.1, 3.7 Hz, 3H), 2.48–2.57 (m, 1H), 4.22–4.32 (m, 2H), 8.84 (s, 1H). The regioisomer was carried through the reaction sequence and separated at the example stage. [0472] Step 2: ethyl 3-cyclopropyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylate

[0473] Silver tetrafluoroborate (13.10 g, 67.29 mmol) was added to ethyl 1- [bromo(difluoro)methyl]-3-cyclopropyl-1H-pyrazole-4-carboxylate (16 g, 51.76 mmol) in DCM (150 mL) at -78°C. The resulting mixture was stirred at rt for 2 hours. The reaction mixture was then diluted with EtOAc (500 mL), washed sequentially with ice water (3 x 300 mL), brine (3 x 300 mL), dried (sodium sulfate), filtered and concentrated to provide the crude title compound as a yellow oil which was used in the next step without further purification (12.30 g, 96 %): ¹H NMR (400 MHz, DMSO, 24°C) δ 0.81–0.9 (m, 2H), 0.96–1.04 (m, 1H), 1.06–1.15 (m, 1H), 1.29 (td, J = 7.1, 3.4 Hz, 3H), 2.45–2.53 (m, 1H), 4.27 (dq, J = 10.6, 7.1 Hz, 2H), 8.95 (s, 1H). [0474] Step 3: 3-cyclopropyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid

[0475] LiOH (3.47 g, 145.04 mmol) was added to ethyl 3-cyclopropyl-1-(trifluoromethyl)-1H- pyrazole-4-carboxylate (12 g, 48.35 mmol) in MeOH (8 mL) and water (4 mL). The resulting mixture was stirred at rt for 2 hours. The reaction mixture was combined with two parallel reaction mixtures starting from ethyl 3-cyclopropyl-1-(trifluoromethyl)-1H-pyrazole-4- carboxylate (0.3 and 1.6 g), then acidified with aq.2 M HCl. The reaction mixture was diluted with EtOAc (500 mL), washed sequentially with water (3 x 300 mL), brine (300 mL), then dried (sodium sulfate), filtered and concentrated to obtain the crude title compound as a yellow solid which was used without further purification in the next step (10.20 g, 73 %): ¹H NMR (400 MHz, DMSO, 24°C) δ 0.86 (dt, J = 4.9, 3.0 Hz, 2H), 0.95–1.02 (m, 2H), 2.59 (tt, J = 8.4, 5.1 Hz, 1H), 8.81 (s, 1H). [0476] Step 4: 3-cyclopropyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0477] 3-cyclopropyl-1-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (5 g, 22.71 mmol) was converted into the title compound similar as described for Intermediate 73, step 3, yellow solid (5.90 g, 98 %): ¹H NMR (400 MHz, DMSO, 24°C) δ 0.79–0.86 (m, 3H), 0.93–0.98 (m, 2H), 2.69 (s, 1H), 7.66 (s, 2H), 8.77 (s, 1H). [0478] Step 5: 3-cyclopropyl-N-[3-(difluoromethoxy)-4-formylphenyl]-1-(trifluoromethyl)-1H- pyrazole-4-carboxamide (Intermediate 74) [0479] The title compound including regioisomer was obtained similar as described for Intermediate 73, step 4. Intermediate 75: 3-cyclopropyl-N-[3-(difluoromethoxy)-4-formylphenyl]-1-(2,2,2- trifluoroethyl)-1H-pyrazole-4-carboxamide

[0480] Step 1: ethyl 3-cyclopropyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate

[0481] Cesium carbonate (5.88 g, 18.03 mmol) was added to a pale yellow solution of ethyl 5- cyclopropyl-1H-pyrazole-4-carboxylate (2.50 g, 13.87 mmol) in DMF (15 mL) in a 10 – 20 mL Biotage microwave vial. Instant colour change to bright orange was observed.1,1,1-trifluoro-2- iodoethane (4.10 mL, 41.62 mmol) was added and the vial was capped. The orange reaction mixture was stirred at 60°C over the weekend. The reaction mixture was then partitioned between EtOAc (75 mL) and water (100 mL). The organic phase was washed with water (2 x 75 mL) and brine (10 mL) before passing through a phase separator and concentrating. The residue was purified by automated flash column chromatography (Biotage Selekt) via a Biotage® Sfär Silica HC D 100 g/20 µm column, preconditioned with heptane. The product was isolated by elution with isocratic heptane (2 CV) followed by gradient elution to 25% EtOAc in heptane over 20 CV. Appropriate fractions were combined and concentrated to afford the title compound a colourless solid (2.10 g, 46 %): ¹H NMR (500 MHz, DMSO-d6, 25°C) δ 0.78–0.84 (2H, m), 0.91–0.97 (2H, m), 1.29 (3H, t), 2.45–2.5 (1H, m), 4.24 (2H, q), 5.09 (2H, q), 8.31 (1H, s).19F NMR (470 MHz, DMSO) δ -70.14. [0482] Step 2: 3-cyclopropyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid

[0483] Ester hydrolysis of ethyl 3-cyclopropyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4- carboxylate (2.10 g, 8.01 mmol) was performed similar as described in step 2 for Intermediate 73 providing the title compound as a colourless solid (1.79 g, 95 %): ¹H NMR (500 MHz, 201260-WO-PCT DMSO-d6, 25°C) δ 0.75–0.82 (2H, m), 0.86–0.95 (2H, m), 5.05 (2H, q), 8.22 (1H, s), 12.43 (1H, s).19F NMR (470 MHz, DMSO-d6) δ -70.18. [0484] Step 3: 3-cyclopropyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide

[0485] 3-cyclopropyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid (1.00 g, 4.27 mmol) was treated similar as described in step 3, Intermediate 73. The title compound was isolated by trituration from DCM (10 mL), then filtered, washed with fresh DCM (2 mL) and dried to provide a colourless powdered solid (0.84 g, 84%): ¹H NMR (500 MHz, DMSO, 25°C) δ 0.65–0.81 (2H, m), 0.81–0.98 (2H, m), 2.58–2.66 (1H, m), 5.05 (2H, q), 7.00 (1H, s), 7.46 (1H, s), 8.16 (1H, s).19F NMR (470 MHz, DMSO) δ -70.20. [0486] Step 4: 3-cyclopropyl-N-[3-(difluoromethoxy)-4-formylphenyl]-1-(2,2,2-trifluoroethyl)- 1H-pyrazole-4-carboxamide (Intermediate 75) [0487] 3-cyclopropyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (233 mg, 1.00 mmol) and 4-bromo-2-(difluoromethoxy)benzaldehyde (0.251 g, 1.00 mmol) was treated similar as described in step 4, intermediate 73 to provide the title compound as a colourless solid (285 mg, 71 %): ¹H NMR (500 MHz, DMSO, 25°C): δ 0.77–0.84 (2H, m), 0.89–0.96 (2H, m), 2.57–2.63 (1H, m), 5.16 (2H, q), 7.33 (1H, t), 7.70 (1H, dd), 7.85 (1H, d), 7.92 (1H, d), 8.48 (1H, s), 10.15 (1H, s), 10.40 (1H, s).19F NMR (470 MHz, DMSO) δ -69.99, -81.77. Intermediate 76: 3-cyclopropyl-N-[3-(difluoromethoxy)-4-formylphenyl]-1-(propan-2-yl)- 1H-pyrazole-4-carboxamide

[0488] Step 1: 3-cyclopropyl-1-(propan-2-yl)-1H-pyrazole-4-carboxamide 158

[0489] To a stirred solution of 3-cyclopropyl-1-isopropyl-1H-pyrazole-4-carboxylic acid (0.4 g, 2.06 mmol) in DCM (10 mL) was added oxalyl dichloride (0.366 ml, 4.32 mmol), and finally was added 1 drop of DMF and the reaction was stirred another 30 minutes, then concentrated. The residue was redissolved in DCM (5 mL) added methanolic 4M NH3 in (10 ml, 40.00 mmol) and was stirred for 30 minutes and concentrated. The residue was slurried in EtOAc (150 mL), washed with water (100mL) and Brine (30 mL), dried (Na2SO4), filtered and concentrated to give a white solid. This solid was triturated with a small amount of DCM, and was then filtered and dried in air, to give the title compound as a white solid (0.30 g, 75 %): ¹H NMR (500 MHz, DMSO) δ 8.12 (s, 1H), 7.23 (s, 1H), 6.84 (s, 1H), 4.33 (hept, 1H), 2.61 (tt, 1H), 1.36 (d, 6H), 0.79 – 0.85 (m, 2H), 0.75 (tt, 2H). [0490] Step 2: 3-cyclopropyl-N-[3-(difluoromethoxy)-4-formylphenyl]-1-(propan-2-yl)-1H- pyrazole-4-carboxamide (Intermediate 75) [0491] 1,4-dioxane (10mL) was added to 3-cyclopropyl-1-isopropyl-1H-pyrazole-4- carboxamide (0.28 g, 1.45 mmol), 4-bromo-2-(difluoromethoxy)benzaldehyde (0.364 g, 1.45 mmol), cesium carbonate (0.944 g, 2.90 mmol), XantPhos Pd G3 (0.041 g, 0.04 mmol), (9,9- dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (8.38 mg, 0.01 mmol) and the resulting suspension was degassed with nitrogen, then stirred at 80 °C for 2h and then allowed to cool to rt. The reaction mixture was then partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated. The residue was dissolved in 10 mL of DCM, applied on a silica gel column, pre-conditioned with EtOAc in heptane (20 %). Gradient elution with 20-50 % EtOAc in heptane followed by concentration of the appropriate fractions gave the title compound as a white solid (0.45g, 85 %): ¹H NMR (500 MHz, DMSO) δ 10.12 – 10.16 (m, 2H), 8.41 (s, 1H), 7.89 – 7.93 (m, 1H), 7.84 (d, 1H), 7.66 – 7.72 (m, 1H), 7.33 (t, 1H), 4.41 (hept, 1H), 2.59 (tt, 1H), 1.40 (d, 6H), 0.85 – 0.93 (m, 2H), 0.76 – 0.85 (m, 2H). Intermediate 77: 3-cyclobutyl-N-[3-(difluoromethoxy)-4-(²H)formylphenyl]-1-methyl-1H- pyrazole-4-carboxamide

[0492] Step 1: [4-bromo-2-(difluoromethoxy)phenyl](²H2)methanol

[0493] LiAlD4 (0.896 g, 21.35 mmol) was added to methyl 4-bromo-2- (difluoromethoxy)benzoate (3 g, 10.67 mmol, CAS RN 553672-24-5) in THF (30 mL) at -20°C under nitrogen. The resulting mixture was stirred at -20 °C for 1 hour. The reaction mixture was then quenched with saturated NH4Cl (75 mL), extracted with EtOAc (3 x 125 mL), the organic layer was dried (Na₂SO₄), filtered and concentrated. Flash chromatography of the residue using EtOAc in petroleum ether (0-20 %, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (2.100 g, 77 %): 1H NMR (400 MHz, DMSO-d6, 27°C) δ 5.28 (s, 1H), 6.98–7.55 (m, 4H). [0494] Step 2: 4-bromo-2-(difluoromethoxy)(formyl-²H)benzaldehyde

[0495] Manganese(IV) oxide (2727 mg, 31.37 mmol) was added to [4-bromo-2- (difluoromethoxy)phenyl](²H2)methanol (400 mg, 1.57 mmol) in DCM (4 mL). The resulting mixture was stirred at 30 °C for 15 hours, then filtered through celite and concentrated. Flash chromatography of the residue using EtOAc in petroleum ether (0-10%, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a white solid (280 mg, 71 %): ¹H NMR (300 MHz, DMSO, 26°C) δ 7.19–7.65 (1H, m), 7.66–7.7 (2H, m), 7.78 (1H, dd). [0496] Step 3: 3-cyclobutyl-1-methyl-1H-pyrazole-4-carboxamide

[0497] 3-cyclobutyl-1-methyl-1H-pyrazole-4-carboxylic acid (950 mg, 5.27 mmol, CAS RN 137614-13-2) was treated similar as described in step 4, Intermediate 73 to provide the title compound as a white solid (620 mg, 66 %): ¹H NMR (400 MHz, DMSO) δ 1.68–1.81 (m, 1H), 1.82–1.95 (m, 1H), 2.11–2.22 (m, 4H), 3.78 (s, 3H), 3.91–4.04 (m, 1H), 6.76 (s, 1H), 7.19 (s, 1H), 8.01 (s, 1H). [0498] Step 4, 3-cyclobutyl-N-[3-(difluoromethoxy)-4-(²H)formylphenyl]-1-methyl-1H- pyrazole-4-carboxamide (Intermediate 77) [0499] 3-cyclobutyl-1-methyl-1H-pyrazole-4-carboxamide (142 mg, 0.79 mmol) and 4-bromo- 2-(difluoromethoxy)(formyl-²H)benzaldehyde (200 mg, 0.79 mmol) was treated similar as described in step 4, intermediate 75 to provide the title compound as a yellow solid (220 mg, 79 %): ¹H NMR (400 MHz, DMSO, 26°C) δ 1.76–1.87 (m, 1H), 1.95 (dt, J = 10.5, 8.9 Hz, 1H), 2.18–2.31 (m, 4H), 3.87 (s, 3H), 3.93–4.02 (m, 1H), 7.14–7.51 (m, 1H), 7.69 (dd, J = 8.6, 1.9 Hz, 1H), 7.79–7.9 (m, 2H), 8.35 (s, 1H), 10.17 (s, 1H). m/z (ES+) [M+H]+ = 351.2. Intermediate 78: 4-cyano-N-[4-(²H)formyl-3-(trifluoromethyl)phenyl]-2-methylbenzamide

[0500] Step 1: [4-bromo-2-(trifluoromethyl)phenyl](²H2)methanol

[0501] Lithium Aluminum Deuteride (1.186 g, 28.26 mmol) was added to methyl 4-bromo-2- (trifluoromethyl)benzoate (2.00 g, 7.07 mmol, CAS RN 957207-58-8) in THF (20 mL) at 0°C under nitrogen. The resulting mixture was stirred at rt for 2 hours. The reaction mixture was then quenched with aq. saturated NH₄Cl (20 mL), extracted with EtOAc (2 x 75 mL), the organic layer was dried (Na2SO4), filtered and concentrated. Flash C18-chromatography of the residue using acetonitrile in water (60 to 70 %, gradient elution) followed by concentration of the 201260-WO-PCT appropriate fractions gave the title compound as a yellow liquid (1.00 g, 55 %): ¹H NMR (300 MHz, DMSO-d6) δ 7.91 (dd, J = 8.3, 2.1 Hz, 1H), 7.83 (d, J = 2.1 Hz, 1H), 7.73 (dd, J = 8.4, 0.9 Hz, 1H), 5.55 (s, 1H). [0502] Step 2: 4-bromo-2-(trifluoromethyl)(formyl-²H)benzaldehyde

[0503] [4-bromo-2-(trifluoromethyl)phenyl](²H2)methanol (810 mg) was treated similar as described in step 2, intermediate 77. Flash chromatography of the crude residue using EtOAc in petroleum ether (0-50 %, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a pale yellow solid (360 mg, 45.0 %): ¹H NMR (400 MHz, DMSO, 26°C) δ 8.02 (d, J = 8.1 Hz, 1H), 8.15 (d, J = 10.1 Hz, 2H). [0504] Step 3: 4-cyano-2-methylbenzamide

[0505] 4-cyano-2-methylbenzoic acid (1.00 g, 6.21 mmol) was treated similar as described in step 4, Intermediate 73 to provide the title compound as a white solid (700 mg, 70 %): ¹H NMR (300 MHz, Methanol-d4) δ 7.67 (dt, J = 1.6, 0.8 Hz, 1H), 7.63 (dd, J = 7.8, 1.6 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 2.48 (s, 3H). [0506] Step 4, 4-cyano-N-[4-(²H)formyl-3-(trifluoromethyl)phenyl]-2-methylbenzamide (Intermediate 78) [0507] 4-cyano-2-methylbenzamide (303 mg, 1.89 mmol) and 4-bromo-2- (trifluoromethyl)(formyl-²H)benzaldehyde (400 mg, 1.57 mmol) was treated similar as described in step 4, intermediate 75 to provide the title compound as a yellow solid (437 mg, 83 %): ¹H NMR (300 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.36 (d, J = 1.7 Hz, 1H), 8.26 – 8.10 (m, 2H), 7.94 – 7.83 (m, 2H), 7.75 (d, J = 7.8 Hz, 1H), 2.44 (s, 3H). Intermediate 79: 4-cyano-N-[4-formyl-3-(trifluoromethyl)phenyl]-2-methylbenzamide 162

[0508] Step 1: (4-amino-2-(trifluoromethyl)phenyl)methanol

[0509] Lithium aluminum hydride (1.0M in diethyl ether, 72.8 ml, 72.82 mmol) was added dropwise, to a chilled solution of methyl 4-amino-2-(trifluoromethyl)benzoate (7.60 g, 34.68 mmol) in THF (300 mL) on an ice/water bath, ensuring T <5°C. The reaction mixture was stirred for 18 hours, while slowly coming to room temperature. The reaction was chilled (ice/water bath) and quenched by the consecutive, dropwise addition of water (2.75 mL), 3.8 M NaOH_(aq) (2.75 mL) and water (8.25 mL) and stirred vigorously for 30 minutes. The mixture was filtered through Celite and the Celite was washed with THF (50 mL). The combined filtrate/wash was concentrated under reduced pressure, taken up in EtOAc (250 mL) and washed with 8 % NaHCO3 (2 x 100 mL). The organic solution was passed through a phase separator to remove water and concentrated to dryness under reduced pressure, to afford (4-amino-2- (trifluoromethyl)phenyl)methanol as an orange solid (5.75 g, 87% yield): ¹H NMR (400 MHz, DMSO-d6) δ 4.46 (d, 2H), 5.05 (t, 1H), 5.43 (s, 2H), 6.78 (dd, 1H), 6.85 (d, 1H), 7.33 (d, 1H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ -58.72. [0510] Step 2: 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(trifluoromethyl)aniline

[0511] (4-Amino-2-(trifluoromethyl)phenyl)methanol (5.75 g, 30.08 mmol) and 1H-imidazole (4.10 g, 60.16 mmol) were combined in DCM (150 mL) and the solution was chilled on an ice/water bath.1.0 M tert-butylchlorodimethylsilane in DCM (39.1 mL, 39.10 mmol) was added and the reaction was stirred for 18 hours, slowly coming to room temperature.8% NaHCO3 (aq) (50 mL) was added and the mixture was stirred vigorously. The organic phase was isolated by passing through a phase separator and concentrated to dryness under reduced pressure. Purification by normal phase flash column chromatography (Puriflash® 120g/25µm silica 201260-WO-PCT column, preconditioned with heptane. Elution with heptane (400 mL), then 5% EtOAc in heptane) afforded 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(trifluoromethyl)aniline as a pale orange oil (7.40 mg, 81% isolated yield): ¹H NMR (400 MHz, DMSO-d6) δ 0.05 (s, 6H), 0.88 (s, 9H), 4.64 (s, 2H), 5.50 (s, 2H), 6.78 (dd, 1H), 6.87 (d, 1H), 7.28 (d, 1H); ¹⁹F-NMR (376 MHz, DMSO-d6) δ -58.82; LCMS m/z (ES⁺) 306.2 [M+H]⁺. [0512] Step 3: N-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(trifluoromethyl)phenyl]-4- cyano-2-methylbenzamide

[0513] A catalytic amount of N,N-DMF was added to a suspension of 4-cyano-2-methylbenzoic acid (4.30 g, 26.7 mmol) with oxalyl dichloride (10.25 mL, 121.15 mmol) in DCM (250 mL). After one hour, the reaction was concentrated to dryness under reduced pressure, to afford a colourless solid. The residue was dissolved in 2-methyl tetrahydrofuran (50 mL) and added to a solution of 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(trifluoromethyl)aniline (7.40 g, 24.23 mmol) and triethylamine (10.1 mL, 72.7 mmol) in 2-methyl tetrahydrofuran (150 mL). The reaction was stirred at room temperature for 18 hours before quenching by slow addition of 8% NaHCO3 (aq) (100 mL). The organic phase was separated and washed consecutively with 8% NaHCO_{3 (aq)} (100 mL), water (100 mL) and brine (25 mL) before passing through a phase separator. Concentration to dryness under reduced pressure afforded N-[4-({[tert- butyl(dimethyl)silyl]oxy}methyl)-3-(trifluoromethyl)phenyl]-4-cyano-2-methylbenzamide as a pale pink solid (10.75 g, 99%): ¹H-NMR (500 MHz, DMSO-d₆) δ 0.09 (s, 6H).0.90 (s, 9H), 2.41 (s, 3H), 4.81 (s, 2H), 7.66 – 7.74 (m, 2H), 7.79 – 7.83 (m, 1H), 7.85 (d, 1H), 7.95 (dd, 1H), 8.18 (d, 1H), 10.79 (s, 1H); ¹⁹F-NMR (470 MHz, DMSO-d6) δ -59.21. LCMS m/z (ES-) 447.3 [M-H]-. [0514] Step 4: 4-cyano-N-[4-(hydroxymethyl)-3-(trifluoromethyl)phenyl]-2-methylbenzamide

164 201260-WO-PCT [0515] N-[4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3-(trifluoromethyl)phenyl]-4-cyano-2- methylbenzamide (10.75 g, 23.97 mmol) was suspended in 1.25 M HCl in MeOH (150 mL, 187.50 mmol). The mixture was stirred at room temperature for 18 hours before being concentrated to dryness under reduced pressure. Purification by normal phase flash column chromatography (Puriflash® 330g/50µM silica column, preconditioned with heptane. Stepped gradient elution with heptane (1000 mL), 20% EtOAc in heptane (1000 mL) and 40% EtOAc in heptane (4000 mL)) afforded 4-cyano-N-[4-(hydroxymethyl)-3-(trifluoromethyl)phenyl]-2- methylbenzamide as a colourless solid (6.00 g, 75% isolated yield): ¹H-NMR (400 MHz, DMSO-d6) δ 2.42 (s, 3H), 4.64 (d, 2H), 5.45 (t, 1H), 7.69 (d, 1H), 7.75 (d, 1H), 7.82 (d, 1H), 7.86 (s, 1H), 7.91 – 7.99 (m, 1H), 8.16 (d, 1H), 10.76 (s, 1H).¹⁹F NMR-(376 MHz, DMSO-d6) δ -59.24; LCMS m/z (ES-) 333.2 [M-H]-. [0516] Step 5: 4-cyano-N-[4-formyl-3-(trifluoromethyl)phenyl]-2-methylbenzamide (Intermediate 79) [0517] Dess-Martin periodinane (9.90 g, 23.33 mmol) was added in one portion to a suspension of 4-cyano-N-[4-(hydroxymethyl)-3-(trifluoromethyl)phenyl]-2-methylbenzamide (6.00 g, 17.95 mmol) in DCM (200 mL). The mixture was stirred at room temperature for 18 hours.15% 3:2 Na₂S₂O₃/NaHCO_3(aq) (300 mL) was added to the reaction and the mixture was stirred vigorously for 30 minutes. The mixture filtered, the phases separated and the aqueous phase was extracted with DCM (2 x 100 mL). The organic solutions were combined, washed with 8% NaHCO3(aq) (200 mL) and passed through a phase separator before concentrating to dryness under reduced pressure. Purification by normal phase flash column chromatography (Puriflash 330g/50µm silica column, preconditioned with heptane; elution with heptane (1000 mL) then 25% EtOAc in heptane (3000 mL)). Concentration of the pure fractions under reduced pressure gave a thick suspension; filtration and drying in vacuo afforded 4-cyano-N-[4-formyl-3- (trifluoromethyl)phenyl]-2-methylbenzamide as a colourless solid (5.05 g, 85% isolated yield): ¹H NMR (400 MHz, DMSO-d6) δ 2.44 (s, 3H), 7.75 (d, 1H), 7.85 (dd, 1H), 7.88 (s, 1H), 8.13 – 8.23 (m, 2H), 8.36 (s, 1H), 10.15 – 10.21 (m, 1H), 11.20 (s, 1H); ¹⁹F-NMR (376 MHz, DMSO- d6) δ -55.98; LCMS m/z (ES-) 331.1 [M-H]-. Intermediate 80: N-{4-[chloro(²H2)methyl]-3-(difluoromethoxy)phenyl}-3-cyclopropyl-1- (propan-2-yl)-1H-pyrazole-4-carboxamide 165

[0518] Step 1: methyl 4-{[3-cyclopropyl-1-(propan-2-yl)-1H-pyrazole-4-carbonyl]amino}-2- (difluoromethoxy)benzoate

[0519] (2'-amino-[1,1'-biphenyl]-2-yl)((5-(diphenylphosphaneyl)-9,9-dimethyl-9H-xanthen-4- yl)diphenyl-l5-phosphaneyl)palladium(III) methanesulfonate (265 mg, 0.28 mmol) was added to methyl 4-bromo-2-(difluoromethoxy)benzoate (785 mg, 2.79 mmol), 3-cyclopropyl-1-isopropyl- 1H-pyrazole-4-carboxamide (540mg, 2.79 mmol, step 1, intermediate 76) and cesium carbonate (1821 mg, 5.59 mmol) in 1,4-dioxane (10mL). The resulting mixture was stirred at 90 °C for overnight under nitrogen, then allowed to cool to rt and filtered through celite. The reaction mixture was diluted with EtOAc (100 mL), washed sequentially with water (100 mL), brine (100 mL), then dried (sodium sulfate), filtered and concentrated. Flash chromatography using EtOAc in petroleum ether (0-10 %, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a white solid (800 mg, 72.8 %): ¹H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.38 (s, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 1.9 Hz, 1H), 7.70 (dd, J = 8.7, 2.0 Hz, 1H), 7.12 (t, J = 74.2 Hz, 1H), 4.39 (hept, J = 6.6 Hz, 1H), 3.80 (s, 3H), 2.65 – 2.53 (m, 1H), 1.39 (d, J = 6.6 Hz, 6H), 0.97 – 0.72 (m, 4H). [0520] Step 2: 3-cyclopropyl-N-{3-(difluoromethoxy)-4-[hydroxy(²H2)methyl]phenyl}-1- (propan-2-yl)-1H-pyrazole-4-carboxamide

201260-WO-PCT [0521] LiAlD4 (240 mg, 5.72 mmol) were added to methyl 4-{[3-cyclopropyl-1-(propan-2-yl)- 1H-pyrazole-4-carbonyl]amino}-2-(difluoromethoxy)benzoate (750mg, 1.91 mmol) in THF (15 mL) at -5°C under nitrogen. The resulting mixture was stirred at 0 °C for 3 hours, then quenched with aq.15% NaOH (0.24ml), filtered and concentrated to provide the title compound as a white solid which was use in the next step without further purification (650 mg, 93 %): ¹H NMR (300 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.34 (s, 1H), 7.66 (s, 1H), 7.53 (dd, J = 8.4, 2.0 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 74.3 Hz, 1H), 5.09 (s, 1H), 4.38 (hept, J = 6.6 Hz, 1H), 2.61 (td, J = 8.3, 4.0 Hz, 1H), 1.39 (d, J = 6.6 Hz, 6H), 0.96 – 0.65 (m, 4H). [0522] Step 3: N-{4-[chloro(²H2)methyl]-3-(difluoromethoxy)phenyl}-3-cyclopropyl-1-(propan- 2-yl)-1H-pyrazole-4-carboxamide (Intermediate 80) [0523] SOCl₂ (0.079 mL, 1.09 mmol) were added dropwise to DMF (0.021 mL, 0.27 mmol) and 3-cyclopropyl-N-{3-(difluoromethoxy)-4-[hydroxy(²H2)methyl]phenyl}-1-(propan-2-yl)-1H- pyrazole-4-carboxamide (200mg, 0.54 mmol) in MeCN (6 mL) at 0°C under nitrogen. The resulting mixture was stirred at RT for 4 hours, then the formed precipitate was collected by filtration, washed with MeCN (2 mL) and dried in vacuum to afford a 1:1 mixture of the starting material and the title compound which was used without further purification in the next step. Intermediate 81: N-{4-[chloro(²H²)methyl]-3-(difluoromethoxy)phenyl}-3-cyclopropyl-1- (2,2-difluoroethyl)-1H-pyrazole-4-carboxamide

[0524] Step 1: methyl 4-{[3-cyclopropyl-1-(2,2-difluoroethyl)-1H-pyrazole-4-carbonyl]amino}- 2-(difluoromethoxy)benzoate

[0525] 4-bromo-2-(difluoromethoxy)benzoate (1.4 g, 4.98 mmol) and 3-cyclopropyl-1-(2,2- difluoroethyl)-1H-pyrazole-4-carboxamide (1.286 g, 5.98 mmol) was treated similar as 167 201260-WO-PCT described in step 1, intermediate 80. Flash alumina chromatography of the residue using EtOAc in petroleum ether (10-25 %, gradient elution), followed by concentration of the appropriate fractions gave the title compound as a yellow solid (1.800 g, 87 %): ¹H NMR (400 MHz, DMSO) δ 0.81 (2H, dt), 0.91 (2H, td), 2.61 (1H, td), 3.81 (3H, s), 4.61 (2H, td), 6.35 (1H, tt), 7.13 (1H, t), 7.73 (1H, dd), 7.8–7.83 (1H, m), 7.89 (1H, d), 8.41 (1H, s), 10.23 (1H, s). [0526] Step 2: 3-cyclopropyl-1-(2,2-difluoroethyl)-N-{3-(difluoromethoxy)-4- [hydroxy(²H₂)methyl]phenyl}-1H-pyrazole-4-carboxamide

[0527] methyl 4-{[3-cyclopropyl-1-(2,2-difluoroethyl)-1H-pyrazole-4-carbonyl]amino}-2- (difluoromethoxy)benzoate (1.5 g, 3.61 mmol) was added to Lithium Aluminum Deuteride (0.606 g, 14.45 mmol) in THF (20 mL) at 0°C under nitrogen. The resulting solution was stirred at 25 °C for 15 hours. The reaction mixture was then poured into aq. saturated NH4Cl (20 mL), extracted with EtOAc (1 x 50 mL), the organic layer was dried (Na2SO4), filtered and concentrated. Flash chromatography of the residue using EtOAc in petroleum ether (0-60 %, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a brown solid (1.100 g, 78 %): ¹H NMR (300 MHz, DMSO, 24°C) δ 0.84 (4H, ddt), 2.61 (1H, td), 4.58 (2H, td), 6.14–6.54 (1H, m), 6.86–7.35 (1H, m), 7.42 (1H, d), 7.55 (1H, dd), 7.67 (1H, d), 8.36 (1H, s), 9.92 (1H, s). [0528] Step 3: N-{4-[chloro(²H2)methyl]-3-(difluoromethoxy)phenyl}-3-cyclopropyl-1-(2,2- difluoroethyl)-1H-pyrazole-4-carboxamide (Intermediate 81) [0529] 3-cyclopropyl-1-(2,2-difluoroethyl)-N-{3-(difluoromethoxy)-4- [hydroxy(²H2)methyl]phenyl}-1H-pyrazole-4-carboxamide (900 mg, 2.31 mmol) was treated similar as described in step 3, intermediate 80. Flash chromatography of the residue using EtOAc in petroleum ether (0-60 %, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a white solid (420 mg, 45 %): ¹H NMR (300 MHz, DMSO, 24°C) δ 0.79 (2H, td), 0.89 (2H, ddt), 2.61 (1H, tt), 4.59 (2H, td), 6.34 (1H, tt), 7.21 (1H, t), 7.48 (1H, d), 7.56 (1H, dd), 7.74–7.8 (1H, m), 8.37 (1H, s), 10.04 (1H, s). 168 201260-WO-PCT Intermediate 82: N-{4-[chloro(²H2)methyl]-3-(difluoromethoxy)phenyl}-3-cyclopropyl-1- (2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide

[0530] Step 1: methyl 4-{[3-cyclopropyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4- carbonyl]amino}-2-(difluoromethoxy)benzoate

[0531] 4-bromo-2-(difluoromethoxy)benzoate (1.4 g, 4.98 mmol) and 3-cyclopropyl-1-(2,2,2- trifluoroethyl)-1H-pyrazole-4-carboxamide (1.286 g, 5.98 mmol) was treated similar as described in step 1, Intermediate 80. Flash alumina chromatography of the residue using EtOAc in petroleum ether (10-25 %, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (1.800 g, 83 %): ¹H NMR (400 MHz, DMSO, 24°C) δ 0.81 (2H, dt), 0.87–0.96 (2H, m), 2.61 (1H, tt), 3.81 (3H, s), 5.16 (2H, q), 7.23 (1H, d), 7.72 (1H, dd), 7.82 (1H, d), 7.90 (1H, d), 8.46 (1H, s), 10.30 (1H, s). [0532] Step 2: 3-cyclopropyl-N-{3-(difluoromethoxy)-4-[hydroxy(²H2)methyl]phenyl}-1-(2,2,2- trifluoroethyl)-1H-pyrazole-4-carboxamide

[0533] Methyl 4-{[3-cyclopropyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carbonyl]amino}-2- (difluoromethoxy)benzoate (1.5 g, 3.46 mmol) was treated similar as described in step 2, intermediate 81, to provide the title compound as a brown solid (1.300 g, 92 %): ¹H NMR (300 169 201260-WO-PCT MHz, DMSO, 24°C) δ 0.73–0.83 (2H, m), 0.86–0.97 (2H, m), 2.62 (1H, tt), 5.09–5.15 (2H, m), 7.10 (1H, s), 7.43 (1H, d), 7.51–7.58 (1H, m), 7.67 (1H, s), 8.41 (1H, s), 9.99 (1H, s). [0534] Step 3: N-{4-[chloro(²H2)methyl]-3-(difluoromethoxy)phenyl}-3-cyclopropyl-1-(2,2,2- trifluoroethyl)-1H-pyrazole-4-carboxamide (Intermediate 82) [0535] 3-cyclopropyl-N-{3-(difluoromethoxy)-4-[hydroxy(²H2)methyl]phenyl}-1-(2,2,2- trifluoroethyl)-1H-pyrazole-4-carboxamide (1.1 g, 2.70 mmol) was treated similar as described in step 3, intermediate 81, to provide the title compound as a white solid (0.64 g, 56 %): ¹H NMR (400 MHz, DMSO, 26°C) δ 0.81 (2H, dt), 0.88–0.99 (2H, m), 2.62 (1H, tt), 5.15 (2H, q), 7.23 (1H, t), 7.51 (1H, d), 7.57 (1H, dd), 7.75–7.81 (1H, m), 8.44 (1H, s), 10.12 (1H, s). Intermediate 83: N-{4-[chloro(²H²)methyl]-3-cyclopropylphenyl}-3-cyclopropyl-1-(2,2- difluoroethyl)-1H-pyrazole-4-carboxamide

[0536] Step 1: methyl 2-cyclopropyl-4-{[3-cyclopropyl-1-(2,2-difluoroethyl)-1H-pyrazole-4- carbonyl]amino}benzoate

[0537] 2'-amino-[1,1'-biphenyl]-2-yl)((5-(diphenylphosphaneyl)-9,9-dimethyl-9H-xanthen-4- yl)diphenyl-l5-phosphaneyl)palladium(III) methanesulfonate (223 mg, 0.24 mmol) was added to methyl 4-bromo-2-cyclopropylbenzoate (600 mg, 2.35 mmol, CAS RN 1422971-97-8), 3- cyclopropyl-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxamide (557 mg, 2.59 mmol) and 3- cyclopropyl-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxamide (557 mg, 2.59 mmol) in 1,4- dioxane (8 mL) at rt under nitrogen. The resulting mixture was stirred at 80 °C for 15 hours. Then the reaction mixture was allowed to cool to rt and diluted with EtOAc (100 mL), and washed sequentially with water (2 x 75 mL) and brine (2 x 75 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford the crude title compound which was used in the next step without further purification (900 mg). 170 201260-WO-PCT [0538] Step 2: 3-cyclopropyl-N-{3-cyclopropyl-4-[hydroxy(²H₂)methyl]phenyl}-1-(2,2- difluoroethyl)-1H-pyrazole-4-carboxamide

[0539] Methyl 2-cyclopropyl-4-{[3-cyclopropyl-1-(2,2-difluoroethyl)-1H-pyrazole-4- carbonyl]amino}benzoate (200 mg, 0.51 mmol) was treated similar as described in step 2, Intermediate 80, to provide the title compound as a yellow solid (120 mg). [0540] Step 3: N-{4-[chloro(²H2)methyl]-3-cyclopropylphenyl}-3-cyclopropyl-1-(2,2- difluoroethyl)-1H-pyrazole-4-carboxamide (Intermediate 83) [0541] 3-cyclopropyl-N-{3-cyclopropyl-4-[hydroxy(²H2)methyl]phenyl}-1-(2,2-difluoroethyl)- 1H-pyrazole-4-carboxamide (50 mg) was treated similar as described in step 3, Intermediate 80, to provide the crude title compound which was used in the next step without further purification. Intermediate 84: 1-(4-fluorophenyl)-N-[4-(²H)formyl-3-methoxyphenyl]-3-methyl-1H- pyrazole-4-carboxamide

[0542] Step 1: methyl 4-{[1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carbonyl]amino}-2- methoxybenzoate

[0543] Methyl 4-bromo-2-methoxybenzoate (400 mg, 1.63 mmol) and intermediate 18 (394 mg, 1.8 mmol) was treated similar as described in step 1, Intermediate 80. The crude material was 171 201260-WO-PCT combined with 2 other batches starting from 100 and 400 mg methyl 4-bromo-2- methoxybenzoate. Flash chromatography of the combined residues using EtOAc in petroleum ether (50-80 %, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a brown solid (1.0 g): ¹H NMR (300 MHz, DMSO, 23°C) δ 2.47 (3H, s), 3.75 (3H, s), 3.82 (3H, s), 7.34–7.4 (3H, m), 7.64 (1H, d), 7.71 (1H, d), 7.78–7.87 (2H, m), 9.06 (1H, s), 10.09 (1H, s). [0544] Step 2: 1-(4-fluorophenyl)-N-{4-[hydroxy(²H₂)methyl]-3-methoxyphenyl}-3-methyl-1H- pyrazole-4-carboxamide

[0545] Methyl 4-{[1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carbonyl]amino}-2- methoxybenzoate (800 mg, 2.09 mmol) was treated similar as described in Step 2, Intermediate 81. Flash chromatography of the residue using EtOAc in petroleum ether (80-100 %, stepwise gradient elution) followed by concentration of the appropriate fraction gave the title compound as a yellow solid (560 mg, 75 %): ¹H NMR (300 MHz, DMSO, 26°C) δ 2.48 (3H, s), 2.74 (1H, d), 2.89 (1H, s), 4.87 (1H, s), 7.22–7.35 (3H, m), 7.37–7.46 (3H, m), 7.8–7.88 (2H, m), 9.04 (1H, s), 9.79 (1H, s). [0546] Step 3: 1-(4-fluorophenyl)-N-[4-(²H)formyl-3-methoxyphenyl]-3-methyl-1H-pyrazole-4- carboxamide [0547] Manganese(IV) oxide (438 mg, 5.04 mmol) was added to 1-(4-fluorophenyl)-N-{4- [hydroxy(²H2)methyl]-3-methoxyphenyl}-3-methyl-1H-pyrazole-4-carboxamide (120 mg, 0.34 mmol) in DCM (2 mL) at rt. The resulting mixture was stirred at 50 °C for 8 hours, then filtered through celite and concentrated to provide the crude title compound (110 mg) which was used without further purification in the next step. Intermediate 85: 1-(4-fluorophenyl)-N-[5-formyl-6-(trifluoromethyl)pyridin-2-yl]-3- methyl-1H-pyrazole-4-carboxamide 172

[0548] Methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2'-amino-1,1'- biphenyl]palladium(II) (204 mg, 0.21 mmol) was added to Cs2CO3 (933 mg, 2.86 mmol), intermediate 18 (377 mg, 1.72 mmol) and 6-chloro-2-(trifluoromethyl)nicotinaldehyde (300 mg, 1.43 mmol, CA RN 1227581-44-3 ) in 1,4-dioxane (8mL) at 25°C under nitrogen. The resulting solution was stirred at 90 °C for 12 hours, then concentrated. Flash chromatography of the residue using EtOAc in petroleum ether (0-50 %, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (0.400 g, 71 %): ¹H NMR (300 MHz, DMSO-d6) δ 11.14 (s, 1H), 10.26 (d, J = 2.1 Hz, 1H), 9.39 (s, 1H), 8.71 – 8.58 (m, 1H), 8.49 (d, J = 8.9 Hz, 1H), 7.88 – 7.78 (m, 2H), 7.43 (t, J = 8.8 Hz, 2H), 2.5 (s, 3H). Intermediate 86: N-[5-(chloromethyl)-4-(trifluoromethyl)pyridin-2-yl]-4-cyano-2- methylbenzamide

[0549] Step 1: 4-cyano-N-[5-formyl-4-(trifluoromethyl)pyridin-2-yl]-2-methylbenzamide

[0550] N-(1-((1-(tert-butyl)-1H-tetrazol-5-yl)methyl)piperidin-4-yl)cyclohexanecarboxamide (125 mg, 0.36 mmol) was added to 6-chloro-4-(trifluoromethyl)pyridine-3-carbaldehyde (250 mg, 1.19 mmol, CAS RN 1005171-96-9), 4-cyano-2-methylbenzamide (191 mg, 1.19 mmol) and Cs2CO3 (777 mg, 2.39 mmol) in 1,4-dioxane (6 mL) at rt under nitrogen. The resulting mixture was stirred at 90 °C for 15 hours, then filtered through celite. The reaction mixture was 201260-WO-PCT diluted with EtOAc (100 mL), filtered through celite and washed sequentially with water (2 x 75 mL), brine (2 x 75 mL), dried (sodium sulfate) filtered and concentrated. Flash chromatography of the residue using EtOAc in petroleum ether (50-100 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (0.222 g, 56 %): ¹H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 10.18 (d, J = 1.6 Hz, 1H), 9.10 (s, 1H), 8.71 (s, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 7.8, 1.6 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 2.43 (s, 3H). [0551] Step 2: 4-cyano-N-[5-(hydroxymethyl)-4-(trifluoromethyl)pyridin-2-yl]-2- methylbenzamide

[0552] Sodium cyanoborohydride (119 mg, 1.89 mmol) was added to 4-cyano-N-[5-formyl-4- (trifluoromethyl)pyridin-2-yl]-2-methylbenzamide (210 mg, 0.63 mmol) in acetic acid (30 µL) and THF (3 mL) at rt under nitrogen. The resulting mixture was stirred at RT for 2 hours, then concentrated. The residue was diluted with EtOAc (75 mL), washed successively with water (2 x 50 mL) and brine (2 x 50 mL), then dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using EtOAc in petroleum ether (50-80 %, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (0.206 g, 98 %): ¹H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.77 (s, 1H), 8.58 (s, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.79 (dd, J = 7.8, 1.6 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 4.92 (s, 2H), 2.41 (s, 3H). [0553] Step 3: N-[5-(chloromethyl)-4-(trifluoromethyl)pyridin-2-yl]-4-cyano-2- methylbenzamide (Intermediate 86) [0554] 4-cyano-N-[5-(hydroxymethyl)-4-(trifluoromethyl)pyridin-2-yl]-2-methylbenzamide was treated similar as described in step 2, intermediate 58 to provide the crude title compound which was used without further purification in the next step. Intermediate 87:(2RS)-N-[3-(difluoromethoxy)-4-formylphenyl]-2-phenylpropanamide

174 201260-WO-PCT [0555] In a microwave vial, was added 2-phenylpropanamide (75 mg, 0.50 mmol, CAS RN 1125-70-8 ), 4-bromo-2-(difluoromethoxy)benzaldehyde (126 mg, 0.50 mmol, from step 1, Intermediate 28), cesium carbonate (328 mg, 1.01 mmol), Xantphos Pd G3 (14.30 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (2.91 mg, 5.03 µmol).1,4- dioxane (3.0 mL) was added and nitrogen is bubbled through the mixture for 10 minutes. The vial was sealed and heated to 80 °C for 2 h, then allowed to cool to rt. The reaction mixture was diluted with water and extracted twice with EtOAc, and the organic layers were washed successively with water, brine, then dried (magnesium sulfate), filtered and concentrated. Column chromatography of the residue using EtOAc in heptane (0-30 %, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (144 mg, 90 %): ¹H NMR (500 MHz, DMSO-d6) 1.43 (3H, d), 3.87 (1H, q), 7.14 – 7.46 (6H, m), 7.51 – 7.55 (1H, m), 7.75 – 7.82 (2H, m), 10.11 (1H, d), 10.64 (1H, s).19F NMR (470 MHz, DMSO-d6) -81.92. Intermediate 88: N-[3-(difluoromethoxy)-4-formylphenyl]-1-phenylcyclopropane-1- carboxamide

[0556] Prepared similar as described for Intermediate 87 starting from 1-phenylcyclopropane-1- carboxamide (81 mg, 0.50 mmol, CAS RN 6120-96-3) and 4-bromo-2- (difluoromethoxy)benzaldehyde (126 mg, 0.50 mmol, from step 1, Intermediate 28) to provide the title compound as a yellow solid (145 mg, 87 %): ¹H NMR (500 MHz, DMSO) 1.15 – 1.19 (2H, m), 1.46 – 1.51 (2H, m), 7.12 – 7.43 (6H, m), 7.56 – 7.66 (1H, m), 7.71 – 7.82 (2H, m), 9.79 (1H, s), 10.12 (1H, d).19F NMR (470 MHz, DMSO) -81.85. Intermediate 89: N-[3-(difluoromethoxy)-4-formylphenyl]-2-methyl-2-phenylpropanamide

[0557] Prepared similar as described for Intermediate 87 starting from 2-methyl-2- phenylpropanamide (82 mg, 0.50 mmol, CAS RN 826-54-0) and 4-bromo-2- (difluoromethoxy)benzaldehyde (126 mg, 0.50 mmol, from step 1, Intermediate 28) to provide 175 201260-WO-PCT the title compound (126 mg, 67 %): ¹H NMR (500 MHz, DMSO) 1.57 (6H, s), 7.09 – 7.31 (2H, m), 7.31 – 7.4 (4H, m), 7.68 – 7.73 (1H, m), 7.77 (1H, d), 7.82 (1H, d), 9.67 (1H, s), 10.12 (1H, d).19F NMR (470 MHz, DMSO) -81.75. Intermediate 90: N-[3-(difluoromethoxy)-4-formylphenyl]-2,2-difluoro-2-phenylacetamide

[0558] Prepared similar as described for Intermediate 87 starting from 2,2-difluoro-2- phenylacetamide (86 mg, 0.50 mmol, CAS RN 383-19-7) and 4-bromo-2- (difluoromethoxy)benzaldehyde (126 mg, 0.50 mmol, from step 1, Intermediate 28). Column chromatography of the residue using EtOAc in heptane (0-50 %, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (104 mg, 61 %): ¹H NMR (500 MHz, DMSO) 7.32 (1H, t), 7.51 – 7.65 (3H, m), 7.65 – 7.72 (2H, m), 7.79 (1H, dd), 7.82 – 7.89 (2H, m), 10.16 (1H, d), 11.31 (1H, s).19F NMR (470 MHz, DMSO) - 101.09, -82.09 (J = 3.4). Intermediate 91: (2S)-2-[(3S)-1-{[4-amino-2-(difluoromethyl)phenyl]methyl}piperidin-3- yl]propane-1,2-diol

[0559] Step 1: 2-(difluoromethyl)-1-methyl-4-nitrobenzene

[0560] DAST (4.80 mL, 36.33 mmol) was added to 2-methyl-5-nitrobenzaldehyde (1.500 g, 9.08 mmol, CAS RN 16634-91-6) in DCM (10mL) at rt under nitrogen. The resulting mixture was stirred at 0 °C for 1 hour then quenched with water (10 mL), extracted with EtOAc (2 x 75 mL), dried (Na2SO4), filtered, combined with an equal batch concentrated. Flash chromatography of the residue using EtOAc in petroleum ether (25-40 %, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a yellow solid 176 201260-WO-PCT (1.500 g, 44 %): ¹H NMR (300 MHz, DMSO, 23°C) δ 2.53 (3H, d), 7.33 (1H, t), 7.62–7.71 (1H, m), 8.23–8.38 (2H, m). [0561] Step 2: 1-(bromomethyl)-2-(difluoromethyl)-4-nitrobenzene

[0562] 1-bromopyrrolidine-2,5-dione (0.984 g, 5.53 mmol) was added to (E)-2,2'-(diazene-1,2- diyl)bis(2-methylpropanenitrile) (0.242 g, 1.47 mmol) and 1-(difluoromethyl)-1-methyl-4- nitrobenzene (0.69 g, 3.69 mmol) in 1,2-dichloroethane (15 mL) at rt under nitrogen. The resulting mixture was stirred at 95 °C for 15 hours. The reaction mixture was then diluted with EtOAc (50 mL), and washed sequentially with water (2 x 50 mL), brine (2 x 50 mL), then dried (sodium sulfate), filtered and concentrated. The residue was purified by preparative HPLC to provide the title compound as a yellow solid which was used directly in the next step (174 mg). [0563] Step 3: (2S)-2-[(3S)-1-{[2-(difluoromethyl)-4-nitrophenyl]methyl}piperidin-3- yl]propane-1,2-diol

[0564] K2CO3 (125 mg, 0.90 mmol) was added to 1-(bromomethyl)-2-(difluoromethyl)-4- nitrobenzene (120mg, 0.45 mmol) and intermediate 16 (71.8 mg, 0.45 mmol) in DMF (2 mL) at rt. The resulting mixture was stirred at rt for 2 hours. Flash C-18 chromatography of the residue, elution gradient 30 to 40% MeCN in water, followed by concentration of the appropriate fractions gave the title compound as a yellow solid (0.045 g, 29.0 %): ¹H NMR (300 MHz, DMSO, 23°C) δ 0.97 (3H, s), 1.23 (2H, p), 1.68 (2H, dd), 1.87 (1H, d), 1.99 (1H, t), 2.98 (2H, d), 3.24 (3H, d), 3.50 (1H, d), 7.50 (1H, t), 8.07 (1H, d), 8.38–8.63 (2H, m), 9.52 (1H, s). [0565] Step 4: (2S)-2-[(3S)-1-{[4-amino-2-(difluoromethyl)phenyl]methyl}piperidin-3- yl]propane-1,2-diol (Intermediate 91) [0566] Ammonium chloride (135 mg, 2.53 mmol) was added to (2S)-2-[(3S)-1-{[2- (difluoromethyl)-4-nitrophenyl]methyl}piperidin-3-yl]propane-1,2-diol (174 mg, 0.51 mmol) and iron (141 mg, 2.53 mmol) in ethanol (4 mL) and water (1 mL) at rt. The resulting mixture was stirred at 60 °C for 2 hours. The reaction mixture was filtered through celite, concentrated and used without further purification in the next step (120 mg). 177 201260-WO-PCT Intermediate 92: (2S)-2-[(3S)-1-{[4-amino-2-(difluoromethoxy)phenyl]methyl}piperidin-3- yl]propane-1,2-diol

[0567] Step 1: tert-butyl [3-(difluoromethoxy)-4-formylphenyl]carbamate

[0568] XantPhos Pd G3 (151 mg, 0.16 mmol) was added to 4-bromo-2- (difluoromethoxy)benzaldehyde (200 mg, 0.80 mmol) and cesium carbonate (260 mg, 0.80 mmol) in 1,4-dioxane (4.5 mL) at RT under nitrogen. The resulting mixture was stirred at 90 °C for 4 hours. The reaction mixture was then diluted with EtOAc (50 mL), and washed sequentially with water (2 x 50 mL) brine (2 x 50 mL), dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using EtOAc in petroleum ether (20-30 %, gradient elution) followed by concentration of the appropriate fraction gave the title compound as a yellow solid (0.100 g, 44 %): ¹H NMR (300 MHz, DMSO-d6) δ 10.09 (d, J = 9.7 Hz, 2H), 7.76 (d, J = 8.6 Hz, 1H), 7.66 – 7.60 (m, 1H), 7.54 – 7.03 (m, 2H), 1.50 (s, 9H). [0569] Step 2: tert-butyl [3-(difluoromethoxy)-4-({(3S)-3-[(2S)-1,2-dihydroxypropan-2- yl]piperidin-1-yl}methyl)phenyl]carbamate

[0570] Intermediate 16 (1.663 g, 10.44 mmol) was added to tert-butyl [3-(difluoromethoxy)-4- formylphenyl]carbamate (3g, 10.44 mmol) in DCE (30mL) over a period of 10 minutes, then added sodium triacetoxyborohydride (6.64 g, 31.33 mmol). The resulting mixture was stirred at 25 °C for 12 hours, then concentrated. Flash C18- chromatography using acetonitrile in water (0-50 %, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a brown solid (3.00 g, 67 %): ¹H NMR (300 MHz, DMSO, 22°C) δ 0.94 (s, 3H), 1.16 (q, J = 15.3, 13.5 Hz, 1H), 1.47 (s, 9H), 1.58 (d, J = 13.3 Hz, 1H), 1.68 (d, J = 13.2 Hz, 1H), 1.89 (dt, J = 27.1, 13.3 Hz, 2H), 2.69–2.88 (m, 2H), 3.15 (s, 1H), 3.27 (d, J = 11.8 Hz, 1H), 3.45 178 201260-WO-PCT (d, J = 12.0 Hz, 1H), 4.21 (d, J = 4.5 Hz, 2H), 7.06 (d, J = 73.1 Hz, 1H), 7.29 (dd, J = 8.4, 2.0 Hz, 1H), 7.46 (t, J = 8.9 Hz, 1H), 7.57 (s, 1H), 9.27 (s, 1H), 9.77 (s, 1H). [0571] Step 3: (2S)-2-[(3S)-1-{[4-amino-2-(difluoromethoxy)phenyl]methyl}piperidin-3- yl]propane-1,2-diol (Intermediate 92) [0572] tert-butyl [3-(difluoromethoxy)-4-({(3S)-3-[(2S)-1,2-dihydroxypropan-2-yl]piperidin-1- yl}methyl)phenyl]carbamate (100mg, 0.23 mmol) in DCM (2 mL), TFA (0.4mL) . The resulting mixture was stirred at 25 °C for 2 hours, then concentrated. Flash C18 chromatography of the residue using acetonitrile in water (0-100 %, gradient elution), followed by concentration of the appropriate fractions gave the title compound as a white solid (0.049 g, 64 %): ¹H NMR (300 MHz, DMSO-d6) δ 7.28 – 6.62 (m, 2H), 6.52 – 6.30 (m, 2H), 5.30 (s, 2H), 4.42 (s, 1H), 3.97 (s, 1H), 3.18 (d, 2H), 2.91 (d, 1H), 2.73 (s, 1H), 1.80 (s, 2H), 1.61 (d, 3H), 1.48 – 1.17 (m, 1H), 0.91 (s, 4H). Example 1. N-[4-{[(3R,4r,5S)-4-hydroxy-3,5-dimethylpiperidin-1-yl]methyl}-3- (trifluoromethyl)phenyl]-2-phenylacetamide

[0573] To a solution of (3R,4r,5S)-1-(4-amino-2-(trifluoromethyl)benzyl)-3,5- dimethylpiperidin-4-ol (Intermediate 1, 1.0 g, 3.31 mmol), 2-phenylacetic acid (0.563 g, 4.13 mmol) and TEA (1.383 ml, 9.92 mmol) in acetonitrile (40 mL) was added HATU (1.572 g, 4.13 mmol) and the mixture was stirred at RT for 1 hour. The crude reaction mixture was then concentrated and redissolved in EtOAc (60 mL), washed with aq. NaOH 0.5M (30 mL), brine (20 mL), then dried (Na₂SO₄) filtered and concentrated. Column chromatography of the residue using EtOAc in Hexane (50-67 %, stepwise gradient elution) followed by purification on an SCX-2 ion exchanger (10 g), giving the title compound as a white foam (0.701 g): ¹H NMR (500 MHz, DMSO) 0.83 (6H, d), 1.42 – 1.54 (2H, m), 1.65 (2H, t), 2.4 – 2.48 (1H, m), 2.64 – 2.7 (2H, m), 3.47 (2H, s), 3.65 (2H, s), 4.47 (1H, d), 7.19 – 7.28 (1H, m), 7.29 – 7.36 (4H, m), 7.65 (1H, d), 7.74 – 7.8 (1H, m), 8.03 (1H, d), 10.44 (1H, s). Examples 2-15. [0574] The compounds shown in Table 6 were prepared using procedures analogous to Example 1 using Intermediate 1 and corresponding carboxylic acids. As is appreciated by those 179 201260-WO-PCT skilled in the art, these analogous examples may involve variations in general reaction conditions and isolation methods. 180 ¹⁸ ₁ 2⁰¹² _60-W O -^P

^C _T ¹⁸ ₂ 2⁰¹² _60-W O -^PC _T

¹⁸ ₃ 2⁰¹² _60-W O -^PC

_T ¹⁸ ₄ 2⁰¹² _60-W O -^P

^C _T Example 16. N-[3-(difluoromethoxy)-4-{[(3R,4r,5S)-4-hydroxy-3,5-dimethylpiperidin-1- yl]methyl}phenyl]- 3-fluor F1-(3-fluorophenyl)-3-methyl-1H-pyrazole-4-carboxamide

[0575] (MgSO N T ) No 1-( O , filtered NH Fop Ohenyl)- N3-methy and concentrated. Th Ol- eH1H-pyrazole-4-carboxylic acid, CAS RN 1250985-70-6 ( F45.8 mg, 0.21 mmol) in DMF (2 mL) was added 1-(bis(dimethylamino)methylene)-1H- [1,2,3]triazolo[4,5-b]pyridine-1-ium 3-oxide hexafluorophosphate(V) (85 mg, 0.22 mmol) followed by N-ethyl-N-isopropylpropan-2-amine (116 µl, 0.67 mmol). The resulting solution was stirred for 10 min before addition of a solution of Intermediate 2 (50 mg, 0.17 mmol) in DMF (1.0 mL). The resulting reaction mixture was stirred at room temperature for 3 days, then diluted with EtOAc (15 mL) and washed with sat. aq. NaHCO3 (10 mL), brine (10 mL), dried 4 residue was purified by preparative LS-MS (Chromatographic conditions: gradient 5-95% ACN in 0.2% NH3, pH10. Column: Waters Xbridge™ C185μ ODB 30x150mm) to provide the title compound (70.7 mg, 0.141 mmol, 85 %): ¹H NMR (600 MHz, DMSO) δ 9.96 (s, 1H), 9.05 (s, 1H), 7.64 (d, 1H), 7.59 – 7.63 (m, 2H), 7.5 – 7.58 (m, 2H), 7.32 (d, 1H), 6.88 – 7.19 (m, 2H), 4.42 (s, 1H), 3.34 (s, 2H), 2.65 – 2.72 (m, 2H), 2.39 – 2.45 (m, 4H), 1.62 (t, 2H), 1.43 (tdd, 2H), 0.81 (d, 6H). m/z (ES+) [M+H]+ = 503. Examples 17-28. [0576] The compounds shown in Table 7 were prepared using procedures analogous to Example 16 using Intermediate 2 and corresponding carboxylic acids. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions and isolation methods. 185 ¹⁸ ₆ 2⁰¹² _60-W O -

^PC _T ¹⁸ ₇ 2⁰¹² _60-W O -^P

^C _T ¹⁸ ₈ 2⁰¹² _60-W O -

^PC _T ¹⁸ ₉ 2⁰¹² _60-W O -^PC

_T 201260-WO-PCT Example 29.4-cyano-N-[3-(difluoromethoxy)-4-{[(3R)-3-(2-hydroxypropan-2- yl)pyrrolidin-1-yl]methyl}phenyl]-2-methylbenzamide

[0577] A mixture of Intermediate 14 (50 mg, 0.14 mmol), (R)-2-(pyrrolidin-3-yl)propan-2-ol (23.02 mg, 0.18 mmol, CAS RN 1245649-03-9) and potassium carbonate (59.1 mg, 0.43 mmol) in acetonitrile (3 mL) was stirred at 50 °C for 16 h. The reaction mixture was then filtered concentrated. Preparative LC-MS (Instrument: FL3. Chromatographic conditions: gradient 5- 95% ACN in 0.2% NH3, pH10. Column: Waters Xbridge™ C185μ ODB 19x150mm) followed by concentration of appropriate fractions gave the title compound (16 mg, 26 %): ¹H NMR (600 MHz, DMSO) δ 0.98 (6H, d), 1.53–1.68 (2H, m), 2.02–2.09 (1H, m), 2.29–2.38 (5H, m), 3.46 (1H, d), 3.51 (1H, d), 4.08 (1H, s), 7.07 (1H, t), 7.36 (1H, d), 7.48 (1H, dd), 7.60 (1H, d), 7.66 (1H, d), 7.76 (1H, dd), 7.80 (1H, d), 10.61 (1H, s). m/z (ES+) [M+H]⁺ = 444. Examples 30-40. [0578] The compounds of Table 8 were prepared using procedures analogous to Example 30 using appropriately substituted starting materials. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions and isolation methods, such as preparative chiral chromatography. 190 ¹⁹ ₁ 2⁰¹² _60-W O -

_, ^PC _T ¹⁹ ₂ 2⁰¹² _60-W O -^PC

_T ¹⁹ ₃ 2⁰¹² _60-W O -^PC

_T ¹⁹ ₄ 2⁰¹² _60-W O -^P

^C _T 201260-WO-PCT Example 41. N-[3-chloro-4-({(3S)-3-[(2S)-1,2-dihydroxypropan-2-yl]piperidin-1- yl}methyl)phenyl]-1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carboxamide

[0579] To a solution of Intermediate 16 (6.13 g, 34.66 mmol) in a mixture of DMF (50 mL) and acetonitrile (200 mL) was added potassium carbonate (12.50 g, 90.42 mmol). The resulting solution was warmed to 50 °C and a solution of N-(3-chloro-4-(chloromethyl)phenyl)-1-(4- fluorophenyl)-3-methyl-1H-pyrazole-4-carboxamide, Intermediate 20 (12 g, 30.14 mmol) in a mixture of acetonitrile (70 mL) and DMF (50 mL) was added by syringe pump (1 mL/min addition). Once the addition was complete, the resulting reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was then filtered and concentrated. The residual yellow oil was dissolved in EtOAc (150 mL), washed successively with water (100 mL) and brine (100 mL), then dried (magnesium sulfate), filtered and concentrated. Flash column chromatography of the residue using methanol in EtOAc (0-10 %, stepwise gradient elution) followed by concentration of pure fractions gave the title compound as a pale orange solid (13.18 g, 87 %). This material was combined with a parallel batch, in total 19.2 g, 38.3 mmol, and added acetonitrile (100 mL) then warmed to 82 °C and stirred for 30 min upon which a clear solution was obtained. The solution was then allowed to slowly reach rt with stirring upon which a homogenous solid mass was obtained. Additional acetonitrile (100 mL) was added and the resulting slurry was stirred another 40 h at rt. The obtained solids were filtered off and washed with acetonitrile, then dried in vacuum for 40 h to afford the crystalline title compound as a white solid (16.48 g, 86%): ¹H NMR (500 MHz, DMSO-d6, 25°C) δ 0.92 (3H, s), 0.96–1.06 (1H, m), 1.37–1.48 (1H, m), 1.59– 1.73 (3H, m), 1.81–1.93 (2H, m), 2.47 (3H, s), 2.74 (1H, d), 2.94–3 (1H, m), 3.19 (2H, d), 3.48 (2H, s), 3.98 (1H, s), 4.44 (1H, t), 7.37–7.45 (3H, m), 7.58 (1H, dd), 7.8–7.86 (2H, m), 7.89 (1H, d), 9.01 (1H, s), 9.96 (1H, s). m/z (ES+) [M+H]⁺ = 501. Example 42. N-[3-chloro-4-({(3S)-3-[(2R)-1,2-dihydroxypropan-2-yl]piperidin-1- yl}methyl)phenyl]-1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carboxamide 195 201260-WO-PCT

[0580] To Intermediate 19 (300 mg, 0.84 mmol) in a mixture of 2-methyl tetrahydrofuran (6.00 mL), methanol (6 mL) and AcOH (1.2 mL) was added Intermediate 17 (200 mg, 1.26 mmol), followed by 2-Methylpyridine borane complex (135 mg, 1.26 mmol). The resulting reaction mixture was stirred at room temperature for 5 days. The reaction was diluted with EtOAc (15 mL) and washed with aq. saturated NaHCO3 (15 mL). The aqueous layer was extracted with EtOAc (2 x 25 mL) and the combined organic layers were washed with brine (20 mL), dried (MgSO₄), filtered and concentrated. The residue was purified by column chromatography on silica gel using methanol in EtOAc (0-10 %, stepwise gradient elution) followed by concentration of the appropriate fractions. The residue was further purified by flash column chromatography on amino silica gel using methanol in EtOAc (0-10 %, stepwise gradient elution) followed by concentration of the appropriate fractions to afford the title compound as a white foam (160 mg, 38 %): ¹H NMR (400 MHz, DMSO, 25°C) δ 0.96 (3H, s), 1.08 (1H, qd), 1.40 (1H, q), 1.58–1.68 (2H, m), 1.74 (1H, d), 1.79–1.92 (2H, m), 2.47 (3H, s), 2.75 (1H, d), 2.89 (1H, d), 3.15 (1H, dd), 3.24 (1H, dd), 3.48 (2H, s), 3.97 (1H, s), 4.43 (1H, t), 7.36–7.47 (3H, m), 7.57 (1H, dd), 7.78–7.87 (2H, m), 7.89 (1H, d), 9.01 (1H, s), 9.95 (1H, s). m/z (ES+) [M+H]⁺ = 501. Examples 43-51. [0581] The compounds of Table 9 were prepared using procedures analogous to Examples 41 using appropriately substituted starting materials. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions and isolation methods. 196 T a^{b e} _{9 C} o_m p^ound _{s of E} xa_m p ^{es 4} _3-5 ¹⁹ ₇ O C O ²⁰¹² _60-W O -^P

^C _T ¹⁹ ₈ O C O O ²⁰¹² _60-W O -^P

^C _T ¹⁹ ₉ 2⁰¹² _60-W O -

^{, , PC} _T 201260-WO-PCT Example 52. N-[3-(difluoromethoxy)-4-({(3S)-3-[(2S)-1,2-dihydroxypropan-2-yl]piperidin- 1-yl}methyl)phenyl]-1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carboxamide

[0582] To a solution of Intermediate 16 (6.174 g, 34.9 mmol) in a mixture of DMF (55 mL) and acetonitrile (280 mL) was added potassium carbonate (1.32 g, 95.2 mmol). The resulting solution was warmed to 50 °C and a solution of Intermediate 28 (13.00 g, 31.72 mmol) in a mixture of acetonitrile (110.00 mL) and DMF (55 mL) was added by syringe pump (1 mL/min addition). Once the addition was complete, the resulting reaction mixture was stirred another 1 h at 50 °C. The reaction mixture was then filtered and concentrated under reduced pressure to give a yellow oil. The resulting oil was dissolved in EtOAc (300 mL) and washed successively with water (200 mL), brine (200 mL), then dried (MgSO4), filtered and concentrated. The compound was recrystallized from MeCN: dissolved in 110 mL of hot MeCN and cooled to room temperature which allowed crystallization. The sample was left in the fridge overnight. The resulting white solid was filtered and washed with cold MeCN (100 mL). The solid was dried under vacuum to yield the title compound as white solid (13.45 g, 25.3 mmol, 80 %): ¹H NMR (500 MHz, DMSO) δ 9.97 (s, 1H), 9.01 (s, 1H), 7.8 – 7.86 (m, 2H), 7.68 (d, 1H), 7.54 (dd, 1H), 7.38 – 7.45 (m, 2H), 7.37 (d, 1H), 7.09 (t, 1H), 4.42 (t, 1H), 3.94 (s, 1H), 3.37 – 3.46 (m, 2H), 3.15 – 3.22 (m, 2H), 2.95 (d, 1H), 2.73 (d, 1H), 2.47 (s, 3H), 1.75 – 1.89 (m, 2H), 1.58 – 1.68 (m, 3H), 1.34 – 1.45 (m, 1H), 0.93 – 1.05 (m, 1H), 0.92 (s, 3H). m/z (ES+) [M+H]+ = 533. Examples 53-81. [0583] The compounds of Table 10 were prepared using procedures analogous to Example 52 using appropriately substituted starting materials. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions and isolation methods. 200 ²⁰ ₁ 2⁰¹² _60-W O -^PC

_T ²⁰ ₂ 2⁰¹² _60-W O -^PC

_T ²⁰ ₃ 2⁰¹² _60-W O -^PC

_T ²⁰ ₄ 2⁰¹² _60-W O -^P

^C _T ²⁰ ₅ 2⁰¹² _60-W O -^P

^C _T ²⁰ ₆ 2⁰¹² _60-W O -^PC

_T ²⁰ ₇ 2⁰¹² _60-W O -^P

^C _T ²⁰ ₈ 2⁰¹² _60-W O -^PC

_T ²⁰ ₉ 2⁰¹² _60-W O

⁾ _{, , ,} ^-PC _T ²¹ ₀ 2⁰¹² _60-W O -^P

^C _T ²¹ ₁ 2⁰¹² _60-W O -^P

^C _T ²¹ ₂ som 1 O S er O O O O ²⁰¹² _60-W O -^P

^C _T ²¹ ₃ 2⁰¹² _60-W O -

⁾ _, ^PC _T ²¹ ₄ 2⁰¹² _60-W O -^P

^C _T 201260-WO-PCT Example 82. N-[4-({(3S)-3-[(2S)-1,2-dihydroxypropan-2-yl]piperidin-1-yl}methyl)-3- fluorophenyl]-1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carboxamide

[0584] To Intermediate 49 (200 mg, 0.59 mmol) in a mixture of 2-methyl tetrahydrofuran (3.00 mL), methanol (3 mL) and AcOH (0.6 mL) was added Intermediate 16 (140 mg, 0.88 mmol), followed by 2-Methylpyridine borane complex (94 mg, 0.88 mmol). The resulting reaction mixture was stirred at room temperature for 20 h. LCMS of the reaction mixture at this point indicated completion of the reaction with no remaining starting material and formation of the desired product at Rt = 0.89 min and ES+ m/z 485.4 [M+H]+. The reaction was diluted with EtOAc (15 mL) and washed with sat. aq. NaHCO3 (15 mL). The aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford a crude oil. Rf = 0.24 (EtOAc:MeOH - 9:1). The crude product was purified by column chromatography on silica gel (EtOAc:MeOH - 1:0 to 85:15) to afford an off-white foam. The foam was recrystallized from MeCN (3 mL), filtered and dried under reduced pressure to give the title compound as an off- white solid (0.115 g, 40 %): ¹H NMR (500 MHz, DMSO, 25°C) δ 0.92 (3H, s), 0.93–1.05 (1H, m), 1.33–1.45 (1H, m), 1.57–1.7 (3H, m), 1.81 (2H, q), 2.47 (3H, s), 2.72 (1H, d), 2.95 (1H, d), 3.19 (2H, d), 3.4–3.49 (2H, m), 3.97 (1H, s), 4.43 (1H, t), 7.33 (1H, t), 7.37–7.44 (3H, m), 7.65 (1H, dd), 7.8–7.86 (2H, m), 9.01 (1H, s), 9.98 (1H, s). m/z (ES+) [M+H]+ = 485. Examples 83-104. [0585] The compounds of Tables 11 and 12 were prepared using procedures analogous to Examples 52 and 82 using appropriately substituted starting materials. The compounds of Table 8 were prepared using procedures analogous to Example 53 or 91. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions and isolation methods. 215 T C _{m E m} ²¹ ₆ 2⁰¹² _60-W O -

_, ^{, PC} _T ²¹ ₇ 2⁰¹² _60-W O - ^{, P}

^C _T ²¹ ₈ 2⁰¹² _60-W O -^P

^C _T ²¹ ₉ 2⁰¹² _60-W O -

^PC _T ²² ₀ 2⁰¹² _60-W O -^P

^C _T ²² ₁ OO O ²⁰¹² _60-W O -^P

^C _T ²² ₂ 2⁰¹² _60-W O

_), ^{, , -PC} _T ²² ₃ 2⁰¹² _60-W O -

⁾, ⁾, ^PC _T 201260-WO-PCT Example 105.3-cyclobutyl-N-[3-(difluoromethoxy)-4-{[(3S)-3-(2-hydroxypropan-2- yl)piperidin-1-yl]methyl}phenyl]-1-me 586] To 3-cyclobutyl-1-methyl-1H-py Fthy raz Fl- ole O1H-pyrazole-4-ca -4-carboxylic acid OrbHoxamide

[0 N O N N (35.8 mg, 0.20 mmol, CAS RN 137614-13-2) in DMF (2 mL) w Nas addedH 1-(bis(dimethylamino)methylene)-1H- [1,2,3]triazolo[4,5-b]pyridine-1-ium 3-oxide hexafluorophosphate(V) (82 mg, 0.21 mmol) followed by N-ethyl-N-isopropylpropan-2-amine (111 µl, 0.64 mmol). The resulting solution was stirred for 10 min before addition of a solution of Intermediate 72 (50 mg, 0.16 mmol) in DMF (1.000 mL). The resulting reaction mixture was stirred at 50 °C for 20 h, then allowed to cool to rt and diluted with EtOAc (15 mL), washed successively with aq. sat. NaHCO₃ (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated. The residue was purified by preparative LC-MS (Chromatographic conditions: gradient 5-90% ACN, pH10. Column: Waters Acquity BEH C181.7μ 2.1x50 mm. Instrument: FL1. Chromatographic conditions: gradient 5- 95% ACN in 0.1M HCO2H, pH 3. Column: Waters Sunfire C18 ODB 5μ 30x150mm). Concentration of the appropriate fractions gave the title compound (34.4 mg, 0.066 mmol, 41.4 %): ¹H NMR (600 MHz, DMSO) δ 9.77 (s, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.64 (d, 1H), 7.49 (dd, 1H), 7.34 (d, 1H), 7.06 (t, 1H), 3.81 (s, 3H), 3.53 – 3.59 (m, 2H), 3.02 – 3.08 (m, 1H), 2.78 – 2.86 (m, 1H), 2.12 – 2.25 (m, 4H), 1.95 – 2.05 (m, 1H), 1.84 – 1.93 (m, 2H), 1.71 – 1.8 (m, 1H), 1.58 – 1.71 (m, 2H), 1.34 – 1.5 (m, 2H), 0.9 – 1.02 (m, 7H). m/z (ES+) [M+H]+ = 477. Example 106.3-cyclopropyl-1-(2,2-difluoroethyl)-N-[3-(difluoromethoxy)-4-{[(3S)-3-(2- hydroxypropan-2-yl)piperidin-1-yl]methyl}phenyl]-1H-pyrazole-4-carboxamide

[0587] Sodium methoxide (30.8 mg, 0.57 mmol) was added to (S)-2-(piperidin-3-yl)propan-2-ol (82 mg, 0.57 mmol, CAS RN 1173880-33-5) in MeOH (1 mL) and stirred for 10 min. Then Intermediate 73 (110 mg, 0.29 mmol) was added and the reaction mixture was stirred additional 10 min, after which acetic acid (0.016 mL, 0.29 mmol) was added and stirred for 10 224 201260-WO-PCT min. Finally, sodium cyanoborohydride (35.9 mg, 0.57 mmol) was added and the resulting mixture was stirred at rt for 2 hours, then concentrated. Preparative LC of the residue (Chromatographic conditions: gradient 17 to 27 % acetonitrile in 0.1 % formic acid in water, Column: Xselect CSH C18 OBD Column 30*150mm 5μm, Flow rate: 60 mL/min, Wave Length: 254; 220 nm; RT1(min): 6.680) followed by concentration of the appropriate fractions gave the title compound as a white solid (28.0 mg, 18.55 %): ¹H NMR (400 MHz, DMSO, 23°C) δ 0.75–0.85 (2H, m), 0.86–0.93 (2H, m), 1.03 (7H, d), 1.47 (2H, p), 1.71 (2H, t), 2.05 (2H, d), 2.62 (1H, tt), 2.90 (1H, d), 3.12 (1H, d), 3.65 (2H, s), 4.22 (1H, s), 4.60 (2H, td), 6.35 (1H, tt), 7.13 (1H, t), 7.41 (1H, d), 7.58 (1H, dd), 7.73 (1H, d), 8.37 (1H, s), 9.99 (1H, s). m/z (ES+) [M+H]+ = 513. Examples 107-110. [0588] The compounds of Table 13 were prepared using procedures analogous to Example 106 using appropriately substituted starting materials. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions and isolation methods. 225 ²² ₆ 2⁰¹² _60-W O -^PC _T

201260-WO-PCT Example 111.3-cyclobutyl-N-[3-(difluoromethoxy)-4-{[(3S)-3-(2-hydroxypropan-2- yl)piperidin-1-yl](²H2)methyl}phenyl]-1-methyl-1H-pyrazole-4-carboxamide

[0589] Sodium cyanoborodeuteride (45.1 mg, 0.69 mmol) was added to intermediate 77 (120 mg, 0.34 mmol) and (S)-2-(piperidin-3-yl)propan-2-ol (73.6 mg, 0.51 mmol, CAS RN 1173880- 33-5) in CD3OD (1 mL) . The resulting mixture was stirred at rt for 2 hours, then the mixture was filtered through a Celite pad. The crude product was purified by preparative Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 65% B in 7 min, 65% B; Wave Length: 254/220 nm; RT1(min): 5.95. Fractions containing the desired compound were evaporated to dryness to afford the title compound (42.9 mg, 26.2 %) as a white solid.¹H NMR (400 MHz, MeOD, 26°C) δ 1.15 (d, J = 5.8 Hz, 7H), 1.54–1.66 (m, 2H), 1.77–1.95 (m, 3H), 1.97–2.16 (m, 3H), 2.25–2.38 (m, 4H), 2.96 (d, J = 11.3 Hz, 1H), 3.16 (d, J = 10.8 Hz, 1H), 3.91 (s, 3H), 4–4.1 (m, 1H), 6.89 (t, J = 74.3 Hz, 1H), 7.4–7.46 (m, 2H), 7.64–7.66 (m, 1H), 8.10 (s, 1H).19F NMR (376 MHz, MeOD) δ -82.325. m/z (ES+) [M+H]+ = 479. Examples 112-127. [0590] The compounds of Table 14 were prepared using procedures analogous to Example 82 or 111 using appropriately substituted starting materials and reagents. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions and isolation methods. 228 ²² ₉ 2⁰¹² _60-W O -^P

^C _T ²³ ₀ 2⁰¹² _60-W O -^PC

_T ²³ ₁ O O ²⁰¹² _60-W O -^PC _T

²³ ₂ 2⁰¹² _60-W O - , ^P

^C _T ²³ ₃ 2⁰¹² _60-W O -^PC

_T ²³ ₄ 2⁰¹² _60-W O -^PC _T

201260-WO-PCT Example 128. N-[3-(difluoromethoxy)-4-({(3S)-3-[(4S)-4-methyl-1,3-dioxolan-4- yl]piperidin-1-yl}methyl)phenyl]-1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carboxamide

[0591] To a suspension of Example 52 (50 mg, 0.09 mmol) in dry DCM (4.53 mL) was added formaldehyde dimethyl acetal (166 µl, 1.88 mmol) followed by phosphorus(V) oxide (66.6 mg, 0.47 mmol). After 18 hours, further formaldehyde dimethyl acetal (80 equiv.) and phosphorus(V) oxide (25 equiv.) were added. After further 14 hours, the reaction mixture was diluted with EtOAc (30 mL), washed successively with aq.5% aqueous K2CO3 (10 mL), water (5 mL) and brine (10 mL). The organic layer was filtered through a phase separator and concentrated. This residue was purified by preparative HPLC: SFC2-MS. Chromatographic conditions: MeOH/H2O/NH397/3/50mM. Column: Waters BEH 5μm 30x250mm to obtain the title compound (4.00 mg, 8 %): 1H NMR (600 MHz, DMSO, 25°C) δ 0.94–1.03 (1H, m), 1.10 (3H, s), 1.39–1.46 (1H, m), 1.54–1.6 (1H, m), 1.6–1.7 (2H, m), 1.74–1.8 (1H, m), 1.82–1.88 (1H, m), 2.47 (3H, s), 2.75–2.8 (1H, m), 2.9–2.96 (1H, m), 3.43 (2H, s), 3.47 (1H, d), 3.66 (1H, d), 4.84 (2H, d), 7.09 (1H, t), 7.36–7.43 (3H, m), 7.55 (1H, dd), 7.68 (1H, d), 7.78–7.87 (2H, m), 9.02 (1H, s), 9.99 (1H, s). m/z (ES+) [M+H]+ = 545. Example 129. Methyl (2S)-2-[(3S)-1-{[2-(difluoromethoxy)-4-{[1-(4-fluorophenyl)-3- methyl-1H-pyrazole-4-carbonyl]amino}phenyl]methyl}piperidin-3-yl]-2- hydroxypropanoate

235 201260-WO-PCT [0592] To a suspension of Example 60 (100 mg, 0.18 mmol) in dry DCM (1.646 mL) was added at room temperature oxalyl dichloride (35.6 µl, 0.42 mmol) followed by 2 drops of DMF. After 15 minutes, dry MeOH (148 µl, 3.66 mmol) was added. After additional 4.5 hours, the reaction mixture was concentrated and the residue purified by preparative-HPLC: SFC1-MS. Chromatographic conditions: MeOH/H2O/NH397/3/50mM. Column: Waters BEH 5μm 30x250mm to yield the title compound (6.20 mg, 6 %).1H NMR (600 MHz, DMSO, 25°C) δ 1– 1.09 (1H, m), 1.21 (3H, s), 1.36–1.46 (1H, m), 1.62–1.68 (2H, m), 1.74–1.88 (3H, m), 2.47 (3H, s), 2.59–2.62 (1H, m), 2.7–2.79 (1H, m), 3.40 (2H, s), 3.57 (3H, s), 5.11 (1H, s), 7.07 (1H, t), 7.34 (1H, d), 7.38–7.44 (2H, m), 7.54 (1H, dd), 7.69 (1H, d), 7.8–7.86 (2H, m), 9.02 (1H, s), 9.98 (1H, s). m/z (ES+) [M+H]+ = 561. Example 130. N-[3-(difluoromethyl)-4-({(3S)-3-[(2S)-1,2-dihydroxypropan-2-yl]piperidin- 1-yl}methyl)phenyl]-1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carboxamide

[0593] DIEA (0.133 mL, 0.76 mmol) was added to HATU (116 mg, 0.31 mmol), Intermediate 13 (56.0 mg, 0.25 mmol) and Intermediate 91 (80mg, 0.25 mmol) in DMF (1mL). The resulting mixture was stirred at 25 °C for 5 hours, then added aq.2N sodium hydroxide (2 mL, 4.00 mmol) and stirred at 25 °C for additional 2 hours. The reaction mixture was filtered through celite and concentrated. The residue was purified by preparative HPLC Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 19% B to 31% B in 7 min, 31% B; Wave Length: 254/220 nm. Appropriate fractions were concentrated to provide the title compound as a white solid (0.018 g, 12.58 %): ¹H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.06 (s, 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.89 – 7.74 (m, 3H), 7.56 – 7.20 (m, 4H), 3.60 – 3.43 (m, 2H), 3.19 (s, 2H), 2.97 (d, 1H), 2.69 (d, 1H), 2.48 (s, 3H), 1.79 (t, 2H), 1.64 (q, 3H), 1.37 (d, 1H), 0.91 (s, 4H). m/z (ES+) [M+H]+ = 517. Example 131. N-[3-(difluoromethoxy)-4-({(3S)-3-[(2S)-1,2-dihydroxypropan-2- yl]piperidin-1-yl}methyl)phenyl]-2-(4-methylphenyl)acetamide 236 201260-WO-PCT

[0594] Prepared similar as described in Example 130 starting from Intermediate 92 (110 mg, 0.33 mmol) and (4-methylphenyl)acetic acid (100 mg, 0.67 mmol). The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water (with 0.1%FA) within 19.5 minutes; rt: 10 minutes. Pure fractions were evaporated to dryness to provide the title compound as a colourless oil (0.036 g, 35 %): ¹H NMR (300 MHz, MeOD, 21°C) δ 1.08 (s, 3H), 1.35 (dd, J = 23.6, 11.3 Hz, 1H), 1.63–1.87 (m, 2H), 1.89–2.07 (m, 2H), 2.31 (s, 3H), 2.78 (t, J = 11.9 Hz, 2H), 3.33–3.55 (m, 4H), 3.64 (s, 2H), 4.16 (s, 2H),6.69- 7.22 (m, 5H), 7.42–7.5 (m, 2H), 7.73 (s, 1H), 8.50 (s, 1H). m/z (ES+) [M+H]+ = 463. Example 132. N-[3-chloro-4-({(3S)-3-[(5S)-5-methyl-2-oxo-1,3-oxazolidin-5-yl]piperidin-1- yl}methyl)phenyl]-1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carboxamide

[0595] To a solution of Example 49 (16 mg, 0.03 mmol) in dry THF (320 µl) was added di(1H- imidazol-1-yl)methanone (6.23 mg, 0.04 mmol). After 4 hours, the reaction mixture was diluted with DMSO (0.7 mL) and purified by preparative HPLC: SFC2-MS. Chromatographic conditions: MeOH/NH320mM, Column: Phenomenex Luna Hilic 5μ 30x250mm to provide the title compound (9.50 mg, 56 %): 1H NMR (600 MHz, DMSO, 25°C) δ 0.89–0.99 (1H, m), 1.21 (3H, s), 1.36–1.46 (1H, m), 1.57–1.67 (2H, m), 1.71–1.82 (2H, m), 1.86–1.92 (1H, m), 2.43 (3H, s), 2.74–2.79 (1H, m), 2.84–2.89 (1H, m), 3.03 (1H, d), 3.49 (2H, s), 7.34–7.42 (4H, m), 7.54 (1H, d), 7.75–7.82 (2H, m), 7.87 (1H, s), 8.97 (1H, s), 9.93 (1H, s). m/z (ES+) [M+H]+ = 526. Example 133. Biological activity of the compounds of Examples 1-132 in the TRPV4 calcium mobilisation assay [0596] Assay summary 237 201260-WO-PCT [0597] The assay utilises primary airway smooth muscle cells which endogenously express the human TRPV4 ion channel. Following revival from cryo-vials the cells are plated in microtiter plates and recovered overnight in incubator. Cells are incubated with a calcium dye, subsequently a compound plate is prepared and transferred to the FDSS µCell instrument, where an agonist effect is recorded. After 10 min compound incubation an antagonist effect is measured by challenge with the EC80 concentration of GSK1016790A, a TRPV4 agonist. [0598] Preparation of assay reagents [0599] Assay buffer: HBSS buffer (10X HBSS with Ca2+/Mg2+, HEPES 20 mM, pH 7.4) [0600] Cells: Human Bronchial Smooth Muscle Cells (Lonza, CC-2576, Donor 30996, lot 0000596065) [0601] Cell assay medium: DMEM/F-12 no phenol red (Gibco # 21041025), 1% FBS (heat inactivated) [0602] Calcium dye: Screen Quest™ Fluo-8 No Wash Calcium Assay Kit (AAT Bioquest #36314) [0603] Protocol for running the assay [0604] 1. Day before the experiment: Cryopreserved BSMCs were thawed in cell assay medium and centrifuged for 5 min, 250g. Supernatant was discarded and cell pellet resuspended in cell medium, cells counted with the NucleoCounter® (ChemoMetec). Cell concentration was adjusted to 0.25x10^6/ml with cell assay medium. Using a Multidrop™ Combi (ThermoFisher) cells were dispensed at 20 µl per well into cell culture 384 well microplates (Greiner #781091), left at room temperature for 20 minutes and then incubated over night at 37°C, 5% CO₂. [0605] 2. Day of the experiment: Cells were loaded with 10 µl calcium dye per well and incubated for 45 min at 37°C. [0606] 3. Test compounds were prepared in 10 point half-log concentration response starting at 10 mM, 240 nL per well. Compounds were diluted in 60 µl assay buffer per well to achieve a 10 µM top concentration f.c. in the experiment. [0607] 4. Agonist challenge compound plate was prepared using GSK1016790A at an EC80 f.c. concentration based on previous results. [0608] 5. To generate data on agonism of compounds towards TRPV4 a cell plate and a compound plate were transferred to the FDSS µCell which first reads a baseline for 30 seconds, then adds 10 µl of compounds. Recording of fluorescent kinetic data continues for a total of 3 minutes. 238 201260-WO-PCT [0609] 6. For the compound antagonism measurement, after 10 minutes incubation time, the same cell plate and the agonist plate were transferred to the FDSS µCell which again reads a baseline for 30 seconds, then proceeds to add 10 µl of EC80 agonist dilution. Recording of fluorescent kinetic data continues for a total of 3 minutes. [0610] Kinetic data was imported into Genedata Screener® Analyzer and the area under curve for each measurement was calculated and normalized to the neutral control (DMSO) and the stimulator control (GSK1016790A) for the agonist measurement or the inhibitor control (1- (((5S,7R)-3-(5-cyclopropylpyrazin-2-yl)-7-hydroxy-2-oxo-1-oxa-3-azaspiro[4.5]decan-7- yl)methyl)-1-H-benzo[d]imidazole-6-carbonitrile) for the antagonist measurement. [0611] The compound of Example 75 was tested according to the TRPV4 calcium mobilisation assay and exhibited an average IC₅₀ value of <0.048 nM. [0612] Table 15 shows the TRPV4 biological activity for the compounds of Examples 1-132 obtained from the TRPV4 calcium mobilisation assay described above with IC50 ranges. Table 15. TRPV4 Biological Activity for Compounds of Examples 1-132.

239 201260-WO-PCT

IC50 Ranges: 0.01-1.0 nM (+++), >1.0-100 nM (++), >100-1000 nM (+) [0613] Table 16 shows the TRPV4 biological activity for reference TRPV4 antagonists in the TRPV4 calcium mobilisation assay described above with IC₅₀ values. Table 16. TRPV4 Biological Activity for Reference TRPV4 Antagonists.

Those skilled in the art will appreciate that the biological assays described above may be performed using alternative equipment and minor variations to the protocol without significantly affecting the results. 240 201260-WO-PCT CLAUSES Further embodiments of the present disclosure are set out in the following clauses. 1. A compound of Formula (I):

wherein: ring A is a 5- to 11-membered N-heteroaryl or phenyl; each R¹, if present, is independently F, Cl, cyano, oxo, C3-C6 cycloalkyl, 3- to 6- membered heterocycle, C1-C5 alkyl, C1-C5 haloalkyl, phenyl, or combinations thereof, wherein the phenyl is optionally substituted with up to three substituents, wherein each substituent is independently selected from halo, cyano, C1-C5 alkyl, and C1-C3 alkoxy; R² is halo, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl, C3-C6 cycloalkoxy, C3-C6 halocycloalkoxy, or -OS(O)2R⁴; wherein R⁴ is C1-C3 alkyl or C1-C3 haloalkyl; R^3a and each R^3b are independently selected from hydroxy, C1-C8 alkyl, C3-C6 cycloalkyl, a 5- to 6-membered heterocycle, -N(R⁵)(S(O)2R⁶), -N(R⁵)C(O)OR⁶, and C1- C6 alkoxy, wherein: the C1-C8 alkyl is optionally substituted with up to three substituents selected from hydroxy, halo, oxo, carboxy, C1-C3 alkoxy, -S(O)2R⁶, -S(O)2NH2, -C(O)OR6, and -NR⁵R⁶; the 5- to 6-membered heterocycle is optionally substituted with up to three substituents selected from oxo and C1-C3 alkyl; the C3-C6 cycloalkyl is optionally substituted with up to three substituents selected from oxo and hydroxy; and 241 201260-WO-PCT each R⁵ and R⁶ is independent selected from C1-C3 alkyl and H; each R⁷ and R⁸, if present, is independently selected from H, halo, and C1-C3 alkyl, or together with the atom to which they are bound create a 3- to 6-membered carbocycle; X, Y, Z are each independently selected from CR⁹ and N; wherein each R⁹ is independently selected from H and halo; R^10a and ^R10b are independently selected from H and D; m is 0 or 1; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; and s is 0, 1, 2, or 3. 2. The compound of clause 1, wherein ring A is phenyl. 3. The compound of clause 2, wherein p is 1, 2, or 3, and wherein each R¹ is independently cyano, C1-C5 alkyl, or C1-C5 haloalkyl. 4. The compound of clause 1, wherein ring A is a 5- to 11-membered N-heteroaryl, wherein the N-heteroaryl comprises a single aromatic ring, or wherein the N-heteroaryl comprises two fused rings, wherein at least one ring comprises N and at least one ring is an aromatic ring. 5. The compound of clause 4, wherein ring A further comprises an oxygen. 6. The compound of clause 4, wherein ring A is a substituted or unsubstituted pyrrole, pyrazole, thiazole, pyridine, thienopyrrole, indole, benzoxazole, benzoxazine, or benzothiazepine. 7. The compound of any one of clauses 1, 2 or 4 to 6, wherein p is 0. 8. The compound of any one of clauses 1, 2 or 4 to 6, wherein p is 1, 2, or 3, and wherein each R¹ is independently F, Cl, cyano, oxo, C1-C5 alkyl, C1-C5 haloalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, or phenyl, wherein the C3-C6 cycloalkyl or the 3- to 6-membered heterocyclyl is optionally substituted with a halo, cyano, C1-C3 alkyl, or C1-C3 alkoxy. 9. The compound of any one of clauses 1 to 8, wherein m is 0. 242 201260-WO-PCT 10. The compound of any one of clauses 1 to 8, wherein m is 1, and R⁷ and R⁸ are each independently H, halo, C1-C3 alkyl, or C1-C3 haloalkyl; or R⁷ and R⁸, together with the atom to which they are bound, create a 3-membered carbocycle. 11. The compound of any one of clauses 1 to 10, wherein each of X, Y, and Z is CR⁹. 12. The compound of clause 11, wherein each R⁹ is H, and R² is halo, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl optionally substituted with one or more halo, C3-C6 cycloalkoxy optionally substituted with one or more halo, C1-C4 haloalkyl, C1-C4 haloalkoxy, or -OS(O)2R⁴, wherein R⁴ is C1-C3 haloalkyl. 13. The compound of clause 11, wherein one R⁹ is halo, the remaining R⁹ are H, and R² is halo. 14. The compound of any one of clauses 1 to 10, wherein each of X and Y is CR⁹ and Z is N; or wherein each of X and Z is CR⁹ and Y is N. 15. The compound of clause 14, wherein R² is C1-C4 haloalkyl or C1-C4 haloalkoxy. 16. The compound of clause 14, wherein R² is halo, trifluoromethyl, or difluoromethoxy. 17. The compound of any one of clauses 1 to 16, wherein at least one of R^3a and R^3b comprises an oxygen. 18. The compound of clause 17, wherein at least one of R^3a and R^3b is hydroxy; C1-C8 alkyl substituted with at least one hydroxy, oxo, carboxy, C1-C3 alkoxy, -S(O)2R⁶, -S(O)2NH2, or -C(O)OR6; C3-C6 cycloalkyl substituted with up to three substituents selected from oxo and hydroxy; 5- to 6-membered O-heterocycle; 5- to 6-membered heterocycle substituted with at least one oxo; -N(R⁵)(S(O)₂R⁶); -N(R⁵)C(O)OR⁶; or C1-C6 alkoxy. 19. The compound of any one of clauses 1 to 18, wherein s is 0, 1, or 3, and R^3a is C1-C8 alkyl substituted with hydroxy. 20. The compound of any one of clauses 1 to 17, wherein s is 2, and R^3a is C1-C8 alkyl, C3- C6 cycloalkyl, or a 5- to 6-membered heterocycle. 21. The compound of clause 20, wherein R^3a is C1-C8 alkyl or C3-C6 cycloalkyl. 243 201260-WO-PCT 22. The compound of clause 21, wherein the C1-C8 alkyl or C3-C6 cycloalkyl is substituted with hydroxy, halo, C1-C3 alkoxy, -S(O)2R⁶, -S(O)2NH2, -C(O)OR6, -NR⁵R⁶, or combination thereof, wherein R⁵ and R⁶ are each independently H or C1-C3 alkyl. 23. The compound of clause 20, wherein R^3a is a 5- to 6-membered heterocycle comprising an N, S, O, or combination thereof. 24. The compound of clause 23, wherein the heterocycle is substituted with oxo or C1-C3 alkyl. 25. The compound of any one of clauses 20 to 24, wherein q is 0. 26. The compound of any one of clauses 20 to 24, wherein q is 1, and R^3b is hydroxy, C1-C8 alkyl optionally substituted with one or more hydroxy, C1-C6 alkoxyl, or -N(R⁵)(S(O)₂R⁶), wherein R⁵ and R⁶ is independently H or C1-C3 alkyl. 27. The compound of any one of clauses 20 to 24, wherein q is 2, and each R^3b is independently hydroxy or C1-C8 alkyl, wherein the C1-C8 alkyl is optionally substituted with 1 to 3 hydroxy. 28. The compound of clause 1, wherein ring A is a 5-membered N-heteroaryl; p is 1, 2, or 3; R¹ is phenyl optionally substituted with halo, m is 0; X, Y, Z are each CR⁹; R² is halo; s is 1 or 2; and R^3a is C1-C8 alkyl substituted with 1 to 3 hydroxy. 29. The compound of clause 28, wherein ring A is pyrazole. 30. The compound of clause 28 or 29, wherein each R⁹ is H. 31. A compound as found in Table 4. 32. A composition comprising the compound of any one of clauses 1 to 31. 33. The composition of clause 32, further comprising a pharmaceutically acceptable excipient. 244 201260-WO-PCT 34. A method of inhibiting activity of Transient Receptor Potential Vanilloid 4 (TRPV4), comprising contacting TRPV4 with the compound of any one of clauses 1 to 31 or the composition of clause 32 or 33. 35. The method of clause 34, wherein the method is performed in vivo or in vitro. 36. A method of inhibiting activity of TRPV4 in a subject in need thereof, comprising administering a therapeutically effective amount of the compound of any one of clauses 1 to 34 or the composition of clause 32 or 33 to the subject. 37. A method of treating, ameliorating, or preventing a TRPV4-associated disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of the compound of any one of clauses 1 to 31 or the composition of clause 32 or 33 to the subject. 38. The method of clause 37, wherein the TRPV4-associated disease or disorder is inflammation, a respiratory disease or disorder, a metabolic disease or disorder, a dermatological disease or disorder, a skeletal disease or disorder, a neuromuscular disease disorder, or combination thereof. 39. The method of clause 37 or 38, wherein the TRPV4-associated disease or disorder is pulmonary edema, systemic edema, hypertension, hyperalgesia, inflammation, brachyolmia, spondylometaphyseal dysplasia Kozlowski type, metatropic dysplasia, peripheral neuropathy, asthma, chronic cough, chronic obstructive pulmonary disease (COPD), overactive bladder, incontinence, acoustic cochlear injury, pancreatitis, epilepsy, arthritis, osteoarthritis, multiple sclerosis, stroke, central nervous system (CNS) autoimmune condition, traumatic brain injury, spinal cord injury, brain edema, CNS infection, neuro-psychiatric disorder, skeletal degenerative-inflammatory disorder, trigeminal pain, colitis, sclerosis, obesity, diabetes, or combination thereof. 245

Claims (1)

1. 201260-WO-PCT CLAIMS What is claimed is: 1. A compound of Formula (I):

   

   or a pharmaceutically acceptable salt thereof, wherein: ring A is a 5- to 11-membered N-heteroaryl or phenyl; each R¹, if present, is independently F, Cl, cyano, oxo, C3-C6 cycloalkyl, 3- to 6- membered heterocycle, C1-C5 alkyl, C1-C5 haloalkyl, phenyl, or combinations thereof, wherein the phenyl is optionally substituted with up to three substituents, wherein each substituent is independently selected from halo, cyano, C1-C5 alkyl, and C1-C3 alkoxy; R² is halo, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl, C3-C6 cycloalkoxy, C3-C6 halocycloalkoxy, or -OS(O)2R⁴; wherein R⁴ is C1-C3 alkyl or C1-C3 haloalkyl; R^3a and each R^3b are independently selected from hydroxy, C1-C8 alkyl, C3-C6 cycloalkyl, a 5- to 6-membered heterocycle, -N(R⁵)(S(O)₂R⁶), -N(R⁵)C(O)OR⁶, and C1- C6 alkoxy, wherein: the C1-C8 alkyl is optionally substituted with up to three substituents selected from hydroxy, halo, oxo, carboxy, C1-C3 alkoxy, -S(O)₂R⁶, -S(O)₂NH₂, -C(O)OR6, and -NR⁵R⁶; the 5- to 6-membered heterocycle is optionally substituted with up to three substituents selected from oxo and C1-C3 alkyl; the C3-C6 cycloalkyl is optionally substituted with up to three substituents selected from oxo and hydroxy; and each R⁵ and R⁶ is independent selected from C1-C3 alkyl and H; 246 201260-WO-PCT each R⁷ and R⁸, if present, is independently selected from H, halo, and C1-C3 alkyl, or together with the atom to which they are bound create a 3- to 6-membered carbocycle; X, Y, Z are each independently selected from CR⁹ and N; wherein each R⁹ is independently selected from H and halo; R^10a and ^R10b are independently selected from H and D; m is 0 or 1; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; and s is 0, 1, 2, or 3. 2. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is phenyl. 3. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to claim 2, wherein p is 1, 2, or 3, and wherein each R¹ is independently cyano, C1-C5 alkyl, or C1-C5 haloalkyl. 4. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is a 5- to 11-membered N-heteroaryl, wherein the N-heteroaryl comprises a single aromatic ring, or wherein the N-heteroaryl comprises two fused rings, wherein at least one ring comprises N and at least one ring is an aromatic ring. 5. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to claim 4, wherein ring A further comprises an oxygen. 6. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to claim 4, wherein ring A is a substituted or unsubstituted pyrrole, pyrazole, thiazole, pyridine, thienopyrrole, indole, benzoxazole, benzoxazine, or benzothiazepine. 7. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1, 2 or 4 to 6, wherein p is 0. 8. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1, 2 or 4 to 6, wherein p is 1, 2, or 3, and wherein each R¹ is independently F, Cl, cyano, oxo, C1-C5 alkyl, C1-C5 haloalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, or phenyl, wherein the C3-C6 cycloalkyl or the 3- to 6-membered heterocyclyl is optionally substituted with a halo, cyano, C1-C3 alkyl, or C1-C3 alkoxy. 247 201260-WO-PCT 9. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein m is 0. 10. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein m is 1, and R⁷ and R⁸ are each independently H, halo, C1-C3 alkyl, or C1-C3 haloalkyl; or R⁷ and R⁸, together with the atom to which they are bound, create a 3-membered carbocycle. 11. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein each of X, Y, and Z is CR⁹. 12. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to claim 11, wherein each R⁹ is H, and R² is halo, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl optionally substituted with one or more halo, C3-C6 cycloalkoxy optionally substituted with one or more halo, C1-C4 haloalkyl, C1-C4 haloalkoxy, or -OS(O)2R⁴, wherein R⁴ is C1-C3 haloalkyl. 13. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to claim 11, wherein one R⁹ is halo, the remaining R⁹ are H, and R² is halo. 14. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein each of X and Y is CR⁹ and Z is N; or wherein each of X and Z is CR⁹ and Y is N. 15. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to claim 14, wherein R² is C1-C4 haloalkyl or C1-C4 haloalkoxy. 16. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to claim 14, wherein R² is halo, trifluoromethyl, or difluoromethoxy. 17. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein at least one of R^3a and R^3b comprises an oxygen. 18. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to claim 17, wherein at least one of R^3a and R^3b is hydroxy; C1-C8 alkyl substituted with at least one hydroxy, oxo, carboxy, C1-C3 alkoxy, -S(O)₂R⁶, -S(O)₂NH₂, or -C(O)OR₆; C3- C6 cycloalkyl substituted with up to three substituents selected from oxo and hydroxy; 5- to 6-membered O-heterocycle; 5- to 6-membered heterocycle substituted with at least one oxo; -N(R⁵)(S(O)2R⁶); -N(R⁵)C(O)OR⁶; or C1-C6 alkoxy. 248 201260-WO-PCT 19. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein s is 0, 1, or 3, and R^3a is C1-C8 alkyl substituted with hydroxy. 20. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein s is 2, and R^3a is C1-C8 alkyl, C3-C6 cycloalkyl, or a 5- to 6-membered heterocycle. 21. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to claim 20, wherein R^3a is C1-C8 alkyl or C3-C6 cycloalkyl. 22. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to claim 21, wherein the C1-C8 alkyl or C3-C6 cycloalkyl is substituted with hydroxy, halo, C1-C3 alkoxy, -S(O)₂R⁶, -S(O)₂NH₂, -C(O)OR₆, -NR⁵R⁶, or combination thereof, wherein R⁵ and R⁶ are each independently H or C1-C3 alkyl. 23. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to claim 20, wherein R^3a is a 5- to 6-membered heterocycle comprising an N, S, O, or combination thereof. 24. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to claim 23, wherein the heterocycle is substituted with oxo or C1-C3 alkyl. 25. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 20 to 24, wherein q is 0. 26. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 20 to 24, wherein q is 1, and R^3b is hydroxy, C1-C8 alkyl optionally substituted with one or more hydroxy, C1-C6 alkoxyl, or -N(R⁵)(S(O)2R⁶), wherein R⁵ and R⁶ is independently H or C1-C3 alkyl. 27. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 20 to 24, wherein q is 2, and each R^3b is independently hydroxy or C1- C8 alkyl, wherein the C1-C8 alkyl is optionally substituted with 1 to 3 hydroxy. 28. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is a 5-membered N-heteroaryl; p is 1, 2, or 3; 249 201260-WO-PCT R¹ is phenyl optionally substituted with halo, m is 0; X, Y, Z are each CR⁹; R² is halo; s is 1 or 2; and R^3a is C1-C8 alkyl substituted with 1 to 3 hydroxy. 29. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to claim 28, wherein ring A is pyrazole. 30. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to claim 28 or 29, wherein each R⁹ is H. 31. A compound of Formula (I), wherein Formula (I) is as defined in any preceding claim. 32. A compound as found in Table 4, or a pharmaceutically acceptable salt thereof. 33. A compound as found in Table 4. 34. A composition comprising the compound or pharmaceutically acceptable salt of any one of claims 1 to 33. 35. The composition of claim 34, further comprising a pharmaceutically acceptable excipient. 36. A method of inhibiting activity of Transient Receptor Potential Vanilloid 4 (TRPV4), comprising contacting TRPV4 with the compound or pharmaceutically acceptable salt of any one of claims 1 to 33 or the composition of claim 34 or 35. 37. The method of claim 36, wherein the method is performed in vivo or in vitro. 38. A method of inhibiting activity of TRPV4 in a subject in need thereof, comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1 to 33 or the composition of claim 34 or 35 to the subject. 39. The compound or pharmaceutically acceptable salt of any one of claims 1 to 33 or the composition of claim 34 or 35, for use in therapy. 250 201260-WO-PCT 40. The compound or pharmaceutically acceptable salt of any one of claims 1 to 33 or the composition of claim 34 or 35, for use in a method of treating, ameliorating, or preventing a TRPV4-associated disease or disorder. 41. Use of the compound or pharmaceutically acceptable salt of any one of claims 1 to 33 or the composition of claim 34 or 35 in the manufacture of a medicament for treating, ameliorating, or preventing a TRPV4-associated disease or disorder. 42. A method of treating, ameliorating, or preventing a TRPV4-associated disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1 to 33 or the composition of claim 34 or 35 to the subject. 43. The compound, pharmaceutically acceptable salt or composition for use of claim 40, the use of claim 41, or the method of claim 42, wherein the TRPV4-associated disease or disorder is inflammation, a respiratory disease or disorder, a metabolic disease or disorder, a dermatological disease or disorder, a skeletal disease or disorder, a neuromuscular disease disorder, or combination thereof. 44. The compound, pharmaceutically acceptable salt or composition for use of claim 40, the use of claim 41, or the method of claim 42, wherein the TRPV4-associated disease or disorder is pulmonary edema, systemic edema, hypertension, hyperalgesia, inflammation, brachyolmia, spondylometaphyseal dysplasia Kozlowski type, metatropic dysplasia, peripheral neuropathy, asthma, chronic cough, chronic obstructive pulmonary disease (COPD), overactive bladder, incontinence, acoustic cochlear injury, pancreatitis, epilepsy, arthritis, osteoarthritis, multiple sclerosis, stroke, central nervous system (CNS) autoimmune condition, traumatic brain injury, spinal cord injury, brain edema, CNS infection, neuro-psychiatric disorder, skeletal degenerative-inflammatory disorder, trigeminal pain, colitis, sclerosis, obesity, diabetes, or combination thereof. 45. The compound, pharmaceutically acceptable salt or composition for use of claim 40, the use of claim 41, or the method of claim 42, wherein the TRPV4-associated disease or disorder is cancer. 46. The compound, pharmaceutically acceptable salt or composition for use, the use, or the method of claim 45, wherein the cancer is hepatocellular carcinoma or colorectal cancer. 251 201260-WO-PCT 47. The compound, pharmaceutically acceptable salt or composition for use of claim 40, the use of claim 41, or the method of claim 42, wherein the TRPV4-associated disease or disorder is a cardiovascular disease or disorder. 48. The compound, pharmaceutically acceptable salt or composition for use, the use, or the method of claim 47, wherein the cardiovascular disease or disorder is hypertrophic cardiomyopathy. 252